JP6903796B2 - Fgfr4阻害剤としての二環式複素環 - Google Patents
Fgfr4阻害剤としての二環式複素環 Download PDFInfo
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- JP6903796B2 JP6903796B2 JP2020100899A JP2020100899A JP6903796B2 JP 6903796 B2 JP6903796 B2 JP 6903796B2 JP 2020100899 A JP2020100899 A JP 2020100899A JP 2020100899 A JP2020100899 A JP 2020100899A JP 6903796 B2 JP6903796 B2 JP 6903796B2
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- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
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- 229960004066 trametinib Drugs 0.000 description 1
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- 238000012546 transfer Methods 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 229950001353 tretamine Drugs 0.000 description 1
- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 description 1
- AYNNSCRYTDRFCP-UHFFFAOYSA-N triazene Chemical compound NN=N AYNNSCRYTDRFCP-UHFFFAOYSA-N 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
- 125000005500 uronium group Chemical group 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
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- 230000029663 wound healing Effects 0.000 description 1
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- 239000011701 zinc Substances 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
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Description
本開示は、FGFR4酵素の阻害剤であり、癌等のFGFR4関連疾患の治療に有用な、二環式複素環及びその医薬組成物に関する。
線維芽細胞成長因子受容体(Fibroblast Growth Factor Receptor)(FGFR)は、線維芽細胞増殖因子(FGF)リガンドに結合する受容体チロシンキナーゼである。リガンドに結合することができ、組織発生、血管新生、創傷治癒及び代謝調節を含む多くの生理学的過程の調節に関与する4つのFGFRタンパク質(FGFR1−4)が存在する。リガンド結合の際、受容体は二量体化及びリン酸化を受け、タンパク質キナーゼ活性の刺激及び多くの細胞内ドッキングタンパク質の増加をもたらす。これらの相互作用は、細胞増殖、組織増殖及び生存にとって重要なRas−MAPK、AKT−PI3K、及びホスホリパーゼCを含む細胞内シグナル伝達経路のアレイの活性化を促進する(Eswarakumarら、Cytokine & Growth Factor Reviews,2005に記載)。FGFリガンドまたはFGFRの過剰発現、またはFGFRにおける活性化突然変異のいずれかによるこの経路の異常な活性化は、腫瘍発生、進行、及び従来の癌治療に対する抵抗をもたらし得る。ヒト癌においては、遺伝子増幅、染色体転座、及びリガンド非依存性受容体活性化をもたらす体細胞突然変異等の遺伝子改変が記載されている。数千もの腫瘍サンプルの大規模DNA塩基配列決定により、FGFR経路の成分がヒト癌において最も頻繁に変異していることが明らかになった。 これらの活性化突然変異の多くは、骨格異形成症候群を引き起こす生殖細胞系突然変異と同一である。ヒト疾患において異常なリガンド依存性シグナル伝達をもたらす機構には、FGFの過剰発現、及びより乱雑なリガンド結合能力を有する受容体をもたらすFGFRスプライシングの変化が含まれる(Knights and Cook Pharmacology & Therapeutics,2010; Turner and Grose,Nature Reviews Cancer,2010に記載)。従って、FGFRを標的とする阻害剤の開発は、FGFまたはFGFR活性が上昇した疾患の臨床的治療に有用であり得る。
化合物
一実施態様において、本開示は、下記の式(I):
(但し、
X1はCR10R11またはNR7であり;
XはNまたはCR6であり;
R1はC1−3アルキルまたはC1−3ハロアルキルであり;
R2はH、ハロ、C1−3アルキル、C1−3ハロアルキル、CNまたはC1−3アルコキシであり;
R3はH、ハロ、C1−3アルキル、C1−3ハロアルキル、CNまたはC1−3アルコキシであり;
R4はC1−3アルキルまたはC1−3ハロアルキルであり;
R5はH、ハロ、C1−3アルキル、C1−3ハロアルキル、CNまたはC1−3アルコキシであり;
R6及びR7は、それぞれ独立して、H、ハロ、CN、ORa4、SRa4、C(O)NRc4Rd4、OC(O)NRc4Rd4、NRc4Rd4、NRc4C(O)Rb4、NRc4C(O)ORa4、NRc4C(O)NRc4Rd4、NRc4S(O)Rb4、NRc4S(O)2Rb4、NRc4S(O)2NRc4Rd4、S(O)Rb4、S(O)NRc4Rd4、S(O)2Rb4、S(O)2NRc4Rd4、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、C1−6ハロアルキル、フェニル、C3−6シクロアルキル、炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する5〜6員のヘテロアリール部分、及び炭素及びN、O及びSから独立して選択される1,2または3個のヘテロ原子を有する4〜7員のヘテロシクロアルキル部分から選択され;前記R6及びR7の、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、フェニル、C3−6シクロアルキル、5〜6員のヘテロアリール、及び4〜7員のヘテロシクロアルキル基は、それぞれ、R10Aから独立に選択される1、2または3個の置換基で任意に置換されており;
Lは、−(CR13R14)n−(但し、R13及びR14はそれぞれ独立してH、C1−6アルキル、C6−10アリール、5〜10員ヘテロアリールまたは4〜7員ヘテロシクロアルキルであり、前記C1−6アルキル、C6−10アリール、5〜10員のヘテロアリールまたは4〜7員のヘテロシクロアルキルは、1〜3個のR17基で任意に置換されていてもよく、またはR13及びR14はそれらが結合する炭素原子と共にC3−6シクロアルキルまたは4〜6員のヘテロシクロアルキル基を形成し;前記C3−6シクロアルキルまたは4〜6員のヘテロシクロアルキル基は1〜3個のR17員で任意に置き換えされ;下付き文字nは1、2または3であるり;いくつかの実施形態では、下付き文字nは1または2である。)であり;
R8は、H、またはハロ、CN、ORa9、C(O)NRc9Rd9、NRc9Rd9、NRc9C(O)Rb9、NRc9C(O)ORa9、NRc9C(O)NRc9Rd9、NRc9S(O)Rb9、NRc9S(O)2Rb9、NRc9S(O)2NRc9Rd9、S(O)Rb9、S(O)NRc9Rd9、S(O)2Rb9、S(O)2NRc9Rd9、フェニル、C3−7シクロアルキル、炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する5〜6員のヘテロアリール部分、または炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する4〜7員のヘテロシクロアルキル部分で任意に置換されたC1−4アルキルであり;前記R8の、フェニル、C3−7シクロアルキル、5〜6員のヘテロアリール、及び4〜7員のヘテロシクロアルキル基は、それぞれ1または2個のR19基で任意に置換されており;
R10及びR11は、それぞれ独立して、H、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、C1−6ハロアルキル、C6−10アリール、C3−10シクロアルキル、炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する5〜10員のヘテロアリール部分、及び炭素及びN、O及びSから独立して選択される1,2または3個のヘテロ原子を有する4〜10員のヘテロシクロアルキル部分から選択され;前記R10及びR11の、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、C6−10アリール、C3−10シクロアルキル、5〜10員のヘテロアリール、及び4〜10員のヘテロシクロアルキル基は、それぞれ1、2、3または4個のR10Aで任意に置換されており;
R10Aは、出現ごとに独立して、ハロ、CN、NO2、ORa4、SRa4、C(O)Rb4、C(O)NRc4Rd4、C(O)ORa4、OC(O)Rb4、OC(O)NRc4Rd4、C(=NRe4)NRc4Rd4、NRc4C(=NRe4)NRc4Rd4、NRc4Rd4、NRc4C(O)Rb4、NRc4C(O)ORa4、NRc4C(O)NRc4Rd4、NRc4S(O)Rb4、NRc4S(O)2Rb4、NRc4S(O)2NRc4Rd4、S(O)Rb4、S(O)NRc4Rd4、S(O)2Rb4、S(O)2NRc4Rd4、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、C1−6ハロアルキル、フェニル、C3−6シクロアルキル、炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する5〜6員のヘテロアリール部分、及び炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する4〜7員のヘテロシクロアルキル部分から選択され;前記R10Aの、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、フェニル、C3−6シクロアルキル、5〜6員のヘテロアリール、及び4〜7員のヘテロシクロアルキル基は、それぞれR19から独立に選択される1、2または3個の置換基で任意に置換されており;
Ra4、Rb4、Rc4、及びRd4は、出現ごとに独立して、H、C1−4アルキル、C2−4アルケニル、C2−4アルキニル、C1−4ハロアルキル、フェニル、C3−6シクロアルキル、炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する5〜6員のヘテロアリール部分、及び炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する4〜7員のヘテロシクロアルキル部分から選択され;前記Ra4、Rb4、Rc4、及びRd4の、C1−4アルキル、C2−4アルケニル、C2−4アルキニル、フェニル、C3−6シクロアルキル、5〜6員のヘテロアリール、及び4〜7員のヘテロシクロアルキル基は、それぞれR19から独立に選択される1、2または3個の置換基で任意に置換されており;
あるいは、Rc4及びRd4は、それらが結合する窒素原子と共に、R19から独立に選択される1、2または3個の置換基で任意に置換された4−、5−、6−または7−員のヘテロシクロアルキル基を形成し;
Re4は、それぞれ独立してHまたはC1−4アルキルであり;
あるいは、R10、及びR11は、それらが結合する炭素原子と共に、3−、4−、5−、6−または7−員のシクロアルキル基または4−、5−、6−、7−、8−、9−または10−員のヘテロシクロアルキル基を形成し、前記3−、4−、5−、6−または7−員のシクロアルキル基または4−、5−、6−、7−、8−、9−または10−員のヘテロシクロアルキル基は1、2、3または4個のR10Aでそれぞれ任意に置換されており;
R12は、H、またはR17で任意に置換されていてもよいC1−4アルキルであり;
R17は、出現ごとに独立して、ハロ、CN、NO2、ORa7、SRa7、C(O)Rb7、C(O)NRc7Rd7、C(O)ORa7、OC(O)Rb7、OC(O)NRc7Rd7、C(=NRe7)NRc7Rd7、NRc7C(=NRe7)NRc7Rd7、NRc7Rd7、NRc7C(O)Rb7、NRc7C(O)ORa7、NRc7C(O)NRc7Rd7、NRc7S(O)Rb7、NRc7S(O)2Rb7、NRc7S(O)2NRc7Rd7、S(O)Rb7、S(O)NRc7Rd7、S(O)2Rb7、S(O)2NRc7Rd7、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、C1−6ハロアルキル、フェニル、C3−6シクロアルキル、炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する5〜6員のヘテロアリール部分、及び炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する4〜7員のヘテロシクロアルキル部分から選択され;前記R17の、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、フェニル、C3−6シクロアルキル、5〜6員のヘテロアリール、及び4〜7員のヘテロシクロアルキル基は、それぞれR19から独立に選択される1、2または3個の置換基で任意に置換されており;
Ra7、Rb7、Rc7、及びRd7は、出現ごとに独立して、H、C1−4アルキル、C2−4アルケニル、C2−4アルキニル、C1−4ハロアルキル、フェニル、C3−6シクロアルキル、炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する5〜6員のヘテロアリール部分、及び炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する4〜7員のヘテロシクロアルキル部分から選択され;前記Ra7、Rb7、Rc7、及びRd7の、C1−4アルキル、C2−4アルケニル、C2−4アルキニル、フェニル、C3−6シクロアルキル、5〜6員のヘテロアリール、及び4〜7員のヘテロシクロアルキル基は、それぞれR19から独立に選択される1、2または3個の置換基で任意に置換されており;
あるいは、Rc7、及びRd7は、それらが結合する窒素原子と共に、R19から独立に選択される1、2または3個の置換基で任意に置換された4−、5−、6−または7−員のヘテロシクロアルキル基を形成し;
Re7は、出現ごとに独立して、HまたはC1−4アルキルであり;
R19は、出現ごとに独立して、ハロ、CN、NO2、ORa9、SRa9、C(O)Rb9、C(O)NRc9Rd9、C(O)ORa9、OC(O)Rb9、OC(O)NRc9Rd9、NRc9Rd9、NRc9C(O)Rb9、NRc9C(O)ORa9、NRc9C(O)NRc9Rd9、NRc9S(O)Rb9、NRc9S(O)2Rb9、NRc9S(O)2NRc9Rd9、S(O)Rb9、S(O)NRc9Rd9、S(O)2Rb9、S(O)2NRc9Rd9、C1−4アルキル、C2−4アルケニル、C2−4アルキニル、及びC1−4ハロアルキルから選択され;
Ra9、Rc9、及びRd9は、出現ごとに独立して、H及びC1−4アルキルから選択され;そして
Rb9は、出現ごとに独立してC1−4アルキルである。)
で表される化合物またはその薬学的に受容可能な塩を提供する。一実施形態では、YはOである。別の実施形態では、YはNR8である。
X1はCR10R11またはNR7であり;
XはNまたはCR6であり;
R1はC1−3アルキルまたはC1−3ハロアルキルであり;
R2はH、ハロ、C1−3アルキル、C1−3ハロアルキル、CNまたはC1−3アルコキシであり;
R3はH、ハロ、C1−3アルキル、C1−3ハロアルキル、CNまたはC1−3アルコキシであり;
R4はC1−3アルキルまたはC1−3ハロアルキルであり;
R5はH、ハロ、C1−3アルキル、C1−3ハロアルキル、CNまたはC1−3アルコキシであり;
R6は、H、ハロ、CN、ORa4、SRa4、C(O)NRc4Rd4、OC(O)NRc4Rd4、NRc4Rd4、NRc4C(O)Rb4、NRc4C(O)ORa4、NRc4C(O)NRc4Rd4、NRc4S(O)Rb4、NRc4S(O)2Rb4、NRc4S(O)2NRc4Rd4、S(O)Rb4、S(O)NRc4Rd4、S(O)2Rb4、S(O)2NRc4Rd4、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、C1−6ハロアルキル、フェニル、C3−6シクロアルキル、炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する5〜6員のヘテロアリール部分、及び炭素及びN、O及びSから独立して選択される1,2または3個のヘテロ原子を有する4〜7員のヘテロシクロアルキル部分から選択され;前記R6の、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、フェニル、C3−6シクロアルキル、5〜6員のヘテロアリール、及び4〜7員のヘテロシクロアルキル基は、それぞれR10Aから独立に選択される1、2または3個の置換基で任意に置換されており;
R7は、H、C(O)NRc4Rd4、S(O)Rb4、S(O)NRc4Rd4、S(O)2Rb4、S(O)2NRc4Rd4、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、C1−6ハロアルキル、フェニル、C3−6シクロアルキル、炭素及びN、O及びSから独立して選択される1,2または3個のヘテロ原子を有する5〜6員のヘテロアリール、及び炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する4〜7員のヘテロシクロアルキル部分から選択され;前記R7の、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、フェニル、C3−6シクロアルキル、5〜6員のヘテロアリール、及び4〜7員のヘテロシクロアルキル基は、それぞれR10Aから独立に選択される1、2または3個の置換基で任意に置換されており;
Lは、−(CR13R14)n−(但し、R13及びR14はそれぞれ独立してH、C1−6アルキル、C6−10アリール、5〜10員ヘテロアリールまたは4〜10員ヘテロシクロアルキルであり、前記C1−6アルキル、C6−10アリール、5〜10員のヘテロアリールまたは4〜7員のヘテロシクロアルキルは、1〜3個のR17基で任意に置換されていてもよく、下付き文字nは1又は2である。)であり;
R8は、H、またはハロ、CN、ORa9、C(O)NRc9Rd9、NRc9Rd9、NRc9C(O)Rb9、NRc9C(O)ORa9、NRc9C(O)NRc9Rd9、NRc9S(O)Rb9、NRc9S(O)2Rb9、NRc9S(O)2NRc9Rd9、S(O)Rb9、S(O)NRc9Rd9、S(O)2Rb9、S(O)2NRc9Rd9、フェニル、C3−7シクロアルキル、炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する5〜6員のヘテロアリール部分、または炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する4〜7員のヘテロシクロアルキル部分で任意に置換されたC1−4アルキルであり;前記R8の、フェニル、C3−7シクロアルキル、5〜6員のヘテロアリール、及び4〜7員のヘテロシクロアルキル基は、それぞれ1又は2個のR19基で任意に置換されており;
R10及びR11は、それぞれ独立して、H、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、C1−6ハロアルキル、C6−10アリール、C3−10シクロアルキル、炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する5〜10員のヘテロアリール部分、及び炭素及びN、O及びSから独立して選択される1,2または3個のヘテロ原子を有する4〜10員のヘテロシクロアルキル部分から選択され;前記R10及びR11の、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、C6−10アリール、C3−10シクロアルキル、5〜10員のヘテロアリール、及び4〜10員のヘテロシクロアルキル基は、それぞれ、1、2、3または4個のR10Aで任意に置換されており;
R10Aは、出現ごとに独立して、ハロ、CN、NO2、ORa4、SRa4、C(O)Rb4、C(O)NRc4Rd4、C(O)ORa4、OC(O)Rb4、OC(O)NRc4Rd4、C(=NRe4)NRc4Rd4、NRc4C(=NRe4)NRc4Rd4、NRc4Rd4、NRc4C(O)Rb4、NRc4C(O)ORa4、NRc4C(O)NRc4Rd4、NRc4S(O)Rb4、NRc4S(O)2Rb4、NRc4S(O)2NRc4Rd4、S(O)Rb4、S(O)NRc4Rd4、S(O)2Rb4、S(O)2NRc4Rd4、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、C1−6ハロアルキル、フェニル、C3−6シクロアルキル、炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する5〜6員のヘテロアリール部分、及び炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する4〜7員のヘテロシクロアルキル部分から選択され;前記R10Aの、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、フェニル、C3−6シクロアルキル、5〜6員のヘテロアリール、及び4〜7員のヘテロシクロアルキル基は、それぞれR19から独立に選択される1、2または3個の置換基で任意に置換されており;
Ra4、Rb4、Rc4、及びRd4は、出現ごとに独立して、H、C1−4アルキル、C2−4アルケニル、C2−4アルキニル、C1−4ハロアルキル、フェニル、C3−6シクロアルキル、炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する5〜6員のヘテロアリール部分、及び炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する4〜7員のヘテロシクロアルキル部分から選択され;前記Ra4、Rb4、Rc4、及びRd4の、C1−4アルキル、C2−4アルケニル、C2−4アルキニル、フェニル、C3−6シクロアルキル、5〜6員のヘテロアリール、及び4〜7員のヘテロシクロアルキル基は、それぞれ、R19から独立に選択される1、2または3個の置換基で任意に置換されており;
あるいは、Rc4、及びRd4は、それらが結合する窒素原子と共に、R19から独立に選択される1、2または3個の置換基で任意に置換された4−、5−、6−または7−員のヘテロシクロアルキル基を形成し;
Re4は、出現ごとにHまたはC1−4アルキルであり;
あるいは、R10及びR11は、それらが結合する炭素原子と共に、3−、4−、5−、6−または7−員のシクロアルキル基または4−、5−、6−、7−、8−、9−または10−員のヘテロシクロアルキル基を形成し、前記3−、4−、5−、6−または7−員のシクロアルキル基または4−、5−、6−、7−、8−、9−または10−員のヘテロシクロアルキル基は1、2、3または4個のR10Aでそれぞれ任意に置換されており;
R12は、H、またはR17で任意に置換されていてもよいC1−4アルキルであり;
R17は、出現ごとに独立して、ハロ、CN、NO2、ORa7、SRa7、C(O)Rb7、C(O)NRc7Rd7、C(O)ORa7、OC(O)Rb7、OC(O)NRc7Rd7、
C(=NRe7)NRc7Rd7、NRc7C(=NRe7)NRc7Rd7、NRc7Rd7、NRc7C(O)Rb7、NRc7C(O)ORa7、NRc7C(O)NRc7Rd7、NRc7S(O)Rb7、NRc7S(O)2Rb7、NRc7S(O)2NRc7Rd7、S(O)Rb7、S(O)NRc7Rd7、S(O)2Rb7、S(O)2NRc7Rd7、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、C1−6ハロアルキル、フェニル、C3−6シクロアルキル、炭素及びN、O及びSから選択される1、2または3個のヘテロ原子を有する5〜6員のヘテロアリール部分、及び炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する4〜7員のヘテロシクロアルキル部分から選択され;前記R17の、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、フェニル、C3−6シクロアルキル、5〜6員のヘテロアリール、及び4〜7員のヘテロシクロアルキル基は、それぞれR19から独立に選択される1、2または3個の置換基で任意に置換されており;
Ra7、Rb7、Rc7、及びRd7は、出現ごとに独立して、H、C1−4アルキル、C2−4アルケニル、C2−4アルキニル、C1−4ハロアルキル、フェニル、C3−6シクロアルキル、炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する5〜6員のヘテロアリール部分、及び炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する4〜7員のヘテロシクロアルキル部分から独立して選択され;前記Ra7、Rb7、Rc7、及びRd7の、C1−4アルキル、C2−4アルケニル、C2−4アルキニル、フェニル、C3−6シクロアルキル、5〜6員のヘテロアリール、及び4〜7員のヘテロシクロアルキル基は、それぞれR19から選択される1、2または3個の置換基で任意に置換されており;
あるいは、Rc7、及びRd7は、それらが結合する窒素原子と共に、R19から独立に選択される1、2または3個の置換基で任意に置換された4−、5−、6−または7−員のヘテロシクロアルキル基を形成し;
Re7は、出現ごとに独立して、HまたはC1−4アルキルであり;
R19は、出現ごとに独立して、ハロ、CN、NO2、ORa9、SRa9、C(O)Rb9、C(O)NRc9Rd9、C(O)ORa9、OC(O)Rb9、OC(O)NRc9Rd9、NRc9Rd9、NRc9C(O)Rb9、NRc9C(O)ORa9、NRc9C(O)NRc9Rd9、NRc9S(O)Rb9、NRc9S(O)2Rb9、NRc9S(O)2NRc9Rd9、S(O)Rb9、S(O)NRc9Rd9、S(O)2Rb9、S(O)2NRc9Rd9、C1−4アルキル、C2−4アルケニル、C2−4アルキニル、及びC1−4ハロアルキルから選択され;
Ra9、Rc9、及びRd9は、出現ごとに独立して、H及びC1−4アルキルから選択され;
Rb9は、出現ごとに独立してC1−4アルキルである。
(但し、
XはNまたはCR6であり;
R1はC1−3アルキルまたはC1−3ハロアルキルであり;
R2はH、ハロ、C1−3アルキル、C1−3ハロアルキル、CNまたはC1−3アルコキシであり;
R3はH、ハロ、C1−3アルキル、C1−3ハロアルキル、CNまたはC1−3アルコキシであり;
R4はC1−3アルキルまたはC1−3ハロアルキルであり;
R5はH、ハロ、C1−3アルキル、C1−3ハロアルキル、CNまたはC1−3アルコキシであり;
R6は、H、ハロ、CN、ORa4、SRa4、C(O)NRc4Rd4、OC(O)NRc4Rd4、NRc4Rd4、NRc4C(O)Rb4、NRc4C(O)ORa4、NRc4C(O)NRc4Rd4、NRc4S(O)Rb4、NRc4S(O)2Rb4、NRc4S(O)2NRc4Rd4、S(O)Rb4、S(O)NRc4Rd4、S(O)2Rb4、S(O)2NRc4Rd4、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、C1−6ハロアルキル、フェニル、C3−6シクロアルキル、炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する5〜6員のヘテロアリール部分、及び炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する4〜7員のヘテロシクロアルキル部分であり;前記R6の、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、フェニル、C3−6シクロアルキル、5〜6員のヘテロアリール、及び4〜7員のヘテロシクロアルキル基は、それぞれ、R10Aから独立に選択される1、2または3個の置換基で任意に置換されており;
Lは、−(CR13R14)n−(但し、R13及びR14はそれぞれ独立してH、C1−6アルキル、C6−10アリール、5〜10員ヘテロアリールまたは4〜10員ヘテロシクロアルキルであり、前記C1−6アルキル、C6−10アリール、5〜10員のヘテロアリールまたは4〜10員のヘテロシクロアルキルは、1〜3個のR17基で任意に置換されていてもよく、各R17は1〜3個のR19で任意に置換されており、下付き文字nは1、2または3である。)であり;
R8は、H、またはハロ、CN、ORa9、C(O)NRc9Rd9、NRc9Rd9、NRc9C(O)Rb9、NRc9C(O)ORa9、NRc9C(O)NRc9Rd9、NRc9S(O)Rb9、NRc9S(O)2Rb9、NRc9S(O)2NRc9Rd9、S(O)Rb9、S(O)NRc9Rd9、S(O)2Rb9、S(O)2NRc9Rd9、フェニル、C3−7シクロアルキル、炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する5〜6員のヘテロアリール部分、及び炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する4〜7員のヘテロシクロアルキル部分で任意に置換されたC1−4アルキルであり;前記R8の、フェニル、C3−7シクロアルキル、5〜6員のヘテロアリール、及び4〜7員のヘテロシクロアルキル基は、それぞれ1又は2個のR19基で任意に置換されており;
R10は、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、C1−6ハロアルキル、C6−10アリール、C3−10シクロアルキル、炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する5〜10員のヘテロアリール部分、及び炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する4〜10員のヘテロシクロアルキル部分から選択され;前記R10の、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、C6−10アリール、C3−10シクロアルキル、5〜10員のヘテロアリール、及び4〜10員のヘテロシクロアルキル基は、それぞれ、1、2、3または4個のR10Aで任意に置換されており;
R10Aは、出現ごとに独立して、ハロ、CN、NO2、ORa4、SRa4、C(O)Rb4、C(O)NRc4Rd4、C(O)ORa4、OC(O)Rb4、OC(O)NRc4Rd4、C(=NRe4)NRc4Rd4、NRc4C(=NRe4)NRc4Rd4、NRc4Rd4、NRc4C(O)Rb4、NRc4C(O)ORa4、NRc4C(O)NRc4Rd4、NRc4S(O)Rb4、NRc4S(O)2Rb4、NRc4S(O)2NRc4Rd4、S(O)Rb4、S(O)NRc4Rd4、S(O)2Rb4、S(O)2NRc4Rd4、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、C1−6ハロアルキル、フェニル、C3−6シクロアルキル、炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する5〜6員のヘテロアリール部分、及び炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する4〜7員のヘテロシクロアルキル部分から選択され;前記R10Aの、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、フェニル、C3−6シクロアルキル、5〜6員のヘテロアリール、及び4〜7員のヘテロシクロアルキル基は、それぞれR19から独立に選択される1、2または3個の置換基で任意に置換されており;
Ra4、Rb4、Rc4、及びRd4は、出現ごとに独立して、H、C1−4アルキル、C2−4アルケニル、C2−4アルキニル、C1−4ハロアルキル、フェニル、C3−6シクロアルキル、炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する5〜6員のヘテロアリール部分、及び炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する4〜7員のヘテロシクロアルキル部分から独立して選択され;前記Ra4、Rb4、Rc4、及びRd4の、C1−4アルキル、C2−4アルケニル、C2−4アルキニル、フェニル、C3−6シクロアルキル、5〜6員のヘテロアリール、及び4〜7員のヘテロシクロアルキル基は、それぞれ、R19から独立に選択される1、2または3個の置換基で任意に置換されており;
あるいは、Rc4、及びRd4は、それらが結合する窒素原子と共に、R19から独立に選択される1、2または3個の置換基で任意に置換された4−、5−、6−または7−員のヘテロシクロアルキル基を形成し;
Re4は、それぞれHまたはC1−4アルキルであり;
R11は、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、及びC1−6ハロアルキル、から選択され;前記C1−6アルキル、C2−6アルケニル、及びC2−6アルキニルは、それぞれ、R19から独立して選択される1、2、または3個の置換基で任意に置換されており;
あるいは、R10及びR11は、それらが結合する炭素原子と共に、3−、4−、5−、6−または7−員のシクロアルキル基、または4−、5−、6−、7−、8−、9−または10−員のヘテロシクロアルキル基を形成し、前記3−、4−、5−、6−または7−員のシクロアルキル基または4−、5−、6−、7−、8−、9−または10−員のヘテロシクロアルキル基は1、2、3または4個のR10Aでそれぞれ任意に置換されており;
R12は、H、またはR17で任意に置換されていてもよいC1−4アルキルであり;
R17は、出現ごとに独立して、ハロ、CN、NO2、ORa7、SRa7、C(O)Rb7、C(O)NRc7Rd7、C(O)ORa7、OC(O)Rb7、OC(O)NRc7Rd7、C(=NRe7)NRc7Rd7、NRc7C(=NRe7)NRc7Rd7、NRc7Rd7、NRc7C(O)Rb7、NRc7C(O)ORa7、NRc7C(O)NRc7Rd7、NRc7S(O)Rb7、NRc7S(O)2Rb7、NRc7S(O)2NRc7Rd7、S(O)Rb7、S(O)NRc7Rd7、S(O)2Rb7、S(O)2NRc7Rd7、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、C1−6ハロアルキル、フェニル、C3−6シクロアルキル、炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する5〜6員のヘテロアリール部分、及び炭素及びN、O及びSから選択される1、2または3個のヘテロ原子を有する4〜7員のヘテロシクロアルキル部分から独立して選択され;前記R17の、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、フェニル、C3−6シクロアルキル、5〜6員のヘテロアリール、及び4〜7員のヘテロシクロアルキル基は、それぞれR19から独立に選択される1、2または3個の置換基で任意に置換されており;
Ra7、Rb7、Rc7、及びRd7は、出現ごとに独立して、H、C1−4アルキル、C2−4アルケニル、C2−4アルキニル、C1−4ハロアルキル、フェニル、C3−6シクロアルキル、炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する5〜6員のヘテロアリール部分、及び炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する4〜7員のヘテロシクロアルキル部分から選択され;前記Ra7、Rb7、Rc7、及びRd7の、C1−4アルキル、C2−4アルケニル、C2−4アルキニル、フェニル、C3−6シクロアルキル、5〜6員のヘテロアリール、及び4〜7員のヘテロシクロアルキル基は、それぞれR19から独立に選択される1、2または3個の置換基で任意に置換されており;
あるいは、Rc7、及びRd7は、それらが結合する窒素原子と共に、R19から独立に選択される1、2または3個の置換基で任意に置換された4−、5−、6−または7−員のヘテロシクロアルキル基を形成し;
Re7は、出現ごとに独立してHまたはC1−4アルキルであり;
R19は、出現ごとに独立して、ハロ、CN、NO2、ORa9、SRa9、C(O)Rb9、C(O)NRc9Rd9、C(O)ORa9、OC(O)Rb9、OC(O)NRc9Rd9、
NRc9Rd9、NRc9C(O)Rb9、NRc9C(O)ORa9、NRc9C(O)NRc9Rd9、NRc9S(O)Rb9、NRc9S(O)2Rb9、NRc9S(O)2NRc9Rd9、S(O)Rb9、S(O)NRc9Rd9、S(O)2Rb9、S(O)2NRc9Rd9、C1−4アルキル、C2−4アルケニル、C2−4アルキニル、及びC1−4ハロアルキルから選択され;
Ra9、Rc9、及びRd9は、出現ごとに独立して、H及びC1−4アルキルから選択され;そして
Rb9は、出現ごとにC1−4アルキルである。]。
変数R1、R2、R3、R4、R5、R10、R11、R12、X及びLは式(I)の化合物のいずれの実施形態においても定義されている。
変数R1、R2、R3、R4、R5、R10、R11、R12、X及びnは式(I)の化合物のいずれの実施形態においても定義されている。
(但し、
R2はFまたClであり;
R5はFまたClであり;
Lは、−(CR13R14)n−(但し、R13及びR14はそれぞれ独立してH、C1−6アルキルまたはC6−10アリールであり、前記C1−6アルキルまたはC6−10アリールは1〜3個のR17基で任意に置換されており;あるいはR13及びR14は、それらが結合する炭素原子と一緒になって、C3−6シクロアルキルまたは4〜6員のヘテロシクロアルキル基を形成し;C3−6シクロアルキルまたは4〜6員のヘテロシクロアルキル基が1〜3個のR17で任意に置換されている。)であり;
