ES2557478T3 - Compuestos de pirazol y triazol como inhibidores de KSP - Google Patents

Compuestos de pirazol y triazol como inhibidores de KSP Download PDF

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Publication number
ES2557478T3
ES2557478T3 ES07844993.1T ES07844993T ES2557478T3 ES 2557478 T3 ES2557478 T3 ES 2557478T3 ES 07844993 T ES07844993 T ES 07844993T ES 2557478 T3 ES2557478 T3 ES 2557478T3
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triazol
amino
ylmethyl
dimethylpropyl
fluorobutyl
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Yi Xia
Kris G. Mendenhall
Paul A. Barsanti
Annette O. Walter
David Duhl
Paul A. Renhowe
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Novartis AG
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Novartis AG
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    • 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
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • 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
    • 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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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Compuesto que tiene la fórmula (Id) o una sal farmacéuticamente aceptable del mismo:**Fórmula** en la que: R1 se selecciona del grupo que consiste en alquilo que tiene desde 1 hasta 6 átomos de carbono; R3 es -L1-A1 en donde L1 >= -CO R4 se selecciona del grupo que consiste en hidrógeno, piperidin-4-ilo, -(CH2)2-NH2, -CH2-azetidin-3-ilo, -CH2-(2,5- dihidropirrol-3-il), -(CH2)3-imidazol-1-ilo, -CH2-(1H-imidazol-4-il), -CH2-piridin-3-ilo, -CH2-(2-hidroxipiridin-4-il), -CH2-(6- hidroxipiridin-3-il), -CH2-morfolin-2-ilo, -CH2-pirrolidin-3-ilo, -CH2-(3-fluoropirrolidin-3-il), -CH2-(3-hidroxipirrolidin-3-il), -CH2-(4-fluoropirrolidin-3-il), -CH2-(4-hidroxipirrolidin-3-il), -CH2-(2-hidroximetilpirrolidin-3-il), -CH2-piperidin-3-ilo, -CH2-[1H-(1,2,3-triazol-4-il)], -CH2CH(NH2)CH2OH, -(CH2)3-OH, -(CH2)3-O(CO)-fenilo, -(CH2)3-NH2, -(CH2)3-NHCH3, -(CH2)3-N(CH3)2, -(CH2)3-NHOCH3, -(CH2)3-NHSO2CH3, -(CH2)3NH-(5-cianopiridin-2-il), -(CH2)3NH-ciclopropilo, -(CH2)3NH-ciclobutilo, -(CH2)3-(1H-imidazol-2-il), -(CH2)3-(2-hidroxietilpiperidin-1-il), -(CH2)3NH(2-hidroximetilfenil), -(CH2)3NH-(5-trifluorometilpiridin-2-il), -(CH2)3NHCH2-ciclopropilo, -(CH2)3NHCH2-{5-(piridin-3-iloxi)-1H-indazol-3-il}, -(CH2)3NHCH2-(5-metoxi-1H-indazol-3-il), -(CH2)3NHCH2-(6-fluoro-1H-indazol-3-il), -CH2CHOHCH2NH2, -CH2CH(CH2OH)CH2NH2, -CH2C(CH3)2CH2-N(CH3)2, -CH2C(CH3)2CH2-(4-metilpiperazin-1-il), -(CH2)2C(O)NH2, -(CH2)2CH(NH2)C(O)NH2, -(CH2)2CH(NH2)C(O)OH, -(CH2)2CH(NH2)CH2C(O)NH2, -(CH2)2CH(NH2)CH2OH, -(CH2)2CH(NH2)CH3, -(CH2)3NHC(O)CH2NH2, -(CH2)3NHC(O)CH(NH2)CH(CH3)2, -CH2CHFCH2NH2, -(CH2)2NHC(O)CH2NH2, -(CH2)3-NHCH2CH2OH, -(CH2)3-NHCH2CO2H, -(CH2)3NHCH2CO2CH2CH3, -(CH2)3- N(CH2CH2OH)2, -(CH2)3-NHCH(CH2OH)2, -(CH2)3CH3, -(CH2)2CH(NH2)CH2OH, -(CH2)2C(CH3)2NH2, -(CH2)2CH(NH2)CH2OCH3, -(CH2)2CH(NH2)CH2F, -CH2CHFCH(NH2)CH2OH y -(CH2)2-espirocilcopropil-NH2; A1 se selecciona del grupo que consiste en alquilo que tiene desde 1 hasta 6 átomos de carbono sustituido con hidroxilo, NR8R9, 1,3-benzotiadiazol-4-ilo, t-butoxilo, butoxilo, n-butoxilo, ciclohexilo, 2,2-dimetilpropoxilo, etoxilo, furan-3-ilo, isoxazol-3-ilo, metoxilo, metilo, 2-metilpropoxilo, fenilo, piperidin-3-ilo, piperidin-4-ilo, n-propoxilo, piridin- 2-ilo, piridin-3-ilo, piridin-4-ilo, pirazin-2-ilo, tetrahidrofuran-2-ilo, tetrahidrofuran-3-ilo, tetrahidro-2H-piran-4-ilo, 1Htetrazol- 1-ilo, 2H-tetrazol-2-ilo, tiazol-4-ilo, 1,3,4-tiadiazol-2-ilo, 1,3-benzotiadiazol-6-ilo, 3,3- dihidrobenzo[1,2,3]tiadiazol-4-ilo, bencimidazol-2-ilo, bencimidazol-6-ilo, benzo[1,2,5]tiadiazol, benzoxadiazol-4-ilo, ciclopentilo, imidazol-4-ilo, indazol-6-ilo, isooxazol-5-ilo, morfolin-2-ilo, morfolino, oxazol-4-ilo, piperidin-N-ilo, pirazol- 