HRP20110470T1 - Inhibitori proteinskih kinaza - Google Patents
Inhibitori proteinskih kinaza Download PDFInfo
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- HRP20110470T1 HRP20110470T1 HR20110470T HRP20110470T HRP20110470T1 HR P20110470 T1 HRP20110470 T1 HR P20110470T1 HR 20110470 T HR20110470 T HR 20110470T HR P20110470 T HRP20110470 T HR P20110470T HR P20110470 T1 HRP20110470 T1 HR P20110470T1
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- 239000003112 inhibitor Substances 0.000 title abstract 2
- 102000001253 Protein Kinase Human genes 0.000 title 1
- 108060006633 protein kinase Proteins 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract 38
- 108091007914 CDKs Proteins 0.000 claims abstract 3
- 108090000266 Cyclin-dependent kinases Proteins 0.000 claims abstract 3
- 102000003903 Cyclin-dependent kinases Human genes 0.000 claims abstract 3
- 201000010099 disease Diseases 0.000 claims abstract 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract 3
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract 2
- 208000035473 Communicable disease Diseases 0.000 claims abstract 2
- 208000002193 Pain Diseases 0.000 claims abstract 2
- 208000026278 immune system disease Diseases 0.000 claims abstract 2
- 208000027866 inflammatory disease Diseases 0.000 claims abstract 2
- 230000004770 neurodegeneration Effects 0.000 claims abstract 2
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract 2
- 230000002062 proliferating effect Effects 0.000 claims abstract 2
- 229910052736 halogen Inorganic materials 0.000 claims 36
- 150000002367 halogens Chemical class 0.000 claims 36
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 25
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 23
- 125000001424 substituent group Chemical group 0.000 claims 23
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 18
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 16
- 125000001072 heteroaryl group Chemical group 0.000 claims 15
- 125000000623 heterocyclic group Chemical group 0.000 claims 15
- 229910052739 hydrogen Inorganic materials 0.000 claims 15
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 15
- 125000003118 aryl group Chemical group 0.000 claims 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 12
- 125000000217 alkyl group Chemical group 0.000 claims 11
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 claims 11
- 125000004970 halomethyl group Chemical group 0.000 claims 10
- 125000004452 carbocyclyl group Chemical group 0.000 claims 9
- -1 methoxy, ethoxy Chemical group 0.000 claims 9
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 7
- 229910052799 carbon Inorganic materials 0.000 claims 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 6
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 6
- 239000001257 hydrogen Substances 0.000 claims 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 6
- 229910052757 nitrogen Inorganic materials 0.000 claims 6
- 125000004043 oxo group Chemical group O=* 0.000 claims 6
- 238000006243 chemical reaction Methods 0.000 claims 5
- 238000006482 condensation reaction Methods 0.000 claims 5
- 125000006574 non-aromatic ring group Chemical group 0.000 claims 5
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 3
- 238000000034 method Methods 0.000 claims 3
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 2
- 125000005037 alkyl phenyl group Chemical group 0.000 claims 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims 2
- 230000000694 effects Effects 0.000 claims 2
- 125000005842 heteroatom Chemical group 0.000 claims 2
- 125000006648 (C1-C8) haloalkyl group Chemical group 0.000 claims 1
- 102100024457 Cyclin-dependent kinase 9 Human genes 0.000 claims 1
- 101000980930 Homo sapiens Cyclin-dependent kinase 9 Proteins 0.000 claims 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims 1
- 125000002619 bicyclic group Chemical group 0.000 claims 1
- 125000002837 carbocyclic group Chemical group 0.000 claims 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 238000009833 condensation Methods 0.000 claims 1
- 230000005494 condensation Effects 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 230000006806 disease prevention Effects 0.000 claims 1
- 150000002431 hydrogen Chemical group 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 125000001624 naphthyl group Chemical group 0.000 claims 1
