HRP20090601T1 - Spojevi pirolotriazina kao inhibitori kinaze - Google Patents
Spojevi pirolotriazina kao inhibitori kinaze Download PDFInfo
- Publication number
- HRP20090601T1 HRP20090601T1 HR20090601T HRP20090601T HRP20090601T1 HR P20090601 T1 HRP20090601 T1 HR P20090601T1 HR 20090601 T HR20090601 T HR 20090601T HR P20090601 T HRP20090601 T HR P20090601T HR P20090601 T1 HRP20090601 T1 HR P20090601T1
- Authority
- HR
- Croatia
- Prior art keywords
- amino
- methyl
- triazin
- pyrrolo
- substituted
- Prior art date
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- 229940043355 kinase inhibitor Drugs 0.000 title claims 3
- 239000003757 phosphotransferase inhibitor Substances 0.000 title claims 3
- 150000003921 pyrrolotriazines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract 20
- 125000000217 alkyl group Chemical group 0.000 claims abstract 18
- 125000003118 aryl group Chemical group 0.000 claims abstract 18
- 125000003545 alkoxy group Chemical group 0.000 claims abstract 12
- -1 pyrrolidyl Chemical group 0.000 claims abstract 12
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract 8
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract 7
- 125000004104 aryloxy group Chemical group 0.000 claims abstract 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract 7
- 239000001257 hydrogen Substances 0.000 claims abstract 7
- 125000001424 substituent group Chemical group 0.000 claims abstract 7
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract 6
- 125000001475 halogen functional group Chemical group 0.000 claims abstract 6
- 125000000547 substituted alkyl group Chemical group 0.000 claims abstract 6
- 125000005236 alkanoylamino group Chemical group 0.000 claims abstract 5
- 125000001769 aryl amino group Chemical group 0.000 claims abstract 5
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract 5
- 125000003342 alkenyl group Chemical group 0.000 claims abstract 4
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract 4
- 125000000304 alkynyl group Chemical group 0.000 claims abstract 4
- 125000004659 aryl alkyl thio group Chemical group 0.000 claims abstract 4
- 125000005110 aryl thio group Chemical group 0.000 claims abstract 4
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract 4
- 150000003839 salts Chemical class 0.000 claims abstract 4
- 125000004423 acyloxy group Chemical group 0.000 claims abstract 3
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract 3
- 125000001691 aryl alkyl amino group Chemical group 0.000 claims abstract 3
- 125000003396 thiol group Chemical class [H]S* 0.000 claims abstract 3
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims abstract 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims abstract 2
- 150000001412 amines Chemical class 0.000 claims abstract 2
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims abstract 2
- 125000005239 aroylamino group Chemical group 0.000 claims abstract 2
- 125000002619 bicyclic group Chemical group 0.000 claims abstract 2
- 229910052799 carbon Inorganic materials 0.000 claims abstract 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract 2
- 125000002541 furyl group Chemical group 0.000 claims abstract 2
- 229910052736 halogen Inorganic materials 0.000 claims abstract 2
- 150000002367 halogens Chemical class 0.000 claims abstract 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims abstract 2
- 125000002883 imidazolyl group Chemical group 0.000 claims abstract 2
- 125000002950 monocyclic group Chemical group 0.000 claims abstract 2
- 125000002757 morpholinyl group Chemical group 0.000 claims abstract 2
- 125000004043 oxo group Chemical group O=* 0.000 claims abstract 2
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- 125000003386 piperidinyl group Chemical group 0.000 claims abstract 2
- 125000004076 pyridyl group Chemical group 0.000 claims abstract 2
