AR057927A1 - MODULATING COMPOUNDS OF THE ACTIVITY OF THROMBOPOYETINE RECEPTORS, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, AND USES IN HEMATOPOYETIC AFFECTIONS. - Google Patents

MODULATING COMPOUNDS OF THE ACTIVITY OF THROMBOPOYETINE RECEPTORS, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, AND USES IN HEMATOPOYETIC AFFECTIONS.

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AR057927A1
AR057927A1 ARP060105179A ARP060105179A AR057927A1 AR 057927 A1 AR057927 A1 AR 057927A1 AR P060105179 A ARP060105179 A AR P060105179A AR P060105179 A ARP060105179 A AR P060105179A AR 057927 A1 AR057927 A1 AR 057927A1
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Argentina
Prior art keywords
optionally substituted
alkyl
heteroalkyl
haloalkyl
optionally
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ARP060105179A
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Spanish (es)
Inventor
L Zhi
J E Dalgard
D P Phillips
R J Penulair
M H Mcneill
J-H Chen
C Cuervo
R Higuchi
Y Li
O Long
Oeveren Cornelis A Van
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Ligand Pharm Inc
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Publication of AR057927A1 publication Critical patent/AR057927A1/en

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    • C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
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    • C07D209/32—Oxygen atoms
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    • A61K31/415—1,2-Diazoles
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    • C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
    • C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
    • C07D207/448—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide
    • C07D207/452—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide with hydrocarbon radicals, substituted by hetero atoms, directly attached to the ring nitrogen atom
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    • C07D209/04—Indoles; Hydrogenated indoles
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    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
    • C07D231/26—1-Phenyl-3-methyl-5- pyrazolones, unsubstituted or substituted on the phenyl ring
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    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
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    • 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
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    • 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
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract

Reivindicacion 1: Un compuesto caracterizado porque responde a la formula (1), (2), (3), (4), (5), o (6), o una sal aceptable para uso farmacéutico, éster, amida o prodroga del mismo, en donde: R1 se selecciona entre H, halogeno, OR14, NO2, CN, NR14R15, un alquilo C1-6 opcionalmente sustituido, un haloalquilo C1-6 opcionalmente sustituido, un heteroalquilo C1-6 opcionalmente sustituido, CO2R14, CONR14R15, SO3R14, SO2NR14R15 y un bioisostero de ácido carboxílico; cada R2 se selecciona en forma independiente entre H, halogeno, OR14, NR14R15, un alquilo C1-6 opcionalmente sustituido, un haloalquilo C1-6 opcionalmente sustituido, y un heteroalquilo C1-6 opcionalmente sustituido; R3 y R4 se seleccionan en forma independiente entre H, un alquilo C1-6 opcionalmente sustituido, un haloalquilo C1-6 opcionalmente sustituido, y un heteroalquilo C1-6 opcionalmente sustituido; R5 se selecciona entre H, halogeno, OR14, alquilo C1-6, haloalquilo C1-6, heteroalquilo C1-6, y haloheteroalquilo C1-6; R6 se selecciona entre un alquilo C1-10 opcionalmente sustituido, un haloalquilo C1-10 opcionalmente