ES2558777T3 - (R)-(E)-2-(4-(2-(5-(1-(3,5-dicloropiridin-4-il)etoxi)-1H-indazol-3-il)vinil)-1H-pirazol-1-il)etanol cristalino y su uso como inhibidor de FGFR - Google Patents
(R)-(E)-2-(4-(2-(5-(1-(3,5-dicloropiridin-4-il)etoxi)-1H-indazol-3-il)vinil)-1H-pirazol-1-il)etanol cristalino y su uso como inhibidor de FGFR Download PDFInfo
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- ES2558777T3 ES2558777T3 ES11771312.3T ES11771312T ES2558777T3 ES 2558777 T3 ES2558777 T3 ES 2558777T3 ES 11771312 T ES11771312 T ES 11771312T ES 2558777 T3 ES2558777 T3 ES 2558777T3
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- dichloropyridin
- ethoxy
- vinyl
- indazol
- pyrazole
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- -1 4- (2- (5- (1- (3,5-dichloropyridin-4-yl) ethoxy) -1H-indazol-3-yl) vinyl) -1H-pyrazole -1-yl Chemical group 0.000 title abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 title description 4
- 229940125829 fibroblast growth factor receptor inhibitor Drugs 0.000 title 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 abstract 1
- 108091008794 FGF receptors Proteins 0.000 description 12
- 102000052178 fibroblast growth factor receptor activity proteins Human genes 0.000 description 12
- 206010028980 Neoplasm Diseases 0.000 description 10
- 102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 description 3
- 101710182386 Fibroblast growth factor receptor 1 Proteins 0.000 description 3
- 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 description 3
- 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 2
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 2
- ZEOWTGPWHLSLOG-UHFFFAOYSA-N Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F Chemical compound Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F ZEOWTGPWHLSLOG-UHFFFAOYSA-N 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 208000034578 Multiple myelomas Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 210000002307 prostate Anatomy 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 229910002483 Cu Ka Inorganic materials 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102100037665 Fibroblast growth factor 9 Human genes 0.000 description 1
- YSWHPLCDIMUKFE-QWRGUYRKSA-N Glu-Tyr Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 YSWHPLCDIMUKFE-QWRGUYRKSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 101001027380 Homo sapiens Fibroblast growth factor 9 Proteins 0.000 description 1
- 101000827746 Homo sapiens Fibroblast growth factor receptor 1 Proteins 0.000 description 1
- 101000917148 Homo sapiens Fibroblast growth factor receptor 3 Proteins 0.000 description 1
- 229910021380 Manganese Chloride Inorganic materials 0.000 description 1
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 238000003016 alphascreen Methods 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000001772 anti-angiogenic effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 239000011152 fibreglass Substances 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 102000055705 human FGFR1 Human genes 0.000 description 1
- 102000055709 human FGFR3 Human genes 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 239000011565 manganese chloride Substances 0.000 description 1
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- 230000035772 mutation Effects 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 208000015347 renal cell adenocarcinoma Diseases 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 210000002536 stromal cell Anatomy 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 208000013077 thyroid gland carcinoma Diseases 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 210000003606 umbilical vein Anatomy 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
((R)-(E)-2-(4-(2-(5-(1-(3,5-dicloropiridin-4-il)etoxi)-1H-indazol-3-il)vinil)-1H-pirazol-1-il)etanol cristalino monohidrato.
Description
analiza un patrón Panalytical para este material, y se valoran la orientación preferida y los efectos estáticos de partícula mediante la comparación del patrón de XRPD simulado con un análisis de cristal único. Se usa un espejo de múltiples capas graduado elípticamente para enfocar los rayos-X de Cu Ka de la fuente a través del espécimen y sobre el detector. Los patrones de difracción se obtienen usando un detector sensible a la posición de exploración (X'Celerator) situado a
5 240 mm del espécimen. Se recogen datos desde 1,01 a 39,99 grados 2θ con un tamaño de paso de 0,017 grados 2θ y una velocidad de exploración de 1,2 grados/min y con una rendija de divergencia de 0,5 grados y una rendija de dispersión de 0,25 grados. Se usa un tope de haz para minimizar el ruido de fondo generado por la dispersión del aire. Se usan rendijas de Soller para los haces incidentes y de difracción para minimizar la divergencia axial. Los picos observados se muestran en la Tabla 1. Se usa un umbral de intensidad del 5%.