R8は、H、またはメチルであり;
R10は、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、C1−6ハロアルキル、C6−10アリール、C3−10シクロアルキル、炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する5〜10員のヘテロアリール部分、及び炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する4〜10員のヘテロシクロアルキル部分から選択され;前記R10の、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、C6−10アリール、C3−10シクロアルキル、5〜10員のヘテロアリール、及び4〜10員のヘテロシクロアルキル基は、それぞれ1、2、3または4個のR10Aで任意に置換されており;
R10Aは、出現ごとに独立して、ハロ、CN、NO2、ORa4、SRa4、C(O)Rb4、C(O)NRc4Rd4、C(O)ORa4、OC(O)Rb4、OC(O)NRc4Rd4、
C(=NRe4)NRc4Rd4、NRc4C(=NRe4)NRc4Rd4、NRc4Rd4、NRc4C(O)Rb4、NRc4C(O)ORa4、NRc4C(O)NRc4Rd4、
NRc4S(O)Rb4、NRc4S(O)2Rb4、NRc4S(O)2NRc4Rd4、S(O)Rb4、S(O)NRc4Rd4、S(O)2Rb4、S(O)2NRc4Rd4、
C1−6アルキル、C2−6アルケニル、C2−6アルキニル、C1−6ハロアルキル、フェニル、C3−6シクロアルキル、炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する5〜6員のヘテロアリール部分、及び炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する4〜7員のヘテロシクロアルキル部分から選択され;前記R10Aの、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、フェニル、C3−6シクロアルキル、5〜6員のヘテロアリール、及び4〜7員のヘテロシクロアルキル基は、それぞれR19から独立に選択される1、2または3個の置換基で任意に置換されており;
Ra4、Rb4、Rc4、及びRd4は、出現ごとに独立して、H、C1−4アルキル、C2−4アルケニル、C2−4アルキニル、C1−4ハロアルキル、フェニル、C3−6シクロアルキル、炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する5〜6員のヘテロアリール部分、及び炭素及びN、O及びSから独立して選択される1、2または3個のヘテロ原子を有する4〜7員のヘテロシクロアルキル部分から選択され;前記Ra4、Rb4、Rc4、及びRd4の、C1−4アルキル、C2−4アルケニル、C2−4アルキニル、フェニル、C3−6シクロアルキル、5〜6員のヘテロアリール、及び4〜7員のヘテロシクロアルキル基は、それぞれR19から独立に選択される1、2または3個の置換基で任意に置換されており;
あるいは、Rc4、及びRd4は、それらが結合する窒素原子と一緒になって、R19から独立に選択される1、2または3個の置換基で任意に置換された4−、5−、6−または7−員のヘテロシクロアルキル基を形成し;
Re4は、出現ごとに独立して、HまたはC1−4アルキルであり;
R11は、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、及びC1−6ハロアルキルから選択され;
あるいは、R10及びR11は、それらが結合する炭素原子と一緒になって、3−、4−、5−、6−または7−員のシクロアルキル基または4−、5−、6−、または7−員のヘテロシクロアルキル基を形成し;前記3−、4−、5−、6−または7−員のシクロアルキル基または4−、5−、6−、または7−員のヘテロシクロアルキル基はそれぞれ1、2、3または4個のR10Aで任意に置換されており;
R17は、出現ごとに独立して、OH、CN、アミノ、ハロ、C1−6アルキル、C1−4アルコキシ、C1−4アルキルチオ、C1−4アルキルアミノ、ジ(C1−4アルキル)アミノ、C1−4ハロアルキル、及びC1−4ハロアルコキシルから選択され;
R19は、出現ごとに独立して、ハロ、CN、NO2、ORa9、SRa9、C(O)Rb9、C(O)NRc9Rd9、C(O)ORa9、OC(O)Rb9、OC(O)NRc9Rd9、NRc9Rd9、NRc9C(O)Rb9、NRc9C(O)ORa9、NRc9C(O)NRc9Rd9、NRc9S(O)Rb9、NRc9S(O)2Rb9、NRc9S(O)2NRc9Rd9、S(O)Rb9、S(O)NRc9Rd9、S(O)2Rb9、S(O)2NRc9Rd9、C1−4アルキル、C2−4アルケニル、C2−4アルキニル、及びC1−4ハロアルキルから選択され;
Ra9、Rc9、及びRd9は、出現ごとに独立して、H及びC1−4アルキルから選択され;そして
Rb9は、出現ごとに独立してC1−4アルキルである。)。
(但し、X、L、R1、R2、R3、R4、R5、R8、R10、R11、R12は本明細書に定義されており、R12aはHであり;R12bはHである。)。
(但し、L、R2、R5、R8、R10、R11、及びR12は本明細書に定義されており、R12aはHであり;R12bはHである。)。
本明細書で使用される「場合により置換された」という語句は、置換されていない、又は置換された、を意味する。
ラセミ混合物の分割はまた、光学活性分割剤(例えば、ジニトロベンゾイルフェニルグリシン)を充填したカラム上への溶出によって行うこともできる。適切な溶出溶媒組成は、当業者によって決定され得る。
本発明の薬学的に受容可能な塩は、従来の化学的方法によって塩基性または酸性部分を含む親化合物から合成することができる。一般に、このような塩は、これらの化合物の遊離酸または塩基形態を、化学量論量の適切な塩基または酸と、水中または有機溶媒中、またはその2種の混合物中で反応させることによって調製することができる;一般に、エーテル、酢酸エチル、アルコール(例えば、メタノール、エタノール、イソプロパノール、またはブタノール)またはアセトニトリル(ACN)等の非水性媒体が好ましい。好適な塩の例示は、Remington’s Pharmaceutical Sciences,第17版,Mack Publishing Company,Easton,Pa.,1985,p.1418及びJournal of Pharmaceutical Science,66,2(1977)に記載されており、その各々は、その全体が参照により本明細書に組み込まれる。
本発明の化合物(その塩を含む)は、公知の有機合成技術を用いて、様々な可能な合成経路に従って調製することができる。
本発明の化合物は、FGFR4酵素の活性を阻害することができる。例えば、本発明の化合物は、阻害する量の本発明の化合物を細胞、個体または患者に投与することによって、酵素の阻害を必要とする細胞もしくは個体または患者におけるFGFR4酵素の活性を阻害するために使用することができる。
例えば、抗ウイルス剤、化学療法剤、または他の抗癌剤、免疫増強剤、免疫抑制剤、放射線、抗腫瘍及び抗ウイルスワクチン、サイトカイン療法(例えば、IL2、GM−CSF等)、及び/またはチロシンキナーゼ阻害剤等の1つまたは複数の追加の医薬品または治療法は、FGFR関連の疾患、障害または状態の治療のために、本発明の化合物と組み合わせて使用することができる。薬剤は、単一の剤形で本発明の化合物と組み合わせることができるか、薬剤を別々の剤形として同時にまたは連続して投与することができる。
これらの治療剤としては、EGFR、Her2、VEGFR、c−Met、Ret、IGFR1またはFlt−3に対する阻害剤または抗体、及びBcr−Abl及びEML4−Alk等の癌関連融合タンパク質キナーゼに対する阻害剤または抗体が挙げられる。EGFRに対する阻害剤としては、ゲフィチニブ及びエルロチニブが挙げられ、EGFR/Her2に対する阻害剤としては、ダコミニブ、アファチニブ、ラピチニブ及びネラチニブが挙げられるが、これらに限定されない。EGFRに対する抗体には、セツキシマブ、パニツムマブ及びネチツムマブが挙げられるが、これらに限定されない。c−Metの阻害剤は、FGFR阻害剤と組み合わせて使用することができる。これらとしては、オナルツズマブ、ティバントニブ、及びINC−280が挙げられる。Abl(またはBcr−Abl)に対する薬剤としては、イマチニブ、ダサチニブ、ニロチニブ、及びポナチニブが挙げられ、Alk(またはEML4−ALK)に対するものとしては、クリゾチニブが挙げられる。
医薬品として使用する場合、本発明の化合物は、本発明の化合物またはその薬学的に受容可能な塩と、少なくとも1つの薬学的に受容可能な担体との組み合わせを意味する医薬組成物の形態で投与することができる。これらの組成物は、医薬分野で周知の方法で調製することができ、局所的または全身的治療が所望されるかどうかに応じて、及び治療される領域に応じて、様々な経路で投与することができる。投与は局所的(例えば、眼、及び鼻腔内、膣及び直腸送達等の粘膜を含む)、肺(例えば、噴霧器による等の、粉末またはエアロゾルの吸入または吹送による;気道または気管内、鼻腔内、表皮及び経皮を含む)、眼、 経口、または非経口であり得る。眼内送達のための方法としては、局所投与(点眼)、結膜下、眼周囲または硝子体内注射、または結膜嚢に外科的に配置されたバルーンカテーテルまたは眼科用インサートによる導入を挙げることができる。非経口投与としては、静脈内、動脈内、皮下、腹腔内、または筋肉内注射または注入が含まれ;または頭蓋内、例えば髄腔内または脳室内投与が挙げられる。非経口投与は、単一ボーラス用量の形態であってもよく、または例えば、連続灌流ポンプによってもよい。局所投与のための医薬組成物及び製剤としては、経皮パッチ剤、軟膏剤、ローション剤、クリーム剤、ゲル剤、滴剤、坐剤、スプレー剤、液体剤及び散剤が挙げられ得る。従来の医薬担体、水性、粉末または油性基剤、増粘剤等が必要または望ましい場合がある。
本発明の別の態様は、本発明の蛍光色素、スピン標識、重金属または放射性標識化合物に関するものであり、これらは、ヒトを含む組織サンプルにおけるFGFR酵素を局在化及び定量するために、及び標識された化合物の結合を阻害することによってFGFR酵素リガンドを同定するために、インビトロ及びインビボの両方で、画像化のみならずアッセイにおいても有用である。従って、本発明は、このような標識化合物を含むFGFR酵素アッセイを含む。
本発明はまた、例えば、FGFR関連疾患または障害、肥満、糖尿病及び本明細書で言及される他の疾患の治療または予防に有用であって、治療有効量の本発明の化合物を含有する医薬組成物を含む1つ以上の容器を含む医薬キットを含む。このようなキットには、必要に応じて、例えば、当業者には容易に明らかであろう、1つ以上の薬学的に受容可能な担体を有する容器、追加の容器等の様々な従来の医薬キット構成要素の1つ以上が含まれ得る。投与されるべき成分の量、投与のためのガイドライン、及び/または成分を混合するためのガイドラインを示す挿入物(inserts)またはラベルのいずれかの指示書も、キットに含めることができる。
pH=2精製:移動相A:0.1%TFA(トリフルオロ酢酸)水及び移動相B:アセトニトリルで溶出する、Waters Sunfire(商標)C185μm粒径、19×100mmカラム;流速は30mL/分であり、分離勾配は、文献に記載されているような化合物特定方法最適化プロトコルを用いて各化合物について最適化された[“Preparative LCMS Purification: Improved Compound Specific Method Optimization”,K.Blom、B.Glass,R.Sparks,A.Combs,J.Comb.Chem.,6,874−883(2004)を参照]。典型的には、30×100mmカラムで使用される流速は60mL/分であった。
pH=10精製:移動相A:0.15%NH4OH水及び移動相B:アセトニトリルで溶出するWaters XBridge C185μm粒径、19×100mmカラム;流速は30mL/分であり、分離勾配は、文献に記載されているような化合物特定方法最適化プロトコルを用いて各化合物について最適化された[“Preparative LCMS Purification: Improved Compound Specific Method Optimization”,K.Blom、B.Glass,R.Sparks,A.Combs,J.Comb.Chem.,6,874−883(2004)を参照]。典型的には、30×100mmカラムで使用される流速は60mL/分であった。
N−{[2’−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−3’−オキソ−2’,3’−ジヒドロ−1’H−スピロ[シクロプロパン−1,4’−[2,7]ナフチリジン] −6’−イル]メチル}アクリルアミド
塩化メチレン(4.0mL)中の6’−(アミノメチル)−2’−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−1’,2’−ジヒドロ−3’H−スピロ[シクロプロパン−1,4’−[2,7]ナフチリジン]−3’−オン(25.5mg、0.068mmol)の撹拌溶液に、N、N−ジイソプロピルエチルアミン(46μL,0.27mmol)及び塩化2−プロペノイル(5.8μL,0.072mmol)を室温で順次添加した。3分後、反応物を飽和NH4Cl水溶液でクエンチし、塩化メチレンで抽出した。有機層を合わせ、Na2SO4で乾燥し、濾過し、減圧下で濃縮乾固した。粗生成物を分取HPLC(pH=2、アセトニトリル/水+TFA)で精製して、そのTFA塩として所望の生成物(15mg)を得た。C22H22F2N3O4 [M+H]+m/zのLCMS計算値:430.2; 実測値:430.1。1H NMR (500 MHz, DMSO−d6): δ8.63 (t, J=5.6 Hz,1H), 8.40 (s,1H), 7.07(t, J=8.2 Hz,1H), 6.97(s, 1H), 6.31(dd, J=17.1, 10.2 Hz,1H),6.11 (dd, J=17.1,2.1 Hz,1H),5.62 (dd,J=10.2,2.1 Hz,1H),4.95(s,2H),4.43(d,J=5.8 Hz,2H),3.89(s, 6H),1.76 (q, J=3.9 Hz, 2H),1.46(q,J=4.0 Hz,2H)。
N−((3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−1−エチル−2−オキソ−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン−7−イル)メチル)アクリルアミド
粗7−(アミノメチル)−3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−1−エチル−3,4−ジヒドロピリド[4,3−d]ピリミジン−2(1H)− オン(0.28、0.74mmol及びトリエチルアミン(350μL、2.5mmol)のアセトニトリル(5mL)溶液に、室温で2−プロペノイルクロリド(70μL、0.86mmol)を加えた。30分後、反応混合物をMeOHで希釈し、RP−HPLC(pH=2)で精製して、所望の生成物をそのTFA塩として得た。C21H23F2N4O4[M+H]+m/zのLC−MS計算値:433.2;実測値433.1。1H NMR(500MHz,DMSO−d6):δ8.87(s,1H),8.38(s,1H),7.33(s,1H),7.08(t,J=8.2Hz、1H),6.32(dd,J=17.1,10.2Hz,1H),6.15(dd、J=17.1,2.0Hz,1H),5.68(dd,J=10.2,2.0Hz,1H),4.84(s,2H)、4.57(d,J=5.6Hz,2H),3.92(q,J=5.0Hz,2H),3.89(s,6H),1.18(t,J=7.0Hz,3H)。
N−((3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−2−オキソ−1−(ピリジン−3−イル)−1,2,3,4−テトラヒドロピリド[4,3−d] ピリミジン−7−イル)メチル)アクリルアミド
標題化合物を、実施例2、工程3〜6について記載した手順と類似の手順を用い、工程3の3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−1−エチル−7−ビニル−3,4−ジヒドロピリド[4,3−d]ピリミジン−2(1H)−オンに代えて3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−1−(ピリジン−3−イル)−7−ビニル−3,4−ジヒドロピリド[4,3−d]ピリミジン−2(1H)−オンを用いて調製した。C24H22F2N5O4[M+H]+m/zのLC−MS計算値:482.2; 実測値:482.2。
N−((6’−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−7’−オキソ−6’,7’−ジヒドロ−5H−スピロ[シクロプロパン−1,8’−ピリド[4,3−d]ピリミジン]−2’−イル)メチル)アクリルアミド
標題の化合物を、実施例2、工程2〜6について記載されたものと類似の手順を用い、工程2の7−クロロ−3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−1−エチル−3,4−ジヒドロピリド[4,3−d]ピリミジン−2(1H)−オンの代わりに2’−クロロ−6’−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−5’,6’−ジヒドロ−7’H−スピロ[シクロプロパン−1,8’−ピリド[4,3−d]ピリミジン]−7’オンを用いて調整した。C21H21F2N3O4[M+H]+m/zのLCMS計算値:431.2;実測値:431.1。
N−((2’−(2,6−ジフルオロ−3,5-ジメトキシフェニル)−3’−オキソ−2’,3’−ジヒドロ−1’H−スピロ[シクロペンタン−1,4’−[2,7]ナフチリジン]−6’−イル)メチル)アクリルアミド
表題の化合物を、実施例2、工程2〜6について記載した手順と類似の手順を用い7−クロロ−3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−1−エチル−3,4−ジヒドロピリド[4,3−d]ピリミジン−2(1H)−オンの代わりに6’−クロロ−2’−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−1’H−スピロ[シクロペンタン−1,4’−[2,7]ナフチリジン]−3’(2’H)− オンを用いて調製した。C24H26F2N3O4[M+H]+m/zのLCMS計算値:458.2;実測値:458.2。1H NMR(600MHz,DMSO)δ8.74(t,J=5.7Hz,1H),8.50(s,1H),7.36(s,1H),7.07(t,J=8.1Hz,1H),6.34(dd,J=17.1,10.3Hz,1H),6.15(dd,J=17.1,2.0Hz,1H),5.65(dd,J=10.3,2.0Hz,1H),4.87(s,2H),4.51(d,J=5.9Hz,2H),3.90(s,6H),2.38(dt,J=14.4,7.4Hz,2H),1.98(dt,J=12.3,6.4Hz,2H),1.87−1.73(m,4H)。
N−((3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−2−オキソ−1−フェニル−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン−7−イル)メチル)アクリルアミド
N−((3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−1−(1−メチル−1H−ピラゾール−3−イル)−2−オキソ−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン−7−イル)メチル)アクリルアミド
(S)−N−((3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−2−オキソ−1−(テトラヒドロフラン−3−イル)−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン−7−イル)メチル)アクリルアミド
N−((3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−1−(3,3−ジフルオロシクロブチル)−2−オキソ−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン−7−イル)メチル)アクリルアミド
N−((1−シクロプロピル−3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−2−オキソ−1,2,3,4-テトラヒドロピリド[4,3−d]ピリミジン−7−イル) メチル)アクリルアミド
N−((3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−1−(2−メトキシエチル)−2−オキソ−1,2,3,4−テトラヒドロピリド[4,3−d] ピリジン−7−イル)メチル)アクリルアミド
N−((3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−2−オキソ−1−プロピル−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン−7−イル) メチル)アクリルアミド
N−((1−(シクロプロピルメチル)−3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−2−オキソ−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン−7−イル)ピリジン−3−イル)メチル)アクリルアミド
N−((3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−1−(2,2−ジフルオロエチル)−2−オキソ−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン−7−イル)メチル)アクリルアミド
N−((3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−1−イソプロピル−2−オキソ−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン−7−イル)メチル)アクリルアミド
N−((3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−1−(3−フルオロベンジル)−2−オキソ−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン−7−イル)メチル)アクリルアミド
N−((3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−2−オキソ−1−(ピリジン−3−イルメチル)−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン−7−イル)メチル)アクリルアミド
N−((3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−1−((1−メチル−1H−ピラゾール−4−イル)メチル)−2−オキソ−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン−7−イル)メチル)アクリルアミド
(R)−N−((3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−2−オキソ−1−((テトラヒドロフラン−3−イル)メチル)−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン−7−イル)メチル)アクリルアミド
N−((1−(シアノメチル)−3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−2−オキソ−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン−7−イル)メチル)アクリルアミド
N−((3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−2−オキソ−1−(2,2,2−トリフルオロエチル)−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン−7−イル)メチル)アクリルアミド
N−((3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−1−メチル−2−オキソ−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン−7−イル)メチル)アクリルアミド
N−((3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−2−オキソ−1−(テトラヒドロ−2H−ピラン−4−イル)−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン−7−イル)メチル)アクリルアミド
N−((7−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−5,5−ジメチル−6−オキソ−5,6,7,8−テトラヒドロ−2,7−ナフチリジン−3−イル)メチル)アクリルアミド
N−((1−シクロブチル−3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−2−オキソ−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン−7−イル)メチル)アクリルアミド
N−((3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−2−オキソ−1−(ピリジン−4−イル)−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン−7−イル)メチル)アクリルアミド
N−((3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−1−(2−フルオロエチル)−2−オキソ−1,2,3,4−テトラヒドロピリド[4,3−d]ピリジン−7−イル)メチル)アクリルアミド
N−((1−シクロペンチル−3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−2−オキソ−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン−7−イル)メチル)アクリルアミド
N−((3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−1−イソブチル−2−オキソ−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン−7−イル)メチル)アクリルアミド
N−((1−(シクロブチルメチル)−3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−2−オキソ−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン−7−イル)メチル)アクリルアミド
(S)−N−((3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−2−オキソ−1−((テトラヒドロフラン−3−イル)メチル)−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン−7−イル)メチル)アクリルアミド
N−((3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−1−((1−メチルピペリジン−4−イル)メチル)−2−オキソ−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン−7−イル)メチル)アクリルアミド
テトラヒドロフラン(1mL)中のN−{[3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−2−オキソ−1−(ピペリジン−4−イルメチル)−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン−7−イル]メチル}アクリルアミド2,2,2−トリフルオロアセテート(15mg、0.030mmol)の撹拌溶液に、ホルムアルデヒド(水中の10.0M、6.2μL、0.062mmol)及びN,N−ジイソプロピルエチルアミン(14μL、0.082mmol)を室温で順次加えた。5分後、トリアセトキシ水素化ホウ素ナトリウム(13mg、0.062mmol)を加えた。さらに2時間後、反応混合物をMeOHで希釈し、RP−HPLC(pH=10、アセトニトリル/水+NH4OH)で精製して、所望の生成物を得た。C26H32F2N5O4[M+H]+m/zのLCMS計算値:516.2;実測値:516.2。
メチル4−((7−(アクリルアミドメチル)−3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−2−オキソ−3,4−ジヒドロピリド[4,3−d]ピリミジン−1(2H)−イル)メチル)ピペリジン−1−カルボキシレート
4−((7−(アクリルアミドメチル)−3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−2−オキソ−3,4−ジヒドロピリド[4,3−d]ピリミジン−1(2H) −イル)メチル)−N−イソプロピルピペリジン−1−カルボキサミド
N−((3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−1−((1−(メチルスルホニル)ピペリジン−4−イル)メチル)−2−オキソ−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン−7−イル)メチル)アクリルアミド
N−((3−(2,6−ジクロロ−3,5−ジメトキシフェニル)−1−エチル−2−オキソ−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン−7−イル)メチル)アクリルアミド
標題化合物を、実施例2に記載の手順と類似の手順を用い、工程1において2,6−ジフルオロ−N−((4,6−ジクロロピリジン−3−イル)メチル)−3,5−ジメトキシアニリンの代わりに2,6−ジクロロ−N−((4,6−ジクロロピリジン−3−イル)メチル)−3,5−ジメトキシアニリン(工程4)を用いて調製した。C21H23Cl2N4O4[M+H]+m/zのLCMS計算値:465.1;実測値:465.1。
N−((2’−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−5’−メチル−3’−オキソ−2’,3’−ジヒドロ−1’H−スピロ[シクロプロパン−1,4’−[2,7]ナフチリジン]−6’−イル)メチル)アクリルアミド
標題化合物を、実施例2、工程2〜6に記載の手順と類似の手順を用い、工程2において7−クロロ−3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−1−エチル−3,4−ジヒドロピリド[4,3−d]ピリミジン−2(1H)−オンの代わりに6’−クロロ−2’−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−5’−メチル−1’H−スピロ[シクロプロパン−1,4’−[2,7]ナフチリジン]−3’(2’H)−オン(工程3)を用いて調製した。C23H24F2N3O4[M+H]+m/zのLCMS計算値:444.2;実測値:444.2。
FGFR酵素アッセイ
例示された化合物の阻害剤効力は、ペプチドリン酸化を、生成物形成を検出するためにFRET測定を用いて測定する酵素アッセイで測定された。阻害剤をDMSO中で連続的に希釈し、0.5μLの容量を384ウェルプレートのウェルに移した。FGFR3については、アッセイ緩衝液(50mM HEPES、10mM MgCl2、1mM EGTA、0.01%Tween−20,5mM DTT、pH7.5)で希釈した10μL容量のFGFR3酵素(Millipore)をプレートに添加し、5〜10分から4時間以下の間予備培養(プレインキュベート)した。適切なコントロール(酵素ブランク及び阻害剤のない酵素)がプレートに盛り込まれた。アッセイ緩衝液中のビオチン化EQEDEPEGDYFEWLEペプチド基質(SEQ ID NO:1)及びATP(それぞれ最終濃度500nM及び140μM)を含む10μL溶液を、ウェルに添加することによってアッセイを開始した。プレートを25℃で1時間インキュベートした。反応を、10μL/ウェルのクエンチ溶液(50mM Tris、150mM NaCl、0.5mg/mL BSA、pH7.8;3.75nM Eu抗体PY20及び180nM APC−StreptavidinにおけるPerkin Elmer Lance Reagentを有する30mM EDTA)を添加して終了させた。プレートを約1時間平衡させた後、PheraStarプレートリーダー(BMG Labtech)でウェルをスキャンした。
Y=Bottom + (Top−Bottom)/(1+10^((LogIC50−X)*HillSlope))
上式において、Xは濃度の対数であり、Yは応答である。1μM以下のIC50を有する化合物が活性であると考えられる。
FGFR4細胞及びインビボアッセイ
細胞、組織及び/または動物における例示化合物のFGFR4阻害活性は、当技術分野例えば、French et al.“Targeting FGFR4 Inihibits Hepatocellular Carcinoma in Preclinical Mouse Models (FGFR4の標的化は、前臨床マウスモデルにおける肝細胞癌を阻害する)”,PLoS ONE,May,2012,Vol.7,Issue 5,e36713(その全体が参照により本明細書に組み込まれる)、に記載されている1つ以上のアッセイまたはモデルに従って、示すことができる。
Claims (37)
- N−{[2’−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−3’−オキソ−2’,3’−ジヒドロ−1’H−スピロ[シクロプロパン−1,4’−[2,7]ナフチリジン]−6’−イル]メチル}アクリルアミド;
N−((3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−1−エチル−2−オキソ−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン−7−イル)メチル)アクリルアミド;
N−((3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−2−オキソ−1−(ピリジン−3−イル)−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン−7−イル)メチル)アクリルアミド;
N−((6’−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−7’−オキソ−6’,7’−ジヒドロ−5’H−スピロ[シクロプロパン−1,8’−ピリド[4,3−d]ピリミジン]−2’−イル)メチル)アクリルアミド;および
N−((2’−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−3’−オキソ−2’,3’−ジヒドロ−1’H−スピロ[シクロペンタン−1,4’−[2,7]ナフチリジン]−6’−イル)メチル)アクリルアミド
から選択される化合物またはその薬学的に受容可能な塩とさらなる治療剤とを含む組合せ医薬であって、癌の治療を必要とする患者に、該化合物またはその薬学的に受容可能な塩と該さらなる治療剤とを、単一の剤形で投与するかまたは別々の剤形として同時にもしくは連続して投与することによる癌治療に用いるための組合せ医薬であり、
該さらなる治療剤が、
i)抗ホルモン剤;
ii)EGFR、Her2、VEGFR、c−Met、Ret、IGFR1またはFlt−3に対する阻害剤または抗体、及び癌関連融合タンパク質キナーゼに対する阻害剤または抗体;
iii)PI3キナーゼに対する薬剤;
iv)mTORの阻害剤;
v)アルキル化剤;
vi)プラチナ併用療法剤(platinum−based doublets);
vii)代謝拮抗物質;
viii)細胞毒性剤;
ix)免疫療法薬;
x)共刺激分子に対する抗体治療剤;
ix)抗癌ワクチン;ならびに
xii)ビンブラスチン、ビンクリスチン、ビンデシン、ブレオマイシン、ダクチノマイシン、ダウノルビシン、ドキソルビシン、エピルビシン、イダルビシン、アラ−C、パクリタキセル、ミトラマイシン、デオキシコホルマイシン、マイトマイシン−C、L−アスパラギナーゼ、インターフェロン、エトポシド、及びテニポシド
から選択される、組合せ医薬。 - 癌が、腎臓癌、胃癌、食道癌、多発性骨髄腫、膵臓癌、肺癌、前立腺癌、乳癌、膀胱癌、肝臓癌、真性赤血球増加症、本態性血小板血症、原発性骨髄線維症、頭頸部癌、卵巣癌、およびグリア芽細胞腫から選択される、請求項1に記載の組合せ医薬。
- 癌が、腎臓癌である、請求項1または2に記載の組合せ医薬。
- 癌が、胃癌である、請求項1または2に記載の組合せ医薬。
- 癌が、食道癌である、請求項1または2に記載の組合せ医薬。
- 癌が、多発性骨髄腫である、請求項1または2に記載の組合せ医薬。
- 癌が、膵臓癌である、請求項1または2に記載の組合せ医薬。
- 癌が、肺癌である、請求項1または2に記載の組合せ医薬。
- 癌が、前立腺癌である、請求項1または2に記載の組合せ医薬。
- 癌が、乳癌である、請求項1または2に記載の組合せ医薬。
- 癌が、膀胱癌である、請求項1または2に記載の組合せ医薬。
- 癌が、肝臓癌である、請求項1または2に記載の組合せ医薬。
- 癌が、真性赤血球増加症である、請求項1または2に記載の組合せ医薬。
- 癌が、本態性血小板血症である、請求項1または2に記載の組合せ医薬。
- 癌が、原発性骨髄線維症である、請求項1または2に記載の組合せ医薬。
- 癌が、頭頸部癌である、請求項1または2に記載の組合せ医薬。
- 癌が、卵巣癌である、請求項1または2に記載の組合せ医薬。
- 癌が、グリア芽細胞腫である、請求項1または2に記載の組合せ医薬。
- さらなる治療剤が、抗ホルモン剤である、請求項1〜18のいずれか1項に記載の組合せ医薬。
- さらなる治療剤が、EGFR、Her2、VEGFR、c−Met、Ret、IGFR1またはFlt−3に対する阻害剤または抗体、および癌関連融合タンパク質キナーゼに対する阻害剤または抗体から選択される、請求項1〜18のいずれか1項に記載の組合せ医薬。
- さらなる治療剤が、PI3キナーゼに対する薬剤である、請求項1〜18のいずれか1項に記載の組合せ医薬。
- さらなる治療剤が、mTORの阻害剤である、請求項1〜18のいずれか1項に記載の組合せ医薬。
- さらなる治療剤が、アルキル化剤である、請求項1〜18のいずれか1項に記載の組合せ医薬。
