HRP20150692T1 - Supstituirani derivati benzopirazina kao inhibitori fgfr kinaze za lijeäśenje raka - Google Patents
Supstituirani derivati benzopirazina kao inhibitori fgfr kinaze za lijeäśenje raka Download PDFInfo
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- HRP20150692T1 HRP20150692T1 HRP20150692TT HRP20150692T HRP20150692T1 HR P20150692 T1 HRP20150692 T1 HR P20150692T1 HR P20150692T T HRP20150692T T HR P20150692TT HR P20150692 T HRP20150692 T HR P20150692T HR P20150692 T1 HRP20150692 T1 HR P20150692T1
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- Prior art keywords
- 6alkyl
- substituted
- 4alkyl
- alkyl
- nr14r15
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- 206010028980 Neoplasm Diseases 0.000 title claims 3
- 201000011510 cancer Diseases 0.000 title claims 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims 2
- 229940043355 kinase inhibitor Drugs 0.000 title 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 title 1
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical class N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 title 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 124
- 125000000217 alkyl group Chemical group 0.000 claims 70
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 38
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 33
- 239000002904 solvent Substances 0.000 claims 29
- 238000006243 chemical reaction Methods 0.000 claims 28
- 125000003545 alkoxy group Chemical group 0.000 claims 24
- 150000001875 compounds Chemical class 0.000 claims 23
- 229910052739 hydrogen Inorganic materials 0.000 claims 22
- 239000001257 hydrogen Substances 0.000 claims 22
- 125000005842 heteroatom Chemical group 0.000 claims 17
- 229910052760 oxygen Inorganic materials 0.000 claims 15
- 125000001424 substituent group Chemical group 0.000 claims 15
- 229910052717 sulfur Inorganic materials 0.000 claims 15
- 150000002431 hydrogen Chemical group 0.000 claims 14
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 12
- 239000003054 catalyst Substances 0.000 claims 11
- 229910052736 halogen Inorganic materials 0.000 claims 10
- 150000002367 halogens Chemical class 0.000 claims 10
- -1 C3-8cycloalkenyl Chemical group 0.000 claims 9
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 7
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 7
- 125000002950 monocyclic group Chemical group 0.000 claims 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 5
- 125000000623 heterocyclic group Chemical group 0.000 claims 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 4
- 239000002253 acid Substances 0.000 claims 4
- 125000003342 alkenyl group Chemical group 0.000 claims 4
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims 4
- 125000004432 carbon atom Chemical group C* 0.000 claims 4
- 239000003638 chemical reducing agent Substances 0.000 claims 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 4
- 239000003446 ligand Substances 0.000 claims 4
- 125000001624 naphthyl group Chemical group 0.000 claims 4
- 125000006239 protecting group Chemical group 0.000 claims 4
- 150000003839 salts Chemical class 0.000 claims 4
- 239000007787 solid Substances 0.000 claims 4
- 239000012453 solvate Substances 0.000 claims 4
- 150000001204 N-oxides Chemical class 0.000 claims 3
- 229910007161 Si(CH3)3 Inorganic materials 0.000 claims 3
- 125000000304 alkynyl group Chemical group 0.000 claims 3
- 229910052799 carbon Inorganic materials 0.000 claims 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 2
- 101100240517 Caenorhabditis elegans nhr-11 gene Proteins 0.000 claims 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims 2
- 101001043818 Mus musculus Interleukin-31 receptor subunit alpha Proteins 0.000 claims 2
- 125000004429 atom Chemical group 0.000 claims 2
- 125000000392 cycloalkenyl group Chemical group 0.000 claims 2
- 238000010511 deprotection reaction Methods 0.000 claims 2
- 239000011777 magnesium Substances 0.000 claims 2
- 229910052749 magnesium Inorganic materials 0.000 claims 2
- 238000000034 method Methods 0.000 claims 2
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 claims 2
- 230000002265 prevention Effects 0.000 claims 2
- 229920006395 saturated elastomer Chemical group 0.000 claims 2
