AR067329A1 - Analogos dipeptidos como inhibidores del factor de coagulacion - Google Patents

Analogos dipeptidos como inhibidores del factor de coagulacion

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AR067329A1
AR067329A1 ARP080102487A ARP080102487A AR067329A1 AR 067329 A1 AR067329 A1 AR 067329A1 AR P080102487 A ARP080102487 A AR P080102487A AR P080102487 A ARP080102487 A AR P080102487A AR 067329 A1 AR067329 A1 AR 067329A1
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substituted
heterocycle
alkyl
heteroatoms selected
carbon atoms
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Donald J Pinto
Mimi L Quan
Ii Leon M Smith
Paul J Gilligan
Michael J Orwat
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Bristol Myers Squibb Co
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D498/04—Ortho-condensed systems

Abstract

Compuestos análogos dipéptidos de formula (1), (2) o (3), o un estereoisomero, un tautomero, una sal farmacéuticamente aceptable, un solvato o un profármaco del mismo, que son inhibidores de factor Xla y/o calicreína plasmática, composiciones que los contienen y uso de los mismos, por ejemplo, para el tratamiento o profilaxis de enfermedades tromboticas. Reivindicacion 1: Un compuesto caracterizado porque tiene la formula (1), (2) o (3), o un estereoisomero, un tautomero o una sal farmacéuticamente aceptable del mismo, en las que: A es un carbociclo C3-10 sustituido además con 0-3 R1 o un heterociclo de 5 a 10 miembros que comprende: átomos de carbono y 1 a 4 heteroátomos seleccionados de N, NR13, O y S(O)p, estando dicho heterociclo sustituido con 0-3 R1; con la condicion de que cuando A es un heterociclo que contiene uno o más átomos de nitrogeno, entonces A no está unido a L a través de cualquiera de los átomos de nitrogeno en el anillo A; L1 es -CH(R5)CH2C(O)NH-, -CH(NR7R8)CH2C(O)NH-, -C(R5)=CHC(O)NH-, -CH=C(R5)C(O)NH-, -C(R5)=C(R5)C(O)NH-, -CH2C(O)NHCH2-, -C:::CC(O)NH-, -CH2NHC(O)NH-, -C(O)NHCH2CH2-, -CH(R5)CH2SO2NH-, -C(R5)=CHSO2NH-, -CH2SO2NHCH2-, -SO2NHCH2CH2-, -NHNHC(O)CH2-, -CH2C(O)NHNH-, -CH(R5)CH2CH2NR10-, - CH2NHC(O)CH2-, -NHC(O)CH2CH2-, -N(R7)CH2C(O)NH-, -NHC(O)NHCH2-, -NHC(O)OCH2-, -CH2NHSO2CH2-, -NHSO2CH2CH2-, -CH2OC(O)NH-, -OCH2C(O)NH- o -S(O)pCH2C(O)NH-; L2 es -NHNHC(O)CH2-. -CH(R5)CH2NHC(O)-, -CH(NR7R8)CH2NHC(O)-, C(R5)=CHNHC(O)-, -CH2NHC(O)CH2-, -C:::CNHC(O)-, -NHC(O)CH2CH2-, -CH(R5)CH2NHSO2-, -C(R5)=CHNHSO2-, -CH2NHSO2CH2-, -NHSO2CH2CH2-, -CH2NHNHC(O)-, -CONHNHC(O)- o -COCH2NHC(O)-; M es (CH2)r-carbociclo C3-10 sustituido con 0-3 R3 o un -(CH2)r-heterociclo de 5 a 12 miembros que comprende: átomos de carbono y 1 a 4 heteroátomos seleccionados de N, NR13, O y S(O)p, estando dicho heterociclo sustituido con 0-3 R3; R1 