- さらなる治療剤がプラチナ併用療法剤(platinum−based doublets)である、請求項1〜18のいずれか1項に記載の組合せ医薬。
- プラチナ併用療法剤(platinum−based doublets)が、シスプラチンとゲムシタビンとの、カルボプラチンとゲムシタビンとの、シスプラチンとドセタキセルとの、カルボプラチンとドセタキセルとの、シスプラチンとパクリタキセルとの、カルボプラチンとパクリタキセルとの、シスプラチンとペメトレキセドとの、カルボプラチンとペメトレキセドとの、およびゲムシタビンとパクリタキセルとの結合粒子から選択される、請求項24に記載の組合せ医薬。
- さらなる治療剤が、代謝拮抗物質である、請求項1〜18のいずれか1項に記載の組合せ医薬。
- さらなる治療剤が、細胞毒性剤である、請求項1〜18のいずれか1項に記載の組合せ医薬。
- さらなる治療剤が、免疫療法薬である、請求項1〜18のいずれか1項に記載の組合せ医薬。
- 免疫療法薬が、共刺激分子に対する抗体治療剤およびサイトカインに対する抗体から選択される、請求項28に記載の組合せ医薬。
- さらなる治療剤が、共刺激分子に対する抗体治療剤である、請求項1〜18のいずれか1項に記載の組合せ医薬。
- さらなる治療剤が、抗癌ワクチンである、請求項1〜18のいずれか1項に記載の組合せ医薬。
- さらなる治療剤が、ビンブラスチン、ビンクリスチン、ビンデシン、ブレオマイシン、ダクチノマイシン、ダウノルビシン、ドキソルビシン、エピルビシン、イダルビシン、アラ−C、パクリタキセル、ミトラマイシン、デオキシコホルマイシン、マイトマイシン−C、L−アスパラギナーゼ、インターフェロン、エトポシド、およびテニポシドから選択される、請求項1〜18のいずれか1項に記載の組合せ医薬。
- 化合物が、N−{[2’−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−3’−オキソ−2’,3’−ジヒドロ−1’H−スピロ[シクロプロパン−1,4’−[2,7]ナフチリジン]−6’−イル]メチル}アクリルアミドまたはその薬学的に受容可能な塩である、請求項1〜32のいずれか1項に記載の組合せ医薬。
- N−((3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−1−エチル−2−オキソ−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン−7−イル)メチル)アクリルアミドまたはその薬学的に受容可能な塩である、請求項1〜32のいずれか1項に記載の組合せ医薬。
- N−((3−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−2−オキソ−1−(ピリジン−3−イル)−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン−7−イル)メチル)アクリルアミドまたはその薬学的に受容可能な塩である、請求項1〜32のいずれか1項に記載の組合せ医薬。
- N−((6’−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−7’−オキソ−6’,7’−ジヒドロ−5’H−スピロ[シクロプロパン−1,8’−ピリド[4,3−d]ピリミジン]−2’−イル)メチル)アクリルアミドまたはその薬学的に受容可能な塩である、請求項1〜32のいずれか1項に記載の組合せ医薬。
- N−((2’−(2,6−ジフルオロ−3,5−ジメトキシフェニル)−3’−オキソ−2’,3’−ジヒドロ−1’H−スピロ[シクロペンタン−1,4’−[2,7]ナフチリジン]−6’−イル)メチル)アクリルアミドまたはその薬学的に受容可能な塩である、請求項1〜32のいずれか1項に記載の組合せ医薬。
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Families Citing this family (35)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012088266A2 (en) | 2010-12-22 | 2012-06-28 | Incyte Corporation | Substituted imidazopyridazines and benzimidazoles as inhibitors of fgfr3 |
CN107652289B (zh) | 2012-06-13 | 2020-07-21 | 因塞特控股公司 | 作为fgfr抑制剂的取代的三环化合物 |
SG11201500125QA (en) | 2012-07-11 | 2015-02-27 | Blueprint Medicines Corp | Inhibitors of the fibroblast growth factor receptor |
WO2014026125A1 (en) | 2012-08-10 | 2014-02-13 | Incyte Corporation | Pyrazine derivatives as fgfr inhibitors |
JP6449244B2 (ja) | 2013-04-19 | 2019-01-09 | インサイト・ホールディングス・コーポレイションIncyte Holdings Corporation | Fgfr抑制剤としての二環式複素環 |
US9434700B2 (en) | 2013-10-25 | 2016-09-06 | Neil Bifulco, JR. | Inhibitors of the fibroblast growth factor receptor |
WO2015108992A1 (en) | 2014-01-15 | 2015-07-23 | Blueprint Medicines Corporation | Heterobicyclic compounds and their use as fgfr4 receptor inhibitors |
US10851105B2 (en) | 2014-10-22 | 2020-12-01 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
MA41551A (fr) | 2015-02-20 | 2017-12-26 | Incyte Corp | Hétérocycles bicycliques utilisés en tant qu'inhibiteurs de fgfr4 |
US9580423B2 (en) | 2015-02-20 | 2017-02-28 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
WO2016134320A1 (en) | 2015-02-20 | 2016-08-25 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
WO2018049233A1 (en) | 2016-09-08 | 2018-03-15 | Nicolas Stransky | Inhibitors of the fibroblast growth factor receptor in combination with cyclin-dependent kinase inhibitors |
WO2018055503A1 (en) | 2016-09-20 | 2018-03-29 | Novartis Ag | Combination comprising a pd-1 antagonist and an fgfr4 inhibitor |
EP3534902B1 (en) | 2016-11-02 | 2022-11-23 | Novartis AG | Combinations of fgfr4 inhibitors and bile acid sequestrants |
AR111960A1 (es) | 2017-05-26 | 2019-09-04 | Incyte Corp | Formas cristalinas de un inhibidor de fgfr y procesos para su preparación |
EP3680236A4 (en) | 2017-09-05 | 2021-04-21 | Bioardis LLC | AROMATIC DERIVATIVE, MANUFACTURING PROCESS FOR IT AND MEDICAL APPLICATION OF IT |
AU2019243289B2 (en) * | 2018-03-30 | 2023-01-12 | Les Laboratoires Servier | Heterobicyclic inhibitors of MAT2A and methods of use for treating cancer |
SG11202010882XA (en) | 2018-05-04 | 2020-11-27 | Incyte Corp | Salts of an fgfr inhibitor |
DK3788047T3 (da) | 2018-05-04 | 2024-09-16 | Incyte Corp | Faste former af en FGFR-inhibitor og fremgangsmåder til fremstilling deraf |
WO2020177067A1 (en) | 2019-03-05 | 2020-09-10 | Bioardis Llc | Aromatic derivatives, preparation methods, and medical uses thereof |
US11628162B2 (en) | 2019-03-08 | 2023-04-18 | Incyte Corporation | Methods of treating cancer with an FGFR inhibitor |
WO2021007269A1 (en) | 2019-07-09 | 2021-01-14 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
MX2022004513A (es) | 2019-10-14 | 2022-07-19 | Incyte Corp | Heterociclos biciclicos como inhibidores de los receptores del factor de crecimiento de fibroblastos (fgfr). |
WO2021076728A1 (en) | 2019-10-16 | 2021-04-22 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
GB201915828D0 (en) * | 2019-10-31 | 2019-12-18 | Cancer Research Tech Ltd | Compounds, compositions and therapeutic uses thereof |
CN112759593A (zh) | 2019-11-01 | 2021-05-07 | 北京伯汇生物技术有限公司 | 桥环并醛基吡啶衍生物及其应用 |
JP2023505258A (ja) | 2019-12-04 | 2023-02-08 | インサイト・コーポレイション | Fgfr阻害剤としての三環式複素環 |
BR112022010664A2 (pt) | 2019-12-04 | 2022-08-16 | Incyte Corp | Derivados de um inibidor de fgfr |
US12012409B2 (en) | 2020-01-15 | 2024-06-18 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
US11351149B2 (en) | 2020-09-03 | 2022-06-07 | Pfizer Inc. | Nitrile-containing antiviral compounds |
CN117062809A (zh) * | 2021-03-26 | 2023-11-14 | 杭州普洛药物研究院有限公司 | 双环杂环fgfr4抑制剂,包含其的药物组合物和制剂,及其应用 |
EP4323405A1 (en) | 2021-04-12 | 2024-02-21 | Incyte Corporation | Combination therapy comprising an fgfr inhibitor and a nectin-4 targeting agent |
CA3220274A1 (en) | 2021-06-09 | 2022-12-15 | Incyte Corporation | Tricyclic heterocycles as fgfr inhibitors |
TW202320792A (zh) | 2021-11-22 | 2023-06-01 | 美商英塞特公司 | 包含fgfr抑制劑及kras抑制劑之組合療法 |
WO2024193542A1 (en) * | 2023-03-20 | 2024-09-26 | Insilico Medicine Ip Limited | Inhibitors of fgfr2 and fgfr3 and uses thereof |
Family Cites Families (807)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE280853C (ja) | ||||
US850370A (en) | 1906-06-05 | 1907-04-16 | William L Hynes | Water-automobile. |
DE2156720A1 (de) | 1971-11-16 | 1973-05-24 | Bayer Ag | Pyrimido eckige klammer auf 4,5-d eckige klammer zu pyrimidine |
US3894021A (en) | 1974-01-28 | 1975-07-08 | Squibb & Sons Inc | Derivatives of 1,7-dihydro-2H-pyrazolo{8 4{40 ,3{40 :5,6{9 pyrido{8 4,3-D{9 pyrimidine-2,4-(3H)-diones |
JPS5120580B2 (ja) | 1974-06-19 | 1976-06-25 | ||
JPS522706Y2 (ja) | 1974-07-31 | 1977-01-21 | ||
US4347348A (en) | 1978-06-05 | 1982-08-31 | Chernikhov Alexei Y | Heat-resistant heterocyclic polymers and methods for producing same |
FR2428654A1 (fr) | 1978-06-13 | 1980-01-11 | Chernikhov Alexei | Polymeres heterocycliques thermostables et leurs procedes de preparation |
CH641470A5 (de) | 1978-08-30 | 1984-02-29 | Ciba Geigy Ag | Imidgruppen enthaltende silane. |
CH635828A5 (de) | 1978-08-30 | 1983-04-29 | Ciba Geigy Ag | N-substituierte imide und bisimide. |
US4339267A (en) | 1980-01-18 | 1982-07-13 | E. I. Du Pont De Nemours And Company | Herbicidal sulfonamides |
US4402878A (en) | 1980-10-22 | 1983-09-06 | Plastics Engineering Company | Addition products of di-acetylene-terminated polyimide derivatives with a polyimide having terminal non-conjugated acetylene groups |
US4405519A (en) | 1980-10-22 | 1983-09-20 | Plastics Engineering Company | Di-Acetylene-terminated polyimide derivatives |
US4405520A (en) | 1980-10-22 | 1983-09-20 | Plastics Engineering Company | Addition products of di-acetylene-terminated polymide derivatives and dienophiles having terminal maleimide grops |
US4405786A (en) | 1980-10-22 | 1983-09-20 | Plastics Engineering Company | Addition products of di-acetylene-terminated polyimide derivatives and an dienophile having ethylene groups |
US4460773A (en) | 1982-02-05 | 1984-07-17 | Lion Corporation | 1-Phenyl-1H-pyrazolo [3,4-b]pyrazine derivatives and process for preparing same |
DE3432983A1 (de) | 1983-09-07 | 1985-04-18 | Lion Corp., Tokio/Tokyo | 1,5-disubstituierte 1h-pyrazolo(3,4-b)-pyrazin-derivate und antitumormittel, die diese enthalten |
JPS62273979A (ja) | 1986-05-21 | 1987-11-28 | Lion Corp | 1,5−置換−1H−ピラゾロ〔3,4−b〕ピラジン誘導体及び該化合物を含有する抗腫瘍剤 |
JPS6310630A (ja) | 1986-06-23 | 1988-01-18 | Teijin Ltd | 芳香族ポリアミドイミドエ−テルの製造法 |
JPS6317882A (ja) | 1986-07-09 | 1988-01-25 | Lion Corp | 5−置換−1H−ピラゾロ〔3,4−b〕ピラジン誘導体及び該化合物を含有する抗腫瘍剤 |
JPS6336665U (ja) | 1986-08-27 | 1988-03-09 | ||
US4859672A (en) | 1986-10-29 | 1989-08-22 | Rorer Pharmaceutical Corporation | Pyrido[2,3-d]pyrimidinone and imidazo[4,5-b]pyrimidinone |
US4874803A (en) | 1987-09-21 | 1989-10-17 | Pennwalt Corporation | Dianhydride coupled polymer stabilizers |
DE3814549A1 (de) | 1987-10-30 | 1989-05-18 | Bayer Ag | N-substituierte derivate von 1-desoxynojirimycin und 1-desoxymannonojirimycin, verfahren zu deren herstellung und deren verwendung in arzneimitteln |
JPH029895A (ja) | 1988-06-28 | 1990-01-12 | Lion Corp | ヌクレオシド類似化合物及び抗腫瘍剤 |
DD280853A1 (de) | 1989-03-21 | 1990-07-18 | Akad Nauk Sssr | Bindemittel fuer elektroden, vorzugsweise fuer polymerelektroden |
US5159054A (en) | 1989-05-16 | 1992-10-27 | The United States Of America As Represented By The Secretary Of The Navy | Synthesis of phthalonitrile resins containing ether and imide linkages |
JP2845957B2 (ja) | 1989-07-17 | 1999-01-13 | 三井化学株式会社 | イミド環を有する新規ジフェノール類およびその製造方法 |
US5726302A (en) | 1989-09-15 | 1998-03-10 | Gensia Inc. | Water soluble adenosine kinase inhibitors |
DE3937633A1 (de) | 1989-11-11 | 1991-05-16 | Bayer Ag | Heterocyclische verbindungen und deren verwendung als pigmente und farbstoffe |
WO1991009835A1 (de) | 1989-12-28 | 1991-07-11 | Hoechst Aktiengesellschaft | Biskationische säureamid- und -imidderivative und verfahren zu ihrer herstellung |
CA2072560A1 (en) | 1989-12-28 | 1991-06-29 | Hans-Tobias Macholdt | Biscationic acid amide and acid imide derivatives as charge controllers |
JP2883670B2 (ja) | 1990-03-23 | 1999-04-19 | 三井化学株式会社 | イミド環を有する新規ビスフェノール類およびその製造方法 |
GB9113137D0 (en) | 1990-07-13 | 1991-08-07 | Ici Plc | Thioxo heterocycles |
CA2093322C (en) | 1990-10-03 | 2002-01-29 | Jonathan H. Hodgkin | Epoxy resins based on diaminobisimide compounds |
JPH04158084A (ja) | 1990-10-22 | 1992-06-01 | Fuji Photo Film Co Ltd | 記録材料 |
JPH04179576A (ja) | 1990-11-14 | 1992-06-26 | Fuji Photo Film Co Ltd | 記録材料 |
JPH04328121A (ja) | 1991-04-26 | 1992-11-17 | Sumitomo Bakelite Co Ltd | 半導体封止用エポキシ樹脂組成物 |
WO1992022552A1 (en) | 1991-06-14 | 1992-12-23 | The Upjohn Company | IMIDAZO[1,5-a]QUINOXALINES |
DE4119767A1 (de) | 1991-06-15 | 1992-12-17 | Dresden Arzneimittel | Verfahren zur herstellung von (pyrimid-2-yl-thio- bzw. seleno)-essigsaeurederivaten |
US5521184A (en) | 1992-04-03 | 1996-05-28 | Ciba-Geigy Corporation | Pyrimidine derivatives and processes for the preparation thereof |
JP3279635B2 (ja) | 1992-05-18 | 2002-04-30 | 鐘淵化学工業株式会社 | ヒドロシリル基含有イミド化合物 |
JP3232123B2 (ja) | 1992-05-20 | 2001-11-26 | 鐘淵化学工業株式会社 | 硬化性組成物 |
NZ252064A (en) | 1992-05-28 | 1995-09-26 | Commw Scient Ind Res Org | Bismaleimide compounds; preparation thereof, curable compositions and impregnated fibre reinforced material containing them |
NZ258488A (en) | 1992-12-07 | 1997-02-24 | Commw Scient Ind Res Org | Preparation of bisnadimides (n,n'-bis(aryl)aryl diimides) from an n,n'-bis (aminoaryl)aryldiimide and nadic acid; curable compositions and fibre reinforced cured composites |
EP0678106A4 (en) | 1993-01-11 | 1995-12-27 | Univ Pennsylvania | POLYCYCLIC AROMATIC COMPOUNDS WITH NON-LINEAR OPTICAL PROPERTIES. |
AU4293193A (en) | 1993-04-28 | 1994-11-21 | Du Pont Merck Pharmaceutical Company, The | Novel trisubstituted aromatic amines useful for the treatment of cognitive deficits |
US5536725A (en) | 1993-08-25 | 1996-07-16 | Fmc Corporation | Insecticidal substituted-2,4-diamino-5,6,7,8-tetrahydroquinazolines |
NZ336428A (en) | 1993-11-30 | 2005-02-25 | G | use of substituted pyrazolyl benzosulphonamides to treat inflammation |
US5480887A (en) | 1994-02-02 | 1996-01-02 | Eli Lilly And Company | Protease inhibitors |
BR9408531A (pt) | 1994-02-02 | 1997-08-05 | Lilly Co Eli | Inibidores da protease hiv e intermediários |
MD1861G2 (ro) | 1994-11-14 | 2002-09-30 | Уорнер-Ламберт Кампэни | Derivaţi ai 6-arilpirido[2,3-d]pirimidinelor şi naftiridinelor, compoziţie farmaceutică pe baza lor, metode de tratament şi de inhibare a proliferării şi migraţiei celulei receptorului tirozinkinazei |
US7067664B1 (en) | 1995-06-06 | 2006-06-27 | Pfizer Inc. | Corticotropin releasing factor antagonists |
US5783577A (en) | 1995-09-15 | 1998-07-21 | Trega Biosciences, Inc. | Synthesis of quinazolinone libraries and derivatives thereof |
JPH09188812A (ja) | 1996-01-11 | 1997-07-22 | Mitsui Toatsu Chem Inc | 結晶化促進剤 |
WO1997047601A1 (fr) | 1996-06-11 | 1997-12-18 | Yoshitomi Pharmaceutical Industries, Ltd. | Composes heterocycliques fusionnes et leurs utilisations medicinales |
BR9710808A (pt) | 1996-08-06 | 1999-08-17 | Pfizer | Derivados biciclicos 6,6 ou 6,7 contendo pirito ou pirimido substitu¡dos |
US6184235B1 (en) | 1996-08-14 | 2001-02-06 | Warner-Lambert Company | 2-phenyl benzimidazole derivatives as MCP-1 antagonists |
JP3669783B2 (ja) | 1996-08-21 | 2005-07-13 | 三井化学株式会社 | 有機電界発光素子 |
US5994364A (en) | 1996-09-13 | 1999-11-30 | Schering Corporation | Tricyclic antitumor farnesyl protein transferase inhibitors |
AU6908398A (en) | 1996-10-28 | 1998-05-22 | Versicor Inc | Fused 2,4-pyrimidinedione combinatorial libraries and biologically active fused 2,4-pyramidinediones |
WO1998028281A1 (en) | 1996-12-23 | 1998-07-02 | Celltech Therapeutics Limited | Fused polycyclic 2-aminopyrimidine derivatives, their preparation and their use as protein tyrosine kinase inhibitors |
WO1998033798A2 (en) | 1997-02-05 | 1998-08-06 | Warner Lambert Company | Pyrido[2,3-d]pyrimidines and 4-amino-pyrimidines as inhibitors of cell proliferation |
CA2285263C (en) | 1997-04-11 | 2009-03-10 | Abbott Laboratories | Furopyridine, thienopyridine, pyrrolopyridine and related pyrimidine, pyridazine and triazine compounds useful in controlling chemical synaptic transmission |
CZ298521B6 (cs) | 1997-05-28 | 2007-10-24 | Aventis Pharmaceuticals Inc. | Derivát chinolinu a chinoxalinu, farmaceutický prostredek obsahující tuto slouceninu a použití tétoslouceniny |
GB9716231D0 (en) | 1997-07-31 | 1997-10-08 | Amersham Int Ltd | Base analogues |
NZ502877A (en) | 1997-08-11 | 2001-11-30 | Cor Therapeutics Inc | Bicyclic aryl azepinone selective factor Xa inhibitors for treating thrombosis related diseases |
EP1003745B1 (en) | 1997-08-20 | 2004-12-29 | Warner-Lambert Company Llc | Naphthyridinones for inhibiting protein tyrosine kinase and cell cycle kinase mediated cellular proliferation |
US6465484B1 (en) | 1997-09-26 | 2002-10-15 | Merck & Co., Inc. | Angiogenesis inhibitors |
JPH11171865A (ja) | 1997-12-04 | 1999-06-29 | Yoshitomi Pharmaceut Ind Ltd | 縮合ヘテロ環化合物 |
WO1999042442A1 (fr) | 1998-02-20 | 1999-08-26 | Takeda Chemical Industries, Ltd. | Derives d'aminoguanidine hydrazone, procedes de production, et medicaments a base de ces derives |
AU9298798A (en) | 1998-05-15 | 1999-12-06 | Guilford Pharmaceuticals Inc. | Fused tricyclic compounds which inhibit parp activity |
US20040044012A1 (en) | 1998-05-26 | 2004-03-04 | Dobrusin Ellen Myra | Bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidines as inhibitors of cellular proliferation |
BR9911590A (pt) | 1998-05-26 | 2001-02-13 | Warner Lambert Co | Pirimidinas bicìclicas e 3,4-diidropirimidinas bicìclicas como inibidores da proliferação celular |
JP2002517486A (ja) | 1998-06-12 | 2002-06-18 | バーテックス ファーマシューティカルズ インコーポレイテッド | p38のインヒビター |
BR9912938B1 (pt) | 1998-08-11 | 2011-06-28 | derivados de isoquinolina, composição que os compreende, processo para preparação e uso dos mesmos. | |
JP2000123973A (ja) | 1998-10-09 | 2000-04-28 | Canon Inc | 有機発光素子 |
CZ20011394A3 (cs) | 1998-10-23 | 2001-12-12 | F. Hoffmann-La Roche Ag | Derivát bicyklických, dusík obsahujících heterocyklických sloučenin, způsob jeho přípravy a farmaceutický prostředek, který ho obsahuje |
GB9823103D0 (en) | 1998-10-23 | 1998-12-16 | Pfizer Ltd | Pharmaceutically active compounds |
US6133031A (en) | 1999-08-19 | 2000-10-17 | Isis Pharmaceuticals Inc. | Antisense inhibition of focal adhesion kinase expression |
GB9905075D0 (en) | 1999-03-06 | 1999-04-28 | Zeneca Ltd | Chemical compounds |
DE19912638A1 (de) | 1999-03-20 | 2000-09-21 | Bayer Ag | Naphthylcarbonsäureamid-substituierte Sulfonamide |
DE19920790A1 (de) | 1999-05-06 | 2000-11-09 | Bayer Ag | Bis-Sulfonamide mit anti-HCMV-Wirkung |
PE20010306A1 (es) | 1999-07-02 | 2001-03-29 | Agouron Pharma | Compuestos de indazol y composiciones farmaceuticas que los contienen utiles para la inhibicion de proteina kinasa |
JP4041624B2 (ja) | 1999-07-21 | 2008-01-30 | 三井化学株式会社 | 有機電界発光素子 |
JP4919566B2 (ja) | 1999-09-24 | 2012-04-18 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | 抗ウイルス組成物 |
DE19946289A1 (de) | 1999-09-28 | 2001-03-29 | Basf Ag | Benzodiazepin-Derivate, deren Herstellung und Anwendung |
TR200201058T2 (tr) | 1999-10-21 | 2002-07-22 | F.Hoffmann-La Roche Ag | P38 protein kinaz inhibitörleri olarak, alkilaminoyla ornatılmış bisiklik, azotlu heterosikller |
JP3961830B2 (ja) | 1999-10-21 | 2007-08-22 | エフ.ホフマン−ラ ロシュ アーゲー | p38プロテインキナーゼのインヒビターとしてのヘテロアルキルアミノ置換二環式窒素複素環 |
TWI271406B (en) | 1999-12-13 | 2007-01-21 | Eisai Co Ltd | Tricyclic condensed heterocyclic compounds, preparation method of the same and pharmaceuticals comprising the same |
ES2281372T3 (es) | 1999-12-29 | 2007-10-01 | Wyeth | Inhibidores de proteina-quinasa triciclicos. |
EA005585B1 (ru) | 2000-01-24 | 2005-04-28 | Уорнер-Ламберт Компани | 3-аминохиназолин-2,4-дионовые антибактериальные агенты |