- JCMSXZKRELRJFO-QHCPKHFHSA-N (3s)-3-(3,5-dimethoxyphenyl)-3-[3-(1-methylpyrazol-4-yl)quinoxalin-6-yl]-n-propan-2-ylpropan-1-amine Chemical compound COC1=CC(OC)=CC([C@@H](CCNC(C)C)C=2C=C3N=C(C=NC3=CC=2)C2=CN(C)N=C2)=C1 JCMSXZKRELRJFO-QHCPKHFHSA-N 0.000 claims 1
- JCMSXZKRELRJFO-UHFFFAOYSA-N 3-(3,5-dimethoxyphenyl)-3-[3-(1-methylpyrazol-4-yl)quinoxalin-6-yl]-n-propan-2-ylpropan-1-amine Chemical compound COC1=CC(OC)=CC(C(CCNC(C)C)C=2C=C3N=C(C=NC3=CC=2)C2=CN(C)N=C2)=C1 JCMSXZKRELRJFO-UHFFFAOYSA-N 0.000 claims 1
- 108091008794 FGF receptors Proteins 0.000 claims 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- 201000010099 disease Diseases 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 102000052178 fibroblast growth factor receptor activity proteins Human genes 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 230000001404 mediated effect Effects 0.000 claims 1
- 239000011877 solvent mixture Substances 0.000 claims 1
Classifications
-
- 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
-
- 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
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
-
- 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
- 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
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
Claims (16)
1. Spoj formule (I):
[image]
uključujući njegov bilo koji tautomerni ili stereokemijski izomerni oblik, gdje
n predstavlja cijeli broj jednak 0, 1, 2, 3 ili 4;
R1 predstavlja vodik, C1-6alkil, C2-4alkenil, hidroksiC1-6alkil, haloC1-6alkil, hidroksihaloC1-6alkil, cijanoC1-4alkil, C1-6alkoksiC1-6alkil gdje svaki C1-6alkil može po izboru biti supstituiran s jednom ili dvije hidroksilne skupine, C1-6alkil supstituiran s -NR4R5, C1-6alkil supstituiran s -C(=O)-NR4R5, -S(=O)2-C1-6alkil, -S(=O)2-haloC1-6alkil, -S(=O)2-NR14R15, C1-6alkil supstituiran s -S(=O)2-C1-6alkil, C1-6alkil supstituiran s -S(=O)2-haloC1-6alkil, C1-6alkil supstituiran s -S(=O)2-NR14R15, C1-6alkil supstituiran s -NHS(=O)2-C1-6alkil, C1-6alkil supstituiran s -NH-S(=O)2-haloC1-6alkil, C1-6alkil supstituiran s -NR12-S(=O)2-NR14R15, R6, C1-6alkil supstituiran s R6, C1-6alkil supstituiran s -C(=O)-R6, hidroksiC1-6alkil supstituiran s R6, C1-6alkil supstituiran s -Si(CH3)3, C1-6alkil supstituiran s -P(=O)(OH)2 ili C1-6alkil supstituiran s -P(=O)(OC1-6alkil)2;
svaki R1a je nezavisno izabran između vodika, C1-4alkil, hidroksiC1-4alkil, C1-4alkil supstituiran s amino ili mono- ili di(C1-4alkil)amino ili -NH(C3-8cikloalkil), cijanoC1-4alkil, C1-4alkoksiC1-4alkil, i C1-4alkil supstituiran s jednim ili više atoma fluora;
svaki R2 je nezavisno izabran između hidroksil, halogen, cijano, C1-4alkil, C2-4alkenil, C2-4alkinil, C1-4alkoksi, hidroksiC1-4alkil, hidroksiC1-4alkoksi, haloC1-4alkil, haloC1-4alkoksi, hidroksihaloC1-4alkil, hidroksihaloC1-4alkoksi, C1-4alkoksiC1-4alkil, haloC1-4alkoksiC1-4alkil, C1-4alkoksiC1-4alkil gdje svaki C1-4alkil može po izboru biti supstituiran s jednom ili dvije hidroksilne skupine, hidroksihaloC1-4alkoksiC1-4alkil, R13, C1-4alkil supstituiran s R13, C1-4alkil supstituiran s -C(=O)-R13, C1-4alkoksi supstituiran s R13, C1-4alkoksi supstituiran s -C(=O)-R13, -C(=O)-R13, C1-4alkil supstituiran s -NR7R8, C1-4alkil supstituiran s -C(=O)-NR7R8, C1-4alkoksi supstituiran s -NR7R8, C1-4alkoksi supstituiran s -C(=O)-NR7R8, -NR7R8 i -C(=O)-NR7R8; ili kada su dvije R2 skupine spojene na susjedne atome ugljika tada se mogu uzeti zajedno i formirati radikal formule:
-O-(C(R17)2)p-O-;
-X-CH=CH-; ili
-X-CH=N-;
gdje R17 predstavlja vodik ili fluor, p predstavlja 1 ili 2 i X predstavlja O ili S;
R3a predstavlja -NR10R11, hidroksil, C1-6alkoksi, hidroksiC1-6alkoksi, C1-6alkoksi supstituiran s -NR10R11, C1-6alkil, C2-6alkenil, C2-6alkinil, haloC1-6alkil po izboru supstituiran s -O-C(=O)-C1-6alkil,
hidroksiC1-6alkil po izboru supstituiran s -O-C(=O)-C1-6alkil, hidroksiC2-6alkenil, hidroksiC2-6alkinil,