10 Tabla 1. Picos observados para el compuesto del Ejemplo 1, XPRD
- º2θ
- Espacio d (Å) Intensidad (%)
- 3,54 ± 0,10
- 24,975 ± 0,726 45
- 7,08 ± 0,10
- 12,485 ± 0,179 10
- 10,62 ± 0,10
- 8,328 ± 0,079 9
- 12,51 ± 0,10
- 7,075 ± 0,057 78
- 13,00 ± 0,10
- 6,812 ± 0,053 37
- 13,60 ± 0,10
- 6,512 ± 0,048 16
- 14,18 ± 0,10
- 6,245 ± 0,044 13
- 14,65 ± 0,10
- 6,046 ± 0,041 100
- 14,97 ± 0,10
- 5,919 ± 0,040 29
- 15,49 ± 0,10
- 5,722 ± 0,037 16
- 16,24 ± 0,10
- 5,459 ± 0,034 35
- 16,59 ± 0,10
- 5,344 ± 0,032 24
- 17,06 ± 0,10
- 5,198 ± 0,030 26
- 17,76 ± 0,10
- 4,995 ± 0,028 20
- 18,49 ± 0,10
- 4,798 ± 0,026 9
- 19,16 ± 0,10
- 4,632 ± 0,024 68
- 20,37 ± 0,10
- 4,361 ± 0,021 44
- 21,67 ± 0,10
- 4,101 ± 0,019 8
- 21,89 ± 0,10
- 4,061 ± 0,018 8
- 22,17 ± 0,10
- 4,010 ± 0,018 22
- 23,02 ± 0,10
- 3,863 ± 0,017 54
- 24,33 ± 0,10
- 3,659 ± 0,015 15
6 5
10
15
20
25
30
35
40
(Cont.)
- 25,25 ± 0,10
- 3,528 ± 0,014 27
- 25,93 ± 0,10
- 3,436 ± 0,013 49
- 26,16 ± 0,10
- 3,406 ± 0,013 16
- 26,77 ± 0,10
- 3,331 ± 0,012 10
- 27,23 ± 0,10
- 3,275 ± 0,012 15
- 28,25 ± 0,10
- 3,159 ± 0,011 10
- 28,59 ± 0,10
- 3,123 ± 0,011 11
- 29,56 ± 0,10
- 3,022 ± 0,010 13
De esta manera, una muestra preparada apropiadamente del Ejemplo 1 puede ser caracterizada por un patrón de difracción de rayos-X usando radiación CuKα, que tiene picos de difracción (valores 2-teta) según se describe en la Tabla 1 y, en particular, que tiene picos en 14,65 en combinación con uno o más de los picos en 3,54, 12,51 y 19,16: y más particularmente que tiene un pico en 14,65; con una tolerancia para los ángulos de difracción de 0,1 grados, más preferiblemente de 0,01 grados.
La regulación aberrante de la ruta FGF/FGFR ha estado implicada en muchas formas de malignidades humanas. Los FGFRs y FGFs están frecuentemente sobre-expresados en numerosos cánceres, y su expresión se correlaciona frecuentemente con un mal pronóstico. Las mutaciones activadoras en el dominio cinasa de FGFR se han encontrado en varios tipos de tumores, incluyendo mama, NSCLC, vejiga, gástrico, próstata, colon y mieloma múltiple. La amplificación genómica del locus FGFR se detectó también en muchos pacientes con cáncer de mama, gástrico y de pulmón. La sobre-expresión de FGFRs o FGFs se ha encontrado también en muchos tipos diferentes de tumores tales como cáncer de vejiga, mieloma múltiple, próstata y de pulmón. Otros cánceres que podrían beneficiarse de la terapia inhibidora de la ruta de la familia del FGFR incluyen AML, cáncer hepático, melanoma, cáncer de cabeza y cuello, cáncer de tiroides, cáncer pancreático, cáncer de células renales, glioblastoma y cáncer testicular. Además de sus papeles en la formación y progreso del tumor, los FGFs y FGFRs son también reguladores clave de angiogénesis, especialmente durante el crecimiento del tumor. El eje FGF/FGFR también desempeña un papel importante en el aumento de otras células estromales del tumor, tales como fibroblastos asociados con cáncer. La regulación ascendente de FGFs conduce también a resistencia a quimioterapias anti-angiogénicas y otras quimioterapias. Finalmente, los inhibidores de molécula pequeña de FGFRs han demostrado actividades anti-tumorales en varios modelos de tumor preclínicos y están siendo explorados en la clínica. Tomada en su conjunto, la ruta FGF/FGFR es esencial para varios procesos celulares importantes en células cancerígenas. Por estas razones, las terapias basadas en usar como objetivo la señalización de FGFRs/FGF pueden afectar tanto a las células tumorales directamente como a la angiogénesis tumoral.
