ES2616458T3 - Pirimidil pirroles sustituidos activos como inhibidores de quinasas - Google Patents
Pirimidil pirroles sustituidos activos como inhibidores de quinasas Download PDFInfo
- Publication number
- ES2616458T3 ES2616458T3 ES12711904.8T ES12711904T ES2616458T3 ES 2616458 T3 ES2616458 T3 ES 2616458T3 ES 12711904 T ES12711904 T ES 12711904T ES 2616458 T3 ES2616458 T3 ES 2616458T3
- Authority
- ES
- Spain
- Prior art keywords
- aminopyrimidin
- carboxamide
- chloro
- pyrrole
- phenyl
- 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.)
- Active
Links
- -1 pyrimidyl pyrroles Chemical class 0.000 title abstract 4
- 229940043355 kinase inhibitor Drugs 0.000 title 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 abstract description 5
- WIVPUMFEYLUDQN-UHFFFAOYSA-N 5-(2-aminopyrimidin-4-yl)-2-(2-chloro-5-ethylphenyl)-1h-pyrrole-3-carboxamide Chemical compound CCC1=CC=C(Cl)C(C2=C(C=C(N2)C=2N=C(N)N=CC=2)C(N)=O)=C1 WIVPUMFEYLUDQN-UHFFFAOYSA-N 0.000 abstract description 2
- GJWYRBQDZYWGDV-UHFFFAOYSA-N 5-(2-aminopyrimidin-4-yl)-2-(5-chloro-2-ethylphenyl)-1h-pyrrole-3-carboxamide Chemical compound CCC1=CC=C(Cl)C=C1C1=C(C(N)=O)C=C(C=2N=C(N)N=CC=2)N1 GJWYRBQDZYWGDV-UHFFFAOYSA-N 0.000 abstract description 2
- KMWLMMWKLAILOY-UHFFFAOYSA-N 5-(2-aminopyrimidin-4-yl)-2-(5-chloro-2-propan-2-ylphenyl)-1h-pyrrole-3-carboxamide Chemical compound CC(C)C1=CC=C(Cl)C=C1C1=C(C(N)=O)C=C(C=2N=C(N)N=CC=2)N1 KMWLMMWKLAILOY-UHFFFAOYSA-N 0.000 abstract description 2
- MOMYBDKTKLWNMV-UHFFFAOYSA-N 5-(2-aminopyrimidin-4-yl)-2-[2,5-bis(trifluoromethyl)phenyl]-1h-pyrrole-3-carboxamide Chemical compound NC(=O)C=1C=C(C=2N=C(N)N=CC=2)NC=1C1=CC(C(F)(F)F)=CC=C1C(F)(F)F MOMYBDKTKLWNMV-UHFFFAOYSA-N 0.000 abstract description 2
- LNLCSFSRFGZNPP-UHFFFAOYSA-N 5-(2-aminopyrimidin-4-yl)-2-[2-chloro-5-(hydroxymethyl)phenyl]-1h-pyrrole-3-carboxamide Chemical compound NC(=O)C=1C=C(C=2N=C(N)N=CC=2)NC=1C1=CC(CO)=CC=C1Cl LNLCSFSRFGZNPP-UHFFFAOYSA-N 0.000 abstract description 2
- DBTPIYXNTFESLE-UHFFFAOYSA-N 5-(2-aminopyrimidin-4-yl)-2-[2-ethyl-5-(trifluoromethyl)phenyl]-1h-pyrrole-3-carboxamide Chemical compound CCC1=CC=C(C(F)(F)F)C=C1C1=C(C(N)=O)C=C(C=2N=C(N)N=CC=2)N1 DBTPIYXNTFESLE-UHFFFAOYSA-N 0.000 abstract description 2
- FWVOSTMZZQGURQ-UHFFFAOYSA-N 5-(2-aminopyrimidin-4-yl)-2-[5-chloro-2-(trifluoromethyl)phenyl]-1h-pyrrole-3-carboxamide Chemical compound NC(=O)C=1C=C(C=2N=C(N)N=CC=2)NC=1C1=CC(Cl)=CC=C1C(F)(F)F FWVOSTMZZQGURQ-UHFFFAOYSA-N 0.000 abstract description 2
- MIEONHFLSVAHFB-UHFFFAOYSA-N 5-(2-aminopyrimidin-4-yl)-2-(2,5-dichlorophenyl)-1h-pyrrole-3-carboxamide Chemical compound NC(=O)C=1C=C(C=2N=C(N)N=CC=2)NC=1C1=CC(Cl)=CC=C1Cl MIEONHFLSVAHFB-UHFFFAOYSA-N 0.000 abstract 1
- CUQICKMLWKMIKB-UHFFFAOYSA-N 5-(2-aminopyrimidin-4-yl)-2-(5-chloro-2-ethylphenyl)-n,n-dimethyl-1h-pyrrole-3-carboxamide Chemical compound CCC1=CC=C(Cl)C=C1C1=C(C(=O)N(C)C)C=C(C=2N=C(N)N=CC=2)N1 CUQICKMLWKMIKB-UHFFFAOYSA-N 0.000 abstract 1
- VKIAXIXFWORXFB-UHFFFAOYSA-N 5-(2-aminopyrimidin-4-yl)-2-(5-chloro-2-ethylphenyl)-n-methyl-1h-pyrrole-3-carboxamide Chemical compound CCC1=CC=C(Cl)C=C1C1=C(C(=O)NC)C=C(C=2N=C(N)N=CC=2)N1 VKIAXIXFWORXFB-UHFFFAOYSA-N 0.000 abstract 1
- CZUQYAXYBOEHCY-UHFFFAOYSA-N 5-(2-aminopyrimidin-4-yl)-2-[2-chloro-5-(trifluoromethyl)phenyl]-1h-pyrrole-3-carboxamide Chemical compound NC(=O)C=1C=C(C=2N=C(N)N=CC=2)NC=1C1=CC(C(F)(F)F)=CC=C1Cl CZUQYAXYBOEHCY-UHFFFAOYSA-N 0.000 abstract 1
- BRIIWIAIUSRCEY-UHFFFAOYSA-N 5-(2-aminopyrimidin-4-yl)-2-[2-chloro-5-(trifluoromethyl)phenyl]-n-methyl-1h-pyrrole-3-carboxamide Chemical compound CNC(=O)C=1C=C(C=2N=C(N)N=CC=2)NC=1C1=CC(C(F)(F)F)=CC=C1Cl BRIIWIAIUSRCEY-UHFFFAOYSA-N 0.000 abstract 1
- JTCAMVAHTMGGBT-UHFFFAOYSA-N 5-(2-aminopyrimidin-4-yl)-2-[2-ethyl-5-(trifluoromethyl)phenyl]-n-methyl-1h-pyrrole-3-carboxamide Chemical compound CCC1=CC=C(C(F)(F)F)C=C1C1=C(C(=O)NC)C=C(C=2N=C(N)N=CC=2)N1 JTCAMVAHTMGGBT-UHFFFAOYSA-N 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 42
- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- TZJNZKZMCLOBOP-UHFFFAOYSA-N 4-chloro-2-iodo-1-propan-2-ylbenzene Chemical compound CC(C)C1=CC=C(Cl)C=C1I TZJNZKZMCLOBOP-UHFFFAOYSA-N 0.000 description 2
- CCLXEGFPYVJSPA-UHFFFAOYSA-N 5-chloro-2-propan-2-ylaniline Chemical compound CC(C)C1=CC=C(Cl)C=C1N CCLXEGFPYVJSPA-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- YHBPFOZIKPNYEI-UHFFFAOYSA-N [2-ethyl-5-(trifluoromethyl)phenyl]boronic acid Chemical compound CCC1=CC=C(C(F)(F)F)C=C1B(O)O YHBPFOZIKPNYEI-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 2
- 235000010288 sodium nitrite Nutrition 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- XINQFOMFQFGGCQ-UHFFFAOYSA-L (2-dodecoxy-2-oxoethyl)-[6-[(2-dodecoxy-2-oxoethyl)-dimethylazaniumyl]hexyl]-dimethylazanium;dichloride Chemical compound [Cl-].[Cl-].CCCCCCCCCCCCOC(=O)C[N+](C)(C)CCCCCC[N+](C)(C)CC(=O)OCCCCCCCCCCCC XINQFOMFQFGGCQ-UHFFFAOYSA-L 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- ONQVHNSLTUHFTN-UHFFFAOYSA-N (5-chloro-2-propan-2-ylphenyl)boronic acid Chemical compound CC(C)C1=CC=C(Cl)C=C1B(O)O ONQVHNSLTUHFTN-UHFFFAOYSA-N 0.000 description 1
- CEWDRCQPGANDRS-UHFFFAOYSA-N 1-ethenyl-4-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=C(C=C)C=C1 CEWDRCQPGANDRS-UHFFFAOYSA-N 0.000 description 1
- RZKOZYMLAGQISR-UHFFFAOYSA-N 1-ethyl-2-iodo-4-(trifluoromethyl)benzene Chemical compound CCC1=CC=C(C(F)(F)F)C=C1I RZKOZYMLAGQISR-UHFFFAOYSA-N 0.000 description 1
- IHHXYTIKYUHTQU-UHFFFAOYSA-N 1-ethyl-4-(trifluoromethyl)benzene Chemical compound CCC1=CC=C(C(F)(F)F)C=C1 IHHXYTIKYUHTQU-UHFFFAOYSA-N 0.000 description 1
- NTAJMBAZJSEPHL-UHFFFAOYSA-N 3-nitro-4-propan-2-ylaniline Chemical compound CC(C)C1=CC=C(N)C=C1[N+]([O-])=O NTAJMBAZJSEPHL-UHFFFAOYSA-N 0.000 description 1
- AOTRFBGCYAXAPY-UHFFFAOYSA-N 4-chloro-2-nitro-1-propan-2-ylbenzene Chemical compound CC(C)C1=CC=C(Cl)C=C1[N+]([O-])=O AOTRFBGCYAXAPY-UHFFFAOYSA-N 0.000 description 1
- OVEPNDUIJPTNEM-UHFFFAOYSA-N 5-(2-aminopyrimidin-4-yl)-2-(2-chloro-5-cyanophenyl)-1h-pyrrole-3-carboxamide Chemical compound NC(=O)C=1C=C(C=2N=C(N)N=CC=2)NC=1C1=CC(C#N)=CC=C1Cl OVEPNDUIJPTNEM-UHFFFAOYSA-N 0.000 description 1
- MEUXPZAVSXUFCT-UHFFFAOYSA-N 5-(2-aminopyrimidin-4-yl)-2-(2-chloro-5-methoxyphenyl)-1h-pyrrole-3-carboxamide Chemical compound COC1=CC=C(Cl)C(C2=C(C=C(N2)C=2N=C(N)N=CC=2)C(N)=O)=C1 MEUXPZAVSXUFCT-UHFFFAOYSA-N 0.000 description 1
- MDONDWLCISBSBA-UHFFFAOYSA-N 5-(2-aminopyrimidin-4-yl)-2-(2-chloro-5-methylphenyl)-1h-pyrrole-3-carboxamide Chemical compound CC1=CC=C(Cl)C(C2=C(C=C(N2)C=2N=C(N)N=CC=2)C(N)=O)=C1 MDONDWLCISBSBA-UHFFFAOYSA-N 0.000 description 1
- WYZSMYOLNHLHHE-UHFFFAOYSA-N 5-(2-aminopyrimidin-4-yl)-2-(5-bromo-2-fluorophenyl)-1h-pyrrole-3-carboxamide Chemical compound NC(=O)C=1C=C(C=2N=C(N)N=CC=2)NC=1C1=CC(Br)=CC=C1F WYZSMYOLNHLHHE-UHFFFAOYSA-N 0.000 description 1
- ZTRQFNINWJXNEQ-UHFFFAOYSA-N 5-(2-aminopyrimidin-4-yl)-2-(5-bromo-2-methoxyphenyl)-1h-pyrrole-3-carboxamide Chemical compound COC1=CC=C(Br)C=C1C1=C(C(N)=O)C=C(C=2N=C(N)N=CC=2)N1 ZTRQFNINWJXNEQ-UHFFFAOYSA-N 0.000 description 1
- BFOWVKRAGHVYJA-UHFFFAOYSA-N 5-(2-aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-n-methyl-1h-pyrrole-3-carboxamide Chemical compound CNC(=O)C=1C=C(C=2N=C(N)N=CC=2)NC=1C1=CC(Cl)=CC=C1C BFOWVKRAGHVYJA-UHFFFAOYSA-N 0.000 description 1
- LIJKTJFYXDIILH-UHFFFAOYSA-N 5-(2-aminopyrimidin-4-yl)-2-(5-cyano-2-methylphenyl)-1h-pyrrole-3-carboxamide Chemical compound CC1=CC=C(C#N)C=C1C1=C(C(N)=O)C=C(C=2N=C(N)N=CC=2)N1 LIJKTJFYXDIILH-UHFFFAOYSA-N 0.000 description 1
- IVXPIHCWBHLFEM-UHFFFAOYSA-N 5-(2-aminopyrimidin-4-yl)-2-[2-chloro-5-(trifluoromethoxy)phenyl]-1h-pyrrole-3-carboxamide Chemical compound NC(=O)C=1C=C(C=2N=C(N)N=CC=2)NC=1C1=CC(OC(F)(F)F)=CC=C1Cl IVXPIHCWBHLFEM-UHFFFAOYSA-N 0.000 description 1
