AR049645A1 - FIVE MEMBER FITS AS INHIBITORS OF SERINA PROTEASA. PHARMACEUTICAL COMPOSITION. - Google Patents

FIVE MEMBER FITS AS INHIBITORS OF SERINA PROTEASA. PHARMACEUTICAL COMPOSITION.

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AR049645A1
AR049645A1 ARP050102438A ARP050102438A AR049645A1 AR 049645 A1 AR049645 A1 AR 049645A1 AR P050102438 A ARP050102438 A AR P050102438A AR P050102438 A ARP050102438 A AR P050102438A AR 049645 A1 AR049645 A1 AR 049645A1
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Argentina
Prior art keywords
substituted
alkyl
heterocycle
nr7r8
independently
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ARP050102438A
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Spanish (es)
Inventor
Jon J Hangeland
Mimi L Quan
James R Corte
Joanne M Smallheer
Gregory S Bisacchi
Todd J Friends
Zhong Sun
Karen A Rossi
Cullen L Cavallaro
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Bristol Myers Squibb Co
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Publication of AR049645A1 publication Critical patent/AR049645A1/en

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Los compuestos pertenecen a la categoría de heterociclos de 5 miembros (imidazoles) utilizados como inhibidores de serina proteica. Composiciones farmacéuticas que los contienen. Reivindicacion 1: Un compuesto caracterizado porque la formula (1) o sus estereoisomeros, tautomeros, sales solvatos o profármacos farmacéuticamente aceptables de los mismos, caracterizado porque: A es carbociclo C3-10 substituido con 0-1 R1 y 0-3 R2, o con un heterociclo de 5 hasta 12 miembros que comprende: átomos de C y 1-4 heteroátomos seleccionados de N, O y S(O)p, en donde el heterociclo está substituido con 0-1 R1 y 0-3 R2; con la condicion de que cuando A es un heterociclo que contiene uno o más átomos de N, A no está unido a L por medio de cualesquiera de los átomos de N en el anillo A; L es -C(O)NR10-, -NR10C(O)-, -CH2C(O)NR10-, -CH2NR10C(O)-, -C(O)NR10CH2-, -NR10C(O)CH2-, -S(O)2NR10, -NR10S(O)2-, -CH2S(O)2NR10-, -CH2NR10S(O)2-, S(O)2NR10CH2-, -NR10S(O)2CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2NR7-, - NR7CH2-, -CH2CH2NR7-, -NR7CH2CH2-, -CH2NR7CH2-, -CH2O-, -OCH2-, -CH2S(O)p-, -S(O)pCH2-, -CH2CH2O-, -OCH2CH2-, CH2OCH2-, -CH2CH2S(O)p, -S(O)pCH2CH2-, -CH2S(O)pCH2-, -CH2C(O), -CH2C(O)CH2-, -CH2CH2C(O)-, C(O)CH2CH2-, o -C(O)CH2-; R1 es, independientemente cada vez que se presenta, -NH2, -NH(alquilo C1-3), -N(alquilo C1-3)2, -C(=NH)NH2, -C(O)NR8R9, -S(O)pNR8R9, -(CH2)rNR7R8, -(CH2)rNR7CO2Ra, -CH2NH2, -CH2NH(alquilo C1-3), -CH2N(alquilo C1-3)2, -CH2CH2NH2, -CH2CH2NH(alquilo C1-3), - CH2CH2N(alquilo C1-3)2, -CH(alquilo C1-4)NH2, -C(alquilo