ES2671354T3 - Inhibidores de ADN-PK - Google Patents
Inhibidores de ADN-PK Download PDFInfo
- Publication number
- ES2671354T3 ES2671354T3 ES14800181.1T ES14800181T ES2671354T3 ES 2671354 T3 ES2671354 T3 ES 2671354T3 ES 14800181 T ES14800181 T ES 14800181T ES 2671354 T3 ES2671354 T3 ES 2671354T3
- Authority
- ES
- Spain
- Prior art keywords
- compound
- mhz
- alkyl
- nmr
- mmol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000003112 inhibitor Substances 0.000 title description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 560
- 150000003839 salts Chemical class 0.000 claims abstract description 36
- 206010028980 Neoplasm Diseases 0.000 claims description 58
- 201000011510 cancer Diseases 0.000 claims description 29
- 238000011282 treatment Methods 0.000 claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 239000003795 chemical substances by application Substances 0.000 claims description 14
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 238000001959 radiotherapy Methods 0.000 claims description 8
- 206010009944 Colon cancer Diseases 0.000 claims description 6
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 5
- 208000005017 glioblastoma Diseases 0.000 claims description 5
- 238000011285 therapeutic regimen Methods 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 4
- 206010060862 Prostate cancer Diseases 0.000 claims description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 4
- 239000002246 antineoplastic agent Substances 0.000 claims description 4
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 4
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 208000020816 lung neoplasm Diseases 0.000 claims description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 4
- 201000001441 melanoma Diseases 0.000 claims description 4
- 201000002528 pancreatic cancer Diseases 0.000 claims description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 4
- 230000001225 therapeutic effect Effects 0.000 claims description 4
- 201000008808 Fibrosarcoma Diseases 0.000 claims description 3
- 206010062878 Gastrooesophageal cancer Diseases 0.000 claims description 3
- 201000006974 gastroesophageal cancer Diseases 0.000 claims description 3
- 230000003902 lesion Effects 0.000 claims description 3
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 230000001235 sensitizing effect Effects 0.000 claims description 2
- 230000001093 anti-cancer Effects 0.000 claims 1
- 201000010536 head and neck cancer Diseases 0.000 claims 1
- 208000014829 head and neck neoplasm Diseases 0.000 claims 1
- 230000003389 potentiating effect Effects 0.000 claims 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 826
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 482
- 238000005481 NMR spectroscopy Methods 0.000 description 318
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 309
- 238000005160 1H NMR spectroscopy Methods 0.000 description 300
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 166
- -1 4,6-disubstituted aminopyrimidine compounds Chemical class 0.000 description 131
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 129
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 106
- 125000000217 alkyl group Chemical group 0.000 description 100
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 99
- 239000000203 mixture Substances 0.000 description 96
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 84
- 230000002829 reductive effect Effects 0.000 description 80
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 78
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 75
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 72
- 239000000243 solution Substances 0.000 description 72
- 239000011541 reaction mixture Substances 0.000 description 68
- 235000019439 ethyl acetate Nutrition 0.000 description 63
- 239000007787 solid Substances 0.000 description 55
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 49
- 238000006243 chemical reaction Methods 0.000 description 42
- 229910052739 hydrogen Inorganic materials 0.000 description 38