- BOOUSDCCWQVKID-UHFFFAOYSA-N 5-(2-aminopyrimidin-4-yl)-2-[2-methyl-5-(trifluoromethyl)phenyl]-1h-pyrrole-3-carboxamide Chemical compound CC1=CC=C(C(F)(F)F)C=C1C1=C(C(N)=O)C=C(C=2N=C(N)N=CC=2)N1 BOOUSDCCWQVKID-UHFFFAOYSA-N 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- 241001572347 Lycaena hermes Species 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical group O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 1
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic 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
- 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
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- 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
- C07D403/04—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 directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Un compuesto, o una sal farmacéuticamente aceptable de este, que se selecciona del grupo que consiste en: 5-(2-Aminopirimidin-4-il)-2-[2-cloro-5-(trifluorometil)fenil]-1H-pirrol-3-carboxamida, 5-(2-Aminopirimidin-4-il)-2-(2,5-diclorofenil)-1H-pirrole-3-carboxamida, 5-(2-Aminopirimidin-4-il)-2-(2-cloro-5-etilfenil)-1H-pirrol-3-carboxamida, 5-(2-Aminopirimidin-4-il)-2-(5-cloro-2-etilfenil)-1H-pirrole-3-carboxamida, 5-(2-Aminopirimidin-4-il)-2-[2-cloro-5-(hidroximetil)fenil]-1H-pirrol-3-carboxamida, 5-(2-Aminopirimidin-4-il)-2-[5-cloro-2-(propan-2-il)fenil]-1H-pirrol-3-carboxamida, 5-(2-Aminopirimidin-4-il)-2-[2,5-bis(trifluorometil)fenil]-1H-pirrol-3-carboxamida, 5-(2-Aminopirimidin-4-il)-2-[2-etil-5-(trifluorometil)fenil]-1H-pirrol-3-carboxamida, 5-(2-Aminopirimidin-4-il)-2-[5-cloro-2-(trifluorometil)fenil]-1H-pirrol-3-carboxamida, 5-(2-Aminopirimidin-4-il)-2-(5-cloro-2-etilfenil)-N-metil-1H-pirrole-3-carboxamida, 5-(2-Aminopirimidin-4-il)-2-(5-cloro-2-etilfenil)-N-etil-1H-prrol-3-carboxamida, 5-(2-aminopirimidin-4-il)-(5-cloro-2-etilfenil)-N-(2-h droxietil)-1H-pirrol-3-carboxamida, 5-(2-Aminopirimidin-4-il)-2-(5-cloro-2-etilfenil)-N,N-dimethyl-1H-pyrrole-3-carboxamide, 5-(2-Aminopirimidin-4-il)-2-[2-cloro-5-(trifluorometil)fenil]-N-metil-1H-pirrol-3-carboxamida, y 5-(2-Aminopirimidin-4-il)-2-[2-etil-5-(trifluorometil)fenil]-N-metil-1H-pirrol-3-carboxamida.
Description
Se añadió gota a gota una solución de nitrito de sodio en agua (3,6 g, 52,2 mmol, 5 M, 10,4 mL) a una solución de 3nitro-4-(propan-2-il)anilina (9,4 g, 52,2 mmol ) en HCl conc. (175 mL) a 0 °C y la mezcla de reacción se agitó a la misma temperatura durante 1,5 h. Se añadió después cloruro de cobre (I) (8,3 g, 83,5 mmol) y la solución se agitó a
5 temperatura ambiente durante 1 h y después a 80 °C durante una hora adicional. Después de enfriar la mezcla de reacción se extrajo con DCM (3 x 100 mL) y las capas orgánicas combinadas se secaron sobre sulfato de sodio. El crudo se purificó después por cromatografía ultrarrápida (hexano/EtOAc 95/5) para obtener el compuesto del título en forma de aceite amarillo (1,8 g, 17 %).1H NMR (400 MHz, DMSO-d6) δ ppm 1,23 (d, J=6,84 Hz, 6 H), 3,14 (spt, J=6,94 Hz, 1 H), 7,67 (d, J=8,54 Hz, 1 H), 7,74 (dd, J=8,54, 2,30 Hz, 1 H), 7,95 (d, J=2,20 Hz, 1 H).
Etapa 3: 5-Cloro-2-(propan-2-il)anilina
Se añadió gota a gota una solución de hidrato de hidrazina (1,7 mL, 35,1 mmoles) en metanol (12 mL) a una
15 solución de 4-cloro-2-nitro-1-(propan-2-il)benceno (1,75 g, 8,8 mmol) en metanol (40 mL), en presencia de cloruro de hierro (III) (146 mg, 0,9 mmol) y carbón activado (146 mg) y la mezcla de reacción se agitó bajo reflujo durante 7 h. El sólido se filtró sobre celita, el filtrado se concentró y se purificó por cromatografía ultrarrápida (hexano/EtOAc 9/1) para obtener el compuesto del título en forma de un aceite de color rosa claro (1,4 g, 94 %).1H NMR (400 MHz, DMSO-d6) δ ppm 1,11 (d, J=6,84 Hz, 6 H), 2,90 (spt, J=6,75 Hz, 1 H), 5,15 (s, 2 H), 6,50 (dd, J=8,18, 2,32 Hz, 1 H), 6,62 (d, J=2,32 Hz, 1 H), 6,96 (d, J=8,18 Hz, 1 H).