3-ilo, pirrolidin-2-ilo, pirrolidin-3-ilo, pirrolidin-N-ilo, tetrazol-5-ilo, tiadiazol-4-ilo, 5-metil-2H-imidazol-4-ilo, 2- aminotiazol-4-ilo, 4-t-butilfenilo, 2-clorofenilo, 2-cloro-6-metilpirid-4-ilo, 3-clorofenilo, 4-clorofenilo, 6-cloropiridin-3-ilo, 3,4-diclorofenilo, 2,4-difluorofenilo, 1,5-dimetil-1H-pirazol-3-ilo, 2,4-dimetiltiazol-5-ilo, 1-etil-3-metil-1H-pirazol-5-ilo, 2- metoxifenilo, 4-metoxifenilo, 4-metilisoxazol-3-ilo, 5-metilisoxazol-4-ilo, 4-metilfenilo, 1-metil-3-trifluorometil-1Hpirazol- 4-ilo, 1-metil-5-cloro-1H-pirazol-4-ilo, 5-metil-1H-pirazol-3-ilo, 6-metilpiridin-3-ilo, 2-pirrolidin-3-ilfenilo, 4- (trifluorometil)fenilo, 6-(trifluorometil)piridin-3-ilo, 2,5-dimetiloxazol-4-ilo, 2-aminotiazol-4-ilo, 4-metilpirazol-5-ilo, 3- trifluorometilpirazol-4-ilo, 2-metil-3-trifluorometilpirazol-5-ilo, 4-cloro-1,3-dimetilpirazolo[3,4]piridina, y 1- metilbencimidazol-2-ilo, 3-[(aminoacetil)amino]ciclohexilo, 3-(2-aminoetilsulfonilamino)ciclohexilo, 1-metilpiperazin-4- ilo, 1-metilcarbonilpiperidin-4-ilo, 1-metoxicarbonilpiperidin-4-ilo, quinuclidin-3-ilo, 2-oxopirrolidin-5-ilo, 2-oxopirrolidin- 4-ilo, 2-oxo-dihidrofuran-5-ilo, 2-oxotiazolidin-4-ilo, y 3-hidroxipirrolidin-5-ilo, 2-(hidroximetil)pirrolidin-1-ilo, 3-amino-2- oxo-1(2H)-piridinilmetilo, cianometilo, (N,N-dimetilamino)metilo, etoximetilo, p-fluorofenoximetilo, hidroximetilo, 1H40 imidazol-1-ilmetilo, metoximetilo, (N-metilamino)metilo, metilsulfonilmetilo, (5-metil-1H-tetrazol-1-il)metilo, (5-metil- 2H-tetrazol-2-il)metilo, morfolin-4-ilmetilo, 1H-pirazol-1-ilmetilo, 1H-1,2,3-triazol-1-ilmetilo, 2H-1,2,3-triazol-2-ilmetilo, 1H-1,2,4-triazol-1-ilmetilo, 2H-1,2,4-triazol-2-ilmetilo, 4H-1,2,4-triazol-4-ilmetilo, 1H-tetrazol-1-ilmetilo, 1H-tetrazol-5- ilmetilo, 2H-tetrazol-2-ilmetilo, imidazol-4-ilmetilo, 1-metilpirazol-3-ilmetilo, piperidin-4-ilmetilo, trifluorometilo, dimetilaminoetilo, y 2-oxo-3-aminopirrolidin-1-ilmetilo; o A1 y R4 junto con los átomos unidos respectivamente a los mismos se unen para formar un grupo heterocicloalquilo o heterocicloalquilo sustituido de cinco a siete miembros seleccionado del grupo que consiste en:**Fórmula**

Description

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Compuesto
Estructura MH+ Nombre
2
imagen48 559,2 N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(1bencil-3-(2,5-difluorofenil)-1H-1,2,4triazol-5-il)-2,2-dimetilpropil)morfolin-4carboxamida
3
518,3 N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(1bencil-3-(2,5-difluorofenil)-1H-1,2,4triazol-5-il)-2,2-dimetilpropil)-2metoxiacetamida
4
504,2 N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(1bencil-3-(2,5-difluorofenil)-1H-1,2,4triazol-5-il)-2,2-dimetilpropil)-2hidroxiacetamida
5
557,3 N-((R)-3-amino-4-fluorobutil)-N-((R)-1-(1bencil-3-(2,5-difluorofenil)-1H-1,2,4triazol-5-il)-2,2-dimetilpropil)piperidin-1carboxamida
6
559,3 N-((R)-3-amino-4-fluorobutil)-N-((R)-1-(1bencil-3-(2,5-difluorofenil)-1H-1,2,4triazol-5-il)-2,2-dimetilpropil)morfolin-4carboxamida
49
Compuesto
Estructura MH+ Nombre
7
imagen49 587,3 (2S,6R)-N-((R)-3-amino-4-fluorobutil)-N((R)-1-(1-bencil-3-(2,5-difluorofenil)-1H1,2,4-triazol-5-il)-2,2-dimetilpropil)-2,6dimetilmorfolin-4-carboxamida
8
517,3 1-((R)-3-amino-4-fluorobutil)-1-((R)-1-(1bencil-3-(2,5-difluorofenil)-1H-1,2,4triazol-5-il)-2,2-dimetilpropil)-3,3dimetilurea
9
503,2 1-((R)-3-amino-4-fluorobutil)-1-((R)-1-(1bencil-3-(2,5-difluorofenil)-1H-1,2,4triazol-5-il)-2,2-dimetilpropil)-3-metilurea
10
587,3 (2S,6R)-N-((S)-3-amino-4-fluorobutil)-N((R)-1-(1-bencil-3-(2,5-difluorofenil)-1H1,2,4-triazol-5-il)-2,2-dimetilpropil)-2,6dimetilmorfolin-4-carboxamida
11
517,3 1-((S)-3-amino-4-fluorobutil)-1-((R)-1-(1bencil-3-(2,5-difluorofenil)-1H-1,2,4triazol-5-il)-2,2-dimetilpropil)-3,3dimetilurea
50
Compuesto
Estructura MH+ Nombre
12