es, independientemente en cada caso, =O, F, CI, Br, OCF3, CF3, CHF2, OCF3, CN, NO2, -(CH)rORa, -(CH2)rSRa, -(CH2)rC(O)Ra, -(CH2)rC(O)ORa, -(CH2)rOC(O)Ra, -(CH2)rNR7R8, -C(=NR8)NR8R9, -(CH2)rC(O)NR8R9, -(CH2)rNR8C(O)Rc, -(CH2)rNR8C(O)ORc, -CO2(CH2)2NR7R8, -NR8C(O)NR8Rc, -S(O)pNR8R9, -(CH2)rNR8C(O)NR8Rc, -(CH2)rS(O)pNR8R9, -(CH2)rNR8S(O)pRc, -(CH2)rS(O)Rc, -(CH2)rS(O)2Rc, alquilo C1-6 sustituido con 0-1 R2, -(CH2)r-carbociclo de 3-7 miembros opcionalmente sustituido con 0-2 R2a o -(CH2)r-heterociclo de 5-7 miembros que comprende átomos de carbono y 1-4 heteroátomos seleccionados de N, NR13, O y S(O)p, estando dicho heterociclo sustituido con 0-2 R2a; R2 es F, OCF3, CF3, ORa, SRa, CN, -NR7R8, -C(O)NR8R9, -NR8C(O)Rc, -NR8C(O)ORc, -NR8C(O)NR8Rc, -S(O)pNR8R9, -NR8SO2Rc o -(CF2)rCF3; R2a es, independientemente en cada caso, =O, F, Br, CI, OCF3, CF3, -(CH2)rORa, -(CH2)rSRa, -(CH2)rCN, -(CH2)rNR7R8, -(CH2)rC(O)ORa, -(CH2)rOC(O)Ra, -(CH2)rC(O)NR8R9, -(CH2)rNR8C(O)Rc, -(CH2)NR8C(O)ORc, -(CH2)r-S(O)pNR8R9, -(CH2)rNR8SO2Rc, alquilo C1-4 o -(CF2)rCF3; R3 es, independientemente en cada caso, =O, F, CI, Br, I, OCF3, CF3, -(CH2)rCN, NO2, -(CH2)rOR3b, -(CH2)rSR3b, -(CH2)rNR7R8, -(CH2)rNHC(O)NR8R9, -C(=NR8)NR8R9, -(C=NH)NHOR3b, -(CH2)rC(O)OR3b, -C(O)-alquilo C1-4, -SO2NHR3b, -SO2NHCOR3c, -SO2NHCO2R3c, -CONHSO2R3c, -(CH2)rNR8C(O)R3b, -(CH2)rNR8CO2R3c, -(CH2)rS(O)pNR8R9, -(CH2)rNR8S(O)pR3c, -NHSO2CF3, -S(O)R3c, -S(O)2R3c, -(CH2)rOC(O)R3b, -(CH2)rC(O)(CH2)rNR8R9, -(CH2)rOC(O)NR8R9, -NHCOCF3, -CONHOR3b, -(CH2)rP(O)(OH)2, -(CH2)rP(O)(O-alquilo C1-4)2, haloalquilo C1-4, haloalcoxi C1-4-, alquilo C1-6 sustituido con R3e, alquenilo C2-6 sustituido con R3e, alquinilo C1-6 sustituido con R3e, cicloalquilo C3-6 sustituido con 0-1 R3d, -(CH2)r-carbociclo C3-10 sustituido con 0-3 R3d o -(CH2)r-heterociclo de 5 a 10 miembros que comprende: átomos de carbono y 1 a 4 heteroátomos seleccionados de N, O y S(O)p, estando dicho heterociclo sustituido con 0-3 R3d; de forma alternativa, cuando dos grupos R3 están sustituidos en átomos adyacentes, éstos pueden tomarse junto con los átomos a los que están unidos formando un carbociclo C3-10 sustituido con 0-2 R3d o un heterociclo de 5 a 10 miembros que comprende: átomos de carbono y 1 a 4 heteroátomos seleccionados de N, O y S(O)p, estando dicho heterociclo sustituido con 0-2 R3d; R3b es, independientemente en cada caso, H, alquilo C1-6 sustituido con 0-2 R3d, alquenilo C2-6 sustituido con 0-2 R3d, alquinilo C2-6 sustituido con 0-2 R3d, -(CH2)r-carbociclo C3-10 sustituido con 0-3 R3d o -(CH2)r-heterociclo de 5 a 10 miembros que comprende: átomos de carbono y 1 a 4 heteroátomos seleccionados de N, O y S(O)p, estando icho heterociclo sustituido con 0-3 R3d; R3c es, independientemente