Etapa 4: 4-Cloro-2-yodo-1-(propan-2-il)benceno
Se molió en un mortero una mezcla de 5-cloro-2-(propan-2-il)anilina (1,4 g, 8,3 mmol), ácido p-toluensulfónico (4,7 g,
25 24,8 mmol) y agua (0,83 mmol) durante unos minutos, para obtener una pasta homogénea a la que se añadió nitrito de sodio sólido (1,42 g, 20,6 mmol) y la pasta se molió durante 10 min. Se añadió yoduro de potasio sólido (3,42 g, 20,6 mmol) y la pasta se molió durante 20 min. La pasta se disolvió a continuación en agua (20 mL) y se trató con sulfito de sodio (solución acuosa al 10 %), antes de extraer con EtOAc (3 x 50 mL). Las capas orgánicas combinadas se secaron sobre sulfato de sodio y el producto bruto se purificó por cromatografía ultrarrápida (hexano) para obtener el compuesto del título en forma de un aceite amarillo claro (1,79 g, 77 %).1H NMR (400 MHz, DMSO-d6) δ ppm 1,17 (d, J=6,84 Hz, 6 H), 3,08 (spt, J=6,88 Hz, 1 H), 7,33 (d, J=8,42 Hz, 1 H), 7,45 (ddd, J=8,42, 2,20, 0,37 Hz, 1 H), 7,87 (d, J=2,20 Hz, 1 H). Etapa 5: Ácido [5-cloro-2-(propan-2-il)fenil]borónico
35 Se añadió gota a gota cloruro de i-propilmagnesio (2 M en THF, 3,34 mL, 6,7 mmoles) a una solución de 4-cloro-2yodo-1-(propan-2-il)benceno (1,7g, 6,7 mmol) en THF seco (15 mL) a -30 °C y la mezcla de reacción se agitó a la misma temperatura durante 30 min, bajo argón. Después de este tiempo, se añadió gota a gota trimetilborato (1,35 mL, 12,1 mmol) y la mezcla de reacción se agitó a la misma temperatura durante 1,5 horas. Se añadió HCl (1 M, 6 mL) y la mezcla de reacción se extrajo con EtOAc (3 x 20 mL). Las capas orgánicas combinadas se secaron sobre sulfato de sodio y, después de la eliminación del disolvente, se obtuvo un sólido, que se trituró con hexano para obtener el compuesto del título en forma de un sólido blanco (1,05 g, 87 %).1H NMR (400 MHz, DMSO-d6) δ ppm 1,16 (d, J=6,84 Hz, 6 H), 3,17-3,25 (m, 1 H), 7,24-7,29 (m, 2 H), 7,29-7,33 (m, 1 H), 8,22 (s, 2 H).
45 Preparación C
Ácido [2-etil-5-(trifluorometil)fenil]borónico (IIIa)
Etapa 1: 1-Etil-4-(trifluorometil)benceno
Se agitó una solución de 1-etenil-4-(trifluorometil)benceno (1,72 ml, 11,6 mmol) en THF (60 mL) en presencia de Pd/C (10 %, 400 mg), bajo una atmósfera de hidrógeno (45 psi) durante 7 h. El sólido se filtró a través de celita (se
55 lavó con DCM) y el filtrado se concentró cuidadosamente, mientras se mantenía la temperatura del baño por debajo de 20 °C a 200 mmHg. La solución concentrada que se obtuvo de esta manera se usó en la siguiente etapa sin manipulación adicional.1H NMR (400 MHz, DMSO-d6) δ ppm 1,20 (t, J=7,63 Hz, 3 H), 2,70 (q, J=7,16 Hz, 2 H), 7,44 (d, J=7,93 Hz, 2 H), 7,63 (d, J=7,93 Hz, 2 H).
Etapa 2: 2-yodo-1-etil-4-(trifluorometil)benceno
18
[(I), R1 = OCH3, R2 = Cl, R3 = R4 = NH2, R12 = H] (compd. 3)
1H NMR (400 MHz, DMSO-d6) δ ppm 3,75 (s, 3 H) 6,35 (bs, 2 H) 6,74 (bs, 1 H) 6,92 (d, J=5,25 Hz, 1 H) 7,08 -7,12 (m, 1H)7,20 (bs, 1 H) 7,25 (d, J=2,56 Hz, 1 H) 7,36 -7,41 (m, 2 H) 8,19 (d, J=5,25 Hz, 1 H) 11,63 (bs, 1 H). 5 HRMS (ESI) calcd for C16H14CIN5O2 + H+ 344,0909, found 344,0912.
5-(2-Aminopirimidin-4-il)-2-(2-cloro-5-etilfenil)-1H-pirrol-3-carboxamida [(I), R1 = Cl, R2 = CH2CH3, R3 = R4 = NH2, R12 = H] (compd. 4)
10 1H NMR (400 MHz, DMSO-d6) δ ppm 1,20 (t, J=7,57 Hz, 3 H) 2,63 (q, J=7,57 Hz, 2 H) 6,33 (bs, 2 H) 6,69 (bs, 1 H) 6,93 (d, J=5,25 Hz, 1 H) 7,14 (bs, 1 H) 7,27 (d, J=2,20 Hz, 1 H) 7,26 (dd, J=7,90, 2,20 Hz, 1 H) 7,32 (d, J=2,56 Hz, 2 H) 7,40 (dd, J=7,81, 0,49 Hz, 1 H) 8,19 (d, J=5,25 Hz, 1 H) 11,87 (bs, 1 H). HRMS (ESI) calcd para C17H16ClN5O + H+ 342,1116, encontrada 342,1120.
15 5-(2-Aminopirimidin-4-il)-2-(5-cloro-2-etilfenil)-1H-pirrol-3-carboxamida [(I),R1 = CH2CH3, R2 = Cl, R3 = R4 = NH2, R12 = H] (compd. 5)
1H NMR (400 MHz, DMSO-d6) δ ppm 0,97 (t, J=7,57 Hz, 3 H) 2,41 -2,49 (m, 2 H) 6,32 (bs, 2 H) 6,71 (bs, 1 H) 6,92 (d, J=5,25 Hz, 1 H) 7,16 (bs, 1 H) 7,25 (d, J=2,20 Hz, 1 H) 7,30 -7,33 (m, 1 H) 7,34 (d, J=2,69 Hz, 1 H) 7,37 -7,46 20 (m, 1 H) 8,19 (d, J=5,25 Hz, 1 H) 11,87 (bs, 1 H). HRMS (ESI) calcd para C17H16ClN5O + H+ 342,1116, encontrada 342,1111.
5-(2-Aminopirimidin-4-il)-2-(2-cloro-5-metilfenil)-1H-pirrol-3-carboxamida [(I), R1 = Cl, R2 = CH3, R3 = R4 = NH2, R12 = H] (compd. 6)
25 1H NMR (400 MHz, DMSO-d6) δ ppm 2,32 (s, 3 H) 6,33 (bs, 2 H) 6,68 (bs, 1 H) 6,93 (d, J=5,25 Hz, 1 H) 7,14 (bs, 1 H) 7,20 -7,24 (m, 1 H) 7,25 (dq, J=2,20, 0,60 Hz, 1 H) 7,31 (d, J=2,56 Hz, 1 H) 7,38 (d, J=8,18 Hz, 1 H) 8,19 (d, J=5,25 Hz, 1 H) 11,85 (bs, 1 H). HRMS (ESI) calcd para C16H14ClN5O + H+ 328,0960, encontrada 328,0965.
