AR074822A1 - Compuestos heterociclicos de pirazina utiles como inhibidores de proteinquinasas atr, composiciones farmaceuticas que los comprenden y uso de los mismos en el tratamiento del cancer - Google Patents
Compuestos heterociclicos de pirazina utiles como inhibidores de proteinquinasas atr, composiciones farmaceuticas que los comprenden y uso de los mismos en el tratamiento del cancerInfo
- Publication number
- AR074822A1 AR074822A1 ARP090105005A ARP090105005A AR074822A1 AR 074822 A1 AR074822 A1 AR 074822A1 AR P090105005 A ARP090105005 A AR P090105005A AR P090105005 A ARP090105005 A AR P090105005A AR 074822 A1 AR074822 A1 AR 074822A1
- Authority
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- Argentina
- Prior art keywords
- aliphatic
- alkyl
- halo
- optionally substituted
- nitrogen
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title abstract 2
- 206010028980 Neoplasm Diseases 0.000 title 1
- 201000011510 cancer Diseases 0.000 title 1
- 239000003112 inhibitor Substances 0.000 title 1
- 239000008194 pharmaceutical composition Substances 0.000 title 1
- 125000001931 aliphatic group Chemical group 0.000 abstract 29
- 229910052760 oxygen Inorganic materials 0.000 abstract 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract 16
- 229910052717 sulfur Inorganic materials 0.000 abstract 15
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 12
- 125000005843 halogen group Chemical group 0.000 abstract 12
- 229910052757 nitrogen Inorganic materials 0.000 abstract 11
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract 10
- 125000005842 heteroatom Chemical group 0.000 abstract 10
- 239000001301 oxygen Chemical group 0.000 abstract 10
- 239000011593 sulfur Chemical group 0.000 abstract 10
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 abstract 9
- 125000000217 alkyl group Chemical group 0.000 abstract 6
- 229920006395 saturated elastomer Polymers 0.000 abstract 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 5
- 125000003118 aryl group Chemical group 0.000 abstract 5
- 125000002950 monocyclic group Chemical group 0.000 abstract 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 abstract 4
- 229910052799 carbon Inorganic materials 0.000 abstract 3
- 125000004429 atom Chemical group 0.000 abstract 2
- 125000002619 bicyclic group Chemical group 0.000 abstract 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract 2
- 229910052736 halogen Inorganic materials 0.000 abstract 2
- 150000002367 halogens Chemical class 0.000 abstract 2
- 125000000623 heterocyclic group Chemical group 0.000 abstract 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 abstract 1
- 125000006163 5-membered heteroaryl group Chemical group 0.000 abstract 1
- -1 NR * Inorganic materials 0.000 abstract 1
- 125000004432 carbon atom Chemical group C* 0.000 abstract 1
- 125000004122 cyclic group Chemical group 0.000 abstract 1
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract 1
- 229910052698 phosphorus Inorganic materials 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
Classifications
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- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/20—Nitrogen atoms
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- 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
- A61K31/4965—Non-condensed pyrazines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
- C07D241/28—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms in which said hetero-bound carbon atoms have double bonds to oxygen, sulfur or nitrogen atoms
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- C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D401/10—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 two hetero rings linked by a carbon chain containing aromatic rings
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- C07D405/02—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 two hetero rings
- C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- 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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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S507/00—Earth boring, well treating, and oil field chemistry
- Y10S507/939—Corrosion inhibitor
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