en cada caso, alquilo C1-6 sustituido con 0-2 R3d, alquenilo C2-6 sustituido con 0-2 R3d, alquinilo C2-6 sustituido con 0-2 R3d, -(CH2)r-carbociclo C3-10 sustituido con 0-3 R3d o -(CH2)r-heterociclo de 5 a 10 miembros que comprende: átomos de carbono y 1 a 4 heteroátomos seleccionados de N, O y S(O)p, estando dicho heterociclo sustituido con 0-3 R3d; R3d es, independientemente en cada caso, =O, F, CI, Br, CN, NO2, -(CH2)rNR7R8, -(CH2)rORa, -C(O)Ra, -C(O)ORa, -OC(O)Ra, -NR8C(O)Rc, -C(O)NR8R9, -S(O)2NR8R9, -NR8S(O)2NR8R9, -NR8S(O)2Rc, -S(O)pRc, -(CF2)rCF3, -(CH2)rP(O)(OH)2, -(CH2)rP(O)(O-alquilo C1-4)2 alquilo C1-6 sustituido con 0-2 Re, alquenilo C2-6 sustituido con 0-2 Re, alquinilo C2-6 sustituido con 0-2 Re, -(CH2)r-carbociclo C3-10 sustituido con 0-3 Rd o -(CH2)r-heterociclo de 5 a 10 miembros que comprende: átomos de carbono y 1 a 4 heteroátomos seleccionados de N, O y S(O)p, estando dicho heterociclo sustituido con 0-3 Rd; R3e es, independientemente en cada caso, -(CH2)rORa, F, =O, CN, NO2, -(CH2)rNR7R8, -C(O)Ra, -C(O)ORa, -OC(O)Ra, -NR8C(O)Rc, -C(O)NR8R9, -S(O)2NR8R9, -NR8S(O)2NR8R9, -NR8S(O)2Rc, -S(O)pRc, -(CF2)rCF3, -(CH2)r-carbociclo C3-10 sustituido con 0-3 Rd o -(CH2)r-heterociclo de 5 a 10 miembros que comprende: átomos de carbono y 1 a 4 heteroátomos seleccionados de N, O y S(O)p, estando dicho heterociclo sustituido con 0-3 Rd; R5 es, independientemente en cada caso, H, F, CF3, -(CH2)rORa, -(CH2)rNR7R8, -S(O)pNR8R9, -(CH2)rCO2Ra, -(CH2)rCONR8R9 o alquilo C1-4; R7 es, independientemente en cada caso, H, alquilo C1-6, -(CH2)n-carbociclo C3-10, -(CH2)n-(heteroarilo de 5 a 10 miembros), -C(O)Rc, -CHO, -C(O)2Rc, -S(O)2Rc, -CONR8Rc, -OCONHRc, -C(O)O-(alquil C1-4)OC(O)-alquilo C1-4 o -C(O)O-(alquil C1-4)OC(O)-arilo C6-10; estando dichos alquilo, carbociclo, heteroarilo y arilo sustituidos con 0-2 Rf; comprendiendo dicho heteroarilo: átomos de carbono y 1-4 heteroátomos seleccionados de N, O y S(O)p; R8 es, independientemente en cada caso, H, alquilo C1-6, -(CH2)n-fenilo o - (CH2)n-heterociclo de 5 a 10 miembros que comprende: átomos de carbono y 1 a 4 heteroátomos seleccionados de N, O y S(O)p; estando dichos alquilo, fenilo y heterociclo opcionalmente sustituidos con 0-2 Rf; de forma alternativa, R7 y R8, cuando están unidos al mismo nitrogeno, se combinan formando un heterociclo de 5 a 10 miembros que comprende: átomos de carbono y 0-3 heteroátomos adicionales seleccionados de N, O y S(O)p, estando dicho heterociclo sustituido con 0-2 Rf; R9 es, independientemente en cada caso, H, alquilo C1-6 o -(CH2)n-fenilo; estando dichos alquilo y fenilo opcionalmente sustituidos con 0-2 Rf; de forma alternativa, R8 y R9, cuando están unidos al mismo nitrogeno, se combinan