- 239000001257 hydrogen Substances 0.000 description 37
- 125000000623 heterocyclic group Chemical group 0.000 description 32
- 239000000284 extract Substances 0.000 description 31
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 30
- 239000000741 silica gel Substances 0.000 description 30
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 29
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
- 210000004027 cell Anatomy 0.000 description 28
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 28
- 238000004587 chromatography analysis Methods 0.000 description 27
- 238000000034 method Methods 0.000 description 27
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 27
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 25
- 125000001153 fluoro group Chemical group F* 0.000 description 25
- 229910052938 sodium sulfate Inorganic materials 0.000 description 25
- 235000011152 sodium sulphate Nutrition 0.000 description 25
- 239000007832 Na2SO4 Substances 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 239000000725 suspension Substances 0.000 description 24
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- 150000002431 hydrogen Chemical group 0.000 description 23
- 235000002639 sodium chloride Nutrition 0.000 description 23
- 230000005865 ionizing radiation Effects 0.000 description 22
- 238000001914 filtration Methods 0.000 description 21
- 238000002360 preparation method Methods 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 19
- 125000001072 heteroaryl group Chemical group 0.000 description 19
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 18
- 239000000543 intermediate Substances 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 16
- 125000001424 substituent group Chemical group 0.000 description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 15
- 239000012267 brine Substances 0.000 description 15
- 229910000029 sodium carbonate Inorganic materials 0.000 description 15
- 235000017550 sodium carbonate Nutrition 0.000 description 15
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 15
- 108010006124 DNA-Activated Protein Kinase Proteins 0.000 description 14
- 239000005909 Kieselgur Substances 0.000 description 14
- 239000002244 precipitate Substances 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 108020004414 DNA Proteins 0.000 description 13
- 102000005768 DNA-Activated Protein Kinase Human genes 0.000 description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 13
- 125000003118 aryl group Chemical group 0.000 description 13
- 239000012298 atmosphere Substances 0.000 description 13
- 238000001816 cooling Methods 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- 229910052736 halogen Inorganic materials 0.000 description 13
- 150000002367 halogens Chemical group 0.000 description 13
- 230000005764 inhibitory process Effects 0.000 description 13
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- 125000002757 morpholinyl group Chemical group 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 235000019198 oils Nutrition 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- 125000004429 atom Chemical group 0.000 description 11
- 239000010410 layer Substances 0.000 description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 239000003039 volatile agent Substances 0.000 description 11
- 125000004122 cyclic group Chemical group 0.000 description 10
- 125000000753 cycloalkyl group Chemical group 0.000 description 10
- 229910001873 dinitrogen Inorganic materials 0.000 description 10
- 239000002552 dosage form Substances 0.000 description 10
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- 239000000463 material Substances 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 125000003386 piperidinyl group Chemical group 0.000 description 10
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 10
- XJPZKYIHCLDXST-UHFFFAOYSA-N 4,6-dichloropyrimidine Chemical compound ClC1=CC(Cl)=NC=N1 XJPZKYIHCLDXST-UHFFFAOYSA-N 0.000 description 9
- 102100022204 DNA-dependent protein kinase catalytic subunit Human genes 0.000 description 9