C1-4)2NH2, -C(=NR8a)NR7R8, -NHC(=NR8a)NR7R8, =NR8, -NR8CR8(=NR8a), F, Cl, Br, I, OCF3, CF3, -(CH2)rORa, -(CH2)rSRa, CN, 1-NH2-1-ciclopropilo, o alquilo C1-6 substituido con 0-1 R1a; R1a es H, - C(=NR8a)NR7R8, -NHC(=NR8a)NR7R8, -NR8CH(=NR8a), -NR7R8, -C(O)NR8R9, F, OCF3, CF3, ORa, SRa, CN, -NR9SO2NR8R9, -NR8SO2Rc, -S(O)p-alquilo C1-4, -S(O)p-fenilo, o -(CF2)rCF3; R2 es, independientemente cada vez que se presenta, H, =O, F, Cl, Br, I, OCF3, CF3, CHF2, CN, NO2, ORa, SRa, -C(O)Ra, -C(O)ORa, -OC(O)Ra, -NR7R8, -C(O)NR7R8, -NR7C(O)Rb, -S(O)2NR8R9, -NR8S(O)2Rc, -S(O)Rc, -S(O)2Rc, alquilo C1-6 substituido con 0-2 R2a, alquenilo C2-6 substituido con 0-2 R2a, alquinilo C2-6 substituido con 0-2 R2a, -(CH2)r-carbociclo C3-10 substituido con 0-3 R2b, o -(CH2)r-heterociclo de 5 hasta 10 miembros que comprende: átomos de C y 1-4 heteroátomos seleccionados de N, O, y S(O)p, en donde el heterociclo está substituido con 0-3 R2b; R2a es, independientemente cada vez que se presenta, H, F, Cl, Br, I, =O, =NR8, CN, OCF3, CF3, ORa, SRa, -NR7R8, -C(O)NR8R9, -NR7C(O)Rb, -S(O)pNR8R9, -NR8SO2Rc, -S(O)Rc, o -S(O)2Rc; R2b es, independientemente cada vez que se presenta, H, F, Cl, Br, I, =O, =NR8, CN, NO2, ORa, SRa, -C(O)Ra, -C(O)ORa, -OC(O)Ra, -NR7R8, -C(O)NR7R8, -NR7C(O)Rb, -S(O)2NR8R9, -S(O)2Rc, -NR8SO2NR8R9, -NR8SO2Rc, -(CF2)rCF3, alquilo C1-6, alquenilo C2-6, alquinilo C2-6, cicloalquilo C3-6, haloalquilo C1-4, o haloalcoxi C1-4-; alternativamente, cuando los grupos R1 y R2 están substituidos en átomos de anillo adyacente, estos se pueden tomar junto con los átomos de anillo al cual están enlazados para formar un carbociclo o heterociclo de 5 a 7 miembros que comprende: átomos de C y 0-4 heteroátomos seleccionados de N, O y S(O)p, en donde el carbociclo o heterociclo está substituido con 0-2 R2b; R3 es -(CH2)rC(O)NR8R9, -(CH2)rC(O)NR8(CH2)sCO2R3b, -(CH2)rCO2R3b, -(CH2)r-carbociclo C3-10 substituido con 0-3 R3a y 0- 1 R3a y 0-1 R3d, o -(CH2)r-heterociclo de 5 a 10- miembros que comprende: átomos de C y 1-4 heteroátomos seleccionados de N, O y S(O)p, en donde el heterociclo está substituido con 0-3 R3a y 0-1 R3d; R3a es, independientemente cada vez que se presenta, =O, F, Cl, Br, I, OCF3, CF3, NO2, CN, -(CH2)rOR3b, -(CH2)rSR3b, -(CH2)rNR7R8, -C(=NR8a)NR8R9, -NHC(=NR8a)NR7R8, -NR8CR8(=NR8a), -(CH2)rNR8C(O)R3b, =NR8, -(CH2)rNR8C(O)R3b, -(CH2)rNR8C(O)2R3b, -(CH2)rS(O)pNR8R9, -(CH2)rNR8S(O)pR3c, - S(O)pR3c, -S(O)pR3c, -C(O)-alquilo C1-4, -(CH2)rCO2R3b, -(CH2)rC(O)NR8R9, -(CH2)rOC(O)NR8R9, -NHCOCF3, -NHSO2CF3, -SO2NHR3b, -SO2NHCOR3c, -SO2NHCO2R3c, -CONHSO2R3c, -NHSO2R3c, -CONHOR3b, haloalquilo C1-4, haloalcoxi C1-4, alquilo C1-6 substituido por R3d, alquenilo C2-6 