hidroksihaloC1-6alkil, cijanoC1-6alkil, C1-6alkil supstituiran s karboksilom, C1-6alkil supstituiran s -C(=O)-C1-6alkil, C1-6alkil supstituiran s -C(=O)-O-C1-6alkil, C1-6alkil supstituiran s C1-6alkoksiC1-6alkil-O-C(=O)-, C1-6alkil supstituiran s C1-6alkoksiC1-6alkil-C(=O)-, C1-6alkil supstituiran s -O-C(=O)-C1-6alkil, C1-6alkoksiC1-6alkil gdje svaki C1-6alkil može po izboru biti supstituiran s jednom ili dvije hidroksilne skupine ili s -O-C(=O)-C1-6alkil, C2-6alkenil supstituiran s C1-6alkoksi, C2-6alkinil supstituiran s C1-6alkoksi, C1-6alkil supstituiran s R9 i po izboru supstituiran s -O-C(=O)-C1-6alkil, C1-6alkil supstituiran s -C(=O)-R9, C1-6alkil supstituiran s hidroksil i R9, C2-6alkenil supstituiran s R9, C2-6alkinil supstituiran s R9, C1-6alkil supstituiran s -NR10R11, C2-6alkenil supstituiran s -NR10R11, C2-6alkinil supstituiran s -NR10R11, C1-6alkil supstituiran s hidroksil i -NR10R11, C1-6alkil supstituiran s jednim ili dva halogena i -NR10R11, -C1-6alkil-C(R12)=NO-R12, C1-6alkil supstituiran s -C(=O)-NR10R11, C1-6alkil supstituiran s -O-C(=O)-NR10R11, -S(=O)2-C1-6alkil, -S(=O)2-haloC1-6alkil, -S(=O)2-NR14R15, C1-6alkil supstituiran s -S(=O)2-C1-6alkil, C1-6alkil supstituiran s -S(=O)2-haloC1-6alkil, C1-6alkil supstituiran s -S(=O)2-NR14R15, C1-6alkil supstituiran s -NR12-S(=O)2-C1-6alkil, C1-6alkil supstituiran s -NH-S(=O)2-haloC1-6alkil, C1-6alkil supstituiran s -NR12-S(=O)2-NR14R15, R13, C1-6alkil supstituiran s -P(=O)(OH)2 ili C1-6alkil supstituiran s -P(=O)(OC1-6alkil)2;
R3b predstavlja vodik ili hidroksil; uz uvjet da ako R3a predstavlja -NR10R11, tada R3b predstavlja vodik; ili
R3a i R3b su uzeti zajedno da formiraju =0, formiraju =NR10, formiraju ciklopropil zajedno s atomom ugljika za koji su spojeni, formiraju =CH-C0-4alkil supstituiran s R3c, ili formiraju
[image]
gdje je prsten A monociklički 5- do 7-eročlani zasićeni heterocikl koji sadrži jedan heteroatom izabran između N, O ili S, taj heteroatom nije smješten na alfa položaju dvostruke veze, gdje je prsten A po izboru supstituiran s cijano, C1-4alkil, hidroksiC1-4alkil, H2N-C1-4alkil, (C1-4alkil)NH-C1-4alkil, (C1-4alkil)2N-C1-4alkil, haloC1-4alkil)NH-C1-4alkil, C1-4alkoksiC1-4alkil, -C(=O)-NH2, -C(=O)-NH(C1-4alkil), -C(=O)-N(C1-4alkil)2;
R3c predstavlja vodik, hidroksil, C1-6alkoksi, R9, -NR10R11, cijano, -C(=O)-C1-6alkil ili -CH(OH)- C1-6alkil;
R4 i R5 svaki nezavisno predstavlja vodik, C1-6alkil, hidroksiC1-6alkil, haloC1-6alkil, hidroksihaloC1-6alkil, C1-6alkoksiC1-6alkil gdje svaki C1-6alkil može po izboru biti supstituiran s jednom ili dvije hidroksilne skupine, -S(=O)2-C1-6alkil, -S(=O)2-haloC1-6alkil, -S(=O)2-NR14R15, C1-6alkil supstituiran s -S(=O)2-C1-6alkil, C1-6alkil supstituiran s -S(=O)2-haloC1-6alkil, C1-6alkil supstituiran s -S(=O)2-NR14R15, C1-6alkil supstituiran s -NH-S(=O)2-C1-6alkil, C1-6alkil supstituiran s -NH-S(=O)2-haloC1-6alkil, C1-6alkil supstituiran s -NH- S(=O)2-NR14R15, R13 ili C1-6alkil supstituiran s R13;
R6 predstavlja C3-8cikloalkil, C3-8cikloalkenil, fenil, 4- do 7-eročlani monociklički heterociklil koji sadrži barem jedan heteroatom izabran između N, O ili S; taj C3-8cikloalkil, C3-8cikloalkenil, fenil, 4- do 7-eročlani monociklički heterociklil, po izboru i svaki je nezavisno supstituiran s 1, 2, 3, 4 ili 5 supstituenata, svaki supstituent je nezavisno izabran između cijano, C1-6alkil, cijanoC1-6alkil, hidroksil, karboksil, hidroksiC1-6alkil, halogen, haloC1-6alkil, hidroksihaloC1-6alkil, C1-6alkoksi, C1-6alkoksiC1-6alkil, C1-6alkil-OC(=O)-, -NR14R15, -C(=O)-NR14R15, C1-6alkil supstituiran s -NR14R15, C1-6alkil supstituiran s -C(=O)-NR14R15, -S(=O)2-C1-6alkil, -S(=O)2-haloC1-6alkil, -S(=O)2-NR14R15, C1-6alkil supstituiran s -S(=O)2-C1-6alkil, C1-6alkil supstituiran s -S(=O)2-haloC1-6alkil, C1-6alkil supstituiran s -S(=O)2-NR14R15, C1-6alkil supstituiran s -NH-S(=O)2-C1-6alkil, C1-6alkil supstituiran s -NH-S(=O)2-halOC1-6alkil ili C1-6alkil supstituiran s -NH-S(=O)2-NR14R15;
R7 i R8 svaki nezavisno predstavlja vodik, C1-6alkil, hidroksiC1-6alkil, haloC1-6alkil, hidroksihaloC1-6alkil ili C1-6alkoksiC1-6alkil;
R9 predstavlja C3-8cikloalkil, C3-8cikloalkenil, fenil, naftil, ili 3- do 12-eročlani monociklički ili biciklički heterociklil koji obuhvaća barem jedan heteroatom izabran između N, O ili S, taj C3-8cikloalkil, C3-8cikloalkenil, fenil, naftil, ili 3- to 12-eročlani monociklički ili biciklički heterociklil svaki po izboru i svaki nezavisno je supstituiran s 1, 2, 3, 4 ili 5 supstituenata, svaki supstituent je nezavisno izabran između =O, C1-4alkil, hidroksil, karboksil, hidroksiC1-4alkil, cijano, cijanoC1-4alkil, C1-4alkil-O-C(=O)-, C1-4alkil supstituiran s C1-4alkil-O-C(=O)-, C1-4alkil-C(=O)-, C1-4alkoksiC1-4alkil gdje svaki C1-4alkil može po izboru biti supstituiran s jednom ili dvije hidroksilne skupine, halogen, haloC1-4alkil, hidroksihaloC1-4alkil, -NR14R15, -C(=O)-NR14R15, C1-4alkil supstituiran s -NR14R15, C1-4alkil supstituiran s -C(=O)-NR14R15, C1-4alkoksi, -S(=O)2-C1-4alkil, -S(=O)2-haloC1-4alkil, -S(=O)2-NR14R15, C1-4alkil supstituiran s -S(=O)2-NR14R15, C1-4alkil supstituiran s -NH-S(=O)2-C1-4alkil, C1-4alkil supstituiran s -NH-S(=O)2-haloC1-4alkil, C1-4alkil supstituiran s -NH-S(=O)2-NR14R15, R13, -C(=O)-R13, C1-4alkil supstituiran s R13, fenil po izboru supstituiran s R16, fenilC1-6alkil gdje je fenil po izboru supstituiran s R16, 5- ili 6-eročlani aromatski monociklički heterociklil koji sadrži barem jedan heteroatom izabran između N, O ili S gdje je taj heterociklil po izboru supstituiran s R16;