imagen50 503,2 1-((S)-3-amino-4-fluorobutil)-1-((R)-1-(1bencil-3-(2,5-difluorofenil)-1H-1,2,4triazol-5-il)-2,2-dimetilpropil)-3-metilurea
13
575,2 N-((R)-3-amino-4-fluorobutil)-N-((R)-1-(1bencil-3-(2,5-difluorofenil)-1H-1,2,4triazol-5-il)-2,2-dimetilpropil)tiomorfolin-4carboxamida
14
575,2 N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(1bencil-3-(2,5-difluorofenil)-1H-1,2,4triazol-5-il)-2,2-dimetilpropil)tiomorfolin-4carboxamida
15
557,2 N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(1bencil-3-(2,5-difluorofenil)-1H-1,2,4triazol-5-il)-2,2-dimetilpropil)piperidin-1carboxamida
16
(R)-6-(aminometil)-4-((R)-1-(1-bencil-3fenil-1H-1,2,4-triazol-5-il)-2,2dimetilpropil)-1,4-oxazepan-3-ona
51
Compuesto
Estructura MH+ Nombre
17
imagen51 (S)-6-(aminometil)-4-((R)-1-(1-bencil-3(2,5-difluorofenil)-1H-1,2,4-triazol-5-il)2,2-dimetilpropil)-1,4-oxazepan-3-ona
18
504,2 N-((R)-3-amino-4-fluorobutil)-N-((R)-1-(2bencil-5-(2,5-difluorofenil)-2H-1,2,4triazol-3-il)-2,2-dimetilpropil)-2hidroxiacetamida
19
551,2 N-((R)-3-amino-4-fluorobutil)-N-((R)-1-(2bencil-5-(2,5-difluorofenil)-2H-1,2,4triazol-3-il)-2,2-dimetilpropil)nicotinamida
20
607,2 N-((R)-3-amino-4-fluorobutil)-N-((R)-1-(2bencil-5-(2,5-difluorofenil)-2H-1,2,4triazol-3-il)-2,2-dimetilpropil)-1,1dioxotiomorfolin-4-carboxamida
21
607,2 N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(2bencil-5-(2,5-difluorofenil)-2H-1,2,4triazol-3-il)-2,2-dimetilpropil)-1,1dioxotiomorfolin-4-carboxamida
52
Compuesto
Estructura MH+ Nombre
22
imagen52 573,3 (2R)-N-((S)-3-amino-4-fluorobutil)-N-((R)1-(2-bencil-5-(2,5-difluorofenil)-2H-1,2,4triazol-3-il)-2,2-dimetilpropil)-2(hidroximetil)pirrolidin-1-carboxamida
23
573,3 (2S)-N-((S)-3-amino-4-fluorobutil)-N-((R)1-(2-bencil-5-(2,5-difluorofenil)-2H-1,2,4triazol-3-il)-2,2-dimetilpropil)-2(hidroximetil)pirrolidin-1-carboxamida
24
573,3 (2R)-N-((R)-3-amino-4-fluorobutil)-N-((R)1-(2-bencil-5-(2,5-difluorofenil)-2H-1,2,4triazol-3-il)-2,2-dimetilpropil)-2(hidroximetil)pirrolidin-1-carboxamida
25
573,3 (2S)-N-((R)-3-amino-4-fluorobutil)-N-((R)1-(2-bencil-5-(2,5-difluorofenil)-2H-1,2,4triazol-3-il)-2,2-dimetilpropil)-2(hidroximetil)pirrolidin-1-carboxamida
26
imagen53 518,2 (2S)-N-((S)-3-amino-4-fluorobutil)-N-((R)1-(2-bencil-5-(2,5-difluorofenil)-2H-1,2,4triazol-3-il)-2,2-dimetilpropil)-2hidroxipropanamida
53
Compuesto
Estructura MH+ Nombre
27
imagen54 519,2 N-(3-aminopropil)-N-((R)-1-(2-bencil-5(2,5-difluorofenil)-2H-1,2,4-triazol-3-il)2,2-dimetilpropil)nicotinamida
28
486,2 (2S)-N-(3-aminopropil)-N-((R)-1-(2-bencil5-(2,5-difluorofenil)-2H-1,2,4-triazol-3-il)2,2-dimetilpropil)-2-hidroxipropanamida
29
472,2 N-(3-aminopropil)-N-((R)-1-(2-bencil-5(2,5-difluorofenil)-2H-1,2,4-triazol-3-il)2,2-dimetilpropil)-2-hidroxiacetamida
30
541,1 (2S)-N-(3-aminopropil)-N-((R)-1-(2-bencil5-(2,5-difluorofenil)-2H-1,2,4-triazol-3-il)2,2-dimetilpropil)-2-(hidroximetil)pirrolidin1-carboxamida
31
527,2 N-(3-aminopropil)-N-((R)-1-(2-bencil-5(2,5-difluorofenil)-2H-1,2,4-triazol-3-il)2,2-dimetilpropil)morfolin-4-carboxamida
54
Compuesto
Estructura MH+ Nombre
32
imagen55 555,2 (2S,6R)-N-(3-aminopropil)-N-((R)-1-(2bencil-5-(2,5-difluorofenil)-2H-1,2,4triazol-3-il)-2,2-dimetilpropil)-2,6dimetilmorfolin-4-carboxamida
33
604,1 N-(3-aminopropil)-N-((R)-1-(2-bencil-5(2,5-difluorofenil)-2H-1,2,4-triazol-3-il)2,2-dimetilpropil)-4(metilsulfonil)piperazin-1-carboxamida
34
518,2 (2S)-N-((R)-3-amino-4-fluorobutil)-N-((R)1-(2-bencil-5-(2,5-difluorofenil)-2H-1,2,4triazol-3-il)-2,2-dimetilpropil)-2hidroxipropanamida
35
559,2 (2S)-N-((S)-3-amino-2-fluoropropil)-N((R)-1-(2-bencil-5-(2,5-difluorofenil)-2H1,2,4-triazol-3-il)-2,2-dimetilpropil)-2(hidroximetil)pirrolidin-1-carboxamida
36
573,2 (2S,6R)-N-((S)-3-amino-2-fluoropropil)-N((R)-1-(2-bencil-5-(2,5-difluorofenil)-2H1,2,4-triazol-3-il)-2,2-dimetilpropil)-2,6dimetilmorfolin-4-carboxamida