30 5-(2-Aminopirimidin-4-il)-2-(2-cloro-5-cianofenil)-1H-pirrol-3-carboxamida [(I), R1 = Cl, R2 = CN, R3 = R4 = NH2, R12 = H] (compd. 7)
1H NMR (400 MHz, DMSO-d6) δ ppm 6,42 (bs, 2 H) 6,79 (bs, 1 H) 6,90 (d, J=5,25 Hz, 1 H) 7,38 (d, J=2,56 Hz, 1 H)
35 7,44 (bs, 1 H) 7,73 (d, J=8,42 Hz, 1 H) 7,88 (dd, J=8,42, 2,07 Hz, 1 H) 7,94 (d, J=2,07 Hz, 1 H) 8,23 (d, J=5,37 Hz, 1 H) 12,07 (bs, 1 H). HRMS (ESI) calcd para C16H11ClN6O + H+ 339,0756, encontrada 339,0761.
5-(2-Aminopirimidin-4-il)-2-(5-bromo-2-metoxifenil)-1H-pirrol-3-carboxamida 40 [(I), R1 = OCH3, R2 = Br, R3 = R4 = NH2, R12 = H] (compd. 8)
1H NMR (400 MHz, DMSO-d6) δ ppm 3,74 (s, 3 H) 6,36 (bs, 2 H) 6,86 (bs, 1H) 7,07 (d, J=8,91 Hz, 1 H) 7,14 (d, J=6,23 Hz, 1 H) 7,29 (bs, 1 H) 7,47 (d, J=2,44 Hz, 1 H) 7,51 (d, J=2,56 Hz, 1 H) 7,55 (dd, J=8,79, 2,56 Hz, 1 H) 8,23 (d, J=6,23 Hz, 1 H) 12,05 (bs, 1 H).
45 HRMS (ESI) calcd para C16H14BrN5O2 + H+ 388,0404, encontrada 388,0410.
5-(2-Aminopirimidin-4-il)-2-(5-bromo-2-fluorofenil)-1H-pirrol-3-carboxamida [(I), R1 = F, R2 = Br, R3 = R4= NH2, R12 = H](compd. 9)
50 1H NMR (400 MHz, DMSO-d6) δ ppm 6,46 (bs, 2 H) 6,91 (bs, 1 H) 7,11 (d, J=6,10 Hz, 1 H) 7,25 (dd, J=9,46, 8,97 Hz, 1 H) 7,33 (bs, 1 H) 7,51 (d, J=2,32 Hz, 2 H) 7,63 (ddd, J=8,76, 4,49, 2,62 Hz, 1 H) 7,69 (dd, J=6,47, 2,56 Hz, 1 H) 8,27 (d, J=5,98 Hz, 1 H) 12,31 (bs, 1 H). HRMS (ESI) calcd para C15H11BrFN5O + H+ 376,0204, encontrada 376,0209.
55 5-(2-Aminopirimidin-4-il)-2-[2-cloro-5-(hidroximetil)fenil]-1H-pirrol-3-carboxamida [(I), R1 = Cl, R2 = CH2OH, R3 = R4 = NH2, R12 = H] (compd. 10)
1H NMR (400 MHz, DMSO-d6) δ ppm 4,53 (d, J=5,74 Hz, 2 H) 5,33 (t, J=5,68 Hz, 1 H) 6,33 (bs, 2 H) 6,68 (bs, 1 H) 6,93 (d, J=5,25 Hz, 1 H) 7,15 (bs, 1 H) 7,32 (d, J=2,56 Hz, 1 H) 7,33 -7,37 (m, 2 H) 7,45 (d, J=8,80 Hz, 1 H) 8,19 60 (d, J=5,25 Hz, 1 H) 11,88 (bs, 1 H). HRMS (ESI) calcd para C16H14ClN5O2 + H+ 344,0909, encontrada 344,0902.
5-(2-Aminopirimidin-4-il)-2-(2-cloro-5-metoxifenil)-1H-pirrol-3-carboxamida [(I), R1 = Cl, R2 = OCH3, R3 = R4 = NH2, R12 = H] (compd,11) 65
24
1H NMR (400 MHz, DMSO-d6) δ ppm 3,78 (s, 3 H) 6,33 (s, 2 H) 6,70 (bs, 1 H) 6,93 (d, J=5,25 Hz, 1 H) 6,97 -7,02 (m, 2 H) 7,15 (bs, 1 H) 7,31 (d, J=2,56 Hz, 1 H) 7,36 -7,42 (m, 1 H) 8,19 (d, J=5,25 Hz, 1 H) 11,88 (bs, 1 H). HRMS (ESI) calcd para C1sH14ClN5O2 + H+ 344,0909, encontrada 344,0907.
5 5-(2-Aminopirimidin-4-il)-2-[2-cloro-5-(trifluorometoxi)fenil]-1H-pirrol-3-carboxamida [(I), R1 = Cl, R2 = OCF3, R3 = R4 = NH2, R12 = H] (compd. 12)
1H NMR (400 MHz, DMSO-d6) δ ppm 6,35 (bs, 2 H) 6,76 (bs, 1 H) 6,90 (d, J=5,13 Hz, 1 H) 7,35 (d, J=2,56 Hz, 1 H) 7,39 (bs, 1 H) 7,41 -7,46 (m, 1 H) 7,42 (dq, J=1,74, 0,90 Hz, 1 H) 7,64 (ddd, J=8,79, 1,46, 1,10 Hz, 1 H) 8,21 10 (d, J=5,25 Hz, 1 H) 12,04 (bs, 1 H). HRMS (ESI) calcd para C16H11ClF3N5O2 + H+ 398,0626, encontrada 398,0624.
5-(2-Aminopirimidin-4-il)-2-[2-metil-5-(trifluorometil)fenil]-1H-pirrol-3-carboxamida [(I), R1 = CH3, R2 = CF3, R3 = R4 = NH2, R12 = H] (compd. 13)
15 1H NMR (400 MHz, DMSO-d6) δ ppm 2,23 (s, 3 H) 6,32 (bs, 2 H) 6,74 (bs, 1 H) 6,92 (d, J=5,25 Hz, 1 H) 7,32 (bs, 1 H) 7,37 (d, J=2,44 Hz, 1 H) 7,49 (d, J=8,06 Hz, 1 H) 7,53 (d, J=1,46 Hz, 1 H) 7,64 (dd, J=8,06, 1,46 Hz, 1 H) 8,20 (d, J=5,25 Hz, 1 H) 11,91 (bs, 1 H). HRMS (ESI) calcd para C17H14F3N5O + H+ 362,1223, encontrada 362,1225.