ili kada su dva od supstituenata od R9 spojeni za isti atom, mogu biti uzeti zajedno da formiraju 4- do 7-eročlani zasićeni monociklički heterociklil koji sadrži barem jedan heteroatom izabran između N, O ili S;
R10 i R11 svaki nezavisno predstavlja vodik, karboksil, C1-6alkil, cijanoC1-6alkil, C1-6alkil supstituiran s -NR14R15, C1-6alkil supstituiran s -C(=O)-NR14R15, haloC1-6alkil, hidroksiC1-6alkil, hidroksihaloC1-6alkil, C1-6alkoksi, C1-6alkoksiC1-6alkil gdje svaki C1-6alkil može po izboru biti supstituiran s jednom ili dvije hidroksilne skupine, R6, C1-6alkil supstituiran s R6, -C(=O)-R6, -C(=O)-C1-6alkil, -C(=O)-hidroksiC1-6alkil, -C(=O)-haloC1-6alkil,-C(=O)-hidroksihaloC1-6alkil, C1-6alkil supstituiran s -Si(CH3)3, -S(=O)2-C1-6alkil, -S(=O)2-haloC1-6alkil, -S(=O)2-NR14R15, C1-6alkil supstituiran s -S(=O)2-C1-6alkil, C1-6alkil supstituiran s -S(=O)2-halOC1-6alkil, C1-6alkil supstituiran s -S(=O)2-NR14R15, C1-6alkil supstituiran s -NH-S(=O)2-C1-6alkil, C1-6alkil supstituiran s -NH-S(=O)2-haloC1-6alkil ili C1-6alkil supstituiran s -NH-S(=O)2-NR14R15;
R12 predstavlja vodik ili C1-4alkil po izboru supstituiran s C1-4alkoksi;
R13 predstavlja C3-8cikloalkil ili zasićeni 4- do 6-eročlani monociklički heterociklil koji sadrži barem jedan heteroatom izabran između N, O ili S, gdje je taj C3-8cikloalkil ili monociklički heterociklil po izboru supstituiran s 1, 2 ili 3 supstituenta od kojih je svaki nezavisno izabran između halogen, hidroksil, C1-6alkil, -C(=O)-C1-6alkil, C1-6alkoksi, ili -NR14R15;
R14 i R15 svaki nezavisno predstavlja vodik, ili haloC1-4alkil, ili C1-4alkil po izboru supstituiran supstituentom izabranim između hidroksil, C1-4alkoksi, amino ili mono- ili di(C1-4alkil)amino;
R16 predstavlja hidroksil, halogen, cijano, C1-4alkil, C1-4alkoksi, -NR14R15 ili -C(=O)NR14R15;
njegov N-oksid, njegova farmaceutski prikladna sol ili solvat.
2. Spoj prema zahtjevu 1 gdje spoj jest spoj formule (I°):
[image]
uključujući njegov bilo koji tautomerni ili stereokemijski izomerni oblik, gdje
n predstavlja cijeli broj jednak 0, 1, 2, 3 ili 4;
R1 predstavlja vodik, C1-6alkil, C2-4alkenil, hidroksiC1-6alkil, haloC1-6alkil, hidroksihaloC1-6alkil, C1-6alkoksiC1-6alkil gdje svaki C1-6alkil može po izboru biti supstituiran s jednom ili dvije hidroksilne skupine, C1-6alkil supstituiran s -NR4R5, C1-6alkil supstituiran s -C(=O)-NR4R5, -S(=O)2-C1-6alkil, -S(=O)2-haloC1-6alkil, -S(=O)2-NR14R15, C1-6alkil supstituiran s -S(=O)2-C1-6alkil, C1-6alkil supstituiran s -S(=O)2-haloC1-6alkil, C1-6alkil supstituiran s -S(=O)2-NR14R15, C1-6alkil supstituiran s -NHS(=O)2-C1-6alkil, C1-6alkil supstituiran s -NH-S(=O)2-haloC1-6alkil, C1-6alkil supstituiran s -NR12-S(=O)2-NR14R15, R6, C1-6alkil supstituiran s R6, C1-6alkil supstituiran s -C(=O)-R6, hidroksiC1-6alkil supstituiran s R6, C1-6alkil supstituiran s -Si(CH3)3, C1-6alkil supstituiran s -P(=O)(OH)2 ili C1-6alkil supstituiran s -P(=O)(OC1-6alkil)2;
svaki R2 je nezavisno izabran između halogen, cijano, C1-4alkil, C2-4alkenil, C2-4alkinil, C1-4alkoksi, hidroksiC1-4alkil, hidroksiC1-4alkoksi, haloC1-4alkil, haloC1-4alkoksi, hidroksihaloC1-4alkil, hidroksihaloC1-4alkoksi, C1-4alkoksiC1-4alkil, haloC1-4alkoksiC1-4alkil, C1-4alkoksiC1-4alkil gdje svaki C1-4alkil može po izboru biti supstituiran s jednom ili dvije hidroksilne skupine, hidroksihaloC1-4alkoksiC1-4alkil, R13, C1-4alkil supstituiran s R13, C1-4alkil supstituiran s -C(=O)-R13, C1-4alkoksi supstituiran s R13, C1-4alkoksi supstituiran s -C(=O)-R13, -C(=O)-R13, C1-4alkil supstituiran s -NR7R8, C1-4alkil supstituiran s -C(=O)-NR7R8, C1-4alkoksi supstituiran s -NR7R8, C1-4alkoksi supstituiran s -C(=O)-NR7R8, -NR7R8 ili -C(=O)-NR7R8;