55
Compuesto
Estructura MH+ Nombre
37
imagen56 490,2 N-((S)-3-amino-2-fluoropropil)-N-((R)-1(2-bencil-5-(2,5-difluorofenil)-2H-1,2,4triazol-3-il)-2,2-dimetilpropil)-2hidroxiacetamida
38
544,2 (2S)-N-((S)-3-amino-4-fluorobutil)-N-((R)1-(2-bencil-5-(2,5-difluorofenil)-2H-1,2,4triazol-3-il)-2,2-dimetilpropil)tetrahidrofuran-2-carboxamida
39
544,2 (2S)-N-((R)-3-amino-4-fluorobutil)-N-((R)1-(2-bencil-5-(2,5-difluorofenil)-2H-1,2,4triazol-3-il)-2,2-dimetilpropil)tetrahidrofuran-2-carboxamida
40
565,2 N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(2bencil-5-(2,5-difluorofenil)-2H-1,2,4triazol-3-il)-2,2-dimetilpropil)-6metilpiridin-3-carboxamida
41
551,2 N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(2bencil-5-(2,5-difluorofenil)-2H-1,2,4triazol-3-il)-2,2dimetilpropil)isonicotinamida
56
Compuesto
Estructura MH+ Nombre
42
imagen57 551,2 N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(2bencil-5-(2,5-difluorofenil)-2H-1,2,4triazol-3-il)-2,2-dimetilpropil)picolinamida
43
566,2 N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(2bencil-5-(2,5-difluorofenil)-2H-1,2,4triazol-3-il)-2,2-dimetilpropil)-2(metilsulfonil)acetamida
44
537,2 N-((S)-3-amino-2-fluoropropil)-N-((R)-1(2-bencil-5-(2,5-difluorofenil)-2H-1,2,4triazol-3-il)-2,2-dimetilpropil)nicotinamida
45
504,2 (2S)-N-((S)-3-amino-2-fluoropropil)-N((R)-1-(2-bencil-5-(2,5-difluorofenil)-2H1,2,4-triazol-3-il)-2,2-dimetilpropil)-2hidroxipropanamida
46
582,2 N-((R)-1-(2-(3-bromobencil)-5-(2,5difluorofenil)-2H-1,2,4-triazol-3-il)-2,2dimetilpropil)-N-((S)-3-amino-4fluorobutil)-2-hidroxiacetamida
57
Compuesto
Estructura MH+ Nombre
47
imagen58 596,2 (2S)-N-((R)-1-(2-(3-bromobencil)-5-(2,5difluorofenil)-2H-1,2,4-triazol-3-il)-2,2dimetilpropil)-N-((S)-3-amino-4fluorobutil)-2-hidroxipropanamida
48
629,2 N-((R)-1-(2-(3-bromobencil)-5-(2,5difluorofenil)-2H-1,2,4-triazol-3-il)-2,2dimetilpropil)-N-((S)-3-amino-4fluorobutil)nicotinamida
49
628,2 N-((R)-1-(2-(3-bromobencil)-5-(2,5difluorofenil)-2H-1,2,4-triazol-3-il)-2,2dimetilpropil)-N-((S)-3-amino-4fluorobutil)benzamida
50
550,2 N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(2bencil-5-(5-cloro-2-fluorofenil)-2H-1,2,4triazol-3-il)-2,2-dimetilpropil)-2metoxiacetamida
51
520,2 N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(2bencil-5-(5-cloro-2-fluorofenil)-2H-1,2,4triazol-3-il)-2,2-dimetilpropil)-2hidroxiacetamida
58
Compuesto
Estructura MH+ Nombre
52
imagen59 534,2 (S)-N-((S)-3-amino-4-fluorobutil)-N-((R)-1(1-bencil-3-(5-cloro-2-fluorofenil)-1H1,2,4-triazol-5-il)-2,2-dimetilpropil)-2hidroxipropanamida
53
566,2 N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(1bencil-3-(5-cloro-2-fluorofenil)-1H-1,2,4triazol-5-il)-2,2-dimetilpropil)benzamida
54
580,3 N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(1bencil-3-(5-cloro-2-fluorofenil)-1H-1,2,4triazol-5-il)-2,2-dimetilpropil)-4metilbenzamida
55
567,2 N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(1bencil-3-(5-cloro-2-fluorofenil)-1H-1,2,4triazol-5-il)-2,2-dimetilpropil)nicotinamida
56
imagen60 622,2 (R)-N-((S)-3-amino-4-fluorobutil)-N-((R)-1(1-(3-bromobencil)-3-(2,5-difluorofenil)1H-1,2,4-triazol-5-il)-2,2dimetilpropil)tetrahidrofuran-2carboxamida
59
Compuesto
Estructura MH+ Nombre
57
imagen61 622,2 (S)-N-((S)-3-amino-4-fluorobutil)-N-((R)-1(1-(3-bromobencil)-3-(2,5-difluorofenil)1H-1,2,4-triazol-5-il)-2,2dimetilpropil)tetrahidrofuran-2carboxamida
58
544,3 (R)-N-((S)-3-amino-4-fluorobutil)-N-((R)-1(1-bencil-3-(2,5-difluorofenil)-1H-1,2,4triazol-5-il)-2,2dimetilpropil)tetrahidrofuran-2carboxamida
59
543,3 (S)-N-((S)-3-amino-4-fluorobutil)-N-((R)-1(1-(3-cianobencil)-3-(2,5-difluorofenil)-1H1,2,4-triazol-5-il)-2,2-dimetilpropil)-2hidroxipropanamida
60
575,3 N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(1bencil-3-(5-cloro-2-fluorofenil)-1H-1,2,4triazol-5-il)-2,2-dimetilpropil)morfolin-4carboxamida