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- 229960000643 adenine Drugs 0.000 claims 1
- BIIVYFLTOXDAOV-YVEFUNNKSA-N alvocidib Chemical compound O[C@@H]1CN(C)CC[C@@H]1C1=C(O)C=C(O)C2=C1OC(C=1C(=CC=CC=1)Cl)=CC2=O BIIVYFLTOXDAOV-YVEFUNNKSA-N 0.000 claims 1
- 229950010817 alvocidib Drugs 0.000 claims 1
- 125000005140 aralkylsulfonyl group Chemical group 0.000 claims 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims 1
- 239000004202 carbamide Substances 0.000 claims 1
- 125000001589 carboacyl group Chemical group 0.000 claims 1
- 230000000694 effects Effects 0.000 claims 1
- 102000054634 human CDK2 Human genes 0.000 claims 1
- FKCHPOABUFANIL-QZTJIDSGSA-N n-[(3r,4r)-4-amino-1-[[4-(3-methoxyanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-yl]methanesulfonamide Chemical compound COC1=CC=CC(NC=2C3=C(CN4C[C@H]([C@H](N)CC4)NS(C)(=O)=O)C=CN3N=CN=2)=C1 FKCHPOABUFANIL-QZTJIDSGSA-N 0.000 claims 1
- FKCHPOABUFANIL-MSOLQXFVSA-N n-[(3s,4r)-4-amino-1-[[4-(3-methoxyanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-yl]methanesulfonamide Chemical compound COC1=CC=CC(NC=2C3=C(CN4C[C@@H]([C@H](N)CC4)NS(C)(=O)=O)C=CN3N=CN=2)=C1 FKCHPOABUFANIL-MSOLQXFVSA-N 0.000 claims 1
- 230000037361 pathway Effects 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 1
- 239000010452 phosphate Substances 0.000 claims 1
- 102000020233 phosphotransferase Human genes 0.000 claims 1
- LKLQWOKKPWCIAW-UHFFFAOYSA-N piperidin-3-yl carbamate Chemical compound NC(=O)OC1CCCNC1 LKLQWOKKPWCIAW-UHFFFAOYSA-N 0.000 claims 1
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims 1
- QCQKTGJRAPFKRX-UHFFFAOYSA-N piperidine-3,5-diol Chemical compound OC1CNCC(O)C1 QCQKTGJRAPFKRX-UHFFFAOYSA-N 0.000 claims 1
- 239000003207 proteasome inhibitor Substances 0.000 claims 1
- 108060006633 protein kinase Proteins 0.000 claims 1
- 206010039073 rheumatoid arthritis Diseases 0.000 claims 1
- 229960001153 serine Drugs 0.000 claims 1
- 230000008054 signal transmission Effects 0.000 claims 1
- 229960000303 topotecan Drugs 0.000 claims 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 claims 1
- QQOWHRYOXYEMTL-UHFFFAOYSA-N triazin-4-amine Chemical compound N=C1C=CN=NN1 QQOWHRYOXYEMTL-UHFFFAOYSA-N 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 abstract 1
- 125000002102 aryl alkyloxo group Chemical group 0.000 abstract 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 abstract 1
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 abstract 1
- 125000004181 carboxyalkyl group Chemical group 0.000 abstract 1
- 125000004663 dialkyl amino group Chemical group 0.000 abstract 1
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- C07D—HETEROCYCLIC COMPOUNDS
- 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
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- 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
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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- A—HUMAN NECESSITIES
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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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- 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
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- Investigating Or Analysing Biological Materials (AREA)
Abstract
Spoj formule naznačen time štoX je direktna veza, -NR3- ili -O- ; Z je ili - NR7;R2 je aril ili supstituirani aril, R3, R4 i R5 nezavisno su izabrani iz skupine koju čine vodik, alkil i supstituirani alkil; R6, R6a nezavisno su izabrani iz grupe koju čine jedan ili više vodik, halogen, alkil, alkoksi, ariloksi, -CN, -NH2, -OH, -COOH, -CH2OR5, -CONHSO2R5, -CONR4R5, -NHalkil, -NHCOalkil, NR4SO2alkil, -NR4SONR4R5, -OCONR4R5, -CF3 i -OCF3, pri čemu dva od njih mogu biti vezana za isti atom ugljika u prstenu; R7 je vodik, alkil ili -NH2, in je 0, 1, 2 ili 3; pri čemu "alkil" označava ravnolančane ili sa granatim lancem nesupstituirane