R3a predstavlja -NR10R11, hidroksil, C1-6alkoksi, hidroksiC1-6alkoksi, C1-6alkoksi supstituiran s -NR10R11, C1-6alkil, C2-6alkenil, C2-6alkinil, haloC1-6alkil, hidroksiC1-6alkil, hidroksiC2-6alkenil, hidroksiC2-6alkinil, hidroksihaloC1-6alkil, cijanoC1-6alkil, C1-6alkil supstituiran s karboksilom, C1-6alkil supstituiran s -C(=O)-C1-6alkil, C1-6alkil supstituiran s -C(=O)-O-C1-6alkil, C1-6alkil supstituiran s C1-6alkoksiC1-6alkil-O-C(=O)-, C1-6alkil supstituiran s C1-6alkoksiC1-6alkil-C(=O)-, C1-6alkil supstituiran s -O-C(=O)-C1-6alkil, C1-6alkoksiC1-6alkil gdje svaki C1-6alkil može po izboru biti supstituiran s jednom ili dvije hidroksilne skupine, C2-6alkenil supstituiran s C1-6alkoksi, C2-6alkinil supstituiran s C1-6alkoksi, C1-6alkil supstituiran s R9, C1-6alkil supstituiran s -C(=O)-R9, C1-6alkil supstituiran s hidroksil i R9, C2-6alkenil supstituiran s R9, C2-6alkinil supstituiran s R9, C1-6alkil supstituiran s -NR10R11, C2-6alkenil supstituiran s -NR10R11, C2-6alkinil supstituiran s -NR10R11, C1-6alkil supstituiran s hidroksil i -NR10R11, C1-6alkil supstituiran s jednim ili dva halogena i -NR10R11, -C1-6alkil-C(R12)=NO-R12, C1-6alkil supstituiran s -C(=O)-NR10R11, C1-6alkil supstituiran s -O-C(=O)-NR10R11, -S(=O)2-C1-6alkil, -S(=O)2-haloC1-6alkil, -S(=O)2-NR14R15, C1-6alkil supstituiran s -S(=O)2-C1-6alkil, C1-6alkil supstituiran s -S(=O)2-haloC1-6alkil, C1-6alkil supstituiran s -S(=O)2-NR14R15, C1-6alkil supstituiran s -NR12-S(=O)2-C1-6alkil, C1-6alkil supstituiran s -NH-S(=O)2-haloC1-6alkil, C1-6alkil supstituiran s -NR12-S(=O)2-NR14R15, R13, C1-6alkil supstituiran s -P(=O)(OH)2 ili C1-6alkil supstituiran s -P(=O)(OC1-6alkil)2;
R3b predstavlja vodik ili hidroksil; uz uvjet da ako R3a predstavlja -NR10R11, tada R3b predstavlja vodik; ili
R3a i R3b su uzeti zajedno da formiraju =0, formiraju =NR10, formiraju ciklopropil zajedno s atomom ugljika za koji su spojeni, formiraju =CH-C0-4alkil supstituiran s R3c, ili formiraju
[image]
gdje je prsten A monociklički 5- do 7-eročlani zasićeni heterocikl koji sadrži jedan heteroatom izabran između N, O ili S, taj heteroatom nije smješten na alfa položaju dvostruke veze, gdje je prsten A po izboru supstituiran s cijano, C1-4alkil, hidroksiC1-4alkil, H2N-C1-4alkil, (C1-4alkil)NH-C1-4alkil, (C1-4alkil)2N-C1-4alkil, haloC1-4alkil)NH-C1-4alkil, C1-4alkoksiC1-4alkil, -C(=O)-NH2, -C(=O)-NH(C1-4alkil), -C(=O)-N(C1-4alkil)2;
R3c predstavlja vodik, hidroksil, C1-6alkoksi, R9, -NR10R11, cijano, -C(=O)-C1-6alkil ili -CH(OH)- C1-6alkil;
R4 i R5 svaki nezavisno predstavlja vodik, C1-6alkil, hidroksiC1-6alkil, haloC1-6alkil, hidroksihaloC1-6alkil, C1-6alkoksiC1-6alkil gdje svaki C1-6alkil može po izboru biti supstituiran s jednom ili dvije hidroksilne skupine, -S(=O)2-C1-6alkil, -S(=O)2-haloC1-6alkil, -S(=O)2-NR14R15, C1-6alkil supstituiran s -S(=O)2-C1-6alkil, C1-6alkil supstituiran s -S(=O)2-haloC1-6alkil, C1-6alkil supstituiran s -S(=O)2-NR14R15, C1-6alkil supstituiran s -NH-S(=O)2-C1-6alkil, C1-6alkil supstituiran s -NH-S(=O)2-haloC1-6alkil, C1-6alkil supstituiran s -NH- S(=O)2-NR14R15, R13 ili C1-6alkil supstituiran s R13;
R6 predstavlja C3-8cikloalkil, C3-8cikloalkenil, fenil, 4- do 7-eročlani monociklički heterociklil koji sadrži barem jedan heteroatom izabran između N, O ili S; taj C3-8cikloalkil, C3-8cikloalkenil, fenil, 4- do 7-eročlani monociklički heterociklil, po izboru i svaki je nezavisno supstituiran s 1, 2, 3, 4 ili 5 supstituenata, svaki supstituent je nezavisno izabran između cijano, C1-6alkil, cijanoC1-6alkil, hidroksil, karboksil, hidroksiC1-6alkil, halogen, haloC1-6alkil, hidroksihaloC1-6alkil, C1-6alkoksi, C1-6alkoksiC1-6alkil, C1-6alkil-OC(=O)-, -NR14R15, -C(=O)-NR14R15, C1-6alkil supstituiran s -NR14R15, C1-6alkil supstituiran s -C(=O)-NR14R15, -S(=O)2-C1-6alkil, -S(=O)2-haloC1-6alkil, -S(=O)2-NR14R15, C1-6alkil supstituiran s -S(=O)2-C1-6alkil, C1-6alkil supstituiran s -S(=O)2-haloC1-6alkil, C1-6alkil supstituiran s -S(=O)2-NR14R15, C1-6alkil supstituiran s -NH-S(=O)2-C1-6alkil, C1-6alkil supstituiran s -NH-S(=O)2-halOC1-6alkil ili C1-6alkil supstituiran s -NH-S(=O)2-NR14R15;
R7 i R8 svaki nezavisno predstavlja vodik, C1-6alkil, hidroksiC1-6alkil, haloC1-6alkil, hidroksihaloC1-6alkil ili C1-6alkoksiC1-6alkil;