- 101710157074 DNA-dependent protein kinase catalytic subunit Proteins 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 125000004193 piperazinyl group Chemical group 0.000 description 9
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- 210000001519 tissue Anatomy 0.000 description 9
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
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- 125000002393 azetidinyl group Chemical group 0.000 description 8
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 230000014759 maintenance of location Effects 0.000 description 8
- 125000003566 oxetanyl group Chemical group 0.000 description 8
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- 125000004433 nitrogen atom Chemical group N* 0.000 description 6
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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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US14/056,560 US9376448B2 (en) | 2012-04-24 | 2013-10-17 | DNA-PK inhibitors |
| US201314056560 | 2013-10-17 | ||
| PCT/US2014/061033 WO2015058031A1 (en) | 2013-10-17 | 2014-10-17 | Dna-pk inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2671354T3 true ES2671354T3 (es) | 2018-06-06 |
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|---|---|---|---|
| ES14800181.1T Active ES2671354T3 (es) | 2013-10-17 | 2014-10-17 | Inhibidores de ADN-PK |
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| CN104364239B (zh) | 2012-06-13 | 2017-08-25 | 霍夫曼-拉罗奇有限公司 | 二氮杂螺环烷烃和氮杂螺环烷烃 |
| ES2753163T3 (es) | 2012-09-25 | 2020-04-07 | Hoffmann La Roche | Derivados de hexahidropirrolo[3,4-c]pirrol y compuestos relacionados como inhibidores de la autotaxina (ATX) y como inhibidores de la producción de ácido lisofosfatídico (LPA) para tratar, por ejemplo, enfermedades renales |
| AR095079A1 (es) | 2013-03-12 | 2015-09-16 | Hoffmann La Roche | Derivados de octahidro-pirrolo[3,4-c]-pirrol y piridina-fenilo |
| CA2923523A1 (en) | 2013-11-26 | 2015-06-04 | F. Hoffmann-La Roche Ag | New octahydro-cyclobuta [1,2-c;3,4-c']dipyrrol-2-yl |
| SG11201607839UA (en) | 2014-03-26 | 2016-10-28 | Hoffmann La Roche | Bicyclic compounds as autotaxin (atx) and lysophosphatidic acid (lpa) production inhibitors |
| JP6554481B2 (ja) | 2014-03-26 | 2019-07-31 | エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ | オートタキシン（ａｔｘ）及びリゾホスファチジン酸（ｌｐａ）産生の阻害剤としての縮合［１，４］ジアゼピン化合物 |
| MA41898A (fr) | 2015-04-10 | 2018-02-13 | Hoffmann La Roche | Dérivés de quinazolinone bicyclique |
| CA2992889A1 (en) | 2015-09-04 | 2017-03-09 | F. Hoffmann-La Roche Ag | Phenoxymethyl derivatives |
| CA2983782A1 (en) | 2015-09-24 | 2017-03-30 | F. Hoffmann-La Roche Ag | Bicyclic compounds as atx inhibitors |
| WO2017050792A1 (en) | 2015-09-24 | 2017-03-30 | F. Hoffmann-La Roche Ag | Bicyclic compounds as atx inhibitors |
| EP3353181B1 (en) | 2015-09-24 | 2021-08-11 | F. Hoffmann-La Roche AG | Bicyclic compounds as dual atx/ca inhibitors |
| JP6877413B2 (ja) | 2015-09-24 | 2021-05-26 | エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ | 二重ａｔｘ／ｃａ阻害剤としての新規な二環式化合物 |
| CR20180323A (es) | 2015-11-20 | 2018-08-06 | Idorsia Pharmaceuticals Ltd | Derivados de indol n-sustituídos como moduladores de los receptores de pge2 |
| TW201815418A (zh) * | 2016-09-27 | 2018-05-01 | Vertex Pharma | 使用dna破壞劑及dna-pk抑制劑之組合治療癌症的方法 |
| KR20190129924A (ko) | 2017-03-16 | 2019-11-20 | 에프. 호프만-라 로슈 아게 | 이중 오토탁신(atx)/탄산 무수화효소(ca) 억제제로서 유용한 헤테로환형 화합물 |
| WO2018167113A1 (en) | 2017-03-16 | 2018-09-20 | F. Hoffmann-La Roche Ag | New bicyclic compounds as atx inhibitors |
| CA3063632A1 (en) | 2017-05-18 | 2018-11-22 | Idorsia Pharmaceuticals Ltd | Benzofurane and benzothiophene derivatives as pge2 receptor modulators |
| WO2018210994A1 (en) * | 2017-05-18 | 2018-11-22 | Idorsia Pharmaceuticals Ltd | Phenyl derivatives as pge2 receptor modulators |
| KR102626982B1 (ko) | 2017-05-18 | 2024-01-18 | 이도르시아 파마슈티컬스 리미티드 | Pge2 수용체 조절제로서의 피리미딘 유도체 |
| PE20191787A1 (es) | 2017-05-18 | 2019-12-24 | Idorsia Pharmaceuticals Ltd | Derivados de indol n-sustituidos |