ugljovodične skupine od 1 do 20 atoma ugljika; "supstituirani alkil" označava alkil skupinu supstituiranu sa, jednim do četiri supstituenta, izabranih iz skupine koju čine halo, hidroksi, alkoksi, okso, alkanol ariloksi, alkanoiloksi, amino, alkilamino, arilamino, aralkilamino, disupstituirani amini u kojima su 2 amino supstituenta izabrana od alkil, aril ili aralkil; alkanoilamino, aroilamino, aralkanoilamino, supstituirani alkanoilamino, supstituirani arilamino, supstituirani aralkanoilamino, tiol, alkiltio, ariltio, aralkiltio, alkiltiono, ariltiono, aralkiltiono, alkilsulfonil, arilsulfonil, aralkilsulfonil, sulfonamido, supstituirani sulfonamido, nitro, cijano, karboksi, karbamil, supstituirani karbamil alkoksikarbonil, aril, supstituirani aril guanidino, heterociklil, imidazolil, furil, tienil, tiazolil, pirolidil, piridil, pirimidil, pirolidinil, piperidinil, morfolinil, piperazinil, homopiperazinil, i supstituirani heterociklil, pri čemu, u slučajevima gdje je supstituent dalje supstituiran on će biti izabran od alkil, alkoksi, aril ili aralkil. "aril" označava monociklične ili biciklične aromatične ugljikovodične skupine koje imaju 6 do 12 atoma ugljika u dijelu molekule koju sadrži prsten; "ariloksi" označava aril ili supstituiranu aril skupinu vezanu direktno preko alkoksi skupine; "supstituirani aril" označava aril skupinu supstituiranu sa jednim do četiri supstituenata izabranih iz skupine koju čine alkil, supstituirani alkil, alkenil, supstituirani alkenil, alkinil, supstituirani alkinil, aril, supstituirani aril, aralkil, halo, trifluorometoksi, trifluorometil hidroksi, alkoksi, alkanoil, alkanoiloksi, ariloksi, aralkiloksi, amino, alkilamino, arilamino, aralkilamino, dialkilamino, alkanoilamino, tiol, alkiltio, ureido, nitio, cijano, karboksi, karboksialkil, karbamil, alkoksikarbonil alkiltiono, ariltiono, arilsulfonilamin, sulfonska kiselina, alkilsulfonil, sulfonamido, ariloksi, pri čemu supstituent može biti dalje supstituiran sa hidroksi, halo, alkil, alkoksi, alkenil, alkinil, aril ili arilkil; ili njegova farmaceutski prihvatljiva sol ili stereoizomer. Patent sadrži još 19 patentnih zahtjeva.
Claims (20)
1. Spoj formule
[image]
naznačen time što
X je direktna veza, -NR3- ili -O- ;
Z je
[image]
ili - NR7;
R2 je aril ili supstituirani aril,
R3, R4 i R5 nezavisno su izabrani iz skupine koju čine vodik, alkil i supstituirani alkil;
R6, R6a nezavisno su izabrani iz grupe koju čine jedan ili više vodik, halogen, alkil, alkoksi, ariloksi, -CN, -NH2, -OH, -COOH, -CH2OR5, -CONHSO2R5, -CONR4R5, -NHalkil, -NHCOalkil, NR4SO2alkil, -NR4SONR4R5, -OCONR4R5, -CF3 i -OCF3, pri čemu dva od njih mogu biti vezana za isti atom ugljika u prstenu;
R7 je vodik, alkil ili -NH2, i
n je 0, 1, 2 ili 3; pri čemu "alkil" označava ravnolančane ili sa granatim lancem nesupstituirane ugljovodične skupine od 1 do 20 atoma ugljika;
"supstituirani alkil" označava alkil skupinu supstituiranu sa, jednim do četiri supstituenta, izabranih iz skupine koju čine halo, hidroksi, alkoksi, okso, alkanol ariloksi, alkanoiloksi, amino, alkilamino, arilamino, aralkilamino, disupstituirani amini u kojima su 2 amino supstituenta izabrana od alkil, aril ili aralkil; alkanoilamino, aroilamino, aralkanoilamino, supstituirani alkanoilamino, supstituirani arilamino, supstituirani aralkanoilamino, tiol, alkiltio, ariltio, aralkiltio, alkiltiono, ariltiono, aralkiltiono, alkilsulfonil, arilsulfonil, aralkilsulfonil, sulfonamido, supstituirani sulfonamido, nitro, cijano, karboksi, karbamil, supstituirani karbamil alkoksikarbonil, aril, supstituirani aril guanidino, heterociklil, imidazolil, furil, tienil, tiazolil, pirolidil, piridil, pirimidil, pirolidinil, piperidinil, morfolinil, piperazinil, homopiperazinil, i supstituirani heterociklil, pri čemu, u slučajevima gdje je supstituent dalje supstituiran on će biti izabran od alkil, alkoksi, aril ili aralkil.