R9 predstavlja C3-8cikloalkil, C3-8cikloalkenil, fenil, naftil, ili 3- do 12-eročlani monociklički ili biciklički heterociklil koji obuhvaća barem jedan heteroatom izabran između N, O ili S, taj C3-8cikloalkil, C3-8cikloalkenil, fenil, naftil, ili 3- to 12-eročlani monociklički ili biciklički heterociklil svaki po izboru i svaki nezavisno je supstituiran s 1, 2, 3, 4 ili 5 supstituenata, svaki supstituent je nezavisno izabran između =O, C1-4alkil, hidroksil, karboksil, hidroksiC1-4alkil, cijano, cijanoC1-4alkil, C1-4alkil-O-C(=O)-, C1-4alkil supstituiran s C1-4alkil-O-C(=O)-, C1-4alkil-C(=O)-, C1-4alkoksiC1-4alkil gdje svaki C1-4alkil može po izboru biti supstituiran s jednom ili dvije hidroksilne skupine, halogen, haloC1-4alkil, hidroksihaloC1-4alkil, -NR14R15, -C(=O)-NR14R15, C1-4alkil supstituiran s -NR14R15, C1-4alkil supstituiran s -C(=O)-NR14R15, C1-4alkoksi, -S(=O)2-C1-4alkil, -S(=O)2-haloC1-4alkil, -S(=O)2-NR14R15, C1-4alkil supstituiran s -S(=O)2-NR14R15, C1-4alkil supstituiran s -NH-S(=O)2-C1-4alkil, C1-4alkil supstituiran s -NH-S(=O)2-haloC1-4alkil, C1-4alkil supstituiran s -NH-S(=O)2-NR14R15, R13, -C(=O)-R13, C1-4alkil supstituiran s R13, fenil po izboru supstituiran s R16, fenilC1-6alkil gdje je fenil po izboru supstituiran s R16, 5- ili 6-eročlani aromatski monociklički heterociklil koji sadrži barem jedan heteroatom izabran između N, O ili S gdje je taj heterociklil po izboru supstituiran s R16;
ili kada su dva od supstituenata od R9 spojeni za isti atom, mogu biti uzeti zajedno da formiraju 4- do 7-eročlani zasićeni monociklički heterociklil koji sadrži barem jedan heteroatom izabran između N, O ili S;
R10 i R11 svaki nezavisno predstavlja vodik, C1-6alkil, cijanoC1-6alkil, C1-6alkil supstituiran s -NR14R15, haloC1-6alkil, hidroksiC1-6alkil, hidroksihaloC1-6alkil, C1-6alkoksiC1-6alkil gdje svaki C1-6alkil može po izboru biti supstituiran s jednom ili dvije hidroksilne skupine, R6, C1-6alkil supstituiran s R6, -C(=O)-R6, -C(=O)-C1-6alkil, -C(=O)-hidroksiC1-6alkil, -C(=O)-haloC1-6alkil,-C(=O)-hidroksihaloC1-6alkil, C1-6alkil supstituiran s -Si(CH3)3, -S(=O)2-C1-6alkil, -S(=O)2-haloC1-6alkil, -S(=O)2-NR14R15, C1-6alkil supstituiran s -S(=O)2-C1-6alkil, C1-6alkil supstituiran s -S(=O)2-haloC1-6alkil, C1-6alkil supstituiran s -S(=O)2-NR14R15, C1-6alkil supstituiran s -NH-S(=O)2-C1-6alkil, C1-6alkil supstituiran s -NH-S(=O)2-haloC1-6alkil ili C1-6alkil supstituiran s -NH-S(=O)2-NR14R15;
R12 predstavlja vodik ili C1-4alkil po izboru supstituiran s C1-4alkoksi;
R13 predstavlja C3-8cikloalkil ili zasićeni 4- do 6-eročlani monociklički heterociklil koji sadrži barem jedan heteroatom izabran između N, O ili S, gdje je taj C3-8cikloalkil ili monociklički heterociklil po izboru supstituiran s 1, 2 ili 3 supstituenta od kojih je svaki nezavisno izabran između halogen, hidroksil, C1-6alkil, -C(=O)-C1-6alkil, C1-6alkoksi, ili -NR14R15;
R14 i R15 svaki nezavisno predstavlja vodik, ili haloC1-4alkil, ili C1-4alkil po izboru supstituiran supstituentom izabranim između hidroksil, C1-4alkoksi, amino ili mono- ili di(C1-4alkil)amino;
R16 predstavlja hidroksil, halogen, cijano, C1-4alkil, C1-4alkoksi, -NR14R15 ili -C(=O)NR14R15;
njegov N-oksid, njegova farmaceutski prikladna sol ili solvat.
3. Spoj prema zahtjevu 1 ili 2 gdje n je 0, 1 ili 2.
4. Spoj prema bilo kojem od prethodnih zahtjeva gdje R1 je C1-6alkil.
5. Spoj prema bilo kojem od prethodnih zahtjeva gdje R2 je C1-4alkoksi.
6. Spoj prema bilo kojem od prethodnih zahtjeva gdje R3a je -NR10R11, hidroksil, hidroksiC1-6alkil, cijanoC1-6alkil, C1-6alkil supstituiran s -C(=O)-C1-6alkil, C1-6alkil supstituiran s -C(=O)-O-C1-6alkil, C1-6alkil supstituiran s R9, C1-6alkil supstituiran s -NR10R11, C1-6alkil supstituiran s hidroksil i -NR10R11, C1-6alkil supstituiran s -C(=O)-NR10R11.
7. Spoj prema bilo kojem od zahtjeva 1 do 5 gdje R3a i R3b uzeti zajedno formiraju =0, formiraju ciklopropil zajedno s atomom ugljika za koji su spojeni, formiraju =CH-C0-4alkil supstituiran s R3c, ili formiraju
[image]
gdje je prsten A monociklički 5- do 7-eročlani zasićeni heterocikl koji sadrži jedan heteroatom izabran između N, O ili S, taj heteroatom nije smješten na alfa položaju dvostruke veze.
8. Spoj prema bilo kojem od zahtjeva 1 do 5, ili 7 gdje R3c predstavlja hidroksil, -NR10R11, cijano, ili -C(=O)-C1-6alkil.
9. Spoj prema bilo kojem od prethodnih zahtjeva gdje je R9 monociklički heterociklil koji sadrži barem jedan heteroatom izabran između N, O ili S, taj monociklički heterociklil po izboru je supstituiran s 1 supstituentom izabranim između =0 ili C1-4alkil.