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 239000012453 solvate Substances 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 125000003107 substituted aryl group Chemical group 0.000 claims 1
- 229910052717 sulfur Inorganic materials 0.000 claims 1
- 239000011593 sulfur Substances 0.000 claims 1
Classifications
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- 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
- 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
- C07D401/02—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
- C07D401/12—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 chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- 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
-
- 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
- C07D405/02—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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—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
- C07D409/12—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 linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
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- 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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- C07—ORGANIC CHEMISTRY
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
Spoj opće Formule I: ili njegova farmaceutski prihvatljiva sol, solvat ili polimorf, uključujući sve njegove tautomere i stereoizomere, naznačen time što: A je N, a B je CH, C(C1-4alkil) ili C(NH2),Ra je H ili metil; R1 se bira iz skupine koju čine: C1-8alkil; -NR6R7, C1-6alkil-NR6R7, R20, -C1-6alkil-R20, -C1-6alkil-C(O)OR4, C1-6alkil-C(O)R4, -NR10-(C1-6alkil)-NR6R7, -NR10-(C1-6alkil)-R20, -NR10-(C1-6alkil)-C(O)OR4, -NR10R20, O-(C1-6alkil)-NR6R7, -O-(C1-6alkil)-R20, -O-(C1-6alkil)-C(O)OR4, -OR20, C1-6alkil-OR20, C1-6alkil-SR20, C1-6alkil-NR10R20, (C1-6alkil)-O-(C1-6alkil)-R20, (C1-6alkil)-S-(C1-6alkil)-R20, C(O)R20;gdje alkilni ostaci mogu biti nerazgranati ili razgranati i mogu biti supstituirani s jednim ili više supstituenata, koje se bira između halogena, metoksi, etoksi, NR6R7 ili heterocikličkog prstena s dušikom; R4 predstavlja H ili C1-4-alkil; svakog od R6 i R7 neovisno se bira iz skupine koju čine H, C1-6alkil, hidroksi-C2-6alkil-;R10 predstavlja H ili C1-4alkil; R20 se bira između arila, heteroarila, karbociklila i heterociklila i mogu biti supstituirani s jednim ili više supstituenata, koje se bira između: C1-6alkila, C2-6alkenila, C2-6alkinila, od kojih bilo koji može biti supstituiran s jednim ili više halogenih ili OH supstituenata; R21, -C1-4alkil-R21; OR21, O(C1-4alkil)R21, SR21, SOR21, SO2R21, C(O)R21, C1-4alkil-OR21,-O(C2-6alkenil), -O(C2-6alkinil), od kojih bilo koji može biti supstituiran s jednim ili više halogenih ili OH supstituenata; OR22, -SR22, -SOR22, -SO2R22, -C(O)R22, -C(O)OR22, -C1-4alkil-O-R22, -C1-4alkil-O-C1-4alkil-O-R22, C1-4alkil-C(O)R22, -C1-4alkil-C(O)R22, NR11C(O)OR22, NR11C(O)R22, -SO2-NR11R12, -C(O)-NR11R12, -C1-4alkil-C(O)-NR11R12, -NH-SO2R15, -N(C1-4alkil)-SO2R15, -(C1-4alkil)NR11R12, NR11R12, -(C1-6alkil)NR11R12, nitro, halogena, cijano i hidroksila; te kada je R20 karbociklilna ili heterociklilna ili aromatska skupina, u kojoj je aromatski prsten kondenziran s nearomatskim prstenom, R20 može dodatno biti supstituiran s okso; R21 se bira između arila, heteroarila, karbociklila i heterociklila i može biti supstituiran s jednim ili više supstituenata, kao što je definirano niže; kada je R21 arilna ili heteroarilna skupina, može biti supstituiran s jednim ili više supstituenata, koje se bira između: metila, metoksi, halogena, halogenmetil fluormetoksi ili trifluormetoksi; kada je R21 karbociklička ili heterociklička skupina, može biti supstituiran s jednim ili više supstituenata, koje se bira između metila, okso ili halogena; R22 je vodik ili C1-6alkil, izborno supstituiran s halogenom ili hidroksilom; svaki od R11 i R12 neovisno predstavlja supstituent kojeg se bira između H ili C1-4alkila, ili su R11 i R12 tako vezani da zajedno tvore 3-8-eročlani nearomatski prsten; R15 predstavlja H ili C1-4alkil; R2 predstavlja H; svaki R3 neovisno predstavlja supstituent kojeg se bira iz skupine koju čine C1-6alkil, C2-6alkenil, C2-6alkinil, C1-6halogenalkil, C3-8cikloalkil (izborno supstituiran s metilom, okso ili h
Claims (21)
1. Spoj opće Formule I:
[image]