20 5-(2-Aminopirimidin-4-il)-2-[5-cloro-2-(propan-2-il)fenil]-1H-pirrol-3-carboxamida [(I), R1 = CH(CH3)2, R2 = Cl, R3 = R4 = NH2, R12 = H] (compd. 14)
1H NMR (400 MHz, DMSO-d6) δ ppm 1,06 (d, J=6,84 Hz, 6 H) 2,79 (spt, J=6,90 Hz, 1 H) 6,32 (bs, 2 H) 6,71 (bs, 1 H) 6,91 (d, J=5,25 Hz, 1 H) 7,11 (bs, 1 H) 7,21 (d, J=2,32 Hz, 1 H) 7,34 (d, J=2,69 Hz, 1 H) 7,38 (d, J=8,30 Hz, 1 H) 7,44 25 (dd, J=8,30, 2,32 Hz, 1 H) 8,18 (d, J=5,25 Hz, 1 H) 11,89 (bs, 1 H). HRMS (ESI) calcd para C18H18ClN5O + H+ 356,1273, encontrada 356,1271.
5-(2-Aminopirimidin-4-il)-2-[2,5-bis(trifluorometil)fenil]-1H-pirrol-3-carboxamida [(I), R1 = CF3, R2 = CF3, R3 = R4 = NH2, R12 = H] (compd. 15)
30 1H NMR (400 MHz, DMSO-d6) δ ppm 6,34 (bs, 2 H) 6,69 (bs, 1 H) 6,85 (d, J=5,25 Hz, 1 H) 7,37 (d, J=2,44 Hz, 1 H) 7,40 (bs, 1 H) 7,79 (bs, 1 H) 8,0 -8,06 (m, 2 H) 8,21 (d, J=5,25 Hz, 1 H) 12,08 (bs, 1 H). HRMS (ESI) calcd para C17H11F6ClN5O + H+416,0941, encontrada 416,0945.
35 5-(2-Aminopirimidin-4-il)-2-[2-etil-5-(trifluorometil)fenil]-1H-pirrol-3-carboxamida [(I), R1 = CH2CH3, R2 = CF3, R3 = R4 = NH2, R12 = H] (compd. 16)
1H NMR (400 MHz, DMSO-d6) δ ppm 1,02 (t, J=7,55 Hz, 3 H) 2,57 (q, J=7,60 Hz, 4 H) 6,37 (bs, 2 H) 6,76 (bs, 1 H) 6,92 (d, J=5,49 Hz, 1 H) 7,33 (bs, 1 H) 7,38 (d, J=2,47 Hz, 1 H) 7,47 -7,57 (m, 2 H) 7,70 (d, J=7,14 Hz, 1 H) 8,21 40 (d, J=5,22 Hz, 1 H) 11,97 (bs, 1 H). HRMS (ESI) calcd para C18H16F3N5O + H+ 376,138, encontrada 376,1384.
5-(2-Aminopirimidin-4-il)-2-[5-cloro-2-(trifluorometil)fenil]-1H-pirrol-3-carboxamida [(I), R1 = CF3, R2 = Cl, R3 = R4 = NH2, R12 = H] (compd. 17)
45 1H NMR (400 MHz, DMSO-d6) δ ppm 6,36 (bs, 2 H) 6,68 (bs, 1 H) 6,86 (d, J=5,25 Hz, 1 H) 7,34 (bs, 1 H) 7,35 (d, J=2,56 Hz, 1 H) 7,54 (d, J=1,95 Hz, 1 H) 7,70 (dd, J=8,48, 1,40 Hz, 1 H) 7,80 (d, J=8,54 Hz, 1 H) 7,95 (s, 1 H) 8,21 (d, J=5,37 Hz, 1 H) 12,03 (bs, 1 H). HRMS (ESI) calcd para C16H11ClF3N5O + H+ 382,0677, encontrada 382,0679.
50 5-(2-Aminopirimidin-4-il)-2-(5-ciano-2-metilfenil)-1H-pirrol-3-carboxamide [(I), R1 = CH3, R2 = CN, R3 = R4 = NH2, R12 = H] (compd. 18)
1H NMR (400 MHz, DMSO-d6) δ ppm 2,22 (s, 3 H) 6,33 (bs, 2 H) 6,76 (bs, 1 H) 6,91 (d, J=5,25 Hz, 2 H) 7,35 (bs, 1
55 H) 7,37 (d, J=2,56 Hz, 1 H) 7,47 (d, J=7,93 Hz, 2 H) 7,69 (d, J=1,83 Hz, 2 H) 7,74 (dd, J=7,93, 1,83 Hz, 2 H) 8,21 (d, J=5,25 Hz, 2 H) 11,90 (bs, 1 H). HRMS (ESI) calcd para C17H14N6O + H+ 319,1302, encontrada 319,1314.