substituido por R3d, alquinilo C2-6 substituido por R3d, cicloalquilo C3-6 substituido por 0-1 R3d, -(CH2)r-carbociclo C3-10 substituido con 0-3 R3d, o -(CH2)r-heterociclo de 5 hasta 10 miembros que comprende: átomos de C y 1- 4 heteroátomos seleccionados de N, O, y S(O)p, en donde el heterociclo está substituido con 0-3 R3d; alternativamente, cuando dos grupos R3a se localizan en átomos adyacentes, estos pueden tomarse junto con los átomos al cual están enlazados para formar un carbociclo C3-10 substituido con 0-2 R3d o un heterociclo de 5 hasta 10 miembros que comprende: átomos de C y 1-4 heteroátomos seleccionados de N, O, y S(O)p, en donde el heterociclo está substituido con 0-2 R3d; R3b es, independientemente cada vez que se presenta, H, alquilo C1-6 substituido con 0-2 R3d, alquenilo C2-6 substituido con 0-2 R3d, alquinilo C2-6 substituido con 0-2 R3d, -(CH2)r-carbociclo C3-10 substituido con 0-3 R3d, o -(CH2)r-heterociclo de 5 hasta 10 miembros que comprende: átomos de C y 1-4 heteroátomos seleccionados de N, O y S(O)p, en donde el heterociclo está substituido con 0-3 R3d; R3c es, independientemente cada vez que se presenta, alquilo C1-6 substituido con 0-2 R3d, alquenilo C2-6 substituido con 0-2 R3d, alquinilo C2-6 substituido con 0-2 R3d, -(CH2)r-carbociclo C3-10 substituido con 0-3 R3d, o -(CH2)r-heterociclo de 5 hasta 10 miembros que comprende: átomos de C y 1-4 heteroátomos seleccionados de N, O y S(O)p, en donde el heterociclo está substituido con 0-3 R3d; R3d es, independientemente cada vez que se presenta, H, =O, -(CH2)rORa, F, Cl, Br, CN, NO2, -(CH2)rNR7R8, -C(O)Ra, -C(O)ORa, -OC(O)Ra, -NR7C(O)Rb, -C(O)NR8R9, -SO2NR8R9, -NR8SO2NR8R9, -NR8SO2Rc, -S(O)pRc, -(CF2)rCF3, alquilo C1-6 substituido con 0-2 Re, alquenilo C2-6 substituido con 0-2 Re, alquinilo C2-6 substituido con 0-2 Re, -(CH2)r-carbociclo C3-10 substituido con 0-3 Rd, o -(CH2)r-heterociclo de 5 hasta 10 miembros que comprende átomos de C y 1-4 heteroátomos seleccionados de N, O y S(O)p, en donde el heterociclo está substituido con 0-3 Rd; R4 es H, F, Cl, Br, I, OCF3, CF3, ORa, SRa, CN, NO2, -C(O)Ra, -C(O)ORa, -OC(O)Ra, -NR7R8, -C(O)NR8R9, -NR7C(O)Rb, -S(O)pNR8R9, -NR8S(O)pRc, -S(O)Rc, -S(O)2Rc, alquilo C1-6 substituido con 0-2 R4a, alquenilo C2-6 substituido con 0-2 R4a, alquinilo C2-6 substituido con 0-2 R4a, -(CH2)r-carbociclo C3-10 substituido con 0-3 R4b, o -(CH2)r-heterociclo de 5 hasta 10 miembros que comprende átomos de C y 1-4 heteroátomos seleccionados de N, O y S(O)p, en donde el heterociclo está substituido con 0-3 R4b; R4a es, independientemente cada vez que se presenta H, F, =O, alquilo C1-6, ORa, SRa, CF3, CN, NO2, -C(O)Ra, -C(O)ORa, -OC(O)Ra, -NR7R8, -C(O)NR8R9, - NR7C(O)Rb, -S(O)pNR8R9, -NR8S(O)2Rc, -S(O)Rc, o -S(O)2Rc; R4b es, independientemente cada vez que se presenta, H, =O, =NR8, F, Cl, Br, I, ORa, SRa, CN, NO2, CF3, -SO2Rc, -NR7R8, -C(O)Ra, -C(O)ORa, -OC(O)Ra, -NR7R8, -C(O)NR8R9, -NR7C(O)Rb, - S(O)pNR8R9, alquilo C1-6, alquenilo C2-6, alquinilo C2-6, cicloalquilo C3-6, haloalquilo C1-4, o haloalcoxi C1-4; alternativamente, los grupos R3 y R4 cuando se localizan en átomos adyacentes, se pueden tomar juntos para formar un carbociclo C3-10 substituido con 0-2 R3d o un heterociclo de 5 hasta 10 miembros que comprende: átomos de C y 1-4 heteroátomos seleccionados de N, O y S(O)p, en donde el heterociclo está substituido con 0-2 R3d; R6 es H; R7 es, independientemente cada vez que se presenta, H, alquilo C1-6, -(CH2)n-carbociclo C3-10, -(CH2)n-(heteroarilo de 5-10 miembros), -C(O)Rc, -CHO, -C(O)2Rc, -S(O)2Rc, -CONR8Rc, -OCONHRc, -C(O)O-(alquilo C1-4)OC(O)-(alquilo C1-4), o -C(O)O-(alquilo C1-4)OC(O)-(arilo C6-10); en donde los alquilo, carbociclo, heteroarilo, y arilo están substituidos opcionalmente con 0-2 Rf; R8 es, independientemente cada vez que se presenta, H, alquilo C1-6, o -(CH2)r-fenilo, o -(CH2)n-heterociclo de 5-10 miembros que comprende: átomos de C y 1-4 heteroátomos seleccionados de N, O y S(O)p; en donde los alquilo, fenilo y heterociclo están substituidos opcionalmente con 0-2 Rf; alternativamente, R7 y R8, cuando se enlazan al mismo N, se combinan para formar un anillo heterocíclico de 5 hasta 10 miembros que comprende átomos de C y 0-2 heteroátomos adicionales seleccionados de N, O, y S(O)p, en donde el heterociclo está substituido con 0-2 Rd; R8a es, independientemente cada vez que se presenta, H, OH, alquilo C1-6, alcoxi C1-4, (arilo C6-10)-alcoxi C1-4, -(CH2)n-fenilo, -(CH2)n-(heteroarilo de 5-10 miembros), -C(O)Rc, -C(O)2Rc, -C(O)O-(alquilo C1-4)OC(O)-(alquilo C1-4), o -C(O)O-(alquilo C1-4)OC(O)-(arilo C6-10); en donde el fenilo, arilo, y heteroarilo están opcionalmente substituidos con 0-2 Rf; R9 es, independientemente cada vez que se presenta, H, alquilo C1-6, o -(CH2)r-fenilo; en donde el alquilo y fenilo están substituidos opcionalmente con 0-2 Rf; R9a es, independientemente cada vez que se presenta, H, alquilo C1-6, o -(CH2)n-fenilo; alternativamente, R8 y R9, cuando se enlazan al mismo N, se combinan para formar un anillo heterocíclico de 5 hasta 10 miembros que comprende átomos de C y 0-2 heteroátomos adicionales seleccionados de N, O, y S(O)p, en donde el heterociclo está substituido con 0-2 Rd; R10 es, independientemente cada vez que se presenta, H, alquilo C1-6 substituido con 0-3 R10a, alquenilo C2-6 substituido con 0-3 R10a, alquinilo C2-6 substituido con 0-3 