sustituido, y un heteroalquilo C1-10 opcionalmente sustituido, cada uno opcionalmente fusionado con un arilo sustituido o un heteroarilo sustituido, o R6 se selecciona entre (CH2)mR18, C(O)NHR18, C:::CR18, CR3=CR4R18, y CR3=R18; R7 se selecciona entre CO2R14, CONR14R15, SO3R14, SO2NR14R15 y un bioisostero de ácido carboxílico; cada R8 y cada R9 se selecciona en forma independiente entre H, OR16, NR16R17, un alquilo C1-6 opcionalmente sustituido, un haloalquilo C1-6 opcionalmente sustituido, un heteroalquilo C1-6 opcionalmente sustituido; (CH2)mR18, y ausente; o R8 y R9 tomados juntos forman una olefina opcionalmente sustituida; o R8 y R9 se unen para formar un anillo C3-8 opcionalmente sustituido; R10 se selecciona entre H, halogeno, oxo, OR16, NR16R17, SR16, un alquilo C1-6 opcionalmente sustituido, un haloalquilo C1-6 opcionalmente sustituido, y un heteroalquilo C1-6 opcionalmente sustituido; R11 se selecciona entre H, halogeno, OR14, NR14R15, y SR14; o R11 y R4 se unen para formar un heterociclo opcionalmente sustituido; R12 se selecciona entre H, halogeno, alquilo C1-6, haloalquilo C1-6, heteroalquilo C1-6, y haloheteroalquilo C1-6; R13 se selecciona entre H, halogeno, CN, NO2, CO2R14, S(O)mR14, alquilo C1-4, haloalquilo C1-4, heteroalquilo C1-4, haloheteroalquilo C1-4; R14 se selecciona entre H, alquilo C1-6, haloalquilo C1-6, heteroalquilo C1-6, y heterohaloalquilo C1-6; R15 se selecciona entre H, SO2R19, alquilo C1-6, haloalquilo C1-6, heteroalquilo C1-6, y heterohaloalquilo C1-6; R16 y R17 se selecciona cada uno en forma independiente entre H, un alquilo C1-6 opcionalmente sustituido, un haloalquilo C1-6 opcionalmente sustituido, un heteroalquilo C1-6 opcionalmente sustituido, y (CH2)mR18; o uno de R16 y R17 es un alquilo C2-6 opcionalmente sustituido y el otro de R16 y R17 está ausente; o R16 y R17 se unen para formar un anillo C3- 8 opcionalmente sustituido; R18 se selecciona entre un sistema de anillo aromático monocíclico o bicíclico opcionalmente sustituido que contiene opcionalmente 1 o más heteroátomos y opcionalmente fusionado con un heterociclo o carbociclo no aromático, en donde cuando R18 contiene un heterociclo o carbociclo no aromático, la posicion de la union puede ser ya sea en el heterociclo o carbociclo no aromático o en el sistema de anillo aromático; R19 se selecciona entre H, alquilo C1-3, haloalquilo C1-3, y un arilo opcionalmente sustituido; D es un sistema de anillo aromático monocíclico o bicíclico que contiene opcionalmente uno o más heteroátomos, y opcionalmente fusionado con un heterociclo o carbociclo no aromático; E es un sistema de anillo aromático monocíclico o bicíclico que contiene opcionalmente uno o más heteroátomos, y opcionalmente fusionado con un heterociclo o carbociclo no aromático; L es NH o está ausente; Q es un sistema de anillo aromático monocíclico o bicíclico que contiene opcionalmente uno o más heteroátomos, y opcionalmente fusionado con un heterociclo o carbociclo no aromático; U se selecciona entre O, NR4, CR3R4, CO, y ausente; W se selecciona entre O, NR4, CR3R4, CO, y ausente; X es N o CR5; Y es un espaciador de 1-4 átomos que comprende uno o más grupos seleccionados entre un alquilo C1-6 opcionalmente sustituido, un heteroalquilo C1-6 opcionalmente sustituido, un fenilo opcionalmente sustituido, y un heteroarilo opcionalmente sustituido; Z se selecciona entre: ausente, un espaciador de 2-5 átomos seleccionado entre un arilo C6-10 opcionalmente sustituido y un heteroarilo C1-8 opcionalmente sustituido, cada uno opcionalmente fusionado con un heterociclo o carbociclo no aromático opcionalmente sustituido, y un espaciador de 1-5 átomos de seleccionado entre un alquilo C1-6 opcionalmente sustituido, un heteroalquilo C1-6 