La Preparación 10 es ensayada esencialmente tal como se describe a continuación en los ensayos siguientes: Ensayo de Enzima FGFR1 (unión a filtro), el Ensayo de Enzima FGFR3 (unión a filtro), ensayo de p-ERK inducido por FGF9 basado en células RT-112 (en presencia de BSA) y la detección AlphaScreen SureFire de fosforilación ERK (Thr202/Tyr204) en ensayos basados en células de las Células Endoteliales de la Vena Umbilical Humana (HUVEC). Estos ensayos demuestran que la Preparación 10 es un inhibidor de la ruta de la familia FGFR y tiene actividad anti-cancerígena. De esta manera, los resultados con la forma amorfa de (R)-(E)-2-(4-(2-(5-(1-(3,5-dicloropiridin-4-il)etoxi)-1H-indazol-3-il)vinil)-1Hpirazol-1-il)etanol son indicativos de los resultados con el compuesto de la presente invención. Las formas cristalinas del compuesto son todavía ventajosas debido a que pueden ofrecer las propiedades relativas a la forma anterior de propiedades superiores de manipulación de sólidos a gran escala, facilidad de purificación mediante cristalización y estabilidad termodinámica bajo condiciones de procesamiento y almacenamiento farmacéutico.
Ensayo de Enzima FGFR1 y FGFR3 (unión a filtro)
Se incuba cinasa FGFR1 o FGFR3 (0,15 ng/μl de FGFR1 humano o 0,32 ng/μl de FGFR3 humano) en 50 μl de un tampón que contiene ácido 4-(2-hidroxietil)-1-piperazinetan-sulfónico (HEPES) 10 mM pH 7,5, tris(hidroximetil)aminometano (Tris-HCI) 8 mM, pH 7,5, ditiotreitol (DTT) 5,0 mM, trifosfato de adenosina (ATP) 10,0 μM, MnCl2 10 mM, NaCI150 mM, 0.01% de TRITON® X-100, 0,5 μCi de 33P-ATP y 0,05 μg/μl de Poly(Glu-Tyr). La reacción se lleva a cabo en un volumen de 50 μl a RT durante 30 minutos y, a continuación, se detiene añadiendo 130 μl de H3PO4 al 10%. La reacción (120 μl) se transfiere a una placa de filtro de fibra de vidrio de 1,0 μm de 96 pocillos, se incuba a RT durante 20-30 minutos y, a continuación, se lava 3x en un dispositivo Zoom TITERTEK® con 0,5% de H3PO4. Los pocillos
7
Claims (1)
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Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US38991110P | 2010-10-05 | 2010-10-05 | |
| US389911P | 2010-10-05 | ||
| PCT/US2011/053798 WO2012047699A1 (en) | 2010-10-05 | 2011-09-29 | Crystalline (r) - (e) -2- (4- (2- (5- (1- (3, 5 -dichloropyridin-4 -yl) ethoxy) - 1h - indazol - 3 - yl) vinyl) -1 h- pyrazol- 1 -yl) ethanol and its use as fgfr inhibitor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2558777T3 true ES2558777T3 (es) | 2016-02-08 |
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| Application Number | Title | Priority Date | Filing Date |
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| ES11771312.3T Active ES2558777T3 (es) | 2010-10-05 | 2011-09-29 | (R)-(E)-2-(4-(2-(5-(1-(3,5-dicloropiridin-4-il)etoxi)-1H-indazol-3-il)vinil)-1H-pirazol-1-il)etanol cristalino y su uso como inhibidor de FGFR |
Country Status (36)
| Country | Link |
|---|---|
| US (1) | US8530665B2 (es) |
| EP (1) | EP2625175B1 (es) |
| JP (1) | JP5940547B2 (es) |
| KR (1) | KR101527661B1 (es) |
| CN (1) | CN103153983B (es) |
| AR (1) | AR083091A1 (es) |
| AU (1) | AU2011312485B2 (es) |
| BR (1) | BR112013006336A2 (es) |