SK10772002A3 (sk) | 2000-01-27 | 2004-01-08 | Warner-Lambert Company | Pyridopyrimidinónové deriváty na liečbu neurodegeneratívnych ochorení |
DE50112961D1 (de) | 2000-02-01 | 2007-10-18 | Abbott Gmbh & Co Kg | Heterozyklische verbindungen und deren anwendung als parp-inhibitoren |
DK1257550T3 (da) | 2000-02-04 | 2006-03-27 | Portola Pharm Inc | Blodplade-ADP-receptor-inhibitor |
ATE295365T1 (de) | 2000-02-09 | 2005-05-15 | Novartis Pharma Gmbh | Pyridinderivative als angiogenese- und/oder vegf- rezeptor-tyrosinkinase-inhibitoren |
GB0004890D0 (en) | 2000-03-01 | 2000-04-19 | Astrazeneca Uk Ltd | Chemical compounds |
AU2001235804A1 (en) | 2000-03-06 | 2001-09-17 | Astrazeneca Ab | Therapy |
JP2001265031A (ja) | 2000-03-15 | 2001-09-28 | Fuji Xerox Co Ltd | 電子写真感光体、プロセスカートリッジ、及び、電子写真装置 |
DE10012549A1 (de) | 2000-03-15 | 2001-09-20 | Bayer Ag | Arzneimittel gegen virale Erkrankungen |
RU2269523C2 (ru) | 2000-04-28 | 2006-02-10 | Акадиа Фармасьютикалз, Инк. | Мускариновые агонисты |
WO2001085722A1 (en) | 2000-05-05 | 2001-11-15 | Cor Therapeutics, Inc. | Heterobicyclic sulfonamides and their use as platelet adp receptor inhibitors |
CN1439008A (zh) | 2000-06-23 | 2003-08-27 | 布里斯托尔-迈尔斯斯奎布药品公司 | 作为因子xa抑制剂的1-(杂芳环基-苯基)-稠合吡唑衍生物 |
CZ303572B6 (cs) | 2000-06-28 | 2012-12-12 | Smithkline Beecham P. L. C. | Jemne rozmelnený prostredek a zpusob jeho prípravy |
US20050009876A1 (en) | 2000-07-31 | 2005-01-13 | Bhagwat Shripad S. | Indazole compounds, compositions thereof and methods of treatment therewith |
EP1325006A2 (en) | 2000-08-07 | 2003-07-09 | Neurogen Corporation | Heterocyclic compounds as ligands of the gaba a? receptor |
WO2002014315A2 (en) | 2000-08-14 | 2002-02-21 | Ortho Mcneil Pharmaceutical, Inc. | Substituted pyrazoles |
CA2421493A1 (en) | 2000-09-06 | 2002-03-14 | Ortho-Mcneil Pharmaceutical, Inc. | A method for treating allergies using substituted pyrazoles |
GB0025782D0 (en) | 2000-10-20 | 2000-12-06 | Pfizer Ltd | Use of inhibitors |
EP1217000A1 (en) | 2000-12-23 | 2002-06-26 | Aventis Pharma Deutschland GmbH | Inhibitors of factor Xa and factor VIIa |
GB0100621D0 (en) | 2001-01-10 | 2001-02-21 | Vernalis Res Ltd | Chemical compounds VI |
GB0103926D0 (en) | 2001-02-17 | 2001-04-04 | Astrazeneca Ab | Chemical compounds |
WO2002076953A1 (en) | 2001-03-21 | 2002-10-03 | Warner-Lambert Company Llc | New spirotricyclic derivatives and their use as phosphodiesterase-7 inhibitors |
US6998408B2 (en) | 2001-03-23 | 2006-02-14 | Bristol-Myers Squibb Pharma Company | 6-5, 6-6, or 6-7 Heterobicycles as factor Xa inhibitors |
JP2002296731A (ja) | 2001-03-30 | 2002-10-09 | Fuji Photo Film Co Ltd | 熱現像カラー画像記録材料 |
CN1300116C (zh) | 2001-04-16 | 2007-02-14 | 卫材株式会社 | 1h-吲唑化合物 |
EP1382603B1 (en) | 2001-04-26 | 2008-07-23 | Eisai R&D Management Co., Ltd. | Nitrogenous fused-ring compound having pyrazolyl group as substituent and medicinal composition thereof |
AR033295A1 (es) | 2001-04-30 | 2003-12-10 | Glaxo Group Ltd | Compuestos biciclicos de pirimidina, proceso para su obtencion, uso de los mismos para la preparacion de una composicion farmaceutica y dicha composicion farmaceutica |
WO2002094825A1 (fr) | 2001-05-22 | 2002-11-28 | Banyu Pharmaceutical Co., Ltd. | Nouveau derive de spiropiperidine |
US20030114448A1 (en) | 2001-05-31 | 2003-06-19 | Millennium Pharmaceuticals, Inc. | Inhibitors of factor Xa |
JP2005501021A (ja) | 2001-06-19 | 2005-01-13 | ワーナー−ランバート・カンパニー、リミテッド、ライアビリティ、カンパニー | 抗細菌剤 |
GB0115109D0 (en) | 2001-06-21 | 2001-08-15 | Aventis Pharma Ltd | Chemical compounds |
US20030114467A1 (en) | 2001-06-21 | 2003-06-19 | Shakespeare William C. | Novel pyrazolo- and pyrrolo-pyrimidines and uses thereof |
WO2003000690A1 (en) | 2001-06-25 | 2003-01-03 | Aventis Pharmaceuticals Inc. | Synthesis of heterocyclic compounds employing microwave technology |
WO2003009852A1 (en) | 2001-07-24 | 2003-02-06 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
US7205417B2 (en) | 2001-08-07 | 2007-04-17 | Banyu Pharmaceutical Co., Ltd. | Spiro compounds |
CN100391958C (zh) | 2001-09-19 | 2008-06-04 | 安万特医药股份有限公司 | 化合物 |
CA2462657C (en) | 2001-10-30 | 2011-04-26 | Novartis Ag | Staurosporine derivatives as inhibitors of flt3 receptor tyrosine kinase activity |
NZ531853A (en) | 2001-11-01 | 2006-02-24 | Janssen Pharmaceutica Nv | Heteroaryl amines as glycogen synthase kinase 3beta inhibitors (gsk3 inhibitors) |
EP1444223A1 (en) | 2001-11-07 | 2004-08-11 | F. Hoffmann-La Roche Ag | Aminopyrimidines and -pyridines |
EP1456652A4 (en) | 2001-11-13 | 2005-11-02 | Dana Farber Cancer Inst Inc | IMMUNOCELL ACTIVATION MODULATING SUBSTANCES AND USE METHOD THEREFOR |
GB0129476D0 (en) | 2001-12-10 | 2002-01-30 | Syngenta Participations Ag | Organic compounds |
GEP20063909B (en) | 2002-01-22 | 2006-08-25 | Warner Lambert Co | 2-(PYRIDIN-2-YLAMINO)-PYRIDO[2,3d] PYRIMIDIN-7-ONES |
PT1482924E (pt) | 2002-03-05 | 2008-08-27 | Axys Pharm Inc | Inibidores de proteases da cisteína catepsina |
US6815519B2 (en) | 2002-03-22 | 2004-11-09 | Chung-Shan Institute Of Science & Technology | Acidic fluorine-containing poly (siloxane amideimide) silica hybrids |
RU2310657C2 (ru) | 2002-04-03 | 2007-11-20 | Ф.Хоффманн-Ля Рош Аг | Имидазоконденсированные соединения и фармацевтическая композиция, содержащая их |
AU2003234567A1 (en) | 2002-05-15 | 2003-12-02 | Janssen Pharmaceutica N.V. | N-substituted tricyclic 3-aminopyrazoles as pdfg receptor inhibitors |
JP4499342B2 (ja) | 2002-05-16 | 2010-07-07 | 株式会社カネカ | SiH基を含有する含窒素有機系化合物の製造方法 |
EP1551834B1 (en) | 2002-05-23 | 2010-08-25 | Novartis Vaccines and Diagnostics, Inc. | Substituted quinazolinone compounds |
US7119111B2 (en) | 2002-05-29 | 2006-10-10 | Amgen, Inc. | 2-oxo-1,3,4-trihydroquinazolinyl derivatives and methods of use |
AR037647A1 (es) | 2002-05-29 | 2004-12-01 | Novartis Ag | Derivados de diarilurea utiles para el tratamiento de enfermedades dependientes de la cinasa de proteina |
US7105526B2 (en) | 2002-06-28 | 2006-09-12 | Banyu Pharmaceuticals Co., Ltd. | Benzimidazole derivatives |
GB0215676D0 (en) | 2002-07-05 | 2002-08-14 | Novartis Ag | Organic compounds |
PA8577501A1 (es) | 2002-07-25 | 2004-02-07 | Warner Lambert Co | Inhibidores de quinasas |
ATE451104T1 (de) | 2002-07-29 | 2009-12-15 | Rigel Pharmaceuticals Inc | Verfahren zur behandlung oder pruvention von autoimmunkrankheiten mit 2,4-pyrimidindiamin- verbindungen |
JP4252534B2 (ja) | 2002-08-06 | 2009-04-08 | エフ.ホフマン−ラ ロシュ アーゲー | p−38MAPキナーゼインヒビターとしての6−アルコキシ−ピリド−ピリミジン類 |
EP1388541A1 (en) | 2002-08-09 | 2004-02-11 | Centre National De La Recherche Scientifique (Cnrs) | Pyrrolopyrazines as kinase inhibitors |
US7084270B2 (en) | 2002-08-14 | 2006-08-01 | Hoffman-La Roche Inc. | Pyrimido compounds having antiproliferative activity |
GB0220187D0 (en) | 2002-08-30 | 2002-10-09 | Novartis Ag | Organic compounds |
GB0223349D0 (en) | 2002-10-08 | 2002-11-13 | Merck Sharp & Dohme | Therapeutic agents |
US7129351B2 (en) | 2002-11-04 | 2006-10-31 | Hoffmann-La Roche Inc. | Pyrimido compounds having antiproliferative activity |
TW200413381A (en) | 2002-11-04 | 2004-08-01 | Hoffmann La Roche | Novel amino-substituted dihydropyrimido [4,5-d]pyrimidinone derivatives, their manufacture and use as pharmaceutical agents |
US7384937B2 (en) | 2002-11-06 | 2008-06-10 | Bristol-Myers Squibb Co. | Fused heterocyclic compounds and use thereof |
CL2003002353A1 (es) | 2002-11-15 | 2005-02-04 | Vertex Pharma | Compuestos derivados de diaminotriazoles, inhibidores d ela proteina quinasa; composicion farmaceutica; procedimiento de preparacion; y su uso del compuesto en el tratamiento de enfermedades de desordenes alergicos, proliferacion, autoinmunes, condic |
EP1565475B1 (en) | 2002-11-18 | 2009-04-08 | F. Hoffmann-La Roche Ag | Diazinopyrimidines and their use as protein kinase inhibitors |
EA200500721A1 (ru) | 2002-11-28 | 2005-12-29 | Шеринг Акциенгезельшафт | Пиримидины, ингибирующие chk, pdk и акт, их получение и применение в качестве лекарственных средств |
EP1567497B1 (en) | 2002-12-06 | 2009-09-23 | Purdue Research Foundation | Pyridines for treating injured mammalian nerve tissue |
US7759336B2 (en) | 2002-12-10 | 2010-07-20 | Ono Pharmaceutical Co., Ltd. | Nitrogen-containing heterocyclic compounds and medicinal use thereof |
UA80171C2 (en) | 2002-12-19 | 2007-08-27 | Pfizer Prod Inc | Pyrrolopyrimidine derivatives |
UA80767C2 (en) | 2002-12-20 | 2007-10-25 | Pfizer Prod Inc | Pyrimidine derivatives for the treatment of abnormal cell growth |
US7098332B2 (en) | 2002-12-20 | 2006-08-29 | Hoffmann-La Roche Inc. | 5,8-Dihydro-6H-pyrido[2,3-d]pyrimidin-7-ones |
ATE514713T1 (de) | 2002-12-23 | 2011-07-15 | Wyeth Llc | Antikörper gegen pd-1 und ihre verwendung |
JP2004203749A (ja) | 2002-12-24 | 2004-07-22 | Kanegafuchi Chem Ind Co Ltd | SiH基を含有する含窒素有機系化合物の製造方法 |
EP1590341B1 (en) | 2003-01-17 | 2009-06-17 | Warner-Lambert Company LLC | 2-aminopyridine substituted heterocycles as inhibitors of cellular proliferation |
GB0305929D0 (en) | 2003-03-14 | 2003-04-23 | Novartis Ag | Organic compounds |
US7135469B2 (en) | 2003-03-18 | 2006-11-14 | Bristol Myers Squibb, Co. | Linear chain substituted monocyclic and bicyclic derivatives as factor Xa inhibitors |
US7550590B2 (en) | 2003-03-25 | 2009-06-23 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
GB0308208D0 (en) | 2003-04-09 | 2003-05-14 | Glaxo Group Ltd | Chemical compounds |
MXPA05010765A (es) | 2003-04-10 | 2005-12-12 | Hoffmann La Roche | Compuestos pirimido. |
CN100372851C (zh) | 2003-05-05 | 2008-03-05 | 弗·哈夫曼-拉罗切有限公司 | 具有crf活性的稠合的嘧啶衍生物 |
JP2004346145A (ja) | 2003-05-21 | 2004-12-09 | Teijin Ltd | イミド組成物およびそれからなる樹脂組成物、及びその製造方法 |
WO2004112793A1 (en) | 2003-05-23 | 2004-12-29 | Chiron Corporation | Guanidino-substituted quinazolinone compounds as mc4-r agonists |
CA2525383C (en) | 2003-06-06 | 2012-03-06 | Arexis Ab | Use of heterocyclic compounds as scce inhibitors |
IL156495A0 (en) | 2003-06-17 | 2004-01-04 | Prochon Biotech Ltd | Use of fgfr3 antagonists for treating t cell mediated diseases |
JP4631703B2 (ja) | 2003-06-18 | 2011-02-16 | 宇部興産株式会社 | ピリミジン−4−オン化合物の製造方法 |
JP2005015395A (ja) | 2003-06-26 | 2005-01-20 | Japan Science & Technology Agency | 新規ピリミドピリミジンヌクレオシドとその構造類縁体 |
CN1984660B (zh) | 2003-07-03 | 2010-12-15 | 美瑞德生物工程公司 | 作为天冬氨酸特异性半胱氨酸蛋白酶活化剂和细胞程序死亡诱导剂的4-芳基氨基-喹唑啉 |
AR045037A1 (es) | 2003-07-10 | 2005-10-12 | Aventis Pharma Sa | Tetrahidro-1h-pirazolo [3,4-c] piridinas sustituidas, composiciones que las contienen y su utilizacion. |
CN1860118A (zh) | 2003-07-29 | 2006-11-08 | Irm责任有限公司 | 作为蛋白激酶抑制剂的化合物和组合物 |
US7390820B2 (en) | 2003-08-25 | 2008-06-24 | Amgen Inc. | Substituted quinolinone derivatives and methods of use |
AU2004274403A1 (en) | 2003-09-03 | 2005-03-31 | Aventis Pharmaceuticals Inc. | 5-aryl-Pyrazolo(4,3-d)pyrimidines, pyridines, and pyrazines and related compounds |
BRPI0414533A (pt) | 2003-09-18 | 2006-11-07 | Conforma Therapeutics Corp | composto, composição farmacêutica, e, métodos para inibir um hsp90 e para tratar um indivìduo tendo um distúrbio mediado por hsp90 |
EP1664046B1 (en) | 2003-09-19 | 2009-06-17 | Gilead Sciences, Inc. | Aza-quinolinol phosphonate integrase inhibitor compounds |
AR045944A1 (es) | 2003-09-24 | 2005-11-16 | Novartis Ag | Derivados de isoquinolina 1.4-disustituidas |
CA2540647C (en) | 2003-10-01 | 2012-07-10 | Bayer Healthcare Ag | Tetrahydro-naphthalene and urea derivatives |
JP4758349B2 (ja) | 2003-10-08 | 2011-08-24 | アイアールエム・リミテッド・ライアビリティ・カンパニー | タンパク質キナーゼ阻害剤としての化合物および組成物 |
US20090099165A1 (en) | 2003-10-14 | 2009-04-16 | Arizona Board Of Regents On Behalf Of The University Of Arizona | Protein Kinase Inhibitors |
CN1897950A (zh) | 2003-10-14 | 2007-01-17 | 惠氏公司 | 稠合芳基和杂芳基衍生物及其使用方法 |
WO2005047289A1 (en) | 2003-11-17 | 2005-05-26 | Pfizer Products Inc. | Pyrrolopyrimidine compounds useful in treatment of cancer |
WO2005056524A2 (en) | 2003-12-09 | 2005-06-23 | Euro-Celtique S.A. | Therapeutic agents useful for treating pain |
US20080188527A1 (en) | 2003-12-23 | 2008-08-07 | Cashman John R | Synthetic Compounds and Derivatives as Modulators of Smoking or Nicotine Ingestion and Lung Cancer |
KR100703068B1 (ko) | 2003-12-30 | 2007-04-05 | 에스케이케미칼주식회사 | 피리딘 유도체와 이의 제조방법, 및 이를 포함하는약제조성물 |
US20050222171A1 (en) | 2004-01-22 | 2005-10-06 | Guido Bold | Organic compounds |
EA011277B1 (ru) | 2004-01-23 | 2009-02-27 | Янссен Фармацевтика Н.В. | Производные хинолина и их применение в качестве ингибиторов микобактерий |
US20050165032A1 (en) | 2004-01-23 | 2005-07-28 | Norman Mark H. | Vanilloid receptor ligands and their use in treatments |
CA2553670A1 (en) | 2004-01-29 | 2005-08-11 | Elixir Pharmaceuticals, Inc. | Anti-viral therapeutics |
GB0402137D0 (en) | 2004-01-30 | 2004-03-03 | Smithkline Beecham Corp | Novel compounds |
CN1918158B (zh) | 2004-02-14 | 2011-03-02 | Irm责任有限公司 | 作为蛋白激酶抑制剂的化合物和组合物 |
WO2005082903A1 (en) | 2004-02-18 | 2005-09-09 | Warner-Lambert Company Llc | 2-(pyridin-3-ylamino)-pyrido[2,3-d]pyrimidin-7-ones |
EP1737865A1 (en) | 2004-02-27 | 2007-01-03 | F.Hoffmann-La Roche Ag | Fused derivatives of pyrazole |
RU2006134021A (ru) | 2004-02-27 | 2008-04-10 | Ф.Хоффманн-Ля Рош Аг (Ch) | Производные гетероарил-конденсированного пиразола |
WO2005087765A1 (en) | 2004-03-04 | 2005-09-22 | Arena Pharmaceuticals, Inc. | Ligands of follicle stimulating hormone receptor and methods of use thereof |
JPWO2005085210A1 (ja) | 2004-03-10 | 2008-01-17 | 小野薬品工業株式会社 | ニトリル化合物およびその化合物を有効成分として含有する医薬組成物 |
JP4627528B2 (ja) | 2004-03-29 | 2011-02-09 | 三井化学株式会社 | 新規化合物、および該化合物を用いた有機エレクトロニクス素子 |
WO2005105097A2 (en) | 2004-04-28 | 2005-11-10 | Gpc Biotech Ag | Pyridopyrimidines for treating inflammatory and other diseases |
JP2005320288A (ja) | 2004-05-10 | 2005-11-17 | Mitsui Chemicals Inc | テトラカルボン酸誘導体、および該化合物を用いた電子写真感光体、電子写真装置 |
US20050256309A1 (en) | 2004-05-12 | 2005-11-17 | Altenbach Robert J | Tri-and bi-cyclic heteroaryl histamine-3 receptor ligands |
WO2005116035A1 (en) | 2004-05-27 | 2005-12-08 | Pfizer Products Inc. | Pyrrolopyrimidine derivatives useful in cancer treatment |
PE20060426A1 (es) | 2004-06-02 | 2006-06-28 | Schering Corp | DERIVADOS DE ACIDO TARTARICO COMO INHIBIDORES DE MMPs, ADAMs, TACE Y TNF-alfa |
US20070254877A1 (en) * | 2004-06-02 | 2007-11-01 | Takada Pharmaceutical Company Limited | Indole Derivative and Use for Treatment of Cancer |
RU2401265C2 (ru) | 2004-06-10 | 2010-10-10 | Айрм Ллк | Соединения и композиции в качестве ингибиторов протеинкиназы |
CN101912400B (zh) | 2004-06-11 | 2013-06-26 | 日本烟草产业株式会社 | 用于治疗癌症的5-氨基-2,4,7-三氧代-3,4,7,8-四氢-2H-吡啶并[2,3-d]嘧啶衍生物和相关化合物 |
GB0512324D0 (en) | 2005-06-16 | 2005-07-27 | Novartis Ag | Organic compounds |
JP2006028027A (ja) | 2004-07-12 | 2006-02-02 | Mitsui Chemicals Inc | テトラカルボン酸誘導体、および該化合物を用いた電子写真感光体、電子写真装置 |
BRPI0514691A (pt) | 2004-08-31 | 2008-06-17 | Astrazeneca Ab | composto ou um sal farmaceuticamente aceitável do mesmo, processo para preparar o mesmo, composição farmacêutica, e, uso de um composto ou um sal farmaceuticamente aceitável do mesmo |
DE602005013248D1 (de) | 2004-08-31 | 2009-04-23 | Hoffmann La Roche | Amidderivate von 3-phenyldihydropyrimidoä4,5-düpyrimidinonen, deren herstellung und verwendung als pharmazeutische mittel |
WO2006024487A1 (en) | 2004-08-31 | 2006-03-09 | F. Hoffmann-La Roche Ag | AMIDE DERIVATIVES OF 7-AMINO-3-PHENYL-DIHYDROPYRIMIDO [4,5-d]PYRIMIDINONES, THEIR MANUFACTURE AND USE AS PHARMACEUTICAL AGENTS |
DE102004042667A1 (de) | 2004-09-01 | 2006-03-30 | Ewald Dörken Ag | Mehrschichtige Gebäudewand |
US7687113B2 (en) | 2004-09-10 | 2010-03-30 | Ube Industries, Inc. | Modified polyimide resin and curable resin composition |
EP1811844A4 (en) | 2004-09-14 | 2009-12-02 | Minerva Biotechnologies Corp | METHOD FOR THE DIAGNOSIS AND TREATMENT OF CANCER |
GB0420719D0 (en) | 2004-09-17 | 2004-10-20 | Addex Pharmaceuticals Sa | Novel allosteric modulators |
WO2006038112A1 (en) | 2004-10-01 | 2006-04-13 | Warner-Lambert Company Llc | Use of kinase inhibitors to promote neochondrogenesis |
FR2876582B1 (fr) | 2004-10-15 | 2007-01-05 | Centre Nat Rech Scient Cnrse | Utilisation de derives de pyrrolo-pyrazines pour la fabrication de medicaments pour le traitement de la mucoviscidose et de maladies liees a un defaut d'adressage des proteines dans les cellules |
WO2006050162A2 (en) | 2004-10-28 | 2006-05-11 | Phenomix Corporation | Imidazole derivatives |
US7855205B2 (en) | 2004-10-29 | 2010-12-21 | Janssen Pharmaceutica Nv | Pyrimidinyl substituted fused-pyrrolyl compounds useful in treating kinase disorders |
MX2007005434A (es) | 2004-11-08 | 2007-07-10 | Baxter Int | Composiciones de nanoparticulado de inhibidor de tubulina. |
MX2007005820A (es) | 2004-11-18 | 2007-07-18 | Incyte Corp | Inhibidores de deshidrogenasa esteroide hidroxilo 11-beta tipo 1 y metodos de uso de los mismos. |
EP2316835A1 (en) | 2004-11-22 | 2011-05-04 | Vertex Pharmceuticals Incorporated | Pyrrolopyrazines and pyrazolopyrazines useful as inhibitors of protein kinases |
US20090156602A1 (en) | 2004-11-24 | 2009-06-18 | Nigel Graham Cooke | Organic Compounds |
MY140748A (en) | 2004-12-06 | 2010-01-15 | Astrazeneca Ab | Novel pyrrolo [3,2-d] pyrimidin-4-one derivatives and their use in therapy |
CA2590294A1 (en) | 2004-12-13 | 2006-06-22 | Sunesis Pharmaceuticals, Inc. | Pyrido pyrimidinones, dihydro pyrimido pyrimidinones and pteridinones useful as raf kinase inhibitors |
US20100152206A1 (en) | 2005-01-07 | 2010-06-17 | Ralph Mazitschek | Bicyclic Dihydropyrimidines and Uses Thereof |
DE102005008310A1 (de) | 2005-02-17 | 2006-08-24 | Schering Ag | Verwendung von CDKII Inhibitoren zur Fertilitätskontrolle |
AU2006219643A1 (en) | 2005-03-01 | 2006-09-08 | Pfizer Limited | Use of PDE7 inhibitors for the treatment of neuropathic pain |