R10a, -(CH2)r-carbociclo C3-10 substituido con 0-3 Rd, o -(CH2)r-heterociclo de 5 hasta 10 miembros que comprende átomos de C y 1-4 heteroátomos seleccionados de N, O y S(O)p, en donde el heterociclo está substituido con 0-3 Rd; R10a es, independientemente cada vez que se presenta, H, =O, alquilo C1-4, ORa, SRa, F, CF3, CN, NO2, -C(O)ORa, -NR7R8, -C(O)NR7R8, -NR7C(O)Rb, -S(O)pNR8R9, -NR8SO2Rc, -SThe compounds belong to the category of 5-membered heterocycles (imidazoles) used as protein serine inhibitors. Pharmaceutical compositions that contain them. Claim 1: A compound characterized in that the formula (1) or its stereoisomers, tautomers, solvate salts or pharmaceutically acceptable prodrugs thereof, characterized in that: A is C3-10 carbocycle substituted with 0-1 R1 and 0-3 R2, or with a 5-12 membered heterocycle comprising: C and 1-4 hetero atoms selected from N, O and S (O) p, wherein the heterocycle is substituted with 0-1 R1 and 0-3 R2; with the proviso that when A is a heterocycle containing one or more N atoms, A is not bound to L by means of any of the N atoms in the A ring; L is -C (O) NR10-, -NR10C (O) -, -CH2C (O) NR10-, -CH2NR10C (O) -, -C (O) NR10CH2-, -NR10C (O) CH2-, -S (O) 2NR10, -NR10S (O) 2-, -CH2S (O) 2NR10-, -CH2NR10S (O) 2-, S (O) 2NR10CH2-, -NR10S (O) 2CH2-, -CH2CH2-, -CH2CH2CH2 -, -CH2NR7-, - NR7CH2-, -CH2CH2NR7-, -NR7CH2CH2-, -CH2NR7CH2-, -CH2O-, -OCH2-, -CH2S (O) p-, -S (O) pCH2-, -CH2CH2O-, -OCH2CH2-, CH2OCH2-, -CH2CH2S (O) p, -S (O) pCH2CH2-, -CH2S (O) pCH2-, -CH2C (O), -CH2C (O) CH2-, -CH2CH2C (O) - , C (O) CH2CH2-, or -C (O) CH2-; R1 is, independently each time it occurs, -NH2, -NH (C1-3 alkyl), -N (C1-3 alkyl) 2, -C (= NH) NH2, -C (O) NR8R9, -S ( O) pNR8R9, - (CH2) rNR7R8, - (CH2) rNR7CO2Ra, -CH2NH2, -CH2NH (C1-3 alkyl), -CH2N (C1-3 alkyl) 2, -CH2CH2NH2, -CH2CH2NH (C1-3 alkyl), - CH2CH2N (C1-3 alkyl) 2, -CH (C1-4 alkyl) NH2, -C (C1-4 alkyl) 2NH2, -C (= NR8a) NR7R8, -NHC (= NR8a) NR7R8, = NR8, - NR8CR8 (= NR8a), F, Cl, Br, I, OCF3, CF3, - (CH2) rORa, - (CH2) rSRa, CN, 1-NH2-1-cyclopropyl, or C1-6 alkyl substituted with 0-1 R1a; R1a is H, - C (= NR8a) NR7R8, -NHC (= NR8a) NR7R8, -NR8CH (= NR8a), -NR7R8, -C (O) NR8R9, F, OCF3, CF3, ORa, SRa, CN, - NR9SO2NR8R9, -NR8SO2Rc, -S (O) p-C1-4alkyl, -S (O) p-phenyl, or - (CF2) rCF3; R2 is, independently each time it occurs, H, = O, F, Cl, Br, I, OCF3, CF3, CHF2, CN, NO2, ORa, SRa, -C (O) Ra, -C (O) ORa , -OC (O) Ra, -NR7R8, -C (O) NR7R8, -NR7C (O) Rb, -S (O) 2NR8R9, -NR8S (O) 2Rc, -S (O) Rc, -S (O ) 2Rc, C1-6 alkyl substituted with 0-2 R2a, C2-6 alkenyl substituted with 0-2 R2a, C2-6 alkynyl substituted with 0-2 R2a, - (CH2) C3-10 r-carbocycle substituted with 0- 3 