"aril" označava monociklične ili biciklične aromatične ugljikovodične skupine koje imaju 6 do 12 atoma ugljika u dijelu molekule koju sadrži prsten;
"ariloksi" označava aril ili supstituiranu aril skupinu vezanu direktno preko alkoksi skupine;
"supstituirani aril" označava aril skupinu supstituiranu sa jednim do četiri supstituenata izabranih iz skupine koju čine alkil, supstituirani alkil, alkenil, supstituirani alkenil, alkinil, supstituirani alkinil, aril, supstituirani aril, aralkil, halo, trifluorometoksi, trifluorometil hidroksi, alkoksi, alkanoil, alkanoiloksi, ariloksi, aralkiloksi, amino, alkilamino, arilamino, aralkilamino, dialkilamino, alkanoilamino, tiol, alkiltio, ureido, nitio, cijano, karboksi, karboksialkil, karbamil, alkoksikarbonil alkiltiono, ariltiono, arilsulfonilamin, sulfonska kiselina, alkilsulfonil, sulfonamido, ariloksi, pri čemu supstituent može biti dalje supstituiran sa hidroksi, halo, alkil, alkoksi, alkenil, alkinil, aril ili arilkil;
ili njegova farmaceutski prihvatljiva sol ili stereoizomer.
2. Spoj prema zahtjevu 1, naznačen time što ima formulu (III)
[image]
3. Spoj prema zahtjevu 2, naznačen time što
R2 je fenil, supstituirani fenil;
R6, R6a i R6b nezavisno su izabrani iz grupe koju čine jedan ili više vodika, -NH2, OH, alkoksi, -CONR4R5, -NR4SO2alkil, -NR4SO2NR4R5, -OCONR4R5, NHalkil i -NHCOalkil;
X je -NH-; i
n je 1 ili 2.
4. Spoj prema bilo kojem od zahtjeva 1 do 3, naznačen time što je izabran iz skupine koju čine
5-[(4-Amino-1-piperidinil)metil]-N-(3-kloro-4-fluorofenil)pirolo[2,1-f][1,2,4]triazin-4-amin,
5-[(4-Amino-1-piperidinil)metil]-N-2-naftalenilpirolo[2,1-f][1,2,4]triazin-4-amin,
5-[(4-Amino-1-piperidinil)metil]-N-fenilpirolo[2,1-f][1,2,4]triazin-4-amin,
5-[(4-Amino-1-piperidinil)metil]-N-(3-metoksifenil)pirolo[2,1-* f][1,2,4]triazin-4-amin,
5-[(4-Amino-1-piperidinil)metil]-N-(3-etinilfenil)pirolo[2,1-f][1,2,4]triazin-4-amin,
5-[(4-aminopiperidin-1-il)metil]-N-(4-fluoro-3-metoksifenil)pirolo[2,1-f][1,2,4]triazin-4-amin,
(3R,4R)-4-amino-1-[[4-[(3-kloro-4-fluorofenil)amino]pirolo[2,1-f][1,2,4]triazin-5-il]metil]piperidin-3-ol,
(3S,4S)-4-amino-1-[[4-[(3-kloro-4-fluorofenil)amino]pirolo[2,1-f][1,2,4]triazin-5-il]metil]piperidin-3-ol,
(3R,4R)-4-amino-1-[[4-[(3-metoksifenil)amino]pirolo[2,1-f][1,2,4]triazin-5-il]metil]piperidin-3-ol,
(3S,4S)-4-amino-1-[[4-[(3-metoksifenil)amino]pirolo[2,1-f][1,2,4]triazin-5-il]metil]piperidin-3-ol,
(3R,4R)-4-amino-1-[[4-[(3-metoksi-4-fluorofenil)amino]pirolo[2,1-f][1,2,4]triazin-5-il]metil]piperidin-3-ol,
(3R,4R)-4-amino-1-({4-[(3-etinilfenil)-amino]pirolo[2,1-f][1,2,4]-triazin-5-il}-metil)piperidin-3-ol,
(3R,4R)-4-amino-1-({4-[(3-etoksifenil)amino]-pirolo[2,1-f]-[1,2,4]triazin-5-il}-metil)piperidin-3-ol,
(3R,4R)-4-amino-1-{[4-(2-naftilamino)-pirolo[2,1-f][1,2,4]-triazin-5-il]metil}piperidin-3-ol,
(3R,4R)-4-amino-1-({4-[(3-metoksi-4-metil-fenil)amino]pirolo[2,1-f][1,2,4]triazin-5-il}-metil)piperidin-3-ol,