| ES2896476T3 (es) * | 2017-05-18 | 2022-02-24 | Idorsia Pharmaceuticals Ltd | Derivados de pirimidina |
| JP2021503486A (ja) | 2017-11-20 | 2021-02-12 | アイカーン スクール オブ メディシン アット マウント サイナイ | キナーゼ阻害剤化合物ならびに組成物および使用法 |
| AU2019205944A1 (en) | 2018-01-05 | 2020-07-09 | Icahn School Of Medicine At Mount Sinai | Method of increasing proliferation of pancreatic beta cells, treatment method, and composition |
| EP3740483B1 (en) | 2018-01-17 | 2023-01-11 | Vertex Pharmaceuticals Incorporated | Quinoxalinone compounds, compositions, methods, and kits for increasing genome editing efficiency |
| JP7466448B2 (ja) | 2018-01-17 | 2024-04-12 | 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 | Ｄｎａ－ｐｋ阻害剤 |
| AU2019240065A1 (en) | 2018-03-20 | 2020-09-24 | Icahn School Of Medicine At Mount Sinai | Kinase inhibitor compounds and compositions and methods of use |
| WO2020142486A1 (en) * | 2018-12-31 | 2020-07-09 | Icahn School Of Medicine At Mount Sinai | Kinase inhibitor compounds and compositions and methods of use |
| CN112300126A (zh) * | 2019-07-31 | 2021-02-02 | 山东轩竹医药科技有限公司 | 杂环类dna-pk抑制剂 |
| CN112574211B (zh) * | 2019-09-29 | 2022-06-14 | 山东轩竹医药科技有限公司 | 杂环类激酶抑制剂 |
| CN112574179B (zh) * | 2019-09-29 | 2022-05-10 | 山东轩竹医药科技有限公司 | Dna-pk抑制剂 |
| CN113121574B (zh) * | 2019-12-31 | 2023-02-17 | 成都百裕制药股份有限公司 | 嘌呤衍生物及其在医药上的用途 |
| AU2024265078A1 (en) | 2023-05-04 | 2025-12-11 | Revolution Medicines, Inc. | Combination therapy for a ras related disease or disorder |
| US20250049810A1 (en) | 2023-08-07 | 2025-02-13 | Revolution Medicines, Inc. | Methods of treating a ras protein-related disease or disorder |
| WO2025080946A2 (en) | 2023-10-12 | 2025-04-17 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2025171296A1 (en) | 2024-02-09 | 2025-08-14 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2025217307A1 (en) | 2024-04-09 | 2025-10-16 | Revolution Medicines, Inc. | Methods for predicting response to a ras(on) inhibitor and combination therapies |
| WO2025229177A1 (en) | 2024-05-02 | 2025-11-06 | Idorsia Pharmaceuticals Ltd | Crystalline forms of an n-substituted indole derivative |
| WO2025240847A1 (en) | 2024-05-17 | 2025-11-20 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2025255438A1 (en) | 2024-06-07 | 2025-12-11 | Revolution Medicines, Inc. | Methods of treating a ras protein-related disease or disorder |
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| US7179912B2 (en) * | 2000-09-01 | 2007-02-20 | Icos Corporation | Materials and methods to potentiate cancer treatment |
| US8084457B2 (en) * | 2003-09-15 | 2011-12-27 | Lead Discovery Center Gmbh | Pharmaceutically active 4,6-disubstituted aminopyrimidine derivatives as modulators of protein kinases |
| EP1901747A2 (en) * | 2005-05-25 | 2008-03-26 | Ingenium Pharmaceuticals AG | Pyrimidine-based cdk inhibitors for treating pain |
| CN101522661A (zh) * | 2006-10-02 | 2009-09-02 | Irm责任有限公司 | 作为蛋白激酶抑制剂的化合物和组合物 |
| NZ601924A (en) * | 2010-03-10 | 2014-10-31 | Astrazeneca Ab | 4-phenyl pyridine analogues as protein kinase inhibitors |
| LT2841428T (lt) * | 2012-04-24 | 2018-12-10 | Vertex Pharmaceuticals Incorporated | Dnr-pk inhibitoriai |
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| CN105636958A (zh) | 2016-06-01 |
| HRP20180804T1 (hr) | 2018-08-10 |
| JP6374959B2 (ja) | 2018-08-15 |
| TR201807411T4 (tr) | 2018-06-21 |
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| PL3057959T3 (pl) | 2018-08-31 |
| BR112016008423A2 (cg-RX-API-DMAC7.html) | 2017-08-01 |
| HUE037516T2 (hu) | 2018-09-28 |
| EP3057959A1 (en) | 2016-08-24 |
| LT3057959T (lt) | 2018-06-11 |
| SI3057959T1 (en) | 2018-07-31 |
| WO2015058031A1 (en) | 2015-04-23 |
| AU2014337208B2 (en) | 2018-05-24 |
| JP2016533366A (ja) | 2016-10-27 |
| DK3057959T3 (en) | 2018-06-06 |
| BR112016008423B1 (pt) | 2022-02-22 |
| RS57306B1 (sr) | 2018-08-31 |
| CN105636958B (zh) | 2018-01-05 |
| CA2927392A1 (en) | 2015-04-23 |
| EP3057959B1 (en) | 2018-02-28 |
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