US7297700B2 (en) | 2005-03-24 | 2007-11-20 | Renovis, Inc. | Bicycloheteroaryl compounds as P2X7 modulators and uses thereof |
EP2527365A3 (en) | 2005-03-30 | 2013-02-20 | Minerva Biotechnologies Corporation | Proliferation of MUC1 expressing cells |
JP2006284843A (ja) | 2005-03-31 | 2006-10-19 | Mitsui Chemicals Inc | テトラカルボン酸誘導体を用いた電子写真感光体、電子写真装置 |
US20060223993A1 (en) | 2005-04-01 | 2006-10-05 | Connor Daniel M | Colorant compounds, intermediates, and compositions |
JP2006316054A (ja) | 2005-04-15 | 2006-11-24 | Tanabe Seiyaku Co Ltd | 高コンダクタンス型カルシウム感受性kチャネル開口薬 |
KR100781704B1 (ko) | 2005-04-20 | 2007-12-03 | 에스케이케미칼주식회사 | 피리딘 유도체와 이의 제조방법, 및 이를 포함하는약제조성물 |
CA2606760C (en) | 2005-05-04 | 2014-12-23 | Renovis, Inc. | Tetrahydronaphthyridine and tetrahydropyrido[4,3-d]pyrimidine compounds and compositions thereof useful in the treatment of conditions associated with neurological and inflammatory disorders and disfunctions |
NZ563193A (en) | 2005-05-09 | 2010-05-28 | Ono Pharmaceutical Co | Human monoclonal antibodies to programmed death 1(PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics |
WO2006124731A2 (en) | 2005-05-12 | 2006-11-23 | Irm Llc | Compounds and compositions as protein kinase inhibitors |
RU2411242C2 (ru) | 2005-05-13 | 2011-02-10 | Айрм, Ллк. | Соединения и композиции в качестве ингибиторов протеинкиназ |
US20060279115A1 (en) | 2005-06-09 | 2006-12-14 | Ash Tisdelle | Vehicular head and neck safety system and method |
GB0512844D0 (en) | 2005-06-23 | 2005-08-03 | Novartis Ag | Organic compounds |
DK1907424T3 (en) | 2005-07-01 | 2015-11-09 | Squibb & Sons Llc | HUMAN MONOCLONAL ANTIBODIES TO PROGRAMMED death ligand 1 (PD-L1) |
US7932257B2 (en) | 2005-07-22 | 2011-04-26 | Sunesis Pharmaceuticals, Inc. | Substituted pyrazolo[4,3-d]pyrimidines as aurora kinase inhibitors |
ES2270715B1 (es) | 2005-07-29 | 2008-04-01 | Laboratorios Almirall S.A. | Nuevos derivados de pirazina. |
JP2009502734A (ja) | 2005-07-29 | 2009-01-29 | アステラス製薬株式会社 | Lck阻害剤としての縮合複素環 |
RU2008108898A (ru) | 2005-08-09 | 2009-09-20 | Айрм Ллк (Bm) | Соединения и композиции в качестве ингибиторов протеинкиназы |
BRPI0614578A2 (pt) | 2005-08-16 | 2011-04-05 | Irm Llc | composto, composição farmacêutica como inibidores de proteìna cinases, bem como seu método e uso |
CA2620104A1 (en) | 2005-08-25 | 2007-03-01 | F. Hoffman-La Roche Ag | Fused pyrazole as p38 map kinase inhibitors |
US7678917B2 (en) | 2005-09-01 | 2010-03-16 | Hoffman-La Roche Inc. | Factor Xa inhibitors |
EP1924572B1 (en) | 2005-09-06 | 2009-12-30 | SmithKline Beecham Corporation | Regioselective process for preparing benzimidazole thiophenes |
US8193356B2 (en) | 2005-09-15 | 2012-06-05 | Aska Pharmaceutical Co., Ltd. | Heterocycle compound, and production process and application thereof |
US20070116984A1 (en) | 2005-09-21 | 2007-05-24 | Doosan Corporation | Spiro-compound for electroluminescent display device and electroluminescent display device comprising the same |
JP2009508966A (ja) | 2005-09-23 | 2009-03-05 | シェーリング コーポレイション | 治療薬としての縮合四環性mGluR1アンタゴニスト |
DE102005048072A1 (de) | 2005-09-24 | 2007-04-05 | Bayer Cropscience Ag | Thiazole als Fungizide |
KR20140033237A (ko) | 2005-10-07 | 2014-03-17 | 엑셀리시스, 인코포레이티드 | 포스파티딜이노시톨 3-키나아제 억제제 및 이의 사용 방법 |
AU2006302148B2 (en) | 2005-10-07 | 2012-12-06 | Exelixis, Inc. | Pyridopyrimidinone inhibitors of PI3Kalpha |
WO2007061554A2 (en) | 2005-10-21 | 2007-05-31 | Purdue Research Foundation | Dosage of 4-aminopyridine derivatives for treatment of central nervous system injuries |
JP2009513603A (ja) | 2005-10-26 | 2009-04-02 | 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 | Mch拮抗活性を有する(ヘテロ)アリール化合物及びこの化合物を含む医薬 |
US8067457B2 (en) | 2005-11-01 | 2011-11-29 | Millennium Pharmaceuticals, Inc. | Compounds useful as antagonists of CCR2 |
US8604042B2 (en) | 2005-11-01 | 2013-12-10 | Targegen, Inc. | Bi-aryl meta-pyrimidine inhibitors of kinases |
US7528143B2 (en) | 2005-11-01 | 2009-05-05 | Targegen, Inc. | Bi-aryl meta-pyrimidine inhibitors of kinases |
EP1945222B1 (en) | 2005-11-02 | 2012-12-26 | Bayer Pharma Aktiengesellschaft | Pyrrolo[2,1-f] [1,2,4]-triazin-4-ylamines as igf-1r kinase inhibitors for the treatment of cancer and other hyperproliferative diseases |
WO2007056075A2 (en) | 2005-11-02 | 2007-05-18 | Targegen, Inc. | Six membered heteroaromatic inhibitors targeting resistant kinase mutations |
ATE486875T1 (de) | 2005-11-10 | 2010-11-15 | Chemocentryx Inc | Substituierte chinolone und verwendungsverfahren |
NZ568292A (en) | 2005-11-10 | 2011-08-26 | Msd Kk | Spiro[cyclohexane-1,1'-(3'H)-4'-azaisobenzofuran]-4-carboxamide derivatives |
WO2007058626A1 (en) | 2005-11-16 | 2007-05-24 | S*Bio Pte Ltd | Indazole compounds |
AR057986A1 (es) | 2005-11-21 | 2008-01-09 | Japan Tobacco Inc | Compuesto heterociclico y su uso farmaceutico |
PE20070855A1 (es) | 2005-12-02 | 2007-10-14 | Bayer Pharmaceuticals Corp | Derivados de 4-amino-pirrolotriazina sustituida como inhibidores de quinasas |
US8143393B2 (en) | 2005-12-02 | 2012-03-27 | Bayer Healthcare Llc | Substituted 4-amino-pyrrolotriazine derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis |
RU2008127486A (ru) | 2005-12-08 | 2010-01-20 | Милленниум Фармасьютикалз, Инк. (Us) | Бициклические соединения с ингибиторной активностью в отношении киназы |
WO2007066189A2 (en) | 2005-12-09 | 2007-06-14 | Pfizer Products Inc. | Salts, prodrugs and formulations of 1-[5-(4-amino-7-isopropyl-7h-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-2-methoxy-phenyl]-3-(2,4-dichloro-phenyl)-urea |
WO2007120339A1 (en) | 2005-12-19 | 2007-10-25 | Genentech, Inc. | Pyrimidine kinase inhibitors |
WO2007071752A2 (en) | 2005-12-21 | 2007-06-28 | Novartis Ag | Pyrimidinyl aryl urea derivatives being fgf inhibitors |
WO2007084314A2 (en) | 2006-01-12 | 2007-07-26 | Incyte Corporation | MODULATORS OF 11-ß HYDROXYL STEROID DEHYDROGENASE TYPE 1, PHARMACEUTICAL COMPOSITIONS THEREOF, AND METHODS OF USING THE SAME |
PE20071025A1 (es) | 2006-01-31 | 2007-10-17 | Mitsubishi Tanabe Pharma Corp | Compuesto amina trisustituido |
WO2007092879A2 (en) | 2006-02-08 | 2007-08-16 | Janssen Pharmaceutica, N.V. | Substituted thiatriazaacenaphthylene-6-carbonitrile kinase inhibitors |
MX2008010611A (es) | 2006-02-17 | 2008-11-12 | Pfizer Ltd | Derivados de 3-desazapurina como moduladores de receptores similares a toll. |
WO2007109334A2 (en) | 2006-03-21 | 2007-09-27 | Epix Delaware, Inc. | Sip receptor modulating compounds and use thereof |
WO2007112347A1 (en) | 2006-03-28 | 2007-10-04 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
EP2233472B1 (en) | 2006-03-28 | 2014-01-15 | Atir Holding S.A. | Heterocyclic compounds and uses thereof in the treatment of sexual disorders |
US20100273776A1 (en) | 2006-03-29 | 2010-10-28 | FOLDRx PHARMACEUTICALS, INC | Inhibition of alpha-synuclein toxicity |
JP2010505739A (ja) | 2006-04-06 | 2010-02-25 | ウイスコンシン アラムニ リサーチ ファンデーション | 2−メチレン−1α,25−ジヒドロキシ−19,21−ジノルビタミンD3類縁体およびその使用 |
CN101472926A (zh) | 2006-04-13 | 2009-07-01 | 阿斯利康(瑞典)有限公司 | 硫代黄嘌呤衍生物以及它们作为髓过氧化物酶抑制剂的用途 |
GB0608386D0 (en) | 2006-04-27 | 2006-06-07 | Senexis Ltd | Compounds |
CA2651072A1 (en) | 2006-05-01 | 2007-11-08 | Pfizer Products Inc. | Substituted 2-amino-fused heterocyclic compounds |
CN101437822B (zh) | 2006-05-11 | 2012-11-28 | Irm责任有限公司 | 作为蛋白激酶抑制剂的化合物和组合物 |
CA2650611A1 (en) | 2006-05-15 | 2007-11-29 | Irm Llc | Compositions and methods for fgf receptor kinases inhibitors |
US7910108B2 (en) | 2006-06-05 | 2011-03-22 | Incyte Corporation | Sheddase inhibitors combined with CD30-binding immunotherapeutics for the treatment of CD30 positive diseases |
DE102006027156A1 (de) | 2006-06-08 | 2007-12-13 | Bayer Schering Pharma Ag | Sulfimide als Proteinkinaseinhibitoren |
ES2474865T3 (es) | 2006-06-22 | 2014-07-09 | Prana Biotechnology Limited | Método de tratamiento de un tumor cerebral glioma |
TW200817391A (en) | 2006-06-30 | 2008-04-16 | Astrazeneca Ab | Novel compounds |
US20090281115A1 (en) | 2006-06-30 | 2009-11-12 | Board of Regents, The University of Texas System, a Texas University | Inhibitors of c-kit and uses thereof |
CA2654670A1 (en) | 2006-07-06 | 2008-01-10 | Boehringer Ingelheim International Gmbh | New compounds |
US8030487B2 (en) | 2006-07-07 | 2011-10-04 | Targegen, Inc. | 2-amino—5-substituted pyrimidine inhibitors |
TW200811134A (en) | 2006-07-12 | 2008-03-01 | Irm Llc | Compounds and compositions as protein kinase inhibitors |
WO2008012635A2 (en) | 2006-07-26 | 2008-01-31 | Pfizer Products Inc. | Amine derivatives useful as anticancer agents |
US20100222345A1 (en) | 2006-08-09 | 2010-09-02 | Caroline Jean Diaz | Novel compounds as antagonists or inverse agonists for opioid receptors |
AU2007284562B2 (en) | 2006-08-16 | 2013-05-02 | Exelixis, Inc. | Using PI3K and MEK modulators in treatments of cancer |
DE102006041382A1 (de) | 2006-08-29 | 2008-03-20 | Bayer Schering Pharma Ag | Carbamoyl-Sulfoximide als Proteinkinaseinhibitoren |
PT2061765E (pt) | 2006-09-01 | 2015-02-06 | Senhwa Biosciences Inc | Moduladores de serina-treonina-proteína-quinase e de parp |
EP2471529A3 (en) | 2006-09-05 | 2012-10-10 | Emory University | Kinase Inhibitors for Preventing or Treating Pathogen Infection and Method of Use Thereof |
JP2010502751A (ja) | 2006-09-11 | 2010-01-28 | シージーアイ ファーマシューティカルズ,インコーポレイティド | キナーゼ阻害物質、およびキナーゼ阻害物質の使用および同定方法 |
US7897762B2 (en) | 2006-09-14 | 2011-03-01 | Deciphera Pharmaceuticals, Llc | Kinase inhibitors useful for the treatment of proliferative diseases |
WO2008034859A1 (en) | 2006-09-21 | 2008-03-27 | Boehringer Ingelheim International Gmbh | Glucopyranosyl-substituted difluorobenzyl-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture |
WO2008034860A1 (en) | 2006-09-22 | 2008-03-27 | Glaxo Group Limited | Pyrrolo[2, 3-b]pyridin-4-yl-benzenesulfonamide compounds as ikk2 inhibitors |
CN101516888A (zh) | 2006-09-28 | 2009-08-26 | 诺瓦提斯公司 | 吡唑并[1,5-a]嘧啶衍生物及其治疗用途 |
MX2009003456A (es) | 2006-10-02 | 2009-04-14 | Irm Llc | Compuestos y composiciones como inhibidores de proteina cinasa. |
TW200825058A (en) | 2006-10-30 | 2008-06-16 | Glaxo Group Ltd | Cysteine protease inhibitors |
US7858645B2 (en) | 2006-11-01 | 2010-12-28 | Hoffmann-La Roche Inc. | Indazole derivatives |
WO2008060907A2 (en) | 2006-11-10 | 2008-05-22 | Bristol-Myers Squibb Company | Pyrrolo-pyridine kinase inhibitors |
WO2008063609A2 (en) | 2006-11-17 | 2008-05-29 | Polyera Corporation | Diimide-based semiconductor materials and methods of preparing and using the same |
US7892454B2 (en) | 2006-11-17 | 2011-02-22 | Polyera Corporation | Acene-based organic semiconductor materials and methods of preparing and using the same |
KR20080045536A (ko) | 2006-11-20 | 2008-05-23 | 에스케이케미칼주식회사 | 피리딘 화합물을 포함하는 간염 치료 및 예방 또는 간 보호효능을 갖는 약제 조성물 |
NZ578329A (en) | 2006-12-13 | 2012-05-25 | Schering Corp | Igf1r inhibitors for treating cancer |
WO2008071455A1 (en) | 2006-12-15 | 2008-06-19 | Bayer Schering Pharma Aktiengesellschaft | Bicyclic acyltryptophanols |
WO2008074068A1 (en) | 2006-12-20 | 2008-06-26 | Prana Biotechnology Limited | Substituted quinoline derivatives as antiamyloidogeneic agents |
US7737149B2 (en) | 2006-12-21 | 2010-06-15 | Astrazeneca Ab | N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(3,5-dimethylpiperazin-1-yl)benzamide and salts thereof |
JP2010514689A (ja) | 2006-12-22 | 2010-05-06 | ノバルティス アーゲー | 癌、炎症およびウイルス感染症の処置のためのcdk阻害剤としてのヘテロアリール−ヘテロアリール化合物 |
AU2007337895C1 (en) | 2006-12-22 | 2014-07-31 | Astex Therapeutics Limited | Tricyclic amine derivatives as protein tyrosine kinase inhibitors |
EP2114941B1 (en) | 2006-12-22 | 2015-03-25 | Astex Therapeutics Limited | Bicyclic heterocyclic compounds as fgfr inhibitors |
FR2911140B1 (fr) | 2007-01-05 | 2009-02-20 | Sanofi Aventis Sa | Nouveaux derives de 2-anilino 4-heteroaryle pyrimides, leur preparation a titre de medicaments, compositions pharmaceutiques et notamment comme inhibiteurs de ikk |
CN101622253B (zh) | 2007-01-08 | 2015-04-29 | 破立纪元有限公司 | 用于制备基于芳烃-双(二羧酰亚胺)的半导体材料的方法和用于制备它们的相关中间体 |
CN101007778A (zh) | 2007-01-10 | 2007-08-01 | 复旦大学 | 一种链延长型芴基双马来酰亚胺及其制备方法 |
NZ578556A (en) | 2007-01-12 | 2012-04-27 | Biocryst Pharm Inc | Antiviral nucleoside analogs |
WO2008084861A1 (ja) | 2007-01-12 | 2008-07-17 | Astellas Pharma Inc. | 縮合ピリジン化合物 |
FR2911604B1 (fr) | 2007-01-19 | 2009-04-17 | Sanofi Aventis Sa | Derives de n-(heteroaryl-1h-indole-2-carboxamides, leur preparation et leur application en therapeutique |
JP5358962B2 (ja) | 2007-02-06 | 2013-12-04 | 住友化学株式会社 | 組成物及び該組成物を用いてなる発光素子 |
JP2008198769A (ja) | 2007-02-13 | 2008-08-28 | Nippon Steel Chem Co Ltd | 有機エレクトロルミネッセント素子 |
WO2008107436A1 (en) | 2007-03-06 | 2008-09-12 | Novartis Ag | Bicyclic organic compounds suitable for the treatment of inflammatory or allergic conditions |
JP2010520293A (ja) | 2007-03-07 | 2010-06-10 | アラントス・フアーマシユーテイカルズ・ホールデイング・インコーポレイテツド | 複素環式部分を含有するメタロプロテアーゼ阻害剤 |
US8486941B2 (en) | 2007-03-12 | 2013-07-16 | Ym Biosciences Australia Pty Ltd | Phenyl amino pyrimidine compounds and uses thereof |
US20080234262A1 (en) | 2007-03-21 | 2008-09-25 | Wyeth | Pyrazolopyrimidine analogs and their use as mtor kinase and pi3 kinase inhibitors |
EP2132207A2 (en) | 2007-03-23 | 2009-12-16 | Amgen Inc. | Heterocyclic compounds and their uses |
EP2896624B1 (en) | 2007-03-28 | 2016-07-13 | Atir Holding S.A. | Heterotricyclic compounds as serotonergic and/or dopaminergic agents and uses thereof |
KR20080091948A (ko) | 2007-04-10 | 2008-10-15 | 에스케이케미칼주식회사 | 락탐형 피리딘 화합물을 포함하는 허혈성 질환의 예방 및치료용 약학조성물 |
US20100112211A1 (en) | 2007-04-12 | 2010-05-06 | Advanced Technology Materials, Inc. | Zirconium, hafnium, titanium, and silicon precursors for ald/cvd |
JP2010524941A (ja) | 2007-04-20 | 2010-07-22 | シェーリング コーポレイション | ピリミジノン誘導体およびそれらの使用方法 |
EP1985612A1 (en) | 2007-04-26 | 2008-10-29 | Bayer Schering Pharma Aktiengesellschaft | Arymethylen substituted N-Acyl-gamma-aminoalcohols |
EP1990342A1 (en) | 2007-05-10 | 2008-11-12 | AEterna Zentaris GmbH | Pyridopyrazine Derivatives, Process of Manufacturing and Uses thereof |
TW200902008A (en) | 2007-05-10 | 2009-01-16 | Smithkline Beecham Corp | Quinoxaline derivatives as PI3 kinase inhibitors |
WO2008144253A1 (en) | 2007-05-14 | 2008-11-27 | Irm Llc | Protein kinase inhibitors and methods for using thereof |
GB2449293A (en) | 2007-05-17 | 2008-11-19 | Evotec | Compounds having Hsp90 inhibitory activity |
JP5622568B2 (ja) | 2007-06-03 | 2014-11-12 | バンダービルト ユニバーシティ | ベンズアミドmGluR5の正のアロステリック調節因子ならびにその作製および使用方法 |
WO2008153852A1 (en) | 2007-06-07 | 2008-12-18 | Merck & Co., Inc. | Tricyclic anilide heterocyclic cgrp receptor antagonists |
US8633186B2 (en) | 2007-06-08 | 2014-01-21 | Senomyx Inc. | Modulation of chemosensory receptors and ligands associated therewith |
US7928111B2 (en) | 2007-06-08 | 2011-04-19 | Senomyx, Inc. | Compounds including substituted thienopyrimidinone derivatives as ligands for modulating chemosensory receptors |
RU2010101052A (ru) | 2007-06-15 | 2011-07-20 | Банью Фармасьютикал Ко., Лтд (Jp) | Производные бициклоанилина |
EP2170959B1 (en) | 2007-06-18 | 2013-10-02 | Merck Sharp & Dohme B.V. | Antibodies to human programmed death receptor pd-1 |
EP2018859A1 (en) | 2007-07-26 | 2009-01-28 | Bayer Schering Pharma Aktiengesellschaft | Arylmethylene substituted N-acyl-beta-amino alcohols |
ES2375425T3 (es) | 2007-07-26 | 2012-02-29 | Novartis Ag | Compuestos org�?nicos. |
EP2020404A1 (en) | 2007-08-01 | 2009-02-04 | Bayer Schering Pharma Aktiengesellschaft | Cyanomethyl substituted N-Acyl Tryptamines |
WO2009019518A1 (en) | 2007-08-09 | 2009-02-12 | Astrazeneca Ab | Pyrimidine compounds having a fgfr inhibitory effect |
JP2010535804A (ja) | 2007-08-09 | 2010-11-25 | グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー | Pi3キナーゼ阻害薬としてのキノキサリン誘導体 |
US7960400B2 (en) | 2007-08-27 | 2011-06-14 | Duquesne University Of The Holy Ghost | Tricyclic compounds having cytostatic and/or cytotoxic activity and methods of use thereof |
WO2009029625A1 (en) | 2007-08-27 | 2009-03-05 | Kalypsys, Inc. | 4- [heterocyclyl-methyl] -8-fluoro-quinolin-2-ones useful as nitric oxide synthase inhibitors |
EP2200436B1 (en) | 2007-09-04 | 2015-01-21 | The Scripps Research Institute | Substituted pyrimidinyl-amines as protein kinase inhibitors |
WO2009030871A1 (en) | 2007-09-07 | 2009-03-12 | Vernalis R & D Ltd | Pyrrolopyrimidine derivatives having hsp90 inhibitory activity |
TW200920357A (en) | 2007-09-10 | 2009-05-16 | Curis Inc | HSP90 inhibitors containing a zinc binding moiety |
EP2215102B1 (en) | 2007-10-01 | 2016-02-17 | Ionis Pharmaceuticals, Inc. | Antisense modulation of fibroblast growth factor receptor 4 expression |
ES2549084T3 (es) | 2007-10-05 | 2015-10-22 | Msd K.K. | Derivados de benzoxazinona |
US20100298289A1 (en) | 2007-10-09 | 2010-11-25 | Ucb Pharma, S.A. | Heterobicyclic compounds as histamine h4-receptor antagonists |
WO2009049018A1 (en) | 2007-10-10 | 2009-04-16 | Syndax Pharmaceuticals, Inc. | Novel compounds and methods of using them |
US8513233B2 (en) | 2007-10-11 | 2013-08-20 | Shanghai Institute Of Materia Medica, Cas | Pyrimidinyl-propionic acid derivatives and their use as PPAR agonists |
GB0720038D0 (en) | 2007-10-12 | 2007-11-21 | Astex Therapeutics Ltd | New compounds |
GB0720041D0 (en) | 2007-10-12 | 2007-11-21 | Astex Therapeutics Ltd | New Compounds |
JP5273052B2 (ja) | 2007-10-13 | 2013-08-28 | コニカミノルタ株式会社 | 有機エレクトロルミネッセンス素子、表示装置及び照明装置 |
BRPI0817681A2 (pt) | 2007-10-16 | 2015-04-14 | Wyeth Llc | Compostos de tienopirimidina e pirazolopirimidina e seu uso como inibidores de mtor quinase e pi3 quinase |
ES2393430T3 (es) | 2007-10-17 | 2012-12-21 | Novartis Ag | Derivados de imidazo[1,2-A]-piridina útiles como inhibidores de ALK |