(3R,4R)-4-amino-1-({4-[(3-bromofenil)amino]pirolo[2,1-f][1,2,4]-triazin-5-il}metil)-piperidin-3-ol,
(3R,4R)-4-amino-1-({4-[(3-fluoro-5-metoksi-fenil)amino]pirolo[2,1-f][1,2,4]triazin-5-il}-metil)piperidin-3-ol,
(3S,4R)-4-amino-1-({4-[(3-metoksifenil)amino]pirolo[2,1-f][1,2,4]triazin-5-il}metil)piperidin-3-ol,
(3R,4S)-4-amino-1-({4-[(3-metoksifenil)amino]pirolo[2,1-f][1,2,4]triazin-5-il}metil)piperidin-3-ol
(3S,4R)4-amino-1-({4-[(3-klorofenil)amino]-pirolo[2,1-f][1,2,4]-triazin-5-il}metil)-piperidin-3-ol,
(3S,4R)-4-amino-1-({4-[(3-kloro-4-fluoro-fenil)amino]pirolo[2,1-f][1,2,4]triazin-5-il}-metil)piperidin-3-ol,
(3S,4R)-4-amino-1-({4-[(3-etinilfenil) amino]pirolo[2,1-f][1,2,4]triazin-5-il}metil) piperidin-3-ol,
(3R,4S)-4-amino-1-({4-[(3-etinilfenil)-amino]pirolo[2,1-f][1,2,4]triazin-5-il}metil)piperidin-3-ol,
(3R,4S)-4-amino-1-({4-[(3-klorofenil)amino]pirolo[2,1-f][1,2,4]-triazin-5-il}metil)-piperidin-3-ol,
(3R,4R)-4-amino-1-({4-[(3-metoksifenil)amino]pirolo[2,1-f][1,2,4]triazin-5-il}metil)piperidin-3-il karbamat,
(3R,4R)-4-amino-1-({4-[(3-etinilfenil)-amino]pirolo[2,1-f][1,2,4]triazin-5-il}-metil)piperidin-3-il karbamat,
(3R,4R)-4-amino-1-({4-[(3-kloro-4-fluoro-fenil)amino]pirolo[2,1-f][1,2,4]triazin-5-il}-metil)piperin-3-il karbamat,
(3S,4R)-4-amino-1-{4-[(3-kloro-4-fluoro-fenil)amino]pirolo[2,1-f][1,2,4]triazin-5-il}-metil)piperidin-3-il karbamat,
(3S,4R)-4-amino-1-({4-[(3-etinilfenil)-amino]pirolo[2,1-f][1,2,4]triazin-5-il}-metil)piperidin-3-il karbamat,
(3S,4R)-4-amino-1-({4-[(3-metoksifenil)amino]pirolo[2,1-f][1,2,4]triazin-5-il}metil)-3-metilpiperidin-3-ol,
(3R/S,5R/S)-4-amino-1-({4-[(3-metoksifenil)amino]pirolo[2,1-f][1,2,4]triazin-5-il}metil)piperidin-3,5-diol,
(3S,5S)-4-amino-1-({4-[(4-fluoro-3-metoksi-fenil)amino]pirolo[2,1-f][1,2,4]triazin-5-il}-metil)piperidin-3,5-diol,
(3R,5R)-4-amino-1-({4-[(3-etinilfenil)-amino]pirolo[2,1-f][1,2,4]triazin-5-il}metil)piperidin-3,5-diol,
5-{[(3R,4R)-4-amino-3-metoksipiperidin-1-il]metil}-N-(3-metoksifenil)pirolo[2,1-f][1,2,4]triazin-4-amin,
(3R,4R)-4-amino-1-({4-[(3-metoksifenil)amino]pirolo[2,1-f][1,2,4]triazin-5-il}metil)-N-(metilsulfonil)piperidin-3-karboksamid,
(3R,4R)-4-amino-1-({4-[(3-etinilfenil)amino]pirolo[2,1-f][1,2,4]triazin-5-il}metil)-N-metilpiperidin-3-karboksamid,
(3R,4R)-4-amino-1-({4-[(3-metoksifenil)amino]pirolo [2,1-f] [1,2,4] triazin-5-il}metil)-N-metilpiperidin-3-karboksamid,
(3R,4R)-4-amino-1-({4-[(3-metoksifenil)amino]pirolo[2,1-f][1,2,4]triazin-5-il}metil)piperidin-3-karboksamid,
((3R,4R)-1-((4-(3-metoksifenilamino)pirolo[1,2-f][1,2,4]triazin-5-il)metil)-4-((R)-1-feniletilamino)piperidin-3-il)metanol,
N-[(3R,4R)4amino-1-({4-[(3-metoksifenil)amino]pirolo[2,1-f][1,2,4]triazin-5-il}metil)piperidin-3-il]urea,
N-[(3R,4R)-4-amino-1-({4-[(3-metoksifenil)amino]pirolo[2,1-f][1,2,4]triazin-5-il}metil)piperidin-3-il]metansulfonamid,
i
N-[(3S,4R)-4-amino-1-({4-[(3-metoksifenil)amino]pirolo[2,1-f][1,2,4]triazin-5-il}metil)piperidin-3-il]metansulfonamid,
ili njegova farmaceutski prihvatljiva sol.