61
603,3 (2S,6R)-N-((S)-3-amino-4-fluorobutil)-N((R)-1-(1-bencil-3-(5-cloro-2-fluorofenil)1H-1,2,4-triazol-5-il)-2,2-dimetilpropil)-2,6dimetilmorfolin-4-carboxamida
60
Compuesto
Estructura MH+ Nombre
62
imagen62 552,2 N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(1bencil-3-(5-cloro-2-fluorofenil)-1H-1,2,4triazol-5-il)-2-metilpropil)benzamida
63
566,2 N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(1bencil-3-(5-cloro-2-fluorofenil)-1H-1,2,4triazol-5-il)-2-metilpropil)-4metilbenzamida
64
520,2 N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(1bencil-3-(5-cloro-2-fluorofenil)-1H-1,2,4triazol-5-il)-2-metilpropil)-2metoxiacetamida
65
506,2 N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(1bencil-3-(5-cloro-2-fluorofenil)-1H-1,2,4triazol-5-il)-2-metilpropil)-2hidroxiacetamida
66
imagen63 520,2 (S)-N-((S)-3-amino-4-fluorobutil)-N-((R)-1(1-bencil-3-(5-cloro-2-fluorofenil)-1H1,2,4-triazol-5-il)-2-metilpropil)-2hidroxipropanamida
61 62 63 64
Compuesto
Estructura MH+ Nombre
67
imagen64 532,3 (S)-N-((S)-3-amino-4-fluorobutil)-N-((R)-1(1-bencil-3-(2,5-difluorofenil)-1H-1,2,4triazol-5-il)-2,2-dimetilpropil)-2metoxipropanamida
68
532,3 (S)-N-((S)-3-amino-4-fluorobutil)-N-((R)-1(3-(2,5-difluorofenil)-1-(3-metilbencil)-1H1,2,4-triazol-5-il)-2,2-dimetilpropil)-2hidroxipropanamida
69
601,3 (2S,6R)-N-((S)-3-amino-4-fluorobutil)-N((R)-1-(3-(2,5-difluorofenil)-1-(3metilbencil)-1H-1,2,4-triazol-5-il)-2,2dimetilpropil)-2,6-dimetilmorfolin-4carboxamida
70
518,3 (S)-N-((S)-3-amino-4-fluorobutil)-N-((R)-1(1-bencil-3-(3,5-difluorofenil)-1H-1,2,4triazol-5-il)-2,2-dimetilpropil)-2hidroxipropanamida
71
imagen65 550,2 (S)-N-((S)-3-amino-4-fluorobutil)-N-((R)-1(1-bencil-3-(3,5-diclorofenil)-1H-1,2,4triazol-5-il)-2,2-dimetilpropil)-2hidroxipropanamida
Compuesto
Estructura MH+ Nombre
72
imagen66 587,3 (2S,6R)-N-((S)-3-amino-4-fluorobutil)-N((R)-1-(1-bencil-3-(3,5-difluorofenil)-1H1,2,4-triazol-5-il)-2,2-dimetilpropil)-2,6dimetilmorfolin-4-carboxamida
73
536,3 (S)-N-((S)-3-amino-4,4-difluorobutil)-N((R)-1-(1-bencil-3-(2,5-difluorofenil)-1H1,2,4-triazol-5-il)-2,2-dimetilpropil)-2hidroxipropanamida
74
536,3 (S)-N-((R)-3-amino-4,4-difluorobutil)-N((R)-1-(1-bencil-3-(2,5-difluorofenil)-1H1,2,4-triazol-5-il)-2,2-dimetilpropil)-2hidroxipropanamida
75
550,3 (S)-N-((R)-3-amino-4,4-difluorobutil)-N((R)-1-(3-(2,5-difluorofenil)-1-(3metilbencil)-1H-1,2,4-triazol-5-il)-2,2dimetilpropil)-2-hidroxipropanamida
76
561,2 (S)-N-((S)-3-amino-4,4-difluorobutil)-N((R)-1-(1-(3-cianobencil)-3-(2,5difluorofenil)-1H-1,2,4-triazol-5-il)-2,2dimetilpropil)-2-hidroxipropanamida
Compuesto
Estructura MH+ Nombre
77
imagen67 561,2 (S)-N-((R)-3-amino-4,4-difluorobutil)-N((R)-1-(1-(3-cianobencil)-3-(2,5difluorofenil)-1H-1,2,4-triazol-5-il)-2,2dimetilpropil)-2-hidroxipropanamida
78
604,2 (S)-N-((R)-3-amino-4,4-difluorobutil)-N((R)-1-(3-(2,5-difluorofenil)-1-(3(trifluorometil)bencil)-1H-1,2,4-triazol-5-il)2,2-dimetilpropil)-2-hidroxipropanamida
79
550,3 (S)-N-((S)-3-amino-4,4-difluorobutil)-N((R)-1-(3-(2,5-difluorofenil)-1-(3metilbencil)-1H-1,2,4-triazol-5-il)-2,2dimetilpropil)-2-hidroxipropanamida
80
604,2 (S)-N-((S)-3-amino-4,4-difluorobutil)-N((R)-1-(3-(2,5-difluorofenil)-1-(3(trifluorometil)bencil)-1H-1,2,4-triazol-5-il)2,2-dimetilpropil)-2-hidroxipropanamida
81
614,2 (S)-N-((S)-3-amino-4,4-difluorobutil)-N((R)-1-(1-(3-bromobencil)-3-(2,5difluorofenil)-1H-1,2,4-triazol-5-il)-2,2dimetilpropil)-2-hidroxipropanamida
82
614,2 (S)-N-((R)-3-amino-4,4-difluorobutil)-N((R)-1-(1-(3-bromobencil)-3-(2,5difluorofenil)-1H-1,2,4-triazol-5-il)-2,2dimetilpropil)-2-hidroxipropanamida
Compuesto
Estructura MH+ Nombre
83
imagen68 534,2 (S)-N-((S)-3-amino-4-fluorobutil)-N-((R)-1(1-bencil-3-(2-cloro-5-fluorofenil)-1H1,2,4-triazol-5-il)-2,2-dimetilpropil)-2hidroxipropanamida
84