| CA (1) | CA2813329C (es) |
| CL (1) | CL2013000884A1 (es) |
| CO (1) | CO6710911A2 (es) |
| DK (1) | DK2625175T3 (es) |
| DO (1) | DOP2013000072A (es) |
| EA (1) | EA021817B1 (es) |
| EC (1) | ECSP13012539A (es) |
| ES (1) | ES2558777T3 (es) |
| HK (1) | HK1184147A1 (es) |
| HR (1) | HRP20151299T1 (es) |
| HU (1) | HUE026379T2 (es) |
| IL (1) | IL224850A (es) |
| JO (1) | JO3062B1 (es) |
| MA (1) | MA34552B1 (es) |
| ME (1) | ME02307B (es) |
| MX (1) | MX2013003907A (es) |
| NZ (1) | NZ608482A (es) |
| PE (1) | PE20140252A1 (es) |
| PH (1) | PH12013500649A1 (es) |
| PL (1) | PL2625175T3 (es) |
| PT (1) | PT2625175E (es) |
| RS (1) | RS54457B1 (es) |
| SG (1) | SG188286A1 (es) |
| SI (1) | SI2625175T1 (es) |
| TW (1) | TWI418554B (es) |
| UA (1) | UA111725C2 (es) |
| WO (1) | WO2012047699A1 (es) |
| ZA (1) | ZA201301560B (es) |
Families Citing this family (32)
| Publication number | Priority date | Publication date | Assignee | Title |
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| DE19945982A1 (de) * | 1999-09-24 | 2001-03-29 | Knoll Ag | Geschwindigkeitsbestimmte Partikel |
| WO2012088266A2 (en) | 2010-12-22 | 2012-06-28 | Incyte Corporation | Substituted imidazopyridazines and benzimidazoles as inhibitors of fgfr3 |
| ES2984771T3 (es) | 2012-06-13 | 2024-10-31 | Incyte Holdings Corp | Compuestos tricíclicos sustituidos como inhibidores de FGFR |
| WO2014026125A1 (en) | 2012-08-10 | 2014-02-13 | Incyte Corporation | Pyrazine derivatives as fgfr inhibitors |
| US9266892B2 (en) | 2012-12-19 | 2016-02-23 | Incyte Holdings Corporation | Fused pyrazoles as FGFR inhibitors |
| DK2986610T5 (en) | 2013-04-19 | 2018-12-10 | Incyte Holdings Corp | BICYCLIC HETEROCYCLES AS FGFR INHIBITORS |
| CN103819396B (zh) * | 2014-02-26 | 2016-06-15 | 四川大学 | 一种手性的1-（3,5-二氯吡啶-4-基）-乙醇的合成方法 |
| US10851105B2 (en) | 2014-10-22 | 2020-12-01 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
| PE20171514A1 (es) | 2015-02-20 | 2017-10-20 | Incyte Corp | Heterociclos biciclicos como inhibidores de fgfr |
| 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 |
| AR111960A1 (es) | 2017-05-26 | 2019-09-04 | Incyte Corp | Formas cristalinas de un inhibidor de fgfr y procesos para su preparación |
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| US6897231B2 (en) * | 2000-07-31 | 2005-05-24 | Signal Pharmaceuticals, Inc. | Indazole derivatives as JNK inhibitors and compositions and methods related thereto |
| DE60115069T2 (de) * | 2000-09-11 | 2006-08-03 | Chiron Corp., Emeryville | Chinolinonderivate als tyrosin-kinase inhibitoren |
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| JP2006163651A (ja) | 2004-12-03 | 2006-06-22 | Sony Computer Entertainment Inc | 表示装置、表示装置の制御方法、プログラム及びフォントデータ |
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| PT2134702T (pt) * | 2007-04-05 | 2017-07-31 | Pfizer Prod Inc | Formas cristalinas de 6-[2-(metilcarbamoil)fenilsulfanil]-3-e-[2-(piridin-2-il)etenil]indazol adequadas para o tratamento de crescimento celular anormal em mamíferos |
| JO2860B1 (en) * | 2009-05-07 | 2015-03-15 | ايلي ليلي اند كومباني | Phenylendazolyl compounds |
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