5. Spoj prema bilo kojem od zahtjeva 1 do 4, naznačen time što ima formulu
[image]
ili njegova farmaceutski prihvatljiva sol.
6. Farmaceutska kompozicija naznačena time što sadrži jedan ili više spojeva prema zahtjevu 1 i farmaceutski prihvatljiv nosač.
7. Farmaceutska kompozicija naznačena time što sadrži jedan ili više spojeva prema zahtjevu 2 i farmaceutski prihvatljiv nosač.
8. Farmaceutska kompozicija naznačena time što sadrži jedan ili više spojeva prema zahtjevu 4 i farmaceutski prihvatljiv nosač.
9. Farmaceutska kompozicija naznačena time što sadrži jedan ili više spojeva prema bilo kojem od zahtjeva 1 do 5 u kombinaciji sa farmaceutski prihvatljivim nosačem i jednim ili više drugih sredstava protiv kancera ili citotoksičnih sredstava.
10. Farmaceutska kompozicija prema zahtjevu 9, naznačena time što je navedeno sredstvo protiv kancera ili citotoksično sredstvo izabrano iz skupine koju čine tamoksifen, toremifen, raloksifen, droloksifen, jodoksifen, megestrol acetat, anastrozol, letrozol, borazol, eksemestan, flutamid, nilutamid, bikalutamid, ciproteron acetat, goserelin acetat, leuprolid, finasterid, inhibitori metaloproteinaze, inhibitori funkcije receptora urokinaza plazminogen aktivatora, antitijela za faktor rasta, antitijela za receptor faktora rasta, bevacizumab, cetuksimab, trastuzumab, erlotinib, inhibitori tirozin kinaze, inhibitori serin/treonin kinaze, metotreksat, 5-fluorouracil, analozi purina i adenozina, citozin arabinozid, doksorubicin, daunomicin, epirubicin, idarubicin, mitomicin-C, daktinomicin, mitramicin, cisplatin, karboplatin, dušikov iperit, melfalan, klorambucil, busulfan, ciklofosfamid, ifosfamid, nitrozouree, tiotepa, vinkristin, vinorelbin, vinblastin, vinflunin paklitaksel, docetaksel, analozi epotilona, analozi diskodermolida, analozi eleuterobina, etoposid, teniposid, amsakrin, tapotekan, flavopiridol bortezomib i modifikatori biološkog odgovora.
11. Jedan ili više spojeva prema bilo kojem od zahtjeva 1 do 5, naznačeni time šti se koriste za primjenu u liječenju proliferativne bolesti kod vrsta sisavaca kod kojih postoji potreba za tim.
12. Jedan ili više spojeva prema zahtjevu 11, naznačeni time što je proliferativna bolest izabrana iz skupine koju čine kancer, psorijaza i reumatoidni artritis.
13. Jedan ili više spojeva prema zahtjevu 12, naznačeni time što je proliferativna bolest kancer.
14. Jedan ili više spojeva prema zahtjevu 13, naznačeni time što se dodatno terapeutski učinkovita količina jednog ili više drugih sredstava protiv kancera ili citotoksičnih sredstava u kombinaciji sa jednim ili više spojeva prema zahtjevu 1 primjenjuje na toplokrvne biološke vrste kod kojih postoji potreba za tim.