591,3 (S)-N-((S)-3-amino-4-fluorobutil)-N-((R)-1(1-bencil-3-(5-cloro-2-fluorofenil)-1H1,2,4-triazol-5-il)-2-metilpropil)-3(hidroximetil)morfolin-4-carboxamida
85
578,3 (S)-N-((S)-3-amino-4,4-difluorobutil)-N((R)-1-(3-(2,5-difluorofenil)-1-(3isopropilbencil)-1H-1,2,4-triazol-5-il)-2,2dimetilpropil)-2-hidroxipropanamida
86
578,3 (S)-N-((R)-3-amino-4,4-difluorobutil)-N((R)-1-(3-(2,5-difluorofenil)-1-(3isopropilbencil)-1H-1,2,4-triazol-5-il)-2,2dimetilpropil)-2-hidroxipropanamida
Ejemplo 12
Ensayo para determinar la actividad de KSP
Este ejemplo proporciona un ensayo in vitro representativo para determinar la actividad de KSP in vitro. Se adquirieron microtúbulos purificados obtenidos de cerebro bovino de Cytoskeleton Inc. (Denver, Colorado, EE.UU.). 5 Se clonó el dominio motor de KSP humana (Eg 5, KNSL1), se expresó y se purificó hasta más del 95% de homogeneidad. Se adquirió Biomol Green de Affinity Research Products Ltd. (Matford Court, Exeter, Devon, Reino Unido). Se diluyeron los microtúbulos y la proteína motora KSP (es decir, el dominio motor de KSP) en tampón de ensayo (Tris-HCl 20 mM (pH 7,5), MgCl2 1 mM, DTT 10 mM y BSA 0,25 mg/ml) hasta una concentración final de microtúbulos 35 µg/ml y KSP 45 nM. Entonces se preincubó la mezcla de microtúbulos/KSP a 37ºC durante 10 min
10 para promover la unión de KSP a microtúbulos.
A cada pocillo de la placa de prueba (placa de 384 pocillos) que contenía 1,25 µl de inhibidor o compuesto de prueba en DMSO (o DMSO sólo en el caso de los controles) se le añadieron 25 µl de disolución de ATP (ATP diluido hasta una concentración de 300 µM en tampón de ensayo) y 25 µl de la disolución de microtúbulos/KSP descrita anteriormente. Se incubaron las placas a TA durante 1 hora. Tras la incubación, se añadieron 65 µl de Biomol Green 15 (un colorante a base de verde malaquita que detecta la liberación de fosfato inorgánico) a cada pocillo. Se incubaron
65
imagen69
imagen70

Claims (1)

  1. imagen1
    imagen2
    imagen3
    imagen4
    imagen5
    fluorobutil)nicotinamida;
    N-((R)-1-(2-(3-bromobencil)-5-(2,5-difluorofenil)-2H-1,2,4-triazol-3-il)-2,2-dimetilpropil)-N-((S)-3-amino-4
    fluorobutil)benzamida; N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(2-bencil-5-(5-cloro-2-fluorofenil)-2H-1,2,4-triazol-3-il)-2,2-dimetilpropil)-2metoxiacetamida;
    N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(2-bencil-5-(5-cloro-2-fluorofenil)-2H-1,2,4-triazol-3-il)-2,2-dimetilpropil)-2
    hidroxiacetamida; (S)-N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(1-bencil-3-(5-cloro-2-fluorofenil)-1H-1,2,4-triazol-5-il)-2,2-dimetilpropil)-2hidroxipropanamida;
    N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(1-bencil-3-(5-cloro-2-fluorofenil)-1H-1,2,4-triazol-5-il)-2,2
    dimetilpropil)benzamida; N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(1-bencil-3-(5-cloro-2-fluorofenil)-1H-1,2,4-triazol-5-il)-2,2-dimetilpropil)-4metilbenzamida;
    N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(1-bencil-3-(5-cloro-2-fluorofenil)-1H-1,2,4-triazol-5-il)-2,2
    dimetilpropil)nicotinamida; (R)-N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(1-(3-bromobencil)-3-(2,5-difluorofenil)-1H-1,2,4-triazol-5-il)-2,2dimetilpropil)tetrahidrofuran-2-carboxamida;
    (S)-N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(1-(3-bromobencil)-3-(2,5-difluorofenil)-1H-1,2,4-triazol-5-il)-2,2
    dimetilpropil)tetrahidrofuran-2-carboxamida; (R)-N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(1-bencil-3-(2,5-difluorofenil)-1H-1,2,4-triazol-5-il)-2,2dimetilpropil)tetrahidrofuran-2-carboxamida;
    (S)-N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(1-(3-cianobencil)-3-(2,5-difluorofenil)-1H-1,2,4-triazol-5-il)-2,2
    dimetilpropil)-2-hidroxipropanamida; N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(1-bencil-3-(5-cloro-2-fluorofenil)-1H-1,2,4-triazol-5-il)-2,2dimetilpropil)morfolin-4-carboxamida;