ili njegova farmaceutski prihvatljiva sol, solvat ili polimorf, uključujući sve njegove tautomere i stereoizomere, naznačen time što:
A je N, a B je CH, C(C1-4alkil) ili C(NH2),
Ra je H ili metil;
R1 se bira iz skupine koju čine:
C1-8alkil; -NR6R7, C1-6alkil-NR6R7, R20, -C1-6alkil-R20, -C1-6alkil-C(O)OR4, C1-6alkil-C(O)R4, -NR10-(C1-6alkil)-NR6R7, -NR10-(C1-6alkil)-R20, -NR10-(C1-6alkil)-C(O)OR4, -NR10R20, O-(C1-6alkil)-NR6R7, -O-(C1-6alkil)-R20, -O-(C1-6alkil)-C(O)OR4, -OR20, C1-6alkil-OR20, C1-6alkil-SR20, C1-6alkil-NR10R20, (C1-6alkil)-O-(C1-6alkil)-R20, (C1-6alkil)-S-(C1-6alkil)-R20, C(O)R20;
gdje alkilni ostaci mogu biti nerazgranati ili razgranati i mogu biti supstituirani s jednim ili više supstituenata, koje se bira između halogena, metoksi, etoksi, NR6R7 ili heterocikličkog prstena s dušikom;
R4 predstavlja H ili C1-4-alkil;
svakog od R6 i R7 neovisno se bira iz skupine koju čine H, C1-6alkil, hidroksi-C2-6alkil-;
R10 predstavlja H ili C1-4alkil;
R20 se bira između arila, heteroarila, karbociklila i heterociklila i mogu biti supstituirani s jednim ili više supstituenata, koje se bira između:
C1-6alkila, C2-6alkenila, C2-6alkinila, od kojih bilo koji može biti supstituiran s jednim ili više halogenih ili OH supstituenata;
R21, -C1-4alkil-R21; OR21, O(C1-4alkil)R21, SR21, SOR21, SO2R21, C(O)R21, C1-4alkil-OR21,
-O(C2-6alkenil), -O(C2-6alkinil), od kojih bilo koji može biti supstituiran s jednim ili više halogenih ili OH supstituenata;
OR22, -SR22, -SOR22, -SO2R22, -C(O)R22, -C(O)OR22, -C1-4alkil-O-R22, -C1-4alkil-O-C1-4alkil-O-R22, C1-4alkil-C(O)R22, -C1-4alkil-C(O)R22, NR11C(O)OR22, NR11C(O)R22, -SO2-NR11R12, -C(O)-NR11R12, -C1-4alkil-C(O)-NR11R12, -NH-SO2R15, -N(C1-4alkil)-SO2R15, -(C1-4alkil)NR11R12, NR11R12, -(C1-6alkil)NR11R12, nitro, halogena, cijano i hidroksila; te kada je R20 karbociklilna ili heterociklilna ili aromatska skupina, u kojoj je aromatski prsten kondenziran s nearomatskim prstenom, R20 može dodatno biti supstituiran s okso;
R21 se bira između arila, heteroarila, karbociklila i heterociklila i može biti supstituiran s jednim ili više supstituenata, kao što je definirano niže;
kada je R21 arilna ili heteroarilna skupina, može biti supstituiran s jednim ili više supstituenata, koje se bira između: metila, metoksi, halogena, halogenmetil fluormetoksi ili trifluormetoksi;
kada je R21 karbociklička ili heterociklička skupina, može biti supstituiran s jednim ili više supstituenata, koje se bira između metila, okso ili halogena;
R22 je vodik ili C1-6alkil, izborno supstituiran s halogenom ili hidroksilom;
svaki od R11 i R12 neovisno predstavlja supstituent kojeg se bira između H ili C1-4alkila, ili su R11 i R12 tako vezani da zajedno tvore 3-8-eročlani nearomatski prsten;
R15 predstavlja H ili C1-4alkil;
R2 predstavlja H;
svaki R3 neovisno predstavlja supstituent kojeg se bira iz skupine koju čine C1-6alkil, C2-6alkenil, C2-6alkinil, C1-6halogenalkil, C3-8cikloalkil (izborno supstituiran s metilom, okso ili halogenom), fenil (izborno supstituiran s metilom, metoksi, halogenom, halogenmetilom, fluormetoksi ili trifluormetoksi), -C1-6alkil-OH, -C1-4alkilfenil (izborno supstituiran s metilom, metoksi, halogenom, halogenmetilom, fluormetoksi ili trifluormetoksi), C1-6alkoksi-, C1-6alkeniloksi, C3-6alkiniloksi-, C1-6halogenalkoksi-, -O-C3-8cikloalkil, -O-C1-4alkil-C3-8cikloalkil, -O-fenil (izborno supstituiran s metilom, metoksi, halogenom, halogenmetilom, fluormetoksi ili trifluormetoksi), -O-C1-4alkilfenil (izborno supstituiran s metilom, metoksi, halogenom, halogenmetilom, fluormetoksi ili trifluormetoksi), -S(C1-6alkil), -SO(C1-6alkil), -SO2C1-6-alkil, -SO2C3-8cikloalkil, -SO2-NR31R32, -C(O)C1-6alkil, -C(O)C3-8cikloalkil, -C(O)OH, -C(O)OC1-6alkil, -C(O)-NR31R32, -C1-4alkil-O-C1-4alkil, -C1-4alkil-O-C1-4alkil-OH, -C1-4alkil-O-C1-4alkil-O-C1-4alkil, -C1-4alkil-O-C3-7cikloalkil, -C1-4alkil-C(O)C1-6alkil, -C1-4alkil-C(O)OH, -C1-4alkil-C(O)C1-4alkil, -C1-4alkil-C(O)-NR31R32, -NH-SO2R33, -N(C1-4alkil)-SO2R33, -(C1-4alkil)NR31R32, NR31R32, -(C1-6alkil)NR31R32, nitro, halogen, cijano, hidroksil;
svaki od R31 i R32 neovisno predstavlja supstituent kojeg se bira između H, C1-4alkila ili C1-4halogenalkila, ili su R31 i R32 tako vezani da zajedno tvore 3-8-eročlani nearomatski prsten;
R33 predstavlja H ili C1-4alkil;
x je 1 ili 2 i predstavlja broj neovisno odabranih supstituenata R3 na fenilnom prstenu.