AU2008315746A1 (en) | 2007-10-25 | 2009-04-30 | Astrazeneca Ab | Pyridine and pyrazine derivatives useful in the treatment of cell proliferative disorders |
RU2007139634A (ru) | 2007-10-25 | 2009-04-27 | Сергей Олегович Бачурин (RU) | Новые тиазол-, триазол- или оксадиазол-содержащие тетрациклические соединения |
WO2009056886A1 (en) | 2007-11-01 | 2009-05-07 | Astrazeneca Ab | Pyrimidine derivatives and their use as modulators of fgfr activity |
ES2734288T3 (es) | 2007-11-28 | 2019-12-05 | Dana Farber Cancer Inst Inc | Inhibidores de miristato de moléculas pequeñas de Bcr-abl y métodos de uso |
JP2011505407A (ja) | 2007-12-03 | 2011-02-24 | 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 | 過剰な又は異常な細胞増殖を特徴とする疾患を治療するためのジアミノピリジン |
MX2010006457A (es) | 2007-12-19 | 2010-07-05 | Amgen Inc | Compuestos fusionados de piridina, pirimidina y triazina como inhibidores de ciclo celular. |
AU2008345688A1 (en) | 2007-12-21 | 2009-07-09 | Wyeth Llc | Imidazo [1,2-b] pyridazine compounds as modulators of liver X receptors |
WO2009086303A2 (en) | 2007-12-21 | 2009-07-09 | University Of Rochester | Method for altering the lifespan of eukaryotic organisms |
US8153827B2 (en) | 2007-12-27 | 2012-04-10 | Purdue Research Foundation | Reagents for biomolecular labeling, detection and quantification employing Raman spectroscopy |
FR2926297B1 (fr) | 2008-01-10 | 2013-03-08 | Centre Nat Rech Scient | Molecules chimiques inhibitrices du mecanisme d'epissage pour traiter des maladies resultant d'anomalies d'epissage. |
JP5584626B2 (ja) | 2008-01-24 | 2014-09-03 | アンドレイ・アレクサンドロビッチ・イワシェンコ | 2−アルキルアミノ−3−(アリールスルホニル)−シクロアルキル[e又はd]ピラゾロ[1,5−a]ピリミジン−セロトニン5−HT6受容体アンタゴニスト、その調製の方法及び使用 |
EP2248814A4 (en) | 2008-01-24 | 2011-01-12 | Alla Chem Llc | SUBSTITUTED CYCLOALKAN [E AND D] PYRAZOLO [1,5-A] PYRIMIDINES / ANTAGONISTS OF SEROTONIN 5-HT6 RECEPTORS AND PROCESS FOR THEIR PREPARATION AND THEIR USE |
EP2238144A1 (en) | 2008-01-24 | 2010-10-13 | UCB Pharma, S.A. | Compounds comprising a cyclobutoxy group |
JP5406215B2 (ja) | 2008-01-25 | 2014-02-05 | ハイ ポイント ファーマシューティカルズ,リミティド ライアビリティ カンパニー | TNF−α合成の調節因子及びPDE4阻害剤としての三環系化合物 |
JP5608099B2 (ja) | 2008-01-30 | 2014-10-15 | ジェネンテック, インコーポレイテッド | ピラゾロピリミジンpi3k阻害剤化合物および使用方法 |
EP2265270A1 (en) | 2008-02-04 | 2010-12-29 | OSI Pharmaceuticals, Inc. | 2-aminopyridine kinase inhibitors |
CA2716330A1 (en) | 2008-02-22 | 2009-08-27 | Irm Llc | Compounds and compositions as modulators of gpr119 activity |
MX2010008700A (es) | 2008-02-22 | 2010-08-30 | Hoffmann La Roche | Moduladores de beta-amiloide. |
WO2009108332A1 (en) | 2008-02-27 | 2009-09-03 | Vitae Pharmaceuticals, Inc. | INHIBITORS OF 11β -HYDROXYSTEROID DEHYDROGENASE TYPE 1 |
WO2009108827A1 (en) | 2008-02-29 | 2009-09-03 | Wyeth | Fused tricyclic pyrazolo[1, 5-a]pyrimidines, methods for preparation and uses thereof |
US8168757B2 (en) | 2008-03-12 | 2012-05-01 | Merck Sharp & Dohme Corp. | PD-1 binding proteins |
GB0804701D0 (en) | 2008-03-13 | 2008-04-16 | Amura Therapeutics Ltd | Compounds |
WO2009114874A2 (en) | 2008-03-14 | 2009-09-17 | Intellikine, Inc. | Benzothiazole kinase inhibitors and methods of use |
JP5547099B2 (ja) | 2008-03-14 | 2014-07-09 | インテリカイン, エルエルシー | キナーゼ阻害剤および使用方法 |
US20090246198A1 (en) | 2008-03-31 | 2009-10-01 | Takeda Pharmaceutical Company Limited | Mapk/erk kinase inhibitors and methods of use thereof |
US20100056524A1 (en) | 2008-04-02 | 2010-03-04 | Mciver Edward Giles | Compound |
US8436005B2 (en) | 2008-04-03 | 2013-05-07 | Abbott Laboratories | Macrocyclic pyrimidine derivatives |
AU2009233951B2 (en) | 2008-04-07 | 2014-02-27 | Amgen Inc. | Gem-disubstituted and spirocyclic amino pyridines/pyrimidines as cell cycle inhibitors |
WO2009124755A1 (en) | 2008-04-08 | 2009-10-15 | European Molecular Biology Laboratory (Embl) | Compounds with novel medical uses and method of identifying such compounds |
WO2009125809A1 (ja) | 2008-04-11 | 2009-10-15 | 第一三共株式会社 | ピペリジン誘導体 |
WO2009125808A1 (ja) | 2008-04-11 | 2009-10-15 | 第一三共株式会社 | アミノシクロヘキシル誘導体 |
EP2444403A1 (en) | 2008-04-18 | 2012-04-25 | Shionogi Co., Ltd. | Heterocyclic compound having inhibitory activity on PI3K |
BRPI0910668A2 (pt) | 2008-04-22 | 2019-09-24 | Portola Pharmaceutiacals Inc | inibidores de proteína quinases |
US7863291B2 (en) | 2008-04-23 | 2011-01-04 | Bristol-Myers Squibb Company | Quinuclidine compounds as alpha-7 nicotinic acetylcholine receptor ligands |
US8309577B2 (en) | 2008-04-23 | 2012-11-13 | Bristol-Myers Squibb Company | Quinuclidine compounds as α-7 nicotinic acetylcholine receptor ligands |
CN103353532B (zh) | 2008-04-29 | 2016-05-11 | 诺瓦提斯公司 | 监测成纤维细胞生长因子受体的激酶活性的调节的方法及所述方法的应用 |
WO2009132980A1 (en) | 2008-04-29 | 2009-11-05 | F. Hoffmann-La Roche Ag | Pyrimidinyl pyridone inhibitors of jnk. |
WO2009133127A1 (en) | 2008-04-30 | 2009-11-05 | Merck Serono S.A. | Fused bicyclic compounds and use thereof as pi3k inhibitors |
US9315449B2 (en) | 2008-05-15 | 2016-04-19 | Duke University | Substituted pyrazoles as heat shock transcription factor activators |
JP5351254B2 (ja) | 2008-05-23 | 2013-11-27 | ノバルティス アーゲー | キノキサリン−およびキノリン−カルボキシアミド誘導体 |
WO2009144205A1 (en) | 2008-05-30 | 2009-12-03 | Basf Se | Rylene-based semiconductor materials and methods of preparation and use thereof |
US8207169B2 (en) | 2008-06-03 | 2012-06-26 | Msd K.K. | Substituted [1,2,4]triazolo[4′,3′:1,6]pyrido[2,3-b]pyrazines of the formula D |
CN102089403A (zh) | 2008-06-10 | 2011-06-08 | 巴斯夫欧洲公司 | 新型过渡金属配合物及其在有机发光二极管中的用途-ⅲ |
EP2303885B1 (en) | 2008-06-12 | 2013-07-03 | Merck Sharp & Dohme Corp. | Process for producing bicycloaniline derivatives |
GB0810902D0 (en) | 2008-06-13 | 2008-07-23 | Astex Therapeutics Ltd | New compounds |
JP2011524888A (ja) | 2008-06-19 | 2011-09-08 | アストラゼネカ アクチボラグ | ピラゾール化合物436 |
JPWO2009157423A1 (ja) | 2008-06-24 | 2011-12-15 | 財団法人乙卯研究所 | 縮合環を有するオキサゾリジノン誘導体 |
US8338439B2 (en) | 2008-06-27 | 2012-12-25 | Celgene Avilomics Research, Inc. | 2,4-disubstituted pyrimidines useful as kinase inhibitors |
WO2010009155A2 (en) | 2008-07-14 | 2010-01-21 | Gilead Colorado, Inc. | Fused heterocyclyc inhibitor compounds |
CN102066370B (zh) | 2008-07-15 | 2014-05-14 | 霍夫曼-拉罗奇有限公司 | 苯基-咪唑并吡啶类和哒嗪类 |
WO2010007099A1 (en) | 2008-07-15 | 2010-01-21 | Cellzome Limited | 2-aminoimidazo[1,2-b]pyridazine derivatives as pi3k inhibitors |
JP2011528365A (ja) | 2008-07-16 | 2011-11-17 | シェーリング コーポレイション | Gpr119モジュレーターとしての二環式ヘテロ環誘導体およびそれらの使用方法 |
UY31982A (es) | 2008-07-16 | 2010-02-26 | Boehringer Ingelheim Int | Derivados de 1,2-dihidropiridin-3-carboxamidas n-sustituidas |
EP2328897A1 (en) | 2008-07-16 | 2011-06-08 | Schering Corporation | Bicyclic heterocycle derivatives and their use as gpcr modulators |
WO2010009735A2 (en) | 2008-07-23 | 2010-01-28 | Dako Denmark A/S | Combinatorial analysis and repair |
US8455477B2 (en) | 2008-08-05 | 2013-06-04 | Merck Sharp & Dohme Corp. | Therapeutic compounds |
WO2010015643A1 (en) | 2008-08-06 | 2010-02-11 | Novartis Ag | New antiviral modified nucleosides |
US9284297B2 (en) | 2008-08-11 | 2016-03-15 | President And Fellows Of Harvard College | Halofuginone analogs for inhibition of tRNA synthetases and uses thereof |
UY32049A (es) | 2008-08-14 | 2010-03-26 | Takeda Pharmaceutical | Inhibidores de cmet |
ES2412780T3 (es) | 2008-09-10 | 2013-07-12 | Mitsubishi Tanabe Pharma Corporation | Compuestos aromáticos de anillo de 6 miembros que contiene nitrógeno y su uso |
CA2998281C (en) | 2008-09-26 | 2022-08-16 | Dana-Farber Cancer Institute, Inc. | Human anti-pd-1 antobodies and uses therefor |
AR073760A1 (es) | 2008-10-03 | 2010-12-01 | Astrazeneca Ab | Derivados heterociclicos y metodos de uso de los mismos |
US20100267748A1 (en) | 2008-10-15 | 2010-10-21 | Gilead Palo Alto, Inc. | HETEROCYCLIC COMPOUNDS USEFUL AS STEAROYL CoA DESATURASE INHIBITORS |
US8110578B2 (en) | 2008-10-27 | 2012-02-07 | Signal Pharmaceuticals, Llc | Pyrazino[2,3-b]pyrazine mTOR kinase inhibitors for oncology indications and diseases associated with the mTOR/PI3K/Akt pathway |
TW201022262A (en) | 2008-10-29 | 2010-06-16 | Astrazeneca Ab | Novel compounds 515 |
US8476282B2 (en) | 2008-11-03 | 2013-07-02 | Intellikine Llc | Benzoxazole kinase inhibitors and methods of use |
WO2010052448A2 (en) | 2008-11-05 | 2010-05-14 | Ucb Pharma S.A. | Fused pyrazine derivatives as kinase inhibitors |
WO2010059552A1 (en) | 2008-11-18 | 2010-05-27 | Glaxosmithkline Llc | Prolyl hydroxylase inhibitors |
UY32251A (es) | 2008-11-20 | 2010-05-31 | Glaxosmithkline Llc | Compuestos quimicos |
JP5522053B2 (ja) | 2008-12-03 | 2014-06-18 | コニカミノルタ株式会社 | 有機エレクトロルミネッセンス素子、有機エレクトロルミネッセンス素子材料、表示装置及び照明装置 |
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 |
WO2010077680A2 (en) | 2008-12-08 | 2010-07-08 | Vm Discovery Inc. | Compositions of protein receptor tyrosine kinase inhibitors |
CN108997498A (zh) | 2008-12-09 | 2018-12-14 | 霍夫曼-拉罗奇有限公司 | 抗-pd-l1抗体及它们用于增强t细胞功能的用途 |
US8110265B2 (en) | 2008-12-09 | 2012-02-07 | The Coca-Cola Company | Pet container and compositions having enhanced mechanical properties and gas barrier properties |
EP2376493B1 (en) | 2008-12-12 | 2016-10-05 | Msd K.K. | Dihydropyrimidopyrimidine derivative |
JP2012511501A (ja) | 2008-12-12 | 2012-05-24 | Msd株式会社 | ジヒドロピリミドピリミジン誘導体 |
BRPI0918360A8 (pt) | 2008-12-19 | 2017-12-05 | Genentech Inc | Composto, composição farmacêutica e usos de um composto |
JO2885B1 (en) | 2008-12-22 | 2015-03-15 | ايلي ليلي اند كومباني | Protein kinase inhibitors |
EP2379551A1 (en) | 2008-12-30 | 2011-10-26 | ArQule, Inc. | Substituted pyrazolo [3, 4-b]pyridine compounds |
KR101714799B1 (ko) | 2008-12-30 | 2017-03-09 | 아르퀼 인코포레이티드 | 치환된 5,6-디히드로-6-페닐벤조[f]이소퀴놀린-2-아민 화합물 |
EP3255047B1 (en) | 2009-01-06 | 2021-06-30 | Dana-Farber Cancer Institute, Inc. | Pyrimido-diazepinone kinase scaffold compounds and uses in treating disorders |
JOP20190230A1 (ar) | 2009-01-15 | 2017-06-16 | Incyte Corp | طرق لاصلاح مثبطات انزيم jak و المركبات الوسيطة المتعلقة به |
EP2387315B1 (en) | 2009-01-16 | 2015-07-15 | Merck Sharp & Dohme Corp. | IMIDAZO[1,2-a]PYRIDINES AND IMIDAZO[1,2-b]PYRIDAZINES AS MARK INHIBITORS |
DE102009007038A1 (de) | 2009-02-02 | 2010-08-05 | Merck Patent Gmbh | Metallkomplexe |
JP2010180147A (ja) | 2009-02-04 | 2010-08-19 | Mitsubishi Gas Chemical Co Inc | シアン酸エステル化合物、およびその硬化物 |
JP5844159B2 (ja) | 2009-02-09 | 2016-01-13 | ユニヴェルシテ デクス−マルセイユUniversite D’Aix−Marseille | Pd−1抗体およびpd−l1抗体ならびにその使用 |
TW201038569A (en) | 2009-02-16 | 2010-11-01 | Abbott Gmbh & Co Kg | Heterocyclic compounds, pharmaceutical compositions containing them, and their use in therapy |
TW201035102A (en) | 2009-03-04 | 2010-10-01 | Gruenethal Gmbh | Sulfonylated tetrahydroazolopyrazines and their use as medicinal products |
US20100278835A1 (en) | 2009-03-10 | 2010-11-04 | Astrazeneca Uk Limited | Novel compounds 660 |
WO2010104047A1 (ja) | 2009-03-11 | 2010-09-16 | 国立大学法人京都大学 | 多環芳香族化合物 |
JP2012520887A (ja) | 2009-03-18 | 2012-09-10 | シェーリング コーポレイション | ジアシルグリセロールアシルトランスフェラーゼの阻害剤としての二環式化合物 |
EP2411057B1 (en) | 2009-03-23 | 2020-05-06 | Eli Lilly and Company | Imaging agents for detecting neurological disorders |
EP2411370B1 (en) | 2009-03-27 | 2015-04-22 | AbbVie Inc. | Compounds as cannabinoid receptor ligands |
TW201102391A (en) | 2009-03-31 | 2011-01-16 | Biogen Idec Inc | Certain substituted pyrimidines, pharmaceutical compositions thereof, and methods for their use |
JP5629752B2 (ja) | 2009-04-06 | 2014-11-26 | ユニバーシティ・ヘルス・ネットワークUniversity Health Network | キナーゼインヒビターおよびこれを用いた癌の治療方法 |
JP5711723B2 (ja) | 2009-04-07 | 2015-05-07 | エメリティ・ファーマ・アクチボラグ | 治療剤としてのイソオキサゾール−3(2h)−オン類似体 |
GB0906470D0 (en) | 2009-04-15 | 2009-05-20 | Astex Therapeutics Ltd | New compounds |
GB0906472D0 (en) | 2009-04-15 | 2009-05-20 | Astex Therapeutics Ltd | New compounds |
JP5531446B2 (ja) | 2009-04-20 | 2014-06-25 | コニカミノルタ株式会社 | 有機エレクトロルミネッセンス素子、有機エレクトロルミネッセンス素子材料、表示装置および照明装置 |
ES2347630B1 (es) | 2009-04-29 | 2011-09-08 | Universitat Ramon Llull | Sintesis y usos de 4-cianopentanoatos y 4-cianopentenoatos sustituidos. |
EP2424368B1 (en) | 2009-04-29 | 2014-12-31 | Locus Pharmaceuticals, Inc. | Pyrrolotriazine compounds |
US20100280067A1 (en) | 2009-04-30 | 2010-11-04 | Pakala Kumara Savithru Sarma | Inhibitors of acetyl-coa carboxylase |
JO2860B1 (en) | 2009-05-07 | 2015-03-15 | ايلي ليلي اند كومباني | Phenylendazolyl compounds |
JP5600891B2 (ja) | 2009-05-15 | 2014-10-08 | コニカミノルタ株式会社 | 有機エレクトロルミネッセンス素子、表示装置および照明装置 |
JP5604808B2 (ja) | 2009-05-20 | 2014-10-15 | コニカミノルタ株式会社 | 有機エレクトロルミネッセンス素子、表示装置及び照明装置 |
JP5629980B2 (ja) | 2009-05-22 | 2014-11-26 | コニカミノルタ株式会社 | 有機エレクトロルミネッセンス素子、表示装置及び照明装置 |
JP5568889B2 (ja) | 2009-05-22 | 2014-08-13 | コニカミノルタ株式会社 | 有機エレクトロルミネッセンス素子、表示装置、照明装置及び有機エレクトロルミネッセンス素子材料 |
JP5499519B2 (ja) | 2009-05-27 | 2014-05-21 | コニカミノルタ株式会社 | 有機エレクトロルミネッセンス素子、表示装置及び照明装置 |
WO2010136031A1 (en) | 2009-05-27 | 2010-12-02 | Københavns Universitet | Fibroblast growth factor receptor-derived peptides binding to ncam |
GB0910003D0 (en) | 2009-06-11 | 2009-07-22 | Univ Leuven Kath | Novel compounds for the treatment of neurodegenerative diseases |
JP5600894B2 (ja) | 2009-06-24 | 2014-10-08 | コニカミノルタ株式会社 | 白色有機エレクトロルミネッセンス素子、表示装置及び照明装置 |
AU2010266018B2 (en) | 2009-06-25 | 2014-01-09 | Alkermes Pharma Ireland Limited | Heterocyclic compounds for the treatment of neurological and psychological disorders |
US8883888B2 (en) | 2009-06-30 | 2014-11-11 | Zeon Corporation | Diarylamine compounds, aging inhibitor, polymer composition, crosslinked rubber product and molded article of the crosslinked product, and method of producing diarylamine compound |
US20120135997A1 (en) | 2009-07-17 | 2012-05-31 | Shionogi & Co., Ltd. | Pharmaceutical composition comprising a lactam or benzenesulfonamide compound |
US8680077B2 (en) | 2009-07-24 | 2014-03-25 | Duke University | Prochelators useful for inhibiting metal-associated toxicity |
FR2948568B1 (fr) | 2009-07-30 | 2012-08-24 | Sanofi Aventis | Formulation pharmaceutique |
TWI468402B (zh) | 2009-07-31 | 2015-01-11 | 必治妥美雅史谷比公司 | 降低β-類澱粉生成之化合物 |
AU2010281265A1 (en) | 2009-08-05 | 2012-03-22 | Versitech Limited | Antiviral compounds and methods of making and using thereof |
JP2012197231A (ja) | 2009-08-06 | 2012-10-18 | Oncotherapy Science Ltd | Ttk阻害作用を有するピリジンおよびピリミジン誘導体 |
BR112012008094A2 (pt) | 2009-08-07 | 2020-08-18 | Chugai Seiyaku Kabushiki Kaisha | derivado de aminopirazol, seu uso, composição farmacêutica que o compreende, agentes para inibir a atividade de fgfr e para prevenir ou tratar câncer |
WO2011018894A1 (en) | 2009-08-10 | 2011-02-17 | Raqualia Pharma Inc. | Pyrrolopyrimidine derivatives as potassium channel modulators |
SG178454A1 (en) | 2009-08-17 | 2012-03-29 | Intellikine Inc | Heterocyclic compounds and uses thereof |
JP5577650B2 (ja) | 2009-08-24 | 2014-08-27 | コニカミノルタ株式会社 | 有機エレクトロルミネッセンス素子、有機エレクトロルミネッセンス素子材料、表示装置及び照明装置 |
KR101184115B1 (ko) | 2009-08-31 | 2012-09-18 | 일동제약주식회사 | 신규 펩티드 데포르밀라제 저해제 화합물 및 그 제조방법 |
JP5696856B2 (ja) | 2009-09-03 | 2015-04-08 | バイオエナジェニックス | Paskの阻害用複素環式化合物 |
US9340528B2 (en) | 2009-09-04 | 2016-05-17 | Bayer Pharma Aktiengesellschaft | Substituted aminoquinoxalines as tyrosine threonine kinase inhibitors |
WO2011031740A1 (en) | 2009-09-09 | 2011-03-17 | Achaogen, Inc. | Antibacterial fluoroquinolone analogs |
EP2475666A2 (en) | 2009-09-11 | 2012-07-18 | Trius Therapeutics, Inc. | Gyrase inhibitors |
WO2011041143A1 (en) | 2009-10-01 | 2011-04-07 | Merck Sharp & Dohme Corp. | HETEROCYCLIC-FUSED PYRAZOLO[4,3-c]PYRIDIN-3-ONE M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS |
US8466155B2 (en) | 2009-10-02 | 2013-06-18 | Boehringer Ingelheim International Gmbh | Pyrimidines |
GB0917571D0 (en) | 2009-10-07 | 2009-11-25 | Karobio Ab | Novel estrogen receptor ligands |
EP2308866A1 (de) | 2009-10-09 | 2011-04-13 | Bayer CropScience AG | Phenylpyri(mi)dinylpyrazole und ihre Verwendung als Fungizide |
FR2951172B1 (fr) | 2009-10-13 | 2014-09-26 | Pf Medicament | Derives pyrazolopyridines en tant qu'agent anticancereux |
CN102666537A (zh) | 2009-10-20 | 2012-09-12 | 艾格尔生物制药股份有限公司 | 治疗黄病毒科病毒感染的氮杂吲唑 |
KR20110043270A (ko) | 2009-10-21 | 2011-04-27 | (주)씨에스엘쏠라 | 유기발광화합물 및 이를 구비한 유기발광소자 |
SI2491035T1 (sl) | 2009-10-22 | 2017-10-30 | Gilead Sciences, Inc. | Derivati purina ali deazapurina uporabni za zdravljenje (med drugimi) virusnih okužb |
WO2011050245A1 (en) | 2009-10-23 | 2011-04-28 | Yangbo Feng | Bicyclic heteroaryls as kinase inhibitors |
MX341704B (es) | 2009-10-26 | 2016-08-31 | Signal Pharm Llc | Métodos de síntesis y purificación de compuestos de heteroarilo. |
WO2011051425A1 (en) | 2009-10-30 | 2011-05-05 | Novartis Ag | N-oxide of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea |
KR20110049217A (ko) | 2009-11-04 | 2011-05-12 | 다우어드밴스드디스플레이머티리얼 유한회사 | 신규한 유기 발광 화합물 및 이를 채용하고 있는 유기 전계 발광 소자 |
GB0919432D0 (en) | 2009-11-05 | 2009-12-23 | Glaxosmithkline Llc | Use |
WO2011057022A1 (en) | 2009-11-06 | 2011-05-12 | Plexxikon, Inc. | Compounds and methods for kinase modulation, and indications therefor |
KR101663637B1 (ko) | 2009-11-13 | 2016-10-07 | 제노스코 | 키나아제 억제제 |
RU2012125070A (ru) | 2009-11-18 | 2013-12-27 | Плексксикон, Инк. | Соединения и способы модулирования киназы и показания к их применению |
JP2013032290A (ja) | 2009-11-20 | 2013-02-14 | Dainippon Sumitomo Pharma Co Ltd | 新規縮合ピリミジン誘導体 |
WO2011062885A1 (en) | 2009-11-23 | 2011-05-26 | Schering Corporation | Fused bicyclic pyrimidine derivatives and methods of use thereof |
US20130017199A1 (en) | 2009-11-24 | 2013-01-17 | AMPLIMMUNE ,Inc. a corporation | Simultaneous inhibition of pd-l1/pd-l2 |
EP2332939A1 (en) | 2009-11-26 | 2011-06-15 | Æterna Zentaris GmbH | Novel Naphthyridine derivatives and the use thereof as kinase inhibitors |