15. Jedan ili više spojeva prema zahtjevu 14, naznačeni time što je navedeno sredstvo protiv kancera ili citotoksično sredstvo izabrano iz skupine koju čine tamoksifen, toremifen, raloksifen, droloksifen, jodoksifen, megestrol acetat, anastrozol, letrozol, borazol, eksemestan, flutamid, nilutamid, bikalutamid, ciproteron acetat, goserelin acetat, leuprolid, finasterid, inhibitori metaloproteinaze, inhibitori funkcije receptora urokinaza plazminogen aktivatora, antitijela za faktor rasta, antitijela za receptor faktora rasta, bevacizumab, cetuksimab, trastuzumab, erlotinib, inhibitori tirozin kinaze, inhibitori serin/treonin kinaze, metotreksat, 5-fluorouracil, analozi purina i adenozina, citozin arabinozid, doksorubicin, daunomicin, epirubicin, idarubicin, mitomicin-C, daktinomicin, mitramicin, cisplatin, karboplatin, dušikov iperit, melfalan, klorambucil, busulfan, ciklofosfamid, ifosfamid, nitrozouree, tiotepa, vinkristin, vinorelbin, vinblastin, vinflunin paklitaksel, docetaksel, analozi epotilona, analozi diskodermolida, analozi eleuterobina, etoposid, teniposid, amsakrin, topotekan, flavopiridoli, inhibitori proteazoma uključujući bortezomib i modifikatore biološkog odgovora.
16. Jedan ili više spojeva prema bilo kojem od zahtjeva 1 do 5, naznačeni time što se koriste za primjenu u modulaciji aktivnosti receptor tirozin kinaze kod vrsta sisavaca kod kojih postoji potreba za tim.
17. Jedan ili više spojeva prema zahtjevu 16, naznačeni time što je navedena receptor tirozin kinaza izabrana iz skupine koju čine HER1, HER2 i HER4.
18. Jedan ili više spojeva prema bilo kojem od zahtjeva 1 do 5, naznačeni time što se koriste za primjenu u liječenju bolesti povezanih sa putevima prijenosa signala koji funkcioniraju preko receptora faktora rasta kod vrsta sisavaca kod kojih postoji potreba za tim.
19. Postupak za identifikaciju ATP-kompetitivnih inhibitora kinaze, naznačen time što sadrži izbor spoja kao što je definirano u bilo kojem od zahtjeva 1 do 5, koji se vezuje u adeninski džep, ribozni džep, džep za vezivanje fosfata, regiju specifičnosti 1 i regiju specifičnosti 2 humane ciklin-zavisne kinaze 2 (CDK2), pri čemu skupina koja zauzima džep za vezivanje riboze i/ili fosfata, može interreagirati sa jednim ili više apsolutno konzervativnih ostataka uključenih u vezivanje fosfata.
20. Postupak prema zahtjevu 19, naznačen time što skupina interreagira sa ostacima Asn 818 i/ili Asp 831 (HER1 numeracija) ili odgovarajućim ostacima u različitoj kinazi džepova za vezivanje riboze i/ili fosfata.
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| US20060235020A1 (en) * | 2005-04-18 | 2006-10-19 | Soojin Kim | Process for preparing salts of 4-[[5-[(cyclopropylamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-propylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide and novel stable forms produced therein |
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| US20100136137A1 (en) * | 2006-11-01 | 2010-06-03 | Bristol-Meyers Squibb Company | Therapeutic combination of a panher/vegfr2 kinase inhibitor and a platinum compound |
| WO2008103248A1 (en) | 2007-02-08 | 2008-08-28 | Codexis, Inc. | Ketoreductases and uses thereof |
| US20090076034A1 (en) * | 2007-09-14 | 2009-03-19 | Protia, Llc | Deuterium-enriched bms-690514 |
| PT2231662E (pt) * | 2007-12-19 | 2011-09-12 | Genentech Inc | 8-anilinoimidazopiridinas e o seu uso como agentes anticancerígenos e/ou anti-inflamatórios |
| JP2010209058A (ja) * | 2008-09-29 | 2010-09-24 | Sumitomo Chemical Co Ltd | １−置換−トランス−４−（置換アミノ）ピペリジン−３−オールの製造方法 |
| US8445676B2 (en) * | 2008-10-08 | 2013-05-21 | Bristol-Myers Squibb Company | Pyrrolotriazine kinase inhibitors |
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| CA2750047A1 (en) | 2009-01-21 | 2010-07-29 | Basilea Pharmaceutica Ag | Novel bicyclic antibiotics |
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