2. Spoj u skladu s patentnim zahtjevom 1, naznačen time što:
A je N, a B je CH, C(C1-4alkil) ili C(NH2),
R1 se bira iz skupine koju čine:
C1-8alkil;
C1-8halogenalkil;
[image]
aril;
heteroaril;
C3-12karbociklil;
heterociklil;
-C1-6alkil-aril;
-C1-6alkil-heteroaril;
-C1-6alkil-karbociklil;
-C1-6alkil-heterociklil;
-C1-6alkil-C(O)OH;
-C1-6alkil-C(O)OC1-4alkil;
[image]
-NR10C1-6alkil-aril;
-NR10C1-6alkil-heteroaril;
-NR10C1-6alkil-karbociklil;
-NR10C1-6alkil-heterociklil;
-NR10C1-6alkil-C(O)OH;
-NR10C1-6alkil-C(O)OC1-4alkil;
-NR10aril;
-NR10heteroaril;
-NR10karbociklil;
-NR10heterociklil;
[image]
-OC1-6alkil-aril;
-OC1-6alkil-heteroaril;
-OC1-6alkil-karbociklil;
-OC1-6alkil-heterociklil;
-OC1-6alkil-C(O)OH;
-OC1-6alkil-C(O)OC1-4alkil;
-Oaril;
-Oheteroaril;
-Okarbociklil; i
-Oheterociklil;
gdje bilo koji od gore navedenih arila i heteroarila može izborno biti supstituiran s jednom ili više skupina, koje se neovisno bira iz skupine koju čine C1-6alkil, C2-6alkenil, C2-6alkinil, C1-6halogenalkil, C3-8cikloalkil (izborno supstituiran s metilom, okso ili halogenom), fenil (izborno supstituiran s metilom, metoksi, halogenom, halogenmetilfluormetoksi ili trifluormetoksi), -C1-6alkil-OH, -C1-4alkilfenil (gdje je fenil izborno supstituiran s metilom, metoksi, halogenom, halogenmetilfluormetoksi ili trifluormetoksi), C1-6alkoksi-, C1-6alkeniloksi, C3-6alkiniloksi-, C1-6halogenalkoksi-, -O-C3-8cikloalkil, -O-C1-4alkil-C3-8cikloalkil, -O-fenil (izborno supstituiran s metilom, metoksi, halogenom, halogenmetilom, fluormetoksi ili trifluormetoksi), -O-C1-4alkilfenil (izborno supstituiran s metilom, metoksi, halogenom, halogenmetilom, fluormetoksi ili trifluormetoksi), -S(C1-6alkil), -SO(C1-6alkil), -SO2(C1-6-alkil), -SO2C3-8cikloalkil, -SO2-NR11R12, -COC1-6alkil, -C(O)C3-8cikloalkil, -C(O)OH, -C(O)OC1-6alkil, -C(O)-NR11R12, -C1-4alkil-O-C1-4alkil, -C1-4alkil-O-C1-4alkil-OH, -C1-4alkil-O-C1-4alkil-O-C1-4alkil, -C1-4alkil-O-C3-7cikloalkil, -C1-4alkil-C(O)C-6alkil, -C1-4alkil-C(O)OH, -C1-4alkil-C(O)OC1-4alkil, -C1-4alkil-C(O)-NR11R12, -NH-SO2R15, -N(C1-4alkil)-SO2R15, -(C1-4alkil)NR11R12, NR11R12, -(C1-6alkil)NR11R12, nitro, halogen, cijano i hidroksil; i
gdje bilo koji od gore navedenih karbociklila i heterociklila može izborno biti supstituiran s jednom ili više skupina, koje se neovisno bira iz skupine koju čine C1-6alkil, C2-6alkenil, C2-6alkinil, C1-6halogenalkil, C3-8cikloalkil (izborno supstituiran s metilom, okso ili halogenom), fenil (izborno supstituiran s metilom, metoksi, halogenom, halogenmetilom, fluormetoksi ili trifluormetoksi), -C1-6alkil-OH, -C1-4alkilfenil (gdje je fenil izborno supstituiran s metilom, metoksi, halogenom, halogenmetilom, fluormetoksi ili trifluormetoksi), C1-6alkoksi-, C1-6alkeniloksi, C3-6alkiniloksi-, C1-6halogenalkoksi-, -O-C3-8cikloalkil, -O-C1-4alkil-C3-8cikloalkil, -O-fenil (izborno supstituiran s metilom, metoksi, halogenom, halogenmetilfluormetoksi ili trifluormetoksi), -O-C1-4alkilfenil (izborno supstituiran s metilom, metoksi, halogenom, halogenmetilfluormetoksi ili trifluormetoksi), -S(C1-6alkil), -SO(C1-6alkil), -SO2C1-6alkil, -SO2C3-8cikloalkil, -SO2-NR11R12, -C(O)C1-6alkil, -C(O)C3-8cikloalkil, -C(O)OH, -C(O)C1-6alkil, -C(O)-NR11R12, -C1-4alkil-O-C1-4alkil, -C1-4alkil-O-C1-4alkil-OH, -C1-4alkil-O-C1-4alkil-O-C1-4alkil, -C1-4alkil-O-C3-7cikloalkil, -C1-4alkil-C(O)C1-6alkil, -C1-4alkil-C(O)OH, -C1-4alkil-C(O)OC1-4alkil, -C1-4alkil-C(O)-NR11R12, -NH-SO2R15, -N(C1-4alkil)-SO2R15, -(C1-4alkil)NR11R12, -NR11R12, -(C1-6alkil)NR11R12, nitro, halogen, cijano, hidroksil i okso;
R2 predstavlja H;
R3 predstavlja supstituent kojeg se bira iz skupine koju čine C1-6alkil, C2-6alkenil, C2-6alkinil, C1-6halogenalkil, C3-8cikloalkil (izborno supstituiran s metilom, okso ili halogenom), fenil (izborno supstituiran s metilom, metoksi, halogenom, halogenmetilom, fluormetoksi ili trifluormetoksi), -C1-6alkil-OH, -C1-4alkilfenil (izborno supstituiran s metilom, metoksi, halogenom, halogenmetilom, fluormetoksi ili trifluormetoksi), C1-6alkoksi-, C1-6alkeniloksi, C3-6alkiniloksi-, C1-6halogenalkoksi-, -O-C3-8cikloalkil, -O-C1-4alkil-C3-8cikloalkil, -O-fenil (izborno supstituiran s metilom, metoksi, halogenom, halogenmetilom, fluormetoksi ili trifluormetoksi), -O-C1-4alkilfenil (izborno supstituiran s metilom, metoksi, halogenom, halogenmetilom, fluormetoksi ili trifluormetoksi), -S(C1-6alkil), -SO(C1-6alkil), -SO2C1-6alkil, -SO2C3-8cikloalkil, -SO2-NR31R32, -C(O)C1-6alkil, -C(O)C3-8cikloalkil, -C(O)OH, -C(O)OC1-6alkil, -C(O)-NR31R32, -C1-4alkil-O-C1-4alkil, -C1-4alkil-O-C1-4alkil-OH, -C1-4alkil-O-C1-4alkil-O-C1-4alkil, -C1-4alkil-O-C3-7cikloalkil, -C1-4alkil-C(O)C1-6alkil, -C1-4alkil-C(O)OH, -C1-4alkil-C(O)OC1-4alkil, -C1-4alkil-C(O)-NR31 R32, -NH-SO2R33, -N(C1-4alkil)-SO2R33, -(C1-4alkil)NR31R32, -NR31R32, -(C1-6alkil)NR31R32, nitro, halogen, cijano, hidroksil;
R4 i R5 neovisno predstavljaju H ili C1-4alkil;
svakog od R6 i R7 neovisno se bira iz skupine koju čine H, C1-6alkil, hidroksi-C2-6alkil-;
R10 predstavlja H ili C1-4alkil;
svaki od R11 i R12 neovisno predstavlja supstituent kojeg se bira između H ili C1-4alkila, ili su R11 i R12 tako vezani da zajedno tvore 3-8-eročlani nearomatski prsten;
R15 predstavlja H ili C1-4alkil;
svaki od R31 i R32 neovisno predstavlja supstituent kojeg se bira između H, C1-4alkila ili C1-4halogenalkila, ili su R31 i R32 tako vezani da zajedno tvore 3-8-eročlani nearomatski prsten;
R33 predstavlja H ili C1-4alkil;
x je 1 ili 2 i predstavlja broj neovisno odabranih supstituenata R3 na fenilnom prstenu;
m predstavlja cijeli broj 1-4; i
n predstavlja cijeli broj 2-4.