R2b, or - (CH2) 5 to 10 membered r-heterocycle comprising: C and 1-4 hetero atoms selected from N, O, and S (O) p, wherein the heterocycle is substituted with 0-3 R2b; R2a is, independently each time it occurs, H, F, Cl, Br, I, = O, = NR8, CN, OCF3, CF3, ORa, SRa, -NR7R8, -C (O) NR8R9, -NR7C (O ) Rb, -S (O) pNR8R9, -NR8SO2Rc, -S (O) Rc, or -S (O) 2Rc; R2b is, independently each time it occurs, H, F, Cl, Br, I, = O, = NR8, CN, NO2, ORa, SRa, -C (O) Ra, -C (O) ORa, -OC (O) Ra, -NR7R8, -C (O) NR7R8, -NR7C (O) Rb, -S (O) 2NR8R9, -S (O) 2Rc, -NR8SO2NR8R9, -NR8SO2Rc, - (CF2) rCF3, C1 alkyl -6, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-4 haloalkyl, or C1-4- haloalkoxy; alternatively, when the groups R1 and R2 are substituted on adjacent ring atoms, these can be taken together with the ring atoms to which they are linked to form a 5- to 7-membered carbocycle or heterocycle comprising: C and 0- atoms 4 heteroatoms selected from N, O and S (O) p, wherein the carbocycle or heterocycle is substituted with 0-2 R2b; R3 is - (CH2) rC (O) NR8R9, - (CH2) rC (O) NR8 (CH2) sCO2R3b, - (CH2) rCO2R3b, - (CH2) r-carbocycle C3-10 substituted with 0-3 R3a and 0 - 1 R3a and 0-1 R3d, or - (CH2) 5 to 10-membered r-heterocycle comprising: C and 1-4 hetero atoms selected from N, O and S (O) p, wherein the heterocycle it is substituted with 0-3 R3a and 0-1 R3d; R3a is, independently each time it occurs, = O, F, Cl, Br, I, OCF3, CF3, NO2, CN, - (CH2) rOR3b, - (CH2) rSR3b, - (CH2) rNR7R8, -C ( = NR8a) NR8R9, -NHC (= NR8a) NR7R8, -NR8CR8 (= NR8a), - (CH2) rNR8C (O) R3b, = NR8, - (CH2) rNR8C (O) R3b, - (CH2) rNR8C (O ) 2R3b, - (CH2) rS (O) pNR8R9, - (CH2) rNR8S (O) pR3c, - S (O) pR3c, -S (O) pR3c, -C (O) -C1-4 alkyl, - ( CH2) rCO2R3b, - (CH2) rC (O) NR8R9, - (CH2) ROC (O) NR8R9, -NHCOCF3, -NHSO2CF3, -SO2NHR3b, -SO2NHCOR3c, -SO2NHCO2R3c, -CONHSO2R3c, -NHSO2R3c, -CONHOR3b, C1 -4, C1-4 haloalkoxy, C1-6 alkyl substituted by R3d, C2-6 alkenyl substituted by R3d, C2-6 alkynyl substituted by R3d, C3-6 cycloalkyl substituted by 0-1 R3d, - (CH2) r-carbocycle C3-10 substituted with 0-3 R3d, or - (CH2) 5 to 10 membered r-heterocycle comprising: C and 1-4 hetero atoms selected from N, O, and S (O) p, wherein the heterocycle is substituted with 0-3 R3d; alternatively, when two R3a groups are located in adjacent atoms, these can be taken together with the atoms to which they are linked to form a C3-10 carbocycle substituted with 0-2 R3d or a 5-10 membered heterocycle comprising: C atoms and 1-4 heteroatoms selected from N, O, and S (O) p, wherein the heterocycle is substituted with 0-2 R3d; R3b is, independently each time it occurs, H, C1-6 alkyl substituted with 0-2 R3d, C2-6 alkenyl