formando un heterociclo de 5 a 12 miembros que comprende: átomos de carbono y 0-2 heteroátomos adicionales seleccionados de N, O y S(o)p, estando dicho heterociclo sustituido con 0-2 Rd; R10 es, independientemente en cada caso, H o alquilo C1-6 sustituido con 0-3 R10a; R10a es, independientemente en cada caso, H, =O, alquilo C1-4, ORa, SRa, F, CF3, CN, NO2, -C(O)Ra, -C(O)ORa, -C(O)NR8R9, -NR8C(O)Rc, -S(O)pNR8R9, -NR8S(O)pRc o -S(O)pRc; R11 es haloalquilo C1-4, -C(O)NR8R9, -CH2C(O)NR8R9, -CH2CH2C(O)NR8R9, -C(O)Ra, -CH2C(O)Ra, -CH2CH2C(O)Ra, -C(O)ORa, -CH2-C(O)ORa, -CH2OCH2C(O)ORa, alquilo C1-6 sustituido con 0-3 R11c, alquenilo C2-6 sustituido con 0- R11a, alquinilo C2-6 sustituido con 0-3 R11a, -(CH2)r-carbociclo C31-0 sustituido con 0-3 R11b o -(CH2)r-heterociclo de 5 a 10 miembros que comprende: átomos de carbono y 1 a 4 heteroátomos seleccionados de N, O y S(O)p estando dicho heterociclo sustituido con 0-3 R11b; R11a es, independientemente en cada caso, =O, ORa, SRa, F, CF3, CN, NO2, -C(O)Ra, -C(O)ORa, -NR7R8, -C(O)NR8R9, -NR8C(O)Rc, -NR8C(O)ORc, -NR8CHO, -S(O)pNR8R9, -NR8S(O)pRc, -S(O)pRc, alquilo C1-4, cicloalquilo C3-6, haloalquilo C1-4, haloalquiloxi C1-4-, -(CH2)r-carbociclo C3-10 sustituido con 0-3 Rd o -(CH2)r-heterociclo de 5 a 10 miembros que comprende átomos de carbono y 1-4 heteroátomos seleccionados de N, O y S(O)p y está sustituido con 0-3 Rd; R11b es, independientemente en cada caso, =O, =NR8, ORa, -CH2ORa, F, Cl, Br, CN, NO2, CF3, OCF3, OCHF2, -C(CH3)2ORa, -C(O)Ra, -C(O)ORa, -NR7R8, -C(O)NR8R9, -NR7C(O)Rb, -NR8C(O)2Rc, -S(O)pNR8R9, -NR8S(O)pRc, -S(O)pRc alquilo C1-6, alquenilo C2-6, alquinilo C2-6, cicloalquilo C3-6, haloalquilo C1-4, haloalquiloxi C1-4-, -(CH2)r-carbociclo C3-10 sustituido con 0-3 Rd o -(CH2)r-heterociclo de 5 a 10 miembros que comprende átomos de carbono y 1-4 heteroátomos seleccionados de N, O y S(O)p y está sustituido con 0-3 Rd; de forma alternativa, cuando dos grupos R11b son sustituyentes en átomos adyacentes, éstos pueden tomarse junto con los átomos a los que están unidos formando un heterociclo de 5 a 7 miembros que comprende átomos de carbono y 1-4 heteroátomos seleccionados de N, O y S(O)p y está sustituido con 0-2 Rg; R11c es, independientemente en cada caso, =O, ORa, SRa, F, CF3, CN, NO2, -NR7R8, -NR8C(O)Rc, -NR8C(O)ORc, -NR8CHO, -NHC(NH2)=N(NO2), -C(=NR8)NR8R9, -S(O)pNR8R9, -NR8S(O)pRc, S(O)pRc, alquilo C1-4, cicloalquilo C3-6, haloalquilo C1-4, haloalquiloxi C1-4-, -(CH2)r-carbociclo C3-10 sustituido con 0-3 Rd o -(CH2)r-heterociclo de 5 a 10 miembros que comprende átomos de carbono y 1-4 heteroátomos seleccionados de N, O y S(O)p y está sustituido. con 0-3 Rd; R12 es, indepe
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