10. Spoj prema bilo kojem od prethodnih zahtjeva gdje R10 i R11 svaki nezavisno predstavlja vodik, C1-6alkil, C1-6alkil supstituiran s -NR14R15 ili haloC1-6alkil, gdje R14 i R15 svaki nezavisno predstavlja vodik ili C1-4alkil.
11. Spoj prema zahtjevu 1 ili 2 gdje je spoj izabran između
{(Z)-3-(3,5-Dimetoksi-fenil)-3-[3-(1-metil-1H-pirazol-4-il)-kinoksalin-6-il]-alil}-dimetil-amin;
{(Z)-3-(3,5-Dimetoksi-fenil)-3-[3-(1-metil-1H-pirazol-4-il)-kinoksalin-6-il]-alil}-izopropil-amin;
{(Z)-3-(3,5-Dimetoksi-fenil)-3-[3-(1-metil-1H-pirazol-4-il)-kinoksalin-6-il]-alil}-(2,2,2-trifluoroetil)-amin;
{(S)-3-(3,5-Dimetoksi-fenil)-3-[3-(1-metil-1H-pirazol-4-il)-kinoksalin-6-il]-propil}-izopropil-amin;
{3-(3,5-Dimetoksi-fenil)-3-[3-(1-metil-1H-pirazol-4-il)-kinoksalin-6-il]-propil}-izopropil-amin;
njegov N-oksid, njegova farmaceutski prikladna sol ili solvat.
12. Spoj prema bilo kojem od zahtjeva 1 do 11 ili njegova farmaceutski prikladna sol ili solvat.
13. Spoj prema bilo kojem od prethodnih zahtjeva za uporabu u
(i) liječenju; ili
(ii) prevenciji ili liječenju bolesti ili stanja posredovanih FGFR kinazom; ili
(iii) prevenciji ili liječenju raka.
14. Farmaceutski oblik koji sadrži spoj formule (I) prema bilo kojem od zahtjeva 1 do 12.
15. Uporaba spoja prema bilo kojem od zahtjeva 1 do 12 za proizvodnju lijeka za prevenciju ili liječenje raka.
16. Postupak pripreme spoja formule (I) prema zahtjevu 1, taj postupak obuhvaća
(I) reakcija intermedijera formule (IV) gdje W1 predstavlja prikladnu odlazeću skupinu, s intermedijerom formule (V) u prisutnosti prikladnog katalizatora, prikladne baze, i prikladnog otapala ili smjese otapala,
[image]
s R1, R2 i n kako su definirani u zahtjevu 1;
(IIa) reakcija intermedijera formule (VI) gdje W3 predstavlja prikladnu odlazeću skupinu, s intermedijerom formule (XIII) u prisutnosti CO, prikladnog katalizatora, prikladnog liganda, prikladne baze, i prikladnog otapala,
[image]
s R1, R2 i n kako su definirani u zahtjevu 1;
(IIb) reakcija intermedijera formule (VI’) gdje W3 predstavlja prikladnu odlazeću skupinu, s intermedijerom formule (XIII) u prisutnosti CO, prikladnog katalizatora, prikladnog liganda, prikladne baze, i prikladnog otapala,
[image]
s R1, R2, R1a i n kako su definirani u zahtjevu 1;
(IIIa) reakcija intermedijera formule (VII) s intermedijerom formule (VIII) gdje W2 predstavlja prikladnu odlazeću skupinu, u prisutnosti katalizatora, prikladne baze, i prikladnog otapala,
[image]
s R1, R2 i n kako su definirani u zahtjevu 1;
(IIIb) reakcija intermedijera formule (VII’) s intermedijerom formule (VIII) gdje W2 predstavlja prikladnu odlazeću skupinu, u prisutnosti katalizatora, prikladne baze, i prikladnog otapala,
[image]
s R1, R2, R1a i n kako su definirani u zahtjevu 1;
(IVa) reakcija intermedijera formule (VI) gdje W3 predstavlja prikladnu odlazeću skupinu s intermedijerom formule (IX) u prisutnosti prikladnog katalizatora, prikladne baze, prikladne krute baze i prikladnog otapala,
[image]
s R1, R2, R3c i n kako su definirani u zahtjevu 1;
(IVb) reakcija intermedijera formule (VI’) gdje W3 predstavlja prikladnu odlazeću skupinu s intermedijerom formule (IX) u prisutnosti prikladnog katalizatora, prikladne baze, prikladne krute baze, i prikladnog otapala,
[image]
s R1, R2, R1a, R3c i n kako su definirani u zahtjevu 1;
(Va) reakcija intermedijera formule (XI) s intermedijerom formule (XII) gdje W4 predstavlja prikladnu odlazeću skupinu, u prisutnosti prikladnog katalizatora, prikladne baze, prikladne krute baze, i prikladnog otapala,
[image]
s R1, R2, R3c i n kako su definirani u zahtjevu 1;
(Vb) reakcija intermedijera formule (XI’) s intermedijerom formule (XII) gdje W4 predstavlja prikladnu odlazeću skupinu, u prisutnosti prikladnog katalizatora, prikladne baze, prikladne krute baze, i prikladnog otapala,
[image]
s R1, R2, R1a, R3c i n kako su definirani u zahtjevu 1;
(VIa) uklanjanje zaštite s intermedijera formule (XIV) gdje P predstavlja prikladnu zaštitnu skupinu u prisutnosti prikladne kiseline i prikladnog otapala,
[image]
s R1, R2, R11 i n kako su definirani u zahtjevu 1;
(Vlb) uklanjanje zaštite s intermedijera formule (XIV’) gdje P predstavlja prikladnu zaštitnu skupinu u prisutnosti prikladne kiseline i prikladnog otapala,
[image]
s R1, R2, R1a, R11 i n kako su definirani u zahtjevu 1;
(VIIa) reakcija intermedijera formule (XIX) s intermedijerom formule (VI) gdje W3 predstavlja prikladnu odlazeću skupinu u prisutnosti prikladnog katalizatora, prikladnog liganda, prikladne baze, i prikladnog otapala,