substituted with 0-2 R3d, C2-6 alkynyl substituted with 0-2 R3d, - (CH2) r -C3-10 carbocycle substituted with 0-3 R3d, or - (CH2) 5-membered r-heterocycle comprising: C and 1-4 hetero atoms selected from N, O and S (O) p, wherein the heterocycle is substituted with 0-3 R3d; R3c is, independently each time it occurs, C1-6 alkyl substituted with 0-2 R3d, C2-6 alkenyl substituted with 0-2 R3d, C2-6 alkynyl substituted with 0-2 R3d, - (CH2) r-carbocycle C3-10 substituted with 0-3 R3d, or - (CH2) 5 to 10 membered r-heterocycle comprising: C and 1-4 hetero atoms selected from N, O and S (O) p, wherein the heterocycle it is substituted with 0-3 R3d; R3d is, independently each time it occurs, H, = O, - (CH2) rORa, F, Cl, Br, CN, NO2, - (CH2) rNR7R8, -C (O) Ra, -C (O) ORa , -OC (O) Ra, -NR7C (O) Rb, -C (O) NR8R9, -SO2NR8R9, -NR8SO2NR8R9, -NR8SO2Rc, -S (O) pRc, - (CF2) rCF3, C1-6 alkyl substituted with 0-2 Re, C2-6 alkenyl substituted with 0-2 Re, C2-6 alkynyl substituted with 0-2 Re, - (CH2) C3-10 r-carbocycle substituted with 0-3 Rd, or - (CH2) r - 5-10 membered heterocycle comprising atoms of C and 1-4 heteroatoms selected from N, O and S (O) p, wherein the heterocycle is substituted with 0-3 Rd; R4 is H, F, Cl, Br, I, OCF3, CF3, ORa, SRa, CN, NO2, -C (O) Ra, -C (O) ORa, -OC (O) Ra, -NR7R8, -C (O) NR8R9, -NR7C (O) Rb, -S (O) pNR8R9, -NR8S (O) pRc, -S (O) Rc, -S (O) 2Rc, C1-6 alkyl substituted with 0-2 R4a , C2-6 alkenyl substituted with 0-2 R4a, C2-6 alkynyl substituted with 0-2 R4a, - (CH2) r-carbocycle C3-10 substituted with 0-3 R4b, or - (CH2) r-heterocycle of 5 up to 10 members comprising atoms of C and 1-4 heteroatoms selected from N, O and S (O) p, wherein the heterocycle is substituted with 0-3 R4b; R4a is, independently each time H, F, = O, C1-6 alkyl, ORa, SRa, CF3, CN, NO2, -C (O) Ra, -C (O) ORa, -OC (O) occur Ra, -NR7R8, -C (O) NR8R9, - NR7C (O) Rb, -S (O) pNR8R9, -NR8S (O) 2Rc, -S (O) Rc, or -S (O) 2Rc; R4b is, independently each time it occurs, H, = O, = NR8, F, Cl, Br, I, ORa, SRa, CN, NO2, CF3, -SO2Rc, -NR7R8, -C (O) Ra, - C (O) ORa, -OC (O) Ra, -NR7R8, -C (O) NR8R9, -NR7C (O) Rb, - S (O) pNR8R9, C1-6 alkyl, C2-6 alkenyl, C2- alkynyl 6, C3-6 cycloalkyl, C1-4 haloalkyl, or C1-4 haloalkoxy; alternatively, groups R3 and R4 when located in adjacent atoms, can be taken together to form a C3-10 carbocycle substituted with 0-2 R3d or a 5-10 membered heterocycle comprising: C atoms and 1-4 heteroatoms selected from N, O and S (O) p, wherein the heterocycle is substituted with 0-2 R3d; R6 is H; R7 is, independently each time it occurs, H, C1-6 alkyl, - (CH2) C3-10 n-carbocycle, - (CH2) n- (5-10 membered heteroaryl), -C (O) Rc, -CHO, -C (O) 