3. Spoj u skladu s patentnim zahtjevom 1 ili patentnim zahtjevom 2, naznačen time što, neovisno ili u bilo kojoj kombinaciji:
Ra je vodik;
B je CH ili C1-4alkil;
R2 je hidrogen,
R3 je halogen, C1-6alkoksi, -O-C1-4alkilfenil (primjerice -O-benzil) ili -OC1-4alkil-C3-8cikloalkil; i
x je 1 ili 2.
4. Spoj u skladu s patentnim zahtjevom 3, naznačen time što, neovisno ili u bilo kojoj kombinaciji:
B je CH;
R2 je vodik; i
R3 je halogen, metoksi, etoksi, izopropiloksi, benziloksi ili -OCH2ciklopropil.
5. Spoj u skladu s bilo kojim od patentnih zahtjeva 3 do 4, naznačen time što x je 1, a R3 predstavlja C1-6alkoksi, -O-C1-4alkilfenil ili -O-C1-4alkil-C3-8cikloalkil;
ili
gdje x je 2, jedna od skupina R3 je metoksi, etoksi, -izopropiloksi, benziloksi ili (1-ciklopropil)metoksi, a druga skupina R3 je halogen.
6. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 5, naznačen time što R1 je:
-C1-6alkil;
-R20;
-C(O)R20;
-C1-6alkil-R20,
gdje je alkilna skupina izborno supstituirana s halogenom, metoksi, etoksi, -NR6R7 ili heterociklilnim prstenom s dušikom;
-C1-6alkil-OR20;
-(C1-6alkil)-O-(C1-C6alkil)-R20;
-C1-6alkil-NR10R20;
-C1-6alkil-SR20;
-NR10R20;
-NR6R7;
-NR10-(C1-6alkil)-NR6R7 ili
-NR10-(C1-6alkil)-C(O)OH;
gdje su R6, R7, R10 i R20 definirani kao u patentnom zahtjevu 1.
7. Spoj u skladu s patentnim zahtjevom 6, naznačen time što R1 predstavlja R20 ili NR10R20, a R20 je supstituirana ili nesupstituirana karbociklilna, heterociklilna, arilna ili heteroarilna skupina;
ili
R1 je supstituirana karbociklilna skupina, gdje je supstitutent na istom atomu koji povezuje karbociklilnu skupinu s ostatkom molekule;
ili
R1 predstavlja C(O)R20, a R20 je arilna ili heteroarilna skupina, koja može biti nesupstituirana ili supstituirana kao što je definirano u patentnom zahtjevu 1, ili heterociklilna skupina.
8. Spoj u skladu s patentnim zahtjevom 7, naznačen time što R20 je fenilna ili 6-eročlana heterociklilna skupina.
9. Spoj u skladu s patentnim zahtjevom 6, naznačen time što R1 predstavlja C1-6alkil-R20, a R20 je arilna, heteroarilna ili heterociklilna skupina, od kojih bilo koja može izborno biti supstituirana kao što je iznijeto u patentnom zahtjevu 1;
ili
R1 predstavlja C1-6alkil-OR20, -(C1-6alkil)-O-(C1-C6alkil)-R20, C1-6alkil-NR10R20 ili C1-6alkil-SR20, a R20 je arilna ili heteroarilna skupina, izborno supstituirana kao što je iznijeto u patentnom zahtjevu 1.
10. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 9, naznačen time što R20 je 5- ili 6-eročlani heterociklilni prsten koji sadrži jedan ili dva heteroatoma, koje se neovisno bira između kisika, sumpora ili dušika.
11. Spoj u skladu s patentnim zahtjevom 10, naznačen time što heterociklilni prsten R20 je nesupstituiran ili je supstituiran s jednim ili više supstituenata, koje se neovisno bira između okso, -C1-4alkila, -C1-4alkil-O-C1-4alkila, -C(O)C1-4alkila, -C(O)OC1-4alkila, halogena i -C1-4alkilR21.
12. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 8, naznačen time što R20 predstavlja cikloalkilnu skupinu, koja je nesupstituirana ili je supstituirana s jednim ili više -C1-8alkila, okso, -NH2, -NHC(O)C1-4alkila, -NHC(O)OC1-4alkila, -C(O)NH2, izborno supstituiranih arilnih ili heteroarilnih skupina.
13. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 9, naznačen time što R20 predstavlja naftil ili fenil, izborno supstituiran s jednim ili više supstituenata, koje se bira između -NH-SO2C1-4alkila, C1-4alkila, -O(C1-4alkil), -NHR12, gdje R12 je definiran kao gore, arila, heteroarila, nitro i halogena.
14. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 9, naznačen time što R20 predstavlja monociklički 5- ili 6-eročlani heteroarilni prstenasti sustav;
ili
R20 predstavlja bicikličku heteroarilnu skupinu, koju čini fenil kondenziran s nezasićenim heterociklilnim prstenom, ili heteroarilni ostatak kondenziran s nezasićenim prstenom, koji izborno sadrži jedan ili više dodatnih heteroatoma.
15. Spoj u skladu s patentnim zahtjevom 14, naznačen time što R20 je nesupstituiran ili je supstituiran s jednim ili više supstituenata, koje se bira između C1-4alkila, halogena, -(C1-4alkil)-O-R21 ili R21, gdje R21 je nesupstituirani fenil ili heteroaril.
16. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 6, naznačen time što R1 je -NR6R7; ili -NR10-(C1-6alkil)-NR6R7, a svaki od R6 i R7 je neovisno vodik ili C1-4alkil
ili
R1 je -C1-6alkil-NR10R20; -NR10R20; -NR10-(C1-C6alkil)-NR6R7 ili -NR10-(C1-6alkil)-C(O)OH; i R10 je vodik ili metil.
17. Spoj u skladu s patentnim zahtjevom 1, naznačen time što navedeni spoj se bira između primjera 1 do 156:
[image]
[image]
[image]
[image]
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[image]
[image]
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[image]
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[image]
[image]
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[image]
ili primjera 1A do 21A i 23A do 34A:
[image]
[image]
[image]
[image]
18. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 17, naznačen time što je namijenjen upotrebi u medicinskom liječenju, osobito u liječenju ili sprječavanju bolesti i stanja uzrokovanih aktivnošću o ciklinu ovisnih kinaza, a osobito CDK9.
19. Spoj u skladu s patentnim zahtjevom 18, naznačen time što bolest ili stanje uzrokovani aktivnošću o ciklinu ovisnih kinaza se bira između boli, upalnih poremećaja, proliferativnih bolesti, imunoloških bolesti, infektivnih bolesti, kardiovaskularnih bolesti i neurodegenerativnih bolesti.
20. Farmaceutski pripravak, naznačen time što sadrži spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 17, namijenjen upotrebi kao aktivni sastojak, uz farmaceutski prihvatljivu pomoćnu tvar ili razrjeđivač.
21. Postupak dobivanja spoja formule (I) u skladu s bilo kojim od patentnih zahtjeva 1 do 17, naznačen time što se navedeni postupak sastoji u
(a) prevođenju jednog spoja formule (I) u drugi spoj formule (I); ili
(b) reakciji spoja formule A
[image]
gdje su A, B, R1, Ra i R2 definirani kao za opću formulu (I), a X je supstituent pogodan za reakciju ukrižene kondenzacije, ili njegovog zaštićenog derivata
sa spojem formule B
[image]
gdje su R3 i x definirani kao za opću formulu (I), a Y je supstituent pogodan za reakciju ukrižene kondenzacije, ili njegov zaštićeni derivat;
gdje X i Y predstavljaju supstituente pogodne za reakciju ukrižene kondenzacije, tako odabrane da mogu međusobno reagirati; ili
(c) reakciji spoja formule E
[image]
ili njegovog zaštićenog derivata
gdje je R1 definiran kao za opću formulu (I), a L4 predstavlja pogodnu izlaznu skupinu;
sa spojem formule F
[image]
gdje su Ra, R2, R3, x, A i B definirani kao za opću formulu (I),
ili njegovim zaštićenim derivatom; ili
(d) dobivanju spoja formule (I), gdje je R1 ostatak koji se veže na glavni karbonil u formuli (I) preko atoma dušika, postupkom koji se sastoji u reakciji odgovarajućeg amina, ili njegovog zaštićenog derivata
sa spojem formule G
[image]
gdje su Ra, R2, R3, x, A i B definirani kao za opću formulu (I), a L2 predstavlja pogodnu izlaznu skupinu;
ili njegovim zaštićenim derivatom;
(e) reakciji spoja formule F, definirane kao gore, ili njegovog zaštićenog derivata
sa spojem formule J
[image]
gdje je R1 definiran kao za opću formulu (I); u prisutnosti pogodnog kondenzacijskog sredstva; ili
(f) reakciji spoja formule K
[image]
gdje su R2, R3, x, A i B definirani kao za opću formulu (I), a Z predstavlja supstituent pogodan za reakciju ukrižene kondenzacije
sa spojem formule L
[image]
gdje su R1 i Ra definirani kao za opću formulu (I);
u uvjetima pogodnim za reakciju kondenzacije; ili
(g) dobivanju spoja formule (I), u kojoj R1 je -NHR20 ili NH-(C1-6alkil)-R20, reakcijom spoja formule F, definirane kao gore, sa spojem formule:
R20N=C=O ili R20-(C1-6alkil)-N=C=O
gdje je R20 definiran kao za opću formulu (I), primjerice R20 predstavlja heteroarilnu skupinu, poput piridina.