WO2011068899A1 (en) | 2009-12-01 | 2011-06-09 | Abbott Laboratories | Novel tricyclic compounds |
JP2011116840A (ja) | 2009-12-02 | 2011-06-16 | Fujifilm Corp | 顔料微粒子分散体、これを用いた光硬化性組成物及びカラーフィルタ |
AR079257A1 (es) | 2009-12-07 | 2012-01-04 | Novartis Ag | Formas cristalinas de 3-(2,6-dicloro-3-5-dimetoxi-fenil)-1-{6-[4-(4-etil-piperazin-1-il)-fenil-amino]-pirimidin-4-il}-1-metil-urea y sales de las mismas |
MA33926B1 (fr) | 2009-12-17 | 2013-01-02 | Merck Sharp & Dohme | Aminopyrimidines en tant qu'inhibiteurs de la syk |
EP2512476A1 (en) | 2009-12-18 | 2012-10-24 | Novartis AG | Method for treating haematological cancers |
AU2010341573B2 (en) | 2009-12-22 | 2016-10-13 | Vertex Pharmaceuticals Incorporated | Isoindolinone inhibitors of phosphatidylinositol 3-kinase |
FR2954317B1 (fr) | 2009-12-23 | 2012-01-27 | Galderma Res & Dev | Nouveaux derives phenoliques, et leur utilisation pharmaceutique ou cosmetique |
FR2954315B1 (fr) | 2009-12-23 | 2012-02-24 | Galderma Res & Dev | Nouveaux derives phenoliques, et leur utilisation pharmaceutique ou cosmetique |
US20110207736A1 (en) | 2009-12-23 | 2011-08-25 | Gatekeeper Pharmaceuticals, Inc. | Compounds that modulate egfr activity and methods for treating or preventing conditions therewith |
US20130096115A1 (en) | 2009-12-28 | 2013-04-18 | Afraxis, Inc. | Methods for treating autism |
US9180127B2 (en) | 2009-12-29 | 2015-11-10 | Dana-Farber Cancer Institute, Inc. | Type II Raf kinase inhibitors |
WO2011082234A1 (en) | 2009-12-29 | 2011-07-07 | Polyera Corporation | Thionated aromatic bisimides as organic semiconductors and devices incorporating them |
WO2011080755A1 (en) | 2009-12-29 | 2011-07-07 | Advinus Therapeutics Private Limited | Fused nitrogen heterocyclic compounds, process of preparation and uses thereof |
EP2519525A4 (en) | 2009-12-30 | 2013-06-12 | Arqule Inc | SUBSTITUTED PYRROLO-AMINOPYRIMIDINE COMPOUNDS |
WO2011082266A2 (en) | 2009-12-30 | 2011-07-07 | Arqule, Inc. | Substituted heterocyclic compounds |
WO2011082267A2 (en) | 2009-12-30 | 2011-07-07 | Arqule, Inc. | Substituted triazolo-pyrazine compounds |
CN102115026A (zh) | 2009-12-31 | 2011-07-06 | 清华大学 | 一维纳米结构、其制备方法及一维纳米结构作标记的方法 |
WO2011082400A2 (en) | 2010-01-04 | 2011-07-07 | President And Fellows Of Harvard College | Modulators of immunoinhibitory receptor pd-1, and methods of use thereof |
WO2011082488A1 (en) | 2010-01-06 | 2011-07-14 | British Columbia Cancer Agency Branch | Bisphenol derivative therapeutics and methods for their use |
KR101483215B1 (ko) | 2010-01-29 | 2015-01-16 | 한미약품 주식회사 | 단백질 키나아제 저해활성을 갖는 비시클릭 헤테로아릴 유도체 |
WO2011094890A1 (en) | 2010-02-02 | 2011-08-11 | Argusina Inc. | Phenylalanine derivatives and their use as non-peptide glp-1 receptor modulators |
WO2011097717A1 (en) | 2010-02-15 | 2011-08-18 | University Of Victoria Innovation And Development Corporation | Synthesis of bicyclic compounds and method for their use as therapeutic agents |
WO2011103196A1 (en) | 2010-02-17 | 2011-08-25 | Amgen Inc. | Aryl carboxamide derivatives as sodium channel inhibitors for treatment of pain |
SA111320200B1 (ar) | 2010-02-17 | 2014-02-16 | ديبيوفارم اس ايه | مركبات ثنائية الحلقة واستخداماتها كمثبطات c-src/jak مزدوجة |
US9193728B2 (en) | 2010-02-18 | 2015-11-24 | Medivation Technologies, Inc. | Fused tetracyclic pyrido [4,3-B] indole and pyrido [3,4-B] indole derivatives and methods of use |
WO2011103441A1 (en) | 2010-02-18 | 2011-08-25 | Schering Corporation | Substituted pyridine and pyrimidine derivatives and their use in treating viral infections |
US9150809B2 (en) | 2010-02-18 | 2015-10-06 | Ntn Corporation | Thickener, grease, method for producing the same, and grease-packed bearing |
UY33227A (es) | 2010-02-19 | 2011-09-30 | Novartis Ag | Compuestos de pirrolopirimidina como inhibidores de la cdk4/6 |
US9403769B2 (en) | 2010-02-22 | 2016-08-02 | Advanced Cancer Therapeutics, Llc | Small molecule inhibitors of PFKFB3 and glycolytic flux and their methods of use as anti-cancer therapeutics |
WO2011105161A1 (ja) | 2010-02-26 | 2011-09-01 | 新日鐵化学株式会社 | 有機電界発光素子 |
US20130045203A1 (en) | 2010-03-02 | 2013-02-21 | Emory University | Uses of Noscapine and Derivatives in Subjects Diagnosed with FAP |
WO2011111880A1 (ko) | 2010-03-08 | 2011-09-15 | 주식회사 메디젠텍 | 세포핵에서 세포질로의 gsk3의 이동을 억제하는 화합물을 함유하는 세포핵에서 세포질로의 gsk3 이동에 의해 발생되는 질환의 치료 또는 예방용 약학적 조성물 |
WO2011112687A2 (en) | 2010-03-10 | 2011-09-15 | Kalypsys, Inc. | Heterocyclic inhibitors of histamine receptors for the treatment of disease |
ES2530449T3 (es) | 2010-03-11 | 2015-03-02 | Gilead Connecticut Inc | Inhibidores de Syk de imidazopiridinas |
CN103080093A (zh) | 2010-03-16 | 2013-05-01 | 达纳-法伯癌症研究所公司 | 吲唑化合物及其应用 |
US8957216B2 (en) | 2010-03-24 | 2015-02-17 | Amitech Therapeutic Solutions, Inc. | Heterocyclic compounds useful for kinase inhibition |
US8791257B2 (en) | 2010-03-31 | 2014-07-29 | Bristol-Myers Squibb Company | Substituted pyrrolotriazines as protein kinase inhibitors |
CN102153551B (zh) | 2010-04-02 | 2012-04-25 | 济南海乐医药技术开发有限公司 | 基于吲唑或氮杂吲唑的双芳基脲或硫脲类结构抗肿瘤药物 |
JP5724204B2 (ja) | 2010-04-07 | 2015-05-27 | コニカミノルタ株式会社 | 有機エレクトロルミネッセンス素子、表示装置、及び照明装置 |
ES2562419T3 (es) | 2010-04-13 | 2016-03-04 | Rigel Pharmaceuticals, Inc. | Compuestos de 2,4-pirimidinodiamina y sus profármacos y sus usos |
PL2558095T3 (pl) | 2010-04-16 | 2019-06-28 | Novartis Ag | Związek organiczny, przeznaczony do stosowania w leczeniu raka wątroby |
US8822447B2 (en) | 2010-04-22 | 2014-09-02 | Janssen Pharmaceutica Nv | Indazole compounds useful as ketohexokinase inhibitors |
CA2812043A1 (en) | 2010-04-23 | 2011-10-27 | Kineta, Inc. | Pyrimidinedione anti-viral compounds |
AR081331A1 (es) | 2010-04-23 | 2012-08-08 | Cytokinetics Inc | Amino- pirimidinas composiciones de las mismas y metodos para el uso de los mismos |
WO2011137313A1 (en) | 2010-04-30 | 2011-11-03 | Bristol-Myers Squibb Company | Aza-bicyclic amine n-oxide compounds as alpha-7 nicotinic acetylcholine receptor ligand pro-drugs |
GB201007286D0 (en) | 2010-04-30 | 2010-06-16 | Astex Therapeutics Ltd | New compounds |
US8759398B2 (en) | 2010-05-03 | 2014-06-24 | Biolink Life Sciences, Inc. | Phosphorus binder composition for treatment of hyperphosphatemia |
US20130137709A1 (en) | 2010-05-05 | 2013-05-30 | Nathanael S. Gray | Compounds that modulate EGFR activity and methods for treating or preventing conditions therewith |
WO2011143318A2 (en) | 2010-05-11 | 2011-11-17 | Aveo Pharmaceuticals, Inc. | Anti-fgfr2 antibodies |
TWI513694B (zh) | 2010-05-11 | 2015-12-21 | Amgen Inc | 抑制間變性淋巴瘤激酶的嘧啶化合物 |
EP2569310A1 (en) | 2010-05-11 | 2013-03-20 | Pfizer Inc | Morpholine compounds as mineralocorticoid receptor antagonists |
CN103037870B (zh) | 2010-05-12 | 2016-05-25 | 斯派克托姆制药公司 | 碱式碳酸镧、碳酸氧镧及其制造方法和用途 |
CN102958927A (zh) | 2010-05-12 | 2013-03-06 | Abbvie公司 | 激酶的吲唑抑制剂 |
GB201008134D0 (en) | 2010-05-14 | 2010-06-30 | Medical Res Council Technology | Compounds |
WO2011147198A1 (en) | 2010-05-28 | 2011-12-01 | Versitech Limited | Compounds and methods for treatment of proliferative diseases |
WO2011147199A1 (en) | 2010-05-28 | 2011-12-01 | Versitech Limited | Compounds and methods for treating viral infections |
WO2011153553A2 (en) | 2010-06-04 | 2011-12-08 | The Regents Of The University Of California | Methods and compositions for kinase inhibition |
US8354420B2 (en) | 2010-06-04 | 2013-01-15 | Genentech, Inc. | Aminopyrimidine derivatives as LRRK2 inhibitors |
WO2011155983A1 (en) | 2010-06-07 | 2011-12-15 | Bikam Pharmaceuticals Inc. | Opsin-binding ligands, compositions and methods of use |
TW201210597A (en) | 2010-06-09 | 2012-03-16 | Gilead Sciences Inc | Inhibitors of hepatitis C virus |
US8299117B2 (en) | 2010-06-16 | 2012-10-30 | Metabolex Inc. | GPR120 receptor agonists and uses thereof |
CA2802344C (en) | 2010-06-18 | 2023-06-13 | The Brigham And Women's Hospital, Inc. | Bi-specific antibodies against tim-3 and pd-1 for immunotherapy in chronic immune conditions |
EP2584903B1 (en) | 2010-06-24 | 2018-10-24 | Merck Sharp & Dohme Corp. | Novel heterocyclic compounds as erk inhibitors |
US8907053B2 (en) | 2010-06-25 | 2014-12-09 | Aurigene Discovery Technologies Limited | Immunosuppression modulating compounds |
US8683564B2 (en) | 2010-06-27 | 2014-03-25 | King Saud University | One-time password authentication with infinite nested hash claims |
EP2588110B1 (en) | 2010-07-02 | 2018-10-17 | University Health Network | Methods of targeting pten mutant diseases and compositions therefor |
US20130109682A1 (en) | 2010-07-06 | 2013-05-02 | Novartis Ag | Cyclic ether compounds useful as kinase inhibitors |
FR2962438B1 (fr) | 2010-07-06 | 2012-08-17 | Sanofi Aventis | Derives d'indolizines, procedes de preparation et application en therapeutique |
FR2962437B1 (fr) | 2010-07-06 | 2012-08-17 | Sanofi Aventis | Derives d'imidazopyridine, leur procede de preparation et leur application en therapeutique |
EP2590982B1 (en) | 2010-07-09 | 2017-08-23 | The Walter and Eliza Hall Institute of Medical Research | Protein kinase inhibitors and methods of treatment |
WO2012009258A2 (en) | 2010-07-13 | 2012-01-19 | Edward Roberts | Peptidomimetic galanin receptor modulators |
US20130210807A1 (en) | 2010-07-14 | 2013-08-15 | Nigel J Liverton | Tricyclic Compounds as Allosteric Modulators of Metabotropic Glutamate Receptors. |
TW201206946A (en) | 2010-07-15 | 2012-02-16 | Bristol Myers Squibb Co | Compounds for the reduction of beta-amyloid production |
EP2594566A4 (en) | 2010-07-16 | 2014-10-01 | Kyowa Hakko Kirin Co Ltd | AROMATIC HETEROCYCLIC NITROGEN CYCLE DERIVATIVE |
WO2012008564A1 (ja) | 2010-07-16 | 2012-01-19 | 協和発酵キリン株式会社 | 含窒素芳香族複素環誘導体 |
WO2012013713A2 (en) | 2010-07-28 | 2012-02-02 | Bayer Pharma Aktiengesellschaft | Substituted imidazo[1,2-b]pyridazines |
EP2413140A1 (en) | 2010-07-29 | 2012-02-01 | Sanofi | Method for identifying a compound having an antiarrhythmic effect as well as uses relating thereto |
TW201300501A (zh) | 2010-07-30 | 2013-01-01 | 羅門哈斯電子材料韓國公司 | 使用電場發光化合物作為發光材料之電場發光裝置 |
WO2012019093A1 (en) | 2010-08-05 | 2012-02-09 | Human Biomolecular Research Institute | Synthetic compounds and methods to decrease nicotine self-administration |
US8883839B2 (en) | 2010-08-13 | 2014-11-11 | Abbott Laboratories | Tetraline and indane derivatives, pharmaceutical compositions containing them, and their use in therapy |
US9051280B2 (en) | 2010-08-13 | 2015-06-09 | AbbVie Deutschland GmbH & Co. KG | Tetraline and indane derivatives, pharmaceutical compositions containing them, and their use in therapy |
WO2012027239A1 (en) | 2010-08-23 | 2012-03-01 | Schering Corporation | NOVEL PYRAZOLO[1,5-a]PYRROLO[3,2-e]PYRIMIDINE DERIVATIVES AS mTOR INHIBITORS |
US8883801B2 (en) | 2010-08-23 | 2014-11-11 | Merck Sharp & Dohme Corp. | Substituted pyrazolo[1,5-a]pyrimidines as mTOR inhibitors |
BR112013007499A2 (pt) | 2010-09-01 | 2016-07-12 | Genentech Inc | piridazinonas - métodos de criação e usos |
WO2012031004A1 (en) | 2010-09-01 | 2012-03-08 | Gilead Connecticut, Inc. | Pyridinones/pyrazinones, method of making, and method of use thereof |
AR082799A1 (es) | 2010-09-08 | 2013-01-09 | Ucb Pharma Sa | Derivados de quinolina y quinoxalina como inhibidores de quinasa |
JP5876051B2 (ja) | 2010-09-08 | 2016-03-02 | グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドGlaxosmithkline Intellectual Property Development Limited | インフルエンザウィルス感染の治療に使用するためのインダゾール誘導体 |
PL2614058T3 (pl) | 2010-09-08 | 2015-12-31 | Glaxosmithkline Ip Dev Ltd | Polimorfy i sole n-[5-[4-(5-{[(2r,6s)-2,6-dimetylo-4-morfolinylo]-metylo}-1,3-oksazol-2-ilo)-1h-indazol-6-ilo]-2-(metyloksy)-3-pirydynylo]metanosulfonamidu |
TWI541243B (zh) | 2010-09-10 | 2016-07-11 | 拜耳知識產權公司 | 經取代咪唑并嗒 |
CN103238117A (zh) | 2010-09-14 | 2013-08-07 | 保土谷化学工业株式会社 | 电荷控制剂和使用其的调色剂 |
CN102399220A (zh) | 2010-09-15 | 2012-04-04 | 黄振华 | 三并环类PI3K和mTOR双重抑制剂 |
CN102399233B (zh) | 2010-09-15 | 2014-08-13 | 山东轩竹医药科技有限公司 | PI3K和mTOR双重抑制剂类化合物 |
WO2012036233A1 (ja) | 2010-09-17 | 2012-03-22 | 塩野義製薬株式会社 | メラニン凝集ホルモン受容体アンタゴニスト活性を有する縮合へテロ環誘導体 |
GB201015949D0 (en) | 2010-09-22 | 2010-11-03 | Medical Res Council Technology | Compounds |
JO3062B1 (ar) | 2010-10-05 | 2017-03-15 | Lilly Co Eli | R)-(e)-2-(4-(2-(5-(1-(3، 5-داي كلورو بيريدين-4-يل)إيثوكسي)-1h-إندازول-3-يل)?ينيل)-1h-بيرازول-1-يل)إيثانول بلوري |
WO2012054364A2 (en) | 2010-10-22 | 2012-04-26 | Merck Sharp & Dohme Corp. | Bicyclic diamines as janus kinase inhibitors |
SG189525A1 (en) | 2010-10-25 | 2013-05-31 | G1 Therapeutics Inc | Cdk inhibitors |
JP2012092049A (ja) | 2010-10-27 | 2012-05-17 | Sumitomo Chemical Co Ltd | 有害動物防除組成物及び有害動物の防除方法 |
WO2012058211A2 (en) | 2010-10-29 | 2012-05-03 | Emory University | Quinazoline derivatives, compositions, and uses related thereto |
WO2012061337A1 (en) | 2010-11-02 | 2012-05-10 | Exelixis, Inc. | Fgfr2 modulators |
JP5847830B2 (ja) | 2010-11-10 | 2016-01-27 | アクテリオン ファーマシューティカルズ リミテッドActelion Pharmaceuticals Ltd | オレキシン受容体拮抗薬として有用なラクタム誘導体 |
WO2012062462A1 (en) | 2010-11-10 | 2012-05-18 | Grünenthal GmbH | Substituted heteroaromatic carboxamide and urea derivatives as vanilloid receptor ligands |
JP2012116825A (ja) | 2010-11-11 | 2012-06-21 | Ehime Univ | アセンジイミド化合物の製造方法 |
KR101171232B1 (ko) | 2010-11-15 | 2012-08-06 | 단국대학교 산학협력단 | 스파이로 화합물 및 이를 포함하는 유기전계 발광소자 |
WO2012065297A1 (en) | 2010-11-16 | 2012-05-24 | Impact Therapeutics, Inc. | 3-ARYL-6-ARYL-[1,2,4]TRIAZOLO[4,3-a]PYRIDINES AS INHIBITORS OF CELL PROLIFERATION AND THE USE THEREOF |
AU2011329806A1 (en) | 2010-11-17 | 2013-05-30 | Amgen Inc. | Quinoline derivatives as PIK3 inhibitors |
EP2640392B1 (en) | 2010-11-18 | 2015-01-07 | Kasina Laila Innova Pharmaceuticals Private Ltd. | Substituted 4-(selenophen-2(or 3)-ylamino)pyrimidine compounds and methods of use thereof |
GB201020179D0 (en) | 2010-11-29 | 2011-01-12 | Astex Therapeutics Ltd | New compounds |
CA2819373A1 (en) | 2010-12-09 | 2012-06-14 | Amgen Inc. | Bicyclic compounds as pim inhibitors |
CA2818903C (en) | 2010-12-14 | 2021-03-23 | Electrophoretics Limited | 5-(1,3-benzoxazol-2-yl)-4-(pyridin-4-yl)pyrimidin-2-amine and its use as a casein kinase 1delta inhibitor |
HUE029617T2 (en) | 2010-12-20 | 2017-03-28 | Merck Serono Sa | Indazolyl triazole derivatives as IRAK inhibitors |
NZ612446A (en) | 2010-12-22 | 2015-09-25 | Leo Lab Ltd | Ingenol-3-acylates iii and ingenol-3-carbamates |
WO2012083866A1 (en) | 2010-12-22 | 2012-06-28 | The Hong Kong Polytechnic University | Quinoline derivatives as anti-cancer agents |
WO2012088266A2 (en) | 2010-12-22 | 2012-06-28 | Incyte Corporation | Substituted imidazopyridazines and benzimidazoles as inhibitors of fgfr3 |
EP2468258A1 (en) | 2010-12-22 | 2012-06-27 | LEK Pharmaceuticals d.d. | Process for the preparation of a pharmaceutical composition comprising a low soluble pharmaceutically active ingredient |
AU2011348638B2 (en) | 2010-12-22 | 2015-05-21 | Leo Laboratories Limited | 3-acyl-ingenols II |
CA2822590A1 (en) | 2010-12-23 | 2012-06-28 | Amgen Inc. | Heterocyclic compounds and their uses |
JP5691508B2 (ja) | 2010-12-27 | 2015-04-01 | Jnc株式会社 | ジイミド化合物ならびにインクジェット用インクおよびその用途 |
KR101466150B1 (ko) | 2010-12-31 | 2014-11-27 | 제일모직 주식회사 | 유기광전소자용 화합물 및 이를 포함하는 유기광전소자 |
US9487726B2 (en) | 2011-01-06 | 2016-11-08 | Jx Nippon Oil & Energy Corporation | Imide compound, method for producing same, thickening agent for grease, and grease composition |
US8362023B2 (en) | 2011-01-19 | 2013-01-29 | Hoffmann-La Roche Inc. | Pyrazolo pyrimidines |
FR2970967B1 (fr) | 2011-01-27 | 2013-02-15 | Pf Medicament | Derives de type azaindazole ou diazaindazole comme medicament |
EP2487159A1 (en) | 2011-02-11 | 2012-08-15 | MSD Oss B.V. | RorgammaT inhibitors |
US9434747B2 (en) | 2011-02-18 | 2016-09-06 | Medivation Technologies, Inc. | Methods of treating diabetes |
JP5808826B2 (ja) | 2011-02-23 | 2015-11-10 | インテリカイン, エルエルシー | 複素環化合物およびその使用 |
TWI532742B (zh) | 2011-02-28 | 2016-05-11 | 艾伯維有限公司 | 激酶之三環抑制劑 |
KR20140012137A (ko) | 2011-03-17 | 2014-01-29 | 노파르티스 아게 | Hr 양성 대상체에서의 유방암용 바이오마커로서의 fgfr 및 이의 리간드 |
CA2830516C (en) | 2011-03-23 | 2017-01-24 | Amgen Inc. | Fused tricyclic dual inhibitors of cdk 4/6 and flt3 |
ITPD20110091A1 (it) | 2011-03-24 | 2012-09-25 | Univ Padova | Inibitori multitirosinchinasi utili per le patologie correlate: modelli farmacoforici, composti identificati tramite questi modelli, metodi per la loro preparazione, la loro formulazione e il loro impiego terapeutico. |
US8802711B2 (en) | 2011-03-25 | 2014-08-12 | Abbvie Inc. | TRPV1 antagonists |
CN103596983B (zh) | 2011-04-07 | 2016-10-26 | 霍夫曼-拉罗奇有限公司 | 抗fgfr4抗体及使用方法 |
FR2974088A1 (fr) | 2011-04-12 | 2012-10-19 | Pf Medicament | Composes pyrazolo[3,4-b]pyridines tri- et tetracycliques comme agent anticancereux |
PT2710035T (pt) | 2011-05-16 | 2017-06-05 | Hoffmann La Roche | Agonistas do fgfr1 e métodos de utilização |
CA2836203A1 (en) | 2011-05-17 | 2012-11-22 | Bayer Intellectual Property Gmbh | Amino-substituted imidazopyridazines as mknk1 kinase inhibitors |
US9376438B2 (en) | 2011-05-17 | 2016-06-28 | Principia Biopharma, Inc. | Pyrazolopyrimidine derivatives as tyrosine kinase inhibitors |
WO2012158994A1 (en) | 2011-05-19 | 2012-11-22 | Novartis Ag | 4-amino-5-fluoro-3- [6- (4 -methylpiperazin- 1 - yl) - 1h - benzimidazol - 2 - yl] - 1h - quinoli n-2-one for use in the treatment of adenoid cystic carcinoma |
CA2837630A1 (en) | 2011-06-01 | 2012-12-06 | Knut Eis | Substituted aminoimidazopyridazines |
TW201316991A (zh) | 2011-06-03 | 2013-05-01 | Millennium Pharm Inc | Mek抑制劑與奧諾拉(aurora)a激酶選擇性抑制劑之組合 |
WO2012173371A2 (ko) | 2011-06-13 | 2012-12-20 | 주식회사 엘지화학 | 신규한 화합물 및 이를 이용한 유기 전자 소자 |
WO2012175591A1 (en) | 2011-06-22 | 2012-12-27 | Bayer Intellectual Property Gmbh | Heterocyclyl aminoimidazopyridazines |