2Rc, -S (O) 2Rc, -CONR8Rc, -OCONHRc, -C (O) O- (C1-4 alkyl) OC (O) - (C1-4 alkyl), or - C (O) O- (C1-4 alkyl) OC (O) - (C6-10 aryl); wherein the alkyl, carbocycle, heteroaryl, and aryl are optionally substituted with 0-2 Rf; R8 is, independently each time it occurs, H, C1-6 alkyl, or - (CH2) r-phenyl, or - (CH2) 5-10 membered n-heterocycle comprising: C atoms and 1-4 heteroatoms selected from N, O and S (O) p; wherein the alkyl, phenyl and heterocycle are optionally substituted with 0-2 Rf; alternatively, R7 and R8, when linked to the same N, combine to form a 5- to 10-membered heterocyclic ring comprising additional C and 0-2 hetero atoms selected from N, O, and S (O) p, in where the heterocycle is substituted with 0-2 Rd; R8a is, independently each time it occurs, H, OH, C1-6 alkyl, C1-4 alkoxy, (C6-10 aryl) -C1-4 alkoxy, - (CH2) n-phenyl, - (CH2) n- (5-10 membered heteroaryl), -C (O) Rc, -C (O) 2Rc, -C (O) O- (C1-4 alkyl) OC (O) - (C1-4 alkyl), or - C (O) O- (C1-4 alkyl) OC (O) - (C6-10 aryl); wherein the phenyl, aryl, and heteroaryl are optionally substituted with 0-2 Rf; R9 is, independently each time it occurs, H, C1-6 alkyl, or - (CH2) r-phenyl; wherein the alkyl and phenyl are optionally substituted with 0-2 Rf; R9a is, independently each time it occurs, H, C1-6 alkyl, or - (CH2) n-phenyl; alternatively, R8 and R9, when linked to the same N, combine to form a 5- to 10-membered heterocyclic ring comprising additional C and 0-2 hetero atoms selected from N, O, and S (O) p, in where the heterocycle is substituted with 0-2 Rd; R10 is, independently each time it occurs, H, C1-6 alkyl substituted with 0-3 R10a, C2-6 alkenyl substituted with 0-3 R10a, C2-6 alkynyl substituted with 0-3 R10a, - (CH2) r -C3-10 carbocycle substituted with 0-3 Rd, or - (CH2) 5 to 10 membered r-heterocycle comprising C and 1-4 hetero atoms selected from N, O and S (O) p, wherein the heterocycle is substituted with 0-3 Rd; R10a is, independently each time it occurs, H, = O, C1-4 alkyl, ORa, SRa, F, CF3, CN, NO2, -C (O) ORa, -NR7R8, -C (O) NR7R8, - NR7C (O) Rb, -S (O) pNR8R9, -NR8SO2Rc, -S

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Publication number Priority date Publication date Assignee Title
CN113228201A (en) * 2018-08-13 2021-08-06 健康科学西部大学 Calpain-2selective inhibitor compounds for the treatment of glaucoma

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113228201A (en) * 2018-08-13 2021-08-06 健康科学西部大学 Calpain-2selective inhibitor compounds for the treatment of glaucoma
CN113228201B (en) * 2018-08-13 2023-03-07 健康科学西部大学 Calpain-2selective inhibitor compounds for the treatment of glaucoma

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