60 5-(2-Aminopirimidin-4-il)-2-(5-cloro-2-metilfenil)-N-metil-1H-pirrol-3-carboxamida [(I), R1 = CH3, R2 = Cl, R3 = NHCH3, R4 = NH2, R12 = H] (compd. 19)
Esquema A, etapa 3 65
25
Claims (1)
-
imagen1 imagen2 imagen3 imagen4 imagen5
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP11162960 | 2011-04-19 | ||
| EP11162960 | 2011-04-19 | ||
| PCT/EP2012/056266 WO2012143248A1 (en) | 2011-04-19 | 2012-04-05 | Substituted pyrimidinyl-pyrroles active as kinase inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2616458T3 true ES2616458T3 (es) | 2017-06-13 |
Family
ID=45928917
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES12711904.8T Active ES2616458T3 (es) | 2011-04-19 | 2012-04-05 | Pirimidil pirroles sustituidos activos como inhibidores de quinasas |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US9283224B2 (es) |
| EP (1) | EP2699564B1 (es) |
| JP (1) | JP5970537B2 (es) |
| CN (1) | CN103502241B (es) |
| BR (1) | BR112013026137B1 (es) |
| ES (1) | ES2616458T3 (es) |
| HK (1) | HK1187905A1 (es) |
| RU (1) | RU2621732C2 (es) |
| WO (1) | WO2012143248A1 (es) |
Families Citing this family (32)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR077468A1 (es) | 2009-07-09 | 2011-08-31 | Array Biopharma Inc | Compuestos de pirazolo (1,5 -a) pirimidina sustituidos como inhibidores de trk- quinasa |
| ES2848700T3 (es) * | 2012-03-30 | 2021-08-11 | Dow Agrosciences Llc | Procedimientos de preparación de 6-trifluorometil-piridinas 3-sustituidas y procedimientos de uso de 6-triclorometil-piridinas halogenadas |
| WO2015040243A2 (en) * | 2013-09-23 | 2015-03-26 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for targeting tumor microenvironment and for preventing metastasis |
| DK3322706T3 (da) | 2015-07-16 | 2021-02-01 | Array Biopharma Inc | Substituerede pyrazolo[1,5-a]pyridin-forbindelser som ret-kinaseinhibitorer |
| TN2018000138A1 (en) | 2015-10-26 | 2019-10-04 | Array Biopharma Inc | Point mutations in trk inhibitor-resistant cancer and methods relating to the same |
| WO2017176744A1 (en) | 2016-04-04 | 2017-10-12 | Loxo Oncology, Inc. | Methods of treating pediatric cancers |
| US10045991B2 (en) | 2016-04-04 | 2018-08-14 | Loxo Oncology, Inc. | Methods of treating pediatric cancers |
| PE20181888A1 (es) | 2016-04-04 | 2018-12-11 | Loxo Oncology Inc | Formulaciones liquidas de (s)-n-(5-((r)-2-(2,5-difluorofenil)-pirrolidin-1-il)-pirazolo[1,5-a]pirimidin-3-il)-3-hidroxipirrolidina-1-carboxamida |
| AU2017268371B2 (en) | 2016-05-18 | 2020-11-19 | Array Biopharma Inc. | Preparation of (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo(1,5-A)pyrimidin-3-y l)-3-hydroxypyrrolidine-1-carboxamide |
| JOP20190077A1 (ar) | 2016-10-10 | 2019-04-09 | Array Biopharma Inc | مركبات بيرازولو [1، 5-a]بيريدين بها استبدال كمثبطات كيناز ret |
| TWI704148B (zh) | 2016-10-10 | 2020-09-11 | 美商亞雷生物製藥股份有限公司 | 作為ｒｅｔ激酶抑制劑之經取代吡唑并[1,5-a]吡啶化合物 |
| JOP20190092A1 (ar) | 2016-10-26 | 2019-04-25 | Array Biopharma Inc | عملية لتحضير مركبات بيرازولو[1، 5-a]بيريميدين وأملاح منها |
| WO2018136661A1 (en) | 2017-01-18 | 2018-07-26 | Andrews Steven W | SUBSTITUTED PYRAZOLO[1,5-a]PYRAZINE COMPOUNDS AS RET KINASE INHIBITORS |
| WO2018136663A1 (en) | 2017-01-18 | 2018-07-26 | Array Biopharma, Inc. | Ret inhibitors |
| JOP20190213A1 (ar) | 2017-03-16 | 2019-09-16 | Array Biopharma Inc | مركبات حلقية ضخمة كمثبطات لكيناز ros1 |
| GB201706806D0 (en) | 2017-04-28 | 2017-06-14 | Sentinel Oncology Ltd | Pharmaceutical compounds |
| TWI812649B (zh) | 2017-10-10 | 2023-08-21 | 美商絡速藥業公司 | 6-(2-羥基-2-甲基丙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮雜雙環[3.1.1]庚-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈之調配物 |
| TWI791053B (zh) | 2017-10-10 | 2023-02-01 | 美商亞雷生物製藥股份有限公司 | 6-(2-羥基-2-甲基丙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮雜雙環[3.1.1]庚-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈之結晶形式及其醫藥組合物 |
| CN107970438B (zh) * | 2017-11-28 | 2021-08-13 | 镇江市中西医结合医院（镇江市第二人民医院） | 一种神经再生凝胶及其制备方法和应用 |
| WO2019143994A1 (en) | 2018-01-18 | 2019-07-25 | Array Biopharma Inc. | Substituted pyrazolyl[4,3-c]pyridinecompounds as ret kinase inhibitors |
| CA3087354C (en) | 2018-01-18 | 2023-01-03 | Array Biopharma Inc. | Substituted pyrrolo[2,3-d]pyrimidines compounds as ret kinase inhibitors |
| CN111630054B (zh) | 2018-01-18 | 2023-05-09 | 奥瑞生物药品公司 | 作为RET激酶抑制剂的取代的吡唑并[3,4-d]嘧啶化合物 |
| EP3829543A1 (en) | 2018-07-31 | 2021-06-09 | Loxo Oncology, Inc. | Spray-dried dispersions and formulations of (s)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoro propan-2-yl)-1h-pyrazole-4-carboxamide |
| CA3111984A1 (en) | 2018-09-10 | 2020-03-19 | Array Biopharma Inc. | Fused heterocyclic compounds as ret kinase inhibitors |
| US20220041579A1 (en) | 2018-12-19 | 2022-02-10 | Array Biopharma Inc. | Substituted quinoxaline compounds as inhibitors of fgfr tyrosine kinases |
| WO2020131627A1 (en) | 2018-12-19 | 2020-06-25 | Array Biopharma Inc. | Substituted pyrazolo[1,5-a]pyridine compounds as inhibitors of fgfr tyrosine kinases |
| US20230101747A1 (en) | 2019-12-06 | 2023-03-30 | Schrödinger, Inc. | Cyclic compounds and methods of using same |
| AU2020413333A1 (en) | 2019-12-27 | 2022-06-16 | Schrödinger, Inc. | Cyclic compounds and methods of using same |
| US20230365584A1 (en) | 2020-09-10 | 2023-11-16 | Schrödinger, Inc. | Heterocyclic pericondensed cdc7 kinase inhibitors for the treatment of cancer |
| US20240285621A1 (en) * | 2020-09-23 | 2024-08-29 | Nerviano Medical Sciences S.R.L. | Pyrazolyl-pyrimidine derivatives as kinase inhibitors |