US8846656B2 (en) | 2011-07-22 | 2014-09-30 | Novartis Ag | Tetrahydropyrido-pyridine and tetrahydropyrido-pyrimidine compounds and use thereof as C5a receptor modulators |
AU2012295802B2 (en) | 2011-08-12 | 2017-03-30 | Nissan Chemical Industries, Ltd. | Tricyclic heterocyclic compounds and JAK inhibitors |
CA2838784A1 (en) | 2011-08-12 | 2013-02-21 | F. Hoffmann-La Roche Ag | Pyrazolo[3,4-c]pyridine compounds and methods of use |
JP2013049251A (ja) | 2011-08-31 | 2013-03-14 | Fujifilm Corp | レーザー彫刻用レリーフ印刷版原版、並びに、レリーフ印刷版及びその製版方法 |
WO2013033981A1 (zh) | 2011-09-06 | 2013-03-14 | 江苏先声药物研究有限公司 | 一类2,7-萘啶衍生物及其制备方法和应用 |
US9345705B2 (en) | 2011-09-15 | 2016-05-24 | Merck Sharp & Dohme Corp. | Compositions and methods for treating cancer |
US9376435B2 (en) | 2011-09-23 | 2016-06-28 | Jawaharlal Nehru Centre For Advanced Scientific Research | Chromophores for the detection of volatile organic compounds |
JP6174586B2 (ja) | 2011-09-23 | 2017-08-02 | バイエル・インテレクチュアル・プロパティ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツングBayer Intellectual Property GmbH | 置換イミダゾピリダジン |
CA2862895A1 (en) | 2011-09-30 | 2013-04-04 | Kineta, Inc. | Anti-viral compounds |
UA111382C2 (uk) | 2011-10-10 | 2016-04-25 | Оріон Корпорейшн | Інгібітори протеїнкінази |
CA2850394C (en) | 2011-10-12 | 2019-05-21 | University Health Network | Indazole compounds as kinase inhibitors and method of treating cancer with same |
KR101897044B1 (ko) | 2011-10-20 | 2018-10-23 | 에스에프씨 주식회사 | 유기금속 화합물 및 이를 포함하는 유기전계발광소자 |
AU2012328979B2 (en) | 2011-10-28 | 2016-04-21 | Novartis Ag | Method of treating gastrointestinal stromal tumors |
WO2013063003A1 (en) | 2011-10-28 | 2013-05-02 | Novartis Ag | Method of treating gastrointestinal stromal tumors |
WO2013088191A1 (en) | 2011-12-12 | 2013-06-20 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Antagonist of the fibroblast growth factor receptor 3 (fgfr3) for use in the treatment or the prevention of skeletal disorders linked with abnormal activation of fgfr3 |
FR2985257B1 (fr) | 2011-12-28 | 2014-02-14 | Sanofi Sa | Composes dimeres agonistes des recepteurs des fgfs (fgfrs), leur procede de preparation et leur application en therapeutique |
FR2985258A1 (fr) | 2011-12-28 | 2013-07-05 | Sanofi Sa | Composes dimeres agonistes des recepteurs des fgfs (fgfrs), leur procede de preparation et leur application en therapeutique |
WO2013109027A1 (ko) | 2012-01-18 | 2013-07-25 | 덕산하이메탈(주) | 화합물, 이를 이용한 유기전기소자 및 그 전자 장치 |
US10026905B2 (en) | 2012-01-18 | 2018-07-17 | Duk San Neolux Co., Ltd. | Compound, organic electric element using the same, and an electronic device thereof |
WO2013108809A1 (ja) | 2012-01-19 | 2013-07-25 | 大鵬薬品工業株式会社 | 3,5-二置換ベンゼンアルキニル化合物及びその塩 |
US9475815B2 (en) | 2012-02-23 | 2016-10-25 | Bayer Intelletual Property Gmbh | Substituted benzothienyl-pyrrolotriazines and uses thereof |
JP2013179181A (ja) | 2012-02-28 | 2013-09-09 | Sumitomo Chemical Co Ltd | 有機光電変換素子 |
WO2013136254A1 (en) | 2012-03-14 | 2013-09-19 | Lupin Limited | Heterocyclyl compounds |
CN104321058A (zh) | 2012-03-30 | 2015-01-28 | 诺华股份有限公司 | 用于治疗低磷血性疾病的fgfr抑制剂 |
JP5120580B1 (ja) | 2012-05-14 | 2013-01-16 | Jsr株式会社 | 液晶配向剤 |
AU2013264730B2 (en) | 2012-05-20 | 2018-02-01 | Tel Hashomer Medical Research Infrastructure And Services Ltd. | Prosthetic mitral valve |
CN107652289B (zh) | 2012-06-13 | 2020-07-21 | 因塞特控股公司 | 作为fgfr抑制剂的取代的三环化合物 |
JP2015522070A (ja) | 2012-07-11 | 2015-08-03 | ノバルティス アーゲー | 消化管間質腫瘍を治療する方法 |
SG11201500125QA (en) * | 2012-07-11 | 2015-02-27 | Blueprint Medicines Corp | Inhibitors of the fibroblast growth factor receptor |
CA2880901A1 (en) | 2012-08-02 | 2014-02-06 | Merck Sharp & Dohme Corp. | Antidiabetic tricyclic compounds |
WO2014019186A1 (en) | 2012-08-02 | 2014-02-06 | Merck Sharp & Dohme Corp. | Antidiabetic tricyclic compounds |
KR101985259B1 (ko) | 2012-08-10 | 2019-06-03 | 제이에스알 가부시끼가이샤 | 액정 배향제 및 화합물 |
WO2014026125A1 (en) | 2012-08-10 | 2014-02-13 | Incyte Corporation | Pyrazine derivatives as fgfr inhibitors |
WO2014044846A1 (en) | 2012-09-24 | 2014-03-27 | Evotec (Uk) Ltd. | 3-(aryl- or heteroaryl-amino)-7-(3,5-dimethoxyphenyl)isoquinoline derivatives as fgfr inhibitors useful for the treatment of proliferative disorders or dysplasia |
WO2014048878A1 (en) | 2012-09-26 | 2014-04-03 | Evotec (Uk) Ltd. | Phenyl- or pyridyl- pyrrolo[2,3b]pyrazine derivatives useful in the treatment or prevention of proliferative disorders or dysplasia |
WO2014062454A1 (en) | 2012-10-15 | 2014-04-24 | Merck Sharp & Dohme Corp. | Compositions and methods for treating cancer |
KR102000211B1 (ko) | 2012-10-29 | 2019-09-30 | 삼성디스플레이 주식회사 | 유기금속 화합물 및 이를 포함한 유기 발광 소자 |
US20140148548A1 (en) | 2012-11-28 | 2014-05-29 | Central Glass Company, Limited | Fluorine-Containing Polymerizable Monomer And Polymer Compound Using Same |
PL2925888T3 (pl) | 2012-11-28 | 2018-03-30 | Merck Sharp & Dohme Corp. | Kompozycje i sposoby do stosowania w leczeniu nowotworów |
CN104968664A (zh) | 2012-12-12 | 2015-10-07 | 山东亨利医药科技有限责任公司 | 作为酪氨酸激酶抑制剂的并环化合物 |
US9266892B2 (en) | 2012-12-19 | 2016-02-23 | Incyte Holdings Corporation | Fused pyrazoles as FGFR inhibitors |
TWI629266B (zh) | 2012-12-28 | 2018-07-11 | 藍印藥品公司 | 纖維母細胞生長因子受體之抑制劑 |
WO2014105849A1 (en) | 2012-12-28 | 2014-07-03 | Xoma (Us) Llc | Antibodies specific for fgfr4 and methods of use |
KR102030587B1 (ko) | 2013-01-09 | 2019-10-10 | 에스에프씨주식회사 | 두 개의 나프틸기를 포함하는 비대칭 안트라센 유도체 및 이를 포함하는 유기 발광 소자 |
CN103694236B (zh) | 2013-01-15 | 2017-05-31 | 苏州开拓药业股份有限公司 | 一种嘧啶骨架具有刺猬通路拮抗剂活性的抗肿瘤化合物 |
WO2014113191A1 (en) | 2013-01-15 | 2014-07-24 | Xiaohu Zhang | Hedgehog pathway signaling inhibitors and therapeutic applications thereof |
KR101456626B1 (ko) | 2013-02-01 | 2014-11-03 | 대영이앤비 주식회사 | 냉장고 부압 방지 장치 |
WO2014136972A1 (ja) | 2013-03-07 | 2014-09-12 | 国立大学法人九州大学 | 超分子複合体、発光体、および有機化合物検出用のセンサー素子 |
WO2014138485A1 (en) | 2013-03-08 | 2014-09-12 | Irm Llc | Ex vivo production of platelets from hematopoietic stem cells and the product thereof |
US9498532B2 (en) | 2013-03-13 | 2016-11-22 | Novartis Ag | Antibody drug conjugates |
EP2968285A4 (en) | 2013-03-13 | 2016-12-21 | Flatley Discovery Lab | COMPOUNDS AND METHODS FOR THE TREATMENT OF CYSTIC FIBROSIS |
EP2970258B1 (en) | 2013-03-14 | 2018-04-18 | AbbVie Deutschland GmbH & Co KG | Novel inhibitor compounds of phosphodiesterase type 10a |
US9499522B2 (en) | 2013-03-15 | 2016-11-22 | Blueprint Medicines Corporation | Compositions useful for treating disorders related to kit |
AR095464A1 (es) * | 2013-03-15 | 2015-10-21 | Celgene Avilomics Res Inc | Compuestos de heteroarilo y usos de los mismos |
KR102350704B1 (ko) | 2013-03-15 | 2022-01-13 | 셀젠 카르 엘엘씨 | 헤테로아릴 화합물 및 이의 용도 |
EA036160B1 (ru) | 2013-03-15 | 2020-10-08 | Селджен Кар Ллс | Гетероарильные соединения и их применение |
TWI628176B (zh) | 2013-04-04 | 2018-07-01 | 奧利安公司 | 蛋白質激酶抑制劑 |
KR101573611B1 (ko) | 2013-04-17 | 2015-12-01 | 주식회사 엘지화학 | 플러렌 유도체, 이를 이용한 유기 태양 전지 및 이의 제조 방법 |
CN105189544A (zh) | 2013-04-19 | 2015-12-23 | 科瓦根股份公司 | 具有抗肿瘤活性的新颖的双特异性结合分子 |
JP6449244B2 (ja) | 2013-04-19 | 2019-01-09 | インサイト・ホールディングス・コーポレイションIncyte Holdings Corporation | Fgfr抑制剤としての二環式複素環 |
GB201307577D0 (en) | 2013-04-26 | 2013-06-12 | Astex Therapeutics Ltd | New compounds |
CA2911706A1 (en) | 2013-05-09 | 2014-11-13 | Principia Biopharma Inc. | Quinolone derivatives as fibroblast growth factor inhibitors |
TR201815333T4 (tr) | 2013-06-14 | 2018-11-21 | Sanofi Sa | Mesane kanserinin tedavisinde kullanıma yönelik pirazolopiridin türevleri. |
US9670203B2 (en) | 2013-06-28 | 2017-06-06 | Beigene, Ltd. | Fused tricyclic urea compounds as Raf kinase and/or Raf kinase dimer inhibitors |
JP6380862B2 (ja) | 2013-06-28 | 2018-08-29 | ベイジーン リミテッド | 複数種類のキナーゼの阻害剤としての縮合三環式アミド系化合物 |
MX2015017821A (es) | 2013-07-02 | 2016-04-15 | Syngenta Participations Ag | Heterociclos bi-o triciclicos activos como plaguicidas con sustituyentes que contienen azufre. |
AU2014287209B2 (en) | 2013-07-09 | 2019-01-24 | Dana-Farber Cancer Institute, Inc. | Kinase inhibitors for the treatment of disease |
JP6018547B2 (ja) | 2013-07-09 | 2016-11-02 | 大成ロテック株式会社 | 舗装機械 |
CA2917364C (en) | 2013-07-11 | 2020-09-29 | Acea Biosciences Inc. | Heterocyclic compounds and uses thereof |
TW201605452A (zh) | 2013-08-28 | 2016-02-16 | 安斯泰來製藥股份有限公司 | 以嘧啶化合物作爲有效成分之醫藥組成物 |
JO3515B1 (ar) | 2013-10-18 | 2020-07-05 | Eisai R&D Man Co Ltd | مثبطات fgfr4 بيريميدين |
US9434700B2 (en) | 2013-10-25 | 2016-09-06 | Neil Bifulco, JR. | Inhibitors of the fibroblast growth factor receptor |
BR112016008276B1 (pt) | 2013-10-25 | 2021-03-02 | Novartis Ag | derivados bicíclicos de piridila fundidos ao anel, seus usos e seu intermediário, e composição farmacêutica |
FR3012330B1 (fr) | 2013-10-29 | 2015-10-23 | Oreal | Composition biphase comprenant un ester d'acide gras et de sucre ou un alkylpolyglucoside liquide, de hlb < 8, et un alcane ramifie en c8-c18 |
WO2015066452A2 (en) | 2013-11-01 | 2015-05-07 | Foundation Medicine, Inc. | Methods of treating pediatric cancers |
WO2015108992A1 (en) | 2014-01-15 | 2015-07-23 | Blueprint Medicines Corporation | Heterobicyclic compounds and their use as fgfr4 receptor inhibitors |
ES2904544T3 (es) | 2014-08-19 | 2022-04-05 | Shanghai Haihe Pharmaceutical Co Ltd | Compuestos de indazol como inhibidores de la cinasa FGFR, preparación y uso de los mismos |
CN104262330B (zh) | 2014-08-27 | 2016-09-14 | 广东东阳光药业有限公司 | 一种脲取代联苯类化合物及其组合物及用途 |
CN107001331A (zh) | 2014-09-19 | 2017-08-01 | 拜耳制药股份公司 | 作为bub1抑制剂的苄基取代的吲唑 |
US20160115164A1 (en) | 2014-10-22 | 2016-04-28 | Incyte Corporation | Bicyclic heterocycles as fgfr4 inhibitors |
US10851105B2 (en) | 2014-10-22 | 2020-12-01 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
MA41551A (fr) | 2015-02-20 | 2017-12-26 | Incyte Corp | Hétérocycles bicycliques utilisés en tant qu'inhibiteurs de fgfr4 |
WO2016134320A1 (en) | 2015-02-20 | 2016-08-25 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
US9701650B2 (en) | 2015-02-20 | 2017-07-11 | Oregon Health & Science University | Derivatives of sobetirome |
US9580423B2 (en) | 2015-02-20 | 2017-02-28 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
KR20180014778A (ko) | 2015-06-03 | 2018-02-09 | 트리아스텍 인코포레이티드 | 제형 및 이의 용도 |
CR20180029A (es) | 2015-07-15 | 2018-06-05 | Protagonist Therapeutics Inc | Inhibidores peotídicos del receptor de interleucina 23 y su uso para tratar enfermedades inflamatorias |
WO2017011561A1 (en) | 2015-07-15 | 2017-01-19 | Cabot Corporation | Methods of making an elastomer composite reinforced with silica and products containing same |
GB201512369D0 (en) | 2015-07-15 | 2015-08-19 | Immatics Biotechnologies Gmbh | Novel peptides and combination of peptides for use in immunotherapy against epithelial ovarian cancer and other cancers |
LT3322701T (lt) | 2015-07-15 | 2019-07-10 | F. Hoffmann-La Roche Ag | Etinilo dariniai kaip metabotropinių glutamato receptorių moduliatoriai |
PL3328419T3 (pl) | 2015-07-30 | 2021-12-27 | Macrogenics, Inc. | Cząsteczki wiążące pd-1 i sposoby ich zastosowania |
WO2017023972A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc. | 3-(1h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[4,3-b]pyridines and therapeutic uses thereof |
WO2017024003A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc | 3-(1h-pyrrolo[3,2-c]pyridin-2-yl)-1h-pyrazolo[4,3-b]pyridines and therapeutic uses thereof |
US10329309B2 (en) | 2015-08-03 | 2019-06-25 | Samumed, Llc | 3-(3H-imidazo[4,5-B]pyridin-2-yl)-1H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
US10519169B2 (en) | 2015-08-03 | 2019-12-31 | Samumed, Llc | 3-(1H-pyrrolo[2,3-C]pyridin-2-yl)-1 H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
US10206909B2 (en) | 2015-08-03 | 2019-02-19 | Samumed, Llc | 3-(1H-pyrrolo[2,3-B]pyridin-2-yl)-1H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
WO2017023988A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc. | 3-(3h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[4,3-b]pyridines and therapeutic uses thereof |
US10392383B2 (en) | 2015-08-03 | 2019-08-27 | Samumed, Llc | 3-(1H-benzo[d]imidazol-2-yl)-1H-pyrazolo[4,3-b]pyridines and therapeutic uses thereof |
CA2996018C (en) | 2015-08-20 | 2024-02-06 | Changzhou Jiekai Pharmatech Co., Ltd. | Pyrazolo fused heterocyclic compounds as erk inhibitors |
US10975071B2 (en) | 2015-09-28 | 2021-04-13 | Araxes Pharma Llc | Inhibitors of KRAS G12C mutant proteins |
EP3365340B1 (en) | 2015-10-19 | 2022-08-10 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US10208024B2 (en) | 2015-10-23 | 2019-02-19 | Array Biopharma Inc. | 2-aryl- and 2-heteroaryl-substituted 2-pyridazin-3(2H)-one compounds as inhibitors of FGFR tyrosine kinases |
HRP20221035T1 (hr) | 2015-11-19 | 2022-11-11 | Incyte Corporation | Heterociklički spojevi kao imunomodulatori |
US20170174671A1 (en) | 2015-12-17 | 2017-06-22 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
PE20230731A1 (es) | 2015-12-22 | 2023-05-03 | Incyte Corp | Compuestos heterociclicos como inmunomoduladores |
AR108396A1 (es) | 2016-05-06 | 2018-08-15 | Incyte Corp | Compuestos heterocíclicos como inmunomoduladores |
EP3464279B1 (en) | 2016-05-26 | 2021-11-24 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
TWI771305B (zh) | 2016-06-20 | 2022-07-21 | 美商英塞特公司 | 作為免疫調節劑之雜環化合物 |
TW201803871A (zh) | 2016-06-24 | 2018-02-01 | 英塞特公司 | 作為PI3K-γ抑制劑之雜環化合物 |
WO2018013789A1 (en) | 2016-07-14 | 2018-01-18 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US20180057486A1 (en) | 2016-08-29 | 2018-03-01 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
CN109641868B (zh) | 2016-08-30 | 2021-12-03 | 广东东阳光药业有限公司 | 流感病毒复制抑制剂及其使用方法和用途 |
US20180072718A1 (en) | 2016-09-09 | 2018-03-15 | Incyte Corporation | Pyrazolopyridine compounds and uses thereof |
CN109890827A (zh) | 2016-10-05 | 2019-06-14 | 芝诺罗耶尔蒂里程碑有限责任公司 | 螺环化合物 |
KR101755556B1 (ko) | 2016-11-18 | 2017-07-07 | 주식회사 케마스 | 육산화사비소의 결정다형을 포함하는 뇌암 예방 또는 치료용 약학 조성물 및 이의 제조방법 |
KR101834366B1 (ko) | 2016-11-21 | 2018-03-05 | 주식회사 케마스 | 육산화사비소의 결정다형을 포함하는 유방암 예방 또는 치료용 약학 조성물 및 이의 제조방법 |
KR101844049B1 (ko) | 2016-12-05 | 2018-03-30 | 주식회사 케마스 | 육산화사비소의 결정다형을 포함하는 간암 예방 또는 치료용 약학 조성물 |
KR101844050B1 (ko) | 2016-12-09 | 2018-05-14 | 주식회사 케마스 | 육산화사비소의 결정다형을 포함하는 암 예방 또는 치료용 약학 조성물 |
PE20200005A1 (es) | 2016-12-22 | 2020-01-06 | Incyte Corp | Derivados de tetrahidro imidazo[4,5-c]piridina como inductores de internalizacion pd-l1 |
ES2874756T3 (es) | 2016-12-22 | 2021-11-05 | Incyte Corp | Derivados de triazolo[1,5-A]piridina como inmunomoduladores |
WO2018119263A1 (en) | 2016-12-22 | 2018-06-28 | Incyte Corporation | Heterocyclic compounds derivatives as pd-l1 internalization inducers |
WO2018119221A1 (en) | 2016-12-22 | 2018-06-28 | Incyte Corporation | Pyridine derivatives as immunomodulators |
WO2018119286A1 (en) | 2016-12-22 | 2018-06-28 | Incyte Corporation | Bicyclic heteroaromatic compounds as immunomodulators |
WO2018119266A1 (en) | 2016-12-22 | 2018-06-28 | Incyte Corporation | Benzooxazole derivatives as immunomodulators |
AR111960A1 (es) | 2017-05-26 | 2019-09-04 | Incyte Corp | Formas cristalinas de un inhibidor de fgfr y procesos para su preparación |
WO2018234354A1 (en) | 2017-06-20 | 2018-12-27 | Grünenthal GmbH | NOVEL SUBSTITUTED 3-INDOLE AND 3-INDAZOLE COMPOUNDS AS PHOSPHODIESTERASE INHIBITORS |
EP3672973A4 (en) | 2017-08-22 | 2021-05-26 | JS Innopharm (Shanghai) Ltd. | HETEROCYCLIC COMPOUNDS USED AS KINASE INHIBITORS, COMPOSITIONS INCLUDING THE HETEROCYCLIC COMPOUND, AND METHODS OF USE THEREOF |
US10793551B2 (en) | 2017-10-19 | 2020-10-06 | Effector Therapeutics Inc. | Benzimidazole-indole inhibitors of Mnk1 and Mnk2 |
CN111433200B (zh) | 2017-12-02 | 2024-03-22 | 加拉帕戈斯股份有限公司 | 用于治疗疾病的化合物及其药物组合物 |
FI3774791T3 (fi) | 2018-03-30 | 2023-03-21 | Incyte Corp | Heterosyklisiä yhdisteitä immunomodulaattoreina |
DK3788047T3 (da) | 2018-05-04 | 2024-09-16 | Incyte Corp | Faste former af en FGFR-inhibitor og fremgangsmåder til fremstilling deraf |
SG11202010882XA (en) | 2018-05-04 | 2020-11-27 | Incyte Corp | Salts of an fgfr inhibitor |
BR112020022936A2 (pt) | 2018-05-11 | 2021-02-02 | Incyte Corporation | derivados de tetra-hidro-imidazo[4,5-c]piridina como imunomoduladores de pd-l1 |
JP2022504011A (ja) | 2018-08-14 | 2022-01-13 | オステオーク インコーポレイティド | ピロロ-ジピリジン化合物 |
CA3111878A1 (en) | 2018-09-07 | 2020-03-12 | Merck Patent Gmbh | 5-morpholin-4-yl-pyrazolo[4,3-b]pyridine derivatives |
US20210355547A1 (en) | 2018-10-20 | 2021-11-18 | The Johns Hopkins University | Non-invasive urinary biomarkers for the detection of urothelial carcinoma of the bladder |
WO2020131674A1 (en) | 2018-12-19 | 2020-06-25 | Array Biopharma Inc. | 7-((3,5-dimethoxyphenyl)amino)quinoxaline derivatives as fgfr inhibitors for treating cancer |
EP3898626A1 (en) | 2018-12-19 | 2021-10-27 | Array Biopharma, Inc. | Substituted pyrazolo[1,5-a]pyridine compounds as inhibitors of fgfr tyrosine kinases |
JP7148802B2 (ja) | 2019-01-25 | 2022-10-06 | 富士通株式会社 | 解析プログラム、解析方法および解析装置 |
WO2021007269A1 (en) | 2019-07-09 | 2021-01-14 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
MX2022004513A (es) | 2019-10-14 | 2022-07-19 | Incyte Corp | Heterociclos biciclicos como inhibidores de los receptores del factor de crecimiento de fibroblastos (fgfr). |
WO2021076728A1 (en) | 2019-10-16 | 2021-04-22 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
BR112022010664A2 (pt) | 2019-12-04 | 2022-08-16 | Incyte Corp | Derivados de um inibidor de fgfr |
JP2023505258A (ja) | 2019-12-04 | 2023-02-08 | インサイト・コーポレイション | Fgfr阻害剤としての三環式複素環 |
US12012409B2 (en) | 2020-01-15 | 2024-06-18 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
EP4323405A1 (en) | 2021-04-12 | 2024-02-21 | Incyte Corporation | Combination therapy comprising an fgfr inhibitor and a nectin-4 targeting agent |
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