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)
  • Life Sciences & Earth Sciences (AREA)
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  • General Chemical & Material Sciences (AREA)
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  • Chemical Kinetics & Catalysis (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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