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| PE20131197A1 (es) | 2008-10-31 | 2013-11-06 | Genentech Inc | Compuestos de pirazolopirimidina como inhibidores de jak y composiciones farmaceuticas que los contienen |
| US20110230497A1 (en) * | 2008-11-07 | 2011-09-22 | H. Lundbeck A/S | Biologically active amides |
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2008
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- 2008-10-13 CA CA2702008A patent/CA2702008A1/en not_active Abandoned
- 2008-10-13 US US12/226,286 patent/US8716296B2/en not_active Expired - Fee Related
- 2008-10-13 SI SI200830286T patent/SI2212297T1/sl unknown
- 2008-10-13 KR KR1020107010451A patent/KR20100090772A/ko not_active Application Discontinuation
- 2008-10-13 AU AU2008309517A patent/AU2008309517B2/en not_active Ceased
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- 2008-10-13 EA EA201000554A patent/EA020439B1/ru not_active IP Right Cessation
- 2008-10-13 BR BRPI0818543A patent/BRPI0818543A2/pt not_active IP Right Cessation
- 2008-10-13 CN CN201410394966.8A patent/CN104151293A/zh active Pending
- 2008-10-13 MX MX2010003987A patent/MX2010003987A/es active IP Right Grant
- 2008-10-13 AT AT08838451T patent/ATE510827T1/de not_active IP Right Cessation
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- 2008-10-13 WO PCT/EP2008/063715 patent/WO2009047359A1/en active Application Filing
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2010
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- 2014-09-03 JP JP2014178745A patent/JP2015038077A/ja active Pending
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2015
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| IL204594A (en) | 2013-12-31 |
| AU2008309517B2 (en) | 2013-03-14 |
| AU2008309517A1 (en) | 2009-04-16 |
| CA2702008A1 (en) | 2009-04-16 |
| JP5681855B2 (ja) | 2015-03-11 |
| SI2212297T1 (sl) | 2011-09-30 |
| IL204594A0 (en) | 2010-11-30 |
| HK1150052A1 (en) | 2011-10-28 |
| CN101889004B (zh) | 2014-09-10 |
| EP2212297B1 (en) | 2011-05-25 |
| EA020439B1 (ru) | 2014-11-28 |
| WO2009047359A1 (en) | 2009-04-16 |
| JP2011500539A (ja) | 2011-01-06 |
| CN101889004A (zh) | 2010-11-17 |
| ZA201001910B (en) | 2011-05-25 |
| BRPI0818543A2 (pt) | 2018-10-23 |
| MX2010003987A (es) | 2010-08-04 |
| EA201000554A1 (ru) | 2011-04-29 |
| HK1203950A1 (en) | 2015-11-06 |
| CN104151293A (zh) | 2014-11-19 |
| US20100249149A1 (en) | 2010-09-30 |
| EP2212297A1 (en) | 2010-08-04 |
| JP2015038077A (ja) | 2015-02-26 |
| KR20100090772A (ko) | 2010-08-17 |
| US20150038516A1 (en) | 2015-02-05 |
| US8716296B2 (en) | 2014-05-06 |
| DK2212297T3 (da) | 2011-09-05 |
| ATE510827T1 (de) | 2011-06-15 |
| NZ584454A (en) | 2011-09-30 |
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