    (2S,6R)-N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(1-bencil-3-(5-cloro-2-fluorofenil)-1H-1,2,4-triazol-5-il)-2,2dimetilpropil)-2,6-dimetilmorfolin-4-carboxamida;
    N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(1-bencil-3-(5-cloro-2-fluorofenil)-1H-1,2,4-triazol-5-il)-2-metilpropil)benzamida; N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(1-bencil-3-(5-cloro-2-fluorofenil)-1H-1,2,4-triazol-5-il)-2-metilpropil)-4metilbenzamida;
    N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(1-bencil-3-(5-cloro-2-fluorofenil)-1H-1,2,4-triazol-5-il)-2-metilpropil)-2
    metoxiacetamida; N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(1-bencil-3-(5-cloro-2-fluorofenil)-1H-1,2,4-triazol-5-il)-2-metilpropil)-2hidroxiacetamida;
    (S)-N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(1-bencil-3-(5-cloro-2-fluorofenil)-1H-1,2,4-triazol-5-il)-2-metilpropil)-2
    hidroxipropanamida; (S)-N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(1-bencil-3-(2,5-difluorofenil)-1H-1,2,4-triazol-5-il)-2,2-dimetilpropil)-2metoxipropanamida;
    (S)-N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(3-(2,5-difluorofenil)-1-(3-metilbencil)-1H-1,2,4-triazol-5-il)-2,2dimetilpropil)-2-hidroxipropanamida; (2S,6R)-N-((S)-3-amino-4-fluorobutil)-N-((R)-1-(3-(2,5-difluorofenil)-1-(3-metilbencil)-1H-1,2,4-triazol-5-il)-2,2
    73
    imagen6
    imagen7
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AU2007323998B2 (en) * 2006-11-13 2011-09-22 Novartis Ag Substituted pyrazole and triazole compounds as KSP inhibitors
AU2008205169B2 (en) * 2007-01-05 2012-02-02 Novartis Ag Imidazole derivatives as kinesin spindle protein inhibitors (Eg-5)
JP2013523867A (ja) 2010-04-15 2013-06-17 ノバルティス アーゲー Ｋｓｐ阻害剤としてのトリアゾール化合物
EP2558452A2 (en) 2010-04-15 2013-02-20 Novartis AG Oxazole and thiazole compounds as ksp inhibitors
BR112015012843B8 (pt) * 2012-12-05 2023-04-25 Merck Sharp & Dohme Método para sintetizar o composto
US9498540B2 (en) 2013-03-15 2016-11-22 Novartis Ag Cell proliferation inhibitors and conjugates thereof
EP2968591A1 (en) * 2013-03-15 2016-01-20 Novartis AG Cell proliferation inhibitors and conjugates thereof
CA2930585A1 (en) 2013-12-04 2015-06-11 Merck Sharp & Dohme Corp. Process for making reverse transcriptase inhibitors
US10786578B2 (en) 2014-08-05 2020-09-29 Novartis Ag CKIT antibody drug conjugates
WO2017097927A1 (en) * 2015-12-11 2017-06-15 Syngenta Participations Ag Pesticidally active 1,2,4-triazole derivatives
CA3166630A1 (en) 2020-01-03 2021-07-08 Berg Llc Polycyclic amides as ube2k modulators for treating cancer

Family Cites Families (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4235871A (en) 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US4501728A (en) 1983-01-06 1985-02-26 Technology Unlimited, Inc. Masking of liposomes from RES recognition
US5023252A (en) 1985-12-04 1991-06-11 Conrex Pharmaceutical Corporation Transdermal and trans-membrane delivery of drugs
US4837028A (en) 1986-12-24 1989-06-06 Liposome Technology, Inc. Liposomes with enhanced circulation time
US5011472A (en) * 1988-09-06 1991-04-30 Brown University Research Foundation Implantable delivery system for biological factors
US5185450A (en) * 1991-02-19 1993-02-09 University Of South Florida Tetrazolium compounds for cell viability assays
AUPP042397A0 (en) * 1997-11-18 1997-12-11 Fujisawa Pharmaceutical Co., Ltd. 5-arylpyrazole compounds
AU4055400A (en) 1999-04-02 2000-10-23 Neurogen Corporation Aryl and heteroaryl fused aminoalkyl-imidazole derivatives and their use as antidiabetics
US6545004B1 (en) 1999-10-27 2003-04-08 Cytokinetics, Inc. Methods and compositions utilizing quinazolinones
ATE327224T1 (de) 1999-10-27 2006-06-15 Cytokinetics Inc Chinazolinone benutzende verfahren und zusammenstellungen