opcionalmente sustituido, y un haloalquilo C1-6 opcionalmente sustituido, cada uno opcionalmente fusionado con un arilo C6-10 opcionalmente sustituido; m es 0, 1, 2 o 3; y n es 0 o 1; cada grupo opcionalmente sustituido está ya sea no sustituido o sustituido con uno o más grupos seleccionados en forma independiente entre alquilo, heteroalquilo, haloalquilo, heterohaloalquilo, cicloalquilo, arilo, arilalquilo, heteroarilo, heterociclo no aromático, hidroxi, alcoxi, ariloxi, mercapto, alquiltio, ariltio, ciano, halo, carbonilo, tiocarbonilo, O- carbamilo, N-carbamilo, O-tiocarbamilo, N- tiocarbamilo, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxi, O-carboxi, isocianato, tiocianato, isotiocianato, nitro, sililo, trihalometansulfonilo, =O, =S, amino, y derivados protegidos de grupos amino; con la salvedad de que si Y está orientado como se muestra en el resto (7) en los compuesto de formulas (1) o (2) para formar un dihidropirazolineno, entonces (i) D no es naftilo si X es N y W es NH; (ii) D no es fenilo si X es CH, W es NH, Z es fenilo, y R10 o R11 es -(CH2)0-6OH, (iii) R11-D-R10 no es pirazolilo o 5-hidroxipirazolilo opcionalmente sustituido, y (iv) U no es NH; también con la salvedad de que si X es N y W es NH, entonces D no es fenilo; y también con la salvedad de que si X es N y W es NH en los compuestos de formulas (3) o (6), entonces R6, R10, y R11 no contienen una funcion carboxílico, amido, éster o sulfurato o un bioisostero de ácido carboxílico.Claim 1: A compound characterized in that it responds to formula (1), (2), (3), (4), (5), or (6), or a salt acceptable for pharmaceutical, ester, amide or prodrug use of the same, wherein: R1 is selected from H, halogen, OR14, NO2, CN, NR14R15, an optionally substituted C1-6 alkyl, an optionally substituted C1-6 haloalkyl, an optionally substituted C1-6 heteroalkyl, CO2R14, CONR14R15, SO3R14 , SO2NR14R15 and a carboxylic acid bioiso ester; each R2 is independently selected from H, halogen, OR14, NR14R15, an optionally substituted C1-6 alkyl, an optionally substituted C1-6 haloalkyl, and an optionally substituted C1-6 heteroalkyl; R3 and R4 are independently selected from H, an optionally substituted C1-6 alkyl, an optionally substituted C1-6 haloalkyl, and an optionally substituted C1-6 heteroalkyl; R5 is selected from H, halogen, OR14, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, and C1-6 haloheteroalkyl; R6 is selected from an optionally substituted C1-10 alkyl, an optionally substituted C1-10 haloalkyl, and an optionally substituted C1-10 heteroalkyl, each optionally fused with a substituted aryl or a substituted heteroaryl, or R6 is selected from (CH2) mR18, C (O) NHR18, C ::: CR18, CR3 = CR4R18, and CR3 = R18; R7 is selected from CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioiso ester; each R8 and each R9 is independently selected from H, OR16, NR16R17, an optionally substituted C1-6 alkyl, an optionally substituted C1-6 haloalkyl, an optionally substituted C1-6 heteroalkyl; (CH2) mR18, and absent; or R8 and R9 taken together form an optionally substituted olefin; or R8 and R9 join to form an optionally substituted C3-8 ring; R10 is selected from H, halogen, oxo, OR16, NR16R17, SR16, an optionally substituted C1-6 alkyl, an optionally substituted C1-6 haloalkyl, and an optionally substituted C1-6 heteroalkyl; R11 is selected from H, halogen, OR14, NR14R15, and SR14; or R11 and R4 join to form an optionally substituted heterocycle; R 12 is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, and C 1-6 haloheteroalkyl; R13 is selected from H, halogen, CN, NO2, CO2R14, S (O) mR14, C1-4 alkyl, C1-4 haloalkyl, C1-4 heteroalkyl, C1-4 haloheteroalkyl; R14 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, and