| EP4284804A1 (en) | 2021-01-26 | 2023-12-06 | Schrödinger, Inc. | Tricyclic compounds useful in the treatment of cancer, autoimmune and inflammatory disorders |
| TW202300150A (zh) | 2021-03-18 | 2023-01-01 | 美商薛定諤公司 | 環狀化合物及其使用方法 |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7419984B2 (en) * | 2002-10-17 | 2008-09-02 | Cell Therapeutics, Inc. | Pyrimidines and uses thereof |
| TW200526626A (en) * | 2003-09-13 | 2005-08-16 | Astrazeneca Ab | Chemical compounds |
| CN101421250A (zh) * | 2006-01-30 | 2009-04-29 | 埃克塞里艾克西斯公司 | 作为jak-2调节剂的4-芳基-2-氨基-嘧啶或4-芳基-2-氨基烷基-嘧啶及包含它们的药物组合物 |
| SG173320A1 (en) * | 2006-03-27 | 2011-08-29 | Nerviano Medical Sciences Srl | Pyridyl- and pyrimidinyl-substituted pyrrole-, thiophene- and furane-derivatives as kinase inhibitors |
| WO2009046416A1 (en) * | 2007-10-05 | 2009-04-09 | Targegen Inc. | Anilinopyrimidines as jak kinase inhibitors |
| TWI426074B (zh) * | 2008-04-30 | 2014-02-11 | Nerviano Medical Sciences Srl | ５－（２－胺基－嘧啶－４－基）－２－芳基－１ｈ－吡咯－３－羧醯胺之製造方法 |
| ES2552282T3 (es) * | 2009-03-27 | 2015-11-26 | Nerviano Medical Sciences S.R.L. | Derivados de N-aril-2-(2-arilaminopirimidin-4-il)pirrol-4-carboxamida como inhibidores de la cinasa MPS1 |
| CN102666527B (zh) * | 2009-11-04 | 2014-10-01 | 内尔维阿诺医学科学有限公司 | 5-(2-氨基-嘧啶-4-基)-2-芳基-1h-吡咯-3-甲酰胺的制备方法 |
| WO2011057960A1 (en) * | 2009-11-11 | 2011-05-19 | Nerviano Medical Sciences S.R.L. | Crystalline cdc7 inhibitor salts |
| EP2736514B1 (en) * | 2011-07-28 | 2017-10-18 | Nerviano Medical Sciences S.r.l. | Alkynyl substituted pyrimidinyl-pyrroles active as kinases inhibitors |
-
2012
- 2012-04-05 RU RU2013151174A patent/RU2621732C2/ru active
- 2012-04-05 BR BR112013026137-4A patent/BR112013026137B1/pt active IP Right Grant
- 2012-04-05 US US14/112,559 patent/US9283224B2/en active Active
- 2012-04-05 WO PCT/EP2012/056266 patent/WO2012143248A1/en active Application Filing
- 2012-04-05 EP EP12711904.8A patent/EP2699564B1/en active Active
- 2012-04-05 CN CN201280018834.4A patent/CN103502241B/zh active Active
- 2012-04-05 ES ES12711904.8T patent/ES2616458T3/es active Active
- 2012-04-05 JP JP2014505570A patent/JP5970537B2/ja active Active
-
2014
- 2014-01-29 HK HK14100953.9A patent/HK1187905A1/zh unknown
Also Published As
| Publication number | Publication date |
|---|---|
| US20140155421A1 (en) | 2014-06-05 |
| RU2621732C2 (ru) | 2017-06-07 |
| HK1187905A1 (zh) | 2014-04-17 |
| CN103502241B (zh) | 2016-03-23 |
| WO2012143248A1 (en) | 2012-10-26 |
| EP2699564A1 (en) | 2014-02-26 |
| CN103502241A (zh) | 2014-01-08 |
| EP2699564B1 (en) | 2016-12-14 |
| JP2014516360A (ja) | 2014-07-10 |
| US9283224B2 (en) | 2016-03-15 |
| RU2013151174A (ru) | 2015-05-27 |
| JP5970537B2 (ja) | 2016-08-17 |
| BR112013026137A2 (pt) | 2017-10-24 |
| BR112013026137B1 (pt) | 2020-12-01 |
| BR112013026137A8 (pt) | 2018-01-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2616458T3 (es) | Pirimidil pirroles sustituidos activos como inhibidores de quinasas | |
| JP3341090B2 (ja) | オキサジアゾール誘導体ならびにその製造法 | |
| JP6635562B2 (ja) | アルキニルピリジンプロリルヒドロキシラーゼ阻害剤、及びその製造法及び医薬用途 | |
| ES2585221T3 (es) | Un proceso para la preparación de 6-(7-((1-aminociclopropil)metoxi)-6-metoxiquinolin-4-iloxi)-n-metil-1-naftamida y productos intermedios sintéticos de la misma | |
| RU2009105669A (ru) | Способ получения 3-замещенных 2-амино-5-галогенбензамидов | |
| Branowska et al. | Synthesis and antiprotozoal activity of 2, 5-bis [amidinoaryl] thiazoles | |
| Hung et al. | Novel synthesis of 5-methyl-5, 10-dihydroindolo [3, 2-b] indoles by Pd-catalyzed C–C and two-fold C–N coupling reactions | |
| JP6341923B2 (ja) | 強蛍光発光性の複素環化合物及びその製造方法 | |
| Xu et al. | Palladium-catalyzed direct ortho-ethoxycarbonylation of azobenzenes and azoxybenzenes with diethyl azodicarboxylate | |
| Tiwari et al. | Copper-catalyzed synthesis of benzoxazoles via tandem cyclization of 2-halophenols with amidines | |
| Liu et al. | Design, synthesis, and fungicidal activity of novel imidazo [4, 5‐b] pyridine derivatives | |
| Huang et al. | Design, synthesis and anticancer activity of novel 6-(aminophenyl)-2, 4-bismorpholino-1, 3, 5-triazine derivatives bearing arylmethylene hydrazine moiety | |
| WO2019151263A1 (ja) | １，１－ジ置換ヒドラジン化合物の製造方法および重合性化合物の製造方法 | |
| RU2568640C1 (ru) | {2-[5-(3,4,5-триметоксифенил)-1,3,4-оксадиазол-2-ил]фенил} ацетат с люминесцентными свойствами | |
| ES2652365T3 (es) | Proceso para la preparación de fenilpropanonas sustituidas | |
| Jagadeesh Prathap et al. | Synthesis of new (Pyrazol‐3‐yl)‐1, 3, 4‐oxadiazole derivatives by unexpected aromatization during oxidative cyclization of 4, 5‐Dihydro‐1H‐pyrazole‐3‐carbohydrazones and their biological activities | |
| Reddy et al. | Design and synthesis of novel methylene‐bis‐fused pyrazoles as biologically active molecules | |
| ME01297B (me) | Postupak i intermedijeri u dobijanju derivata n-(1-benzhidril-azetidin-3-il)-n-fenil-metilsulfonamida | |
| Huang et al. | Synthesis, crystal structure, and biological activity of novel anthranilic diamide insecticide containing propargyl ether group | |
| WO2021022061A1 (en) | Aryl hydrocarbon receptor activators | |
| JP2017128525A (ja) | 含フッ素化合物の製造方法 | |
| MX2020014044A (es) | Metodo para producir un derivado de (alfa)-azidoanilina o un derivado de (alfa), (alfa)'-diazida. | |
| Mamgain et al. | Transition-metal-free synthesis and photophysical studies of highly functionalized (E)-stilbenes | |
| JP2011148751A (ja) | 含窒素縮合複素環化合物の製造方法 | |
| JP5900675B2 (ja) | ピロリル多環芳香族化合物の製造方法 |