KR20030060904A (ko) 2000-10-06 2003-07-16 뉴로젠 코포레이션 Ｃｒｆ 수용체 조절자로서 벤즈이미다졸 및 인돌 유도체
WO2002056880A1 (en) 2001-01-19 2002-07-25 Cytokinetics, Inc. Triphenylmethane kinesin inhibitors
WO2002057244A1 (en) 2001-01-19 2002-07-25 Cytokinetics, Inc. Phenothiazine kinesin inhibitors
CA2465491A1 (en) 2001-11-07 2003-05-15 Merck & Co., Inc. Mitotic kinesin inhibitors
CA2466033A1 (en) 2001-11-08 2003-05-15 The University Of Chicago Method of treating disorder related to high cholesterol concentration
AU2002346471A1 (en) 2001-11-20 2003-06-10 Cytokinetics, Inc. Process for the racemization of chiral quinazolinones
US7378411B2 (en) 2001-12-06 2008-05-27 Merck & Co., Inc. Substituted thienopyrimidinones as a mitotic kinesin inhibitor
AU2002364128B2 (en) 2001-12-06 2008-03-06 Merck Sharp & Dohme Corp. Mitotic kinesin inhibitors
US7262187B2 (en) 2001-12-06 2007-08-28 Merck & Co., Inc. Substituted oxazolo- and thizaolopyrimidinones as a mitotic kinesin inhibitor
US20050107404A1 (en) 2001-12-06 2005-05-19 Fraley Mark E. Mitotic kinesin inhibitors
AU2002363960B2 (en) 2001-12-06 2008-07-10 Merck Sharp & Dohme Corp. Mitotic kinesin inhibitors
AU2002357114B2 (en) * 2001-12-07 2008-07-24 Virginia Commonwealth University Treatment of neoplasia
EP1465888A2 (en) 2002-01-10 2004-10-13 Neurogen Corporation Melanin concentrating hormone receptor ligands: substituted benzoimidazole analogues
WO2003070701A2 (en) 2002-02-15 2003-08-28 Cytokinetics, Inc. Syntheses of quinazolinones
EP1492487B1 (en) 2002-03-08 2009-11-11 Merck & Co., Inc. Mitotic kinesin inhibitors
US7214800B2 (en) 2002-05-09 2007-05-08 Cytokinetics, Inc. Compounds, compositions, and methods
CA2485148A1 (en) 2002-05-09 2003-11-20 Cytokinetics, Inc. Pyrimidinone compounds, compositions and methods
WO2004026226A2 (en) 2002-05-10 2004-04-01 Cytokinetics, Inc. Compounds, compositions and methods
EP1513820A4 (en) 2002-05-23 2006-09-13 Cytokinetics Inc COMPOUNDS, COMPOSITIONS AND METHODS
JP2005530806A (ja) 2002-05-23 2005-10-13 メルク　エンド　カムパニー　インコーポレーテッド 有糸分裂キネシン阻害薬
MXPA04012642A (es) 2002-06-14 2005-03-23 Merck & Co Inc Inhibidores de la cinesina mitotica.
ES2282647T3 (es) 2002-06-14 2007-10-16 MERCK & CO., INC. Inhibidores de cinesina mitotica.
GB0214139D0 (en) * 2002-06-19 2002-07-31 Glaxo Group Ltd Chemical compounds
CA2489562A1 (en) 2002-07-08 2004-01-15 Merck & Co., Inc. Mitotic kinesin binding site
JP2005533119A (ja) 2002-07-17 2005-11-04 サイトキネティクス・インコーポレーテッド 化合物、組成物、及び方法
AU2003256805A1 (en) 2002-07-23 2004-02-09 Cytokinetics, Inc. Compounds compositions and methods
US20040048853A1 (en) 2002-08-21 2004-03-11 Gustave Bergnes Compounds, compositions, and methods
EP1554265A4 (en) 2002-09-13 2008-05-07 Cytokinetics Inc COMPOSITIONS, COMPOSITIONS AND M THODES
EP1620092A4 (en) 2003-05-07 2008-04-16 Cytokinetics Inc COMPOUNDS, COMPOSITIONS AND METHODS
EP1622878A4 (en) 2003-05-15 2008-04-09 Cytokinetics Inc COMPOUNDS, COMPOSITIONS AND METHODS
ATE419249T1 (de) * 2004-04-06 2009-01-15 Novartis Vaccines & Diagnostic Inhibitoren von mitotischem kinesin
RS50670B (sr) * 2004-05-21 2010-06-30 Novartis Vaccines And Diagnostics Inc. Supstitucionisani derivati hinolina kao mitotički kinezinski inhibitori
KR101170925B1 (ko) * 2004-06-18 2012-08-07 노바티스 백신즈 앤드 다이아그노스틱스 인코포레이티드 암 치료용 키네신 방추 단백질 (ｋｓｐ) 억제제로서의ｎ-(1-(1-벤질-4-페닐-1ｈ-이미다졸-2-일)-2,2-디메틸프로필)벤자미드 유도체 및 관련 화합물
JP2008517057A (ja) 2004-10-19 2008-05-22 ノバルティス ヴァクシンズ アンド ダイアグノスティクス， インコーポレイテッド インドールおよびベンゾイミダゾール誘導体
US7829589B2 (en) * 2005-06-10 2010-11-09 Elixir Pharmaceuticals, Inc. Sulfonamide compounds and uses thereof
TW200800951A (en) * 2005-08-09 2008-01-01 Novartis Ag Substituted imidazole compounds as KSP inhibitors
AU2007323998B2 (en) * 2006-11-13 2011-09-22 Novartis Ag Substituted pyrazole and triazole compounds as KSP inhibitors

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