Reivindicación 1: Un compuesto de la fórmula (1) o una sal farmacéuticamente aceptable del mismo; caracterizado porque Y es una cadena alifática de C1-10 donde hasta tres unidades de metileno de la cadena alifática opcionalmente son reemplazados por O, NR0, S, C(O), o S(O)2; el anillo A es un anillo heteroarilo de 5 miembros seleccionado entre el grupo de fórmulas (2); J3 es H o alquilo de C1-4 donde 1 unidad de metileno del grupo alquilo opcionalmente puede ser reemplazada por O, NR0, N(alquilo de C1-4), o S y opcionalmente sustituido con 1 - 3 halo; Q es un anillo aromático monocíclico de 5 - 6 miembros que contiene 0 - 4 heteroátomos seleccionados independientemente entre nitrógeno, oxigeno o azufre; o un anillo aromático bicíclico de 8 - 10 miembros que contiene 0 - 6 heteroátomos seleccionados independientemente entre nitrógeno, oxígeno o azufre; R5 es H; un anillo monocíclico de 3 - 7 miembros completamente saturado, parcialmente saturado o aromático que contiene 0 - 4 heteroátomos seleccionados independientemente entre nitrógeno, oxigeno o azufre; un anillo bicíclico de 8 - 10 miembros, completamente saturado, parcialmente saturado o aromático que contiene 0 - 6 heteroátomos seleccionados independientemente entre nitrógeno, oxigeno o azufre; R5 está opcionalmente sustituido con 1-5 grupos J5; L es una cadena alquilo de C1-4 donde hasta dos unidades de metileno de la cadena alquilo, opcionalmente, son reemplazadas por O, NR6, S, -C(O)-, -SO-, o -SO2-; R0 es H o alquilo de C1-6 donde una unidad de metileno de la cadena alquilo puede ser, opcionalmente. reemplazada por O, NH, N(alquilo C1-4), o S; R1 es H o alquilo de C1-6; R2 es H, alquilo de C1-6, -(alquilo de C2-6)-Z o un anillo cíclico de 4 - 8 miembros que contiene 0 - 2 átomos de nitrógeno; donde dicho anillo está ligado mediante un átomo de carbono y está opcionalmente sustituido con una presencia de JZ; o R1 y R2, tomados junto con el átomo al que están ligados, forman un anillo heterocíclico de 4 - 8 miembros que contiene 1 - 2 heteroátomos seleccionados entre oxigeno, nitrógeno o azufre; donde dicho anillo heterocíclico está opcionalmente sustituido con una presencia de JZ1; JZ1 es halo, CN, un grupo alifático de C1-8, -(X)t-CN, o -(X)r-Z; donde dichas hasta dos unidades de metileno de dicho grupo alifático C1-8 pueden ser, opcionalmente, reemplazadas por O, NR, S, P(O), C(O), S(O), o S(O)2; donde dicho grupo alifático de C1-8 está opcionalmente sustituido con halo, CN, o NO2; X es alquilo de C1-4; cada t, r y m es, independientemente, 0 ó 1; Z es-NR3R4; R3 es H o alquilo de C1-2; R4 es H o alquilo de C1-6; o R3 y R4, tomados junto con el átomo al que están ligados, forman un anillo heterocíclico de 4 - 8 miembros que contiene 1 - 2 heteroátomos seleccionados entre oxigeno, nitrógeno o azufre; donde dicho anillo está opcionalmente sustituido con una presencia de JZ; R6 es H, o alquilo de C1-6; JZ es, independientemente, NH2, NH(alifático de C1-4), N(alifático de C1-4)2, halógeno, alifático de C1-4, OH, O(alifático de C1-4), NO2, CN, CO2H, CO(alifático de C1-4), CO2(alifático de C1-4), O(haloalifático de C1-4), o haloalifático de C1-4; J5 es halo, oxo, CN, NO2, X'-R, o -(X1)p-Q4; X1 es un grupo alifático de C1-10 donde 1-3 unidades de metileno de dicho grupo alifático de C1-10 opcionalmente son reemplazadas por -NR'-, -O-, -S-, C(=NR'), C(O), S(O)2, o S(O); donde X1 está opcional e independientemente sustituido con 1 - 4 presencias de NH2, NH(alifático de C1-4), N(alifático de C1-4)2, halógeno, alifático de C1-4, OH, O(alifático de C1-4), NO2, CN, CO2H, CO2(alifático de C1-4), C(O)NH2, C(O)NH(alifático de C1-4), C(O)N(alifático de C1-4)2, SO(alifático de C1-4), SO2(alifático de C1-4), SO2NH(alifático de C1-4), SO2NH(alifático de C1-4), NHC(O)(alifático de C1-4), N(alifático de C1-4)C(O)(alifático de C1-4), donde dicho grupo alifático de C1-4 está opcionalmente sustituido con 1 - 3 presencias de halo; Q4 es un anillo monocíclico de 3 - 8 miembros saturado o insaturado que tiene 0 - 4 heteroátomos seleccionados independientemente entre nitrógeno, oxigeno o azufre, o un anillo bicíclico de 8 - 10 miembros saturado o insaturado que tiene 0 - 6 heteroátomos seleccionados independientemente entre nitrógeno, oxígeno o azufre; cada Q4 está opcionalmente sustituido con 1 - 5 JQ4; JQ4 es halo, CN, o alquilo de C1-4 donde hasta 2 unidades de metileno opcionalmente son reemplazadas por O, NR*, S, C(O). S(O), o S(O)2; R es H o alquilo de C1-4 donde dicho grupo alquilo de C1-4 está opcionalmente sustituido con 1-4 halo; J2 es halo; CN; un anillo monocíclico de 5 - 6 miembros aromático o no aromático que tiene 0 - 3 heteroátomos seleccionados entre oxígeno, nitrógeno o azufre; o un grupo alifático de C1-10 donde hasta 2 unidades de metileno opcionalmente son reemplazadas por O, NR'', C(O), S, S(O), o S(O)2 donde dicho grupo alifático de C1-10 está opcionalmente sustituido con 1 - 3 halo o CN; y dicho anillo monocíclico está opcionalmente sustituido con 1 - 3 presencias de halo; CN; un grupo cicloalquilo de C3-6; un heterociclilo de 3 - 7 miembros que contiene 0 - 2 heteroátomos seleccionados entre oxígeno, nitrógeno o azufre; o un grupo alquilo de C1-4 donde hasta una unidad de metileno de la cadera alquilo está opcionalmente reemplazada con O, NR'' o S; y donde dicho grupo alquilo de C1-4 está opcionalmente sustituido con 1 - 3 halo; q es 0, 1 ó 2; p es 0 ó 1; R', R'' y R* son, cada uno, independientemente H, alquilo de C1-4, o está ausente; donde dicho alquilo de C1-4 está opcionalmente sustituido con 1 - 4 halo.
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