[image]
s R1, R2, R10, R11 i n kako su definirani u zahtjevu 1;
(VIIb) reakcija intermedijera formule (XIX) s intermedijerom formule (VI’) gdje W3 predstavlja prikladnu odlazeću skupinu u prisutnosti prikladnog katalizatora, prikladnog liganda, prikladne baze, i prikladnog otapala,
[image]
s R1, R2, R1a, R10, R11 i n kako su definirani u zahtjevu 1;
(VIIIa) reakcija intermedijera formule (XXI) s prikladnim reducensom i prikladnim otapalom,
[image]
s R1, R2, i n kako su definirani u zahtjevu 1;
(Vlllb) reakcija intermedijera formule (XXI’) s prikladnim reducensom i prikladnim otapalom,
[image]
s R1, R2, R1a, i n kako su definirani u zahtjevu 1;
(IXa) reakcija intermedijera formule (XXIII) gdje W5 predstavlja prikladnu odlazeću skupinu, s NHR11 u prisutnosti prikladnog otapala,
[image]
s R1, R2, R11 i n kako su definirani u zahtjevu 1;
(IXb) reakcija intermedijera formule (XXIII’) gdje W5 predstavlja prikladnu odlazeću skupinu, s NHR11 u prisutnosti prikladnog otapala,
[image]
s R1, R2, R1a, R11 i n kako su definirani u zahtjevu 1;
(Xa) reakcija intermedijera formule (XXI) s magnezijem u prisutnosti prikladnog otapala,
[image]
s R1, R2 i n kako su definirani u zahtjevu 1;
(Xb) reakcija intermedijera formule (XXI’) s magnezijem u prisutnosti prikladnog otapala,
[image]
s R1, R2, R1a i n kako su definirani u zahtjevu 1;
(XIa) reakcija intermedijera formule (XXIV) s kalijevim cijanidom u prisutnosti prikladnog otapala,
[image]
s R1, R2 i n kako su definirani u zahtjevu 1;
(XIb) reakcija intermedijera formule (XXIV’) s kalijevim cijanidom u prisutnosti prikladnog otapala,
[image]
s R1, R2, R1a i n kako su definirani u zahtjevu 1;
(XIIa) reakcija intermedijera formule (XXIV) s HR9 u prisutnosti prikladne baze i prikladnog
otapala,
[image]
s R1, R2, R9 i n kako su definirani u zahtjevu 1;
(XIIb) reakcija intermedijera formule (XXIV’) s HR9 u prisutnosti prikladne baze i prikladnog
otapala,
[image]
s R1, R2, R1a, R9 i n kako su definirani u zahtjevu 1;
(XIIIa) reakcija intermedijera formule (XXV) s NHR10R11 u prisutnosti prikladnog otapala,
[image]
s R1, R2, R10, R11 i n kako su definirani u zahtjevu 1;
(XIIIb) reakcija intermedijera formule (XXV’) s NHR10R11 u prisutnosti prikladnog otapala,
[image]
s R1, R2, R1a, R10, R11 i n kako su definirani u zahtjevu 1;
(XIVa) reakcija intermedijera formule (XXX) gdje P predstavlja prikladnu zaštitnu skupinu, s prikladnom kiselinom u prisutnosti prikladnog otapala
[image]
s R1, R2 i n kako su definirani u zahtjevu 1;
(XIVb) reakcija intermedijera formule (XXX’) gdje P predstavlja prikladnu zaštitnu skupinu, s prikladnom kiselinom u prisutnosti prikladnog otapala
[image]
s R1, R2, R1a i n kako su definirani u zahtjevu 1;
(XVa) reakcija spoja formule (I-b-3) s reducensom H- u prisutnosti prikladnog otapala,
[image]
s R1, R2 i n kako su definirani u zahtjevu 1;
(XVb) reakcija spoja formule (I-b’-3) s reducensom H- u prisutnosti prikladnog otapala,
[image]
s R1, R2, R1a i n kako su definirani u zahtjevu 1;
(XVI) konverzija jednog spoja formule (I) u drugi spoj formule (I).
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PCT/GB2011/052356 WO2012073017A1 (en) | 2010-11-29 | 2011-11-29 | Substituted benzopyrazin derivatives as fgfr kinase inhibitors for the treatment of cancer diseases |
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HRP20150692T8 (en) | 2015-09-25 |
HK1187916A1 (en) | 2014-04-17 |
EP2646432A1 (en) | 2013-10-09 |
CA2819009A1 (en) | 2012-06-07 |
AU2011334624B2 (en) | 2016-09-15 |
BR112013013435B1 (pt) | 2020-10-20 |
CA2819009C (en) | 2020-02-25 |
HUE025091T2 (en) | 2016-01-28 |
AU2011334624A1 (en) | 2013-06-13 |
US20130267525A1 (en) | 2013-10-10 |
KR101914720B1 (ko) | 2018-11-05 |
EP2646432B1 (en) | 2015-04-08 |
GB201020179D0 (en) | 2011-01-12 |
DK2646432T3 (en) | 2015-07-13 |
US20160031856A1 (en) | 2016-02-04 |
MX2013005897A (es) | 2013-10-25 |
RU2013129820A (ru) | 2015-01-10 |
ES2541493T3 (es) | 2015-07-21 |
WO2012073017A1 (en) | 2012-06-07 |
SMT201500191B (it) | 2015-09-07 |
US9290478B2 (en) | 2016-03-22 |
RU2602233C2 (ru) | 2016-11-10 |
KR20130132509A (ko) | 2013-12-04 |
SI2646432T1 (sl) | 2015-08-31 |
CN103370314A (zh) | 2013-10-23 |
JP5868992B2 (ja) | 2016-02-24 |
BR112013013435A2 (pt) | 2016-10-11 |
US9856236B2 (en) | 2018-01-02 |
JP2013543883A (ja) | 2013-12-09 |
CN103370314B (zh) | 2015-10-21 |
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