C1-6 heterohaloalkyl; R15 is selected from H, SO2R19, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, and C1-6 heterohaloalkyl; R16 and R17 are each independently selected from H, an optionally substituted C1-6 alkyl, an optionally substituted C1-6 haloalkyl, an optionally substituted C1-6 heteroalkyl, and (CH2) mR18; or one of R16 and R17 is an optionally substituted C2-6 alkyl and the other of R16 and R17 is absent; or R16 and R17 join to form an optionally substituted C3-8 ring; R18 is selected from an optionally substituted monocyclic or bicyclic aromatic ring system that optionally contains 1 or more heteroatoms and optionally fused with a non-aromatic heterocycle or carbocycle, where when R18 contains a non-aromatic heterocycle or carbocycle, the position of the junction may be either in the non-aromatic heterocycle or carbocycle or in the aromatic ring system; R19 is selected from H, C1-3 alkyl, C1-3 haloalkyl, and an optionally substituted aryl; D is a monocyclic or bicyclic aromatic ring system that optionally contains one or more heteroatoms, and optionally fused with a non-aromatic heterocycle or carbocycle; E is a monocyclic or bicyclic aromatic ring system that optionally contains one or more heteroatoms, and optionally fused with a non-aromatic heterocycle or carbocycle; L is NH or is absent; Q is a monocyclic or bicyclic aromatic ring system that optionally contains one or more heteroatoms, and optionally fused with a non-aromatic heterocycle or carbocycle; U is selected from O, NR4, CR3R4, CO, and absent; W is selected from O, NR4, CR3R4, CO, and absent; X is N or CR5; Y is a 1-4 atom spacer comprising one or more groups selected from an optionally substituted C1-6 alkyl, an optionally substituted C1-6 heteroalkyl, an optionally substituted phenyl, and an optionally substituted heteroaryl; Z is selected from: absent, a 2-5 atom spacer selected from an optionally substituted C6-10 aryl and an optionally substituted C1-8 heteroaryl, each optionally fused with an optionally substituted non-aromatic heterocycle or carbocycle, and a spacer of 1-5 atoms selected from an optionally substituted C1-6 alkyl, an optionally substituted C1-6 heteroalkyl, and an optionally substituted C1-6 haloalkyl, each optionally fused with an optionally substituted C6-10 aryl; m is 0, 1, 2 or 3; and n is 0 or 1; Each optionally substituted group is either unsubstituted or substituted with one or more groups independently selected from alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic heterocycle, hydroxy, alkoxy, aryloxy, mercapto, alkylthio , arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy , isocyanate, thiocyanate, isothiocyanate, nitro, silyl, trihalomethanesulfonyl, = O, = S, amino, and protected derivatives of amino groups; with the proviso that if Y is oriented as shown in the remainder (7) in the compounds of formulas (1) or (2) to form a dihydropyrazolinine, then (i) D is not naphthyl if X is N and W is NH; (ii) D is not phenyl if X is CH, W is NH, Z is phenyl, and R10 or R11 is - (CH2) 0-6OH, (iii) R11-D-R10 is not pyrazolyl or optionally substituted 5-hydroxypyrazolyl , and (iv) U is not NH; also with the proviso that if X is N and W is NH, then D is not phenyl; and also with the proviso that if X is N and W is NH in the compounds of formulas (3) or (6), then R6, R10, and R11 do not contain a carboxylic, amido, ester or sulphurate function or a bioisoester of carboxylic acid.

ARP060105179A 2005-11-23 2006-11-23 MODULATING COMPOUNDS OF THE ACTIVITY OF THROMBOPOYETINE RECEPTORS, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, AND USES IN HEMATOPOYETIC AFFECTIONS. AR057927A1 (en)

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