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AR084765A1 - COMPOUNDS OF 2,3,5-THIOPHEN TRISUBSTITUIDOS - Google Patents

COMPOUNDS OF 2,3,5-THIOPHEN TRISUBSTITUIDOS

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Publication number
AR084765A1
AR084765A1 ARP120100004A ARP120100004A AR084765A1 AR 084765 A1 AR084765 A1 AR 084765A1 AR P120100004 A ARP120100004 A AR P120100004A AR P120100004 A ARP120100004 A AR P120100004A AR 084765 A1 AR084765 A1 AR 084765A1
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AR
Argentina
Prior art keywords
alkyl
substituted
alkoxy
independently selected
cyclic
Prior art date
Application number
ARP120100004A
Other languages
Spanish (es)
Inventor
Jiping Fu
Scott Louis Cohen
Rui Zheng
Lei Shu
Davis Barnes
Original Assignee
Novartis Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/EP2011/062545 external-priority patent/WO2012010663A1/en
Application filed by Novartis Ag filed Critical Novartis Ag
Publication of AR084765A1 publication Critical patent/AR084765A1/en

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Abstract

La presente provee compuestos de fórmula (1), un método para la preparación de los compuestos de la presente y sus usos terapéuticos. La presente además provee una combinación de agentes farmacéuticamente activos y una composición farmacéutica. Estos compuestos son útiles para el tratamiento de la hepatitis C.Reivindicación 1: Un compuesto de la fórmula (1) o una sal del mismo, en donde m es 0, 1 ó 2; n es 0 ó 1, en donde m + n es 1, 2 ó 3; R1 es alquinilo C3-10 o fenilo, tal fenilo es sustituido por 0, 1, 2 ó 3 sustituyentes los cuales son independientemente seleccionados del grupo que consta de halógeno, hidroxilo, ciano, alquilo C1-4, haloalquilo C1-4 y alcoxilo C1-4, y cuyo alquinilo es opcionalmente sustituido por un sustituyente cicloalquilo C3-7, tal cicloalquilo es opcionalmente sustituido por 1 ó 2 grupos alquilo C1-4 independientemente seleccionados; R2 es CO2H, tetrazol o un isóstero de ácido carboxílico; R3 es cicloalquilo C3-7 el cual es sustituido por 0, 1, 2 ó 3 átomos de halógeno; R3a representa 0, 1, 2, 3 ó 4 residuos independientemente seleccionados en cada ocurrencia desde el grupo que consta de hidroxilo, amino, ciano, halógeno, alquilo C1-6, alcoxilo C1-6, en donde cada sustituyente alquilo o alcoxilo es sustituido por 0, 1 ó 2 sustituyentes independientemente seleccionados a partir de hidroxilo, ciano, alcoxilo C1-4, alquil C1-4sulfona, N(R3b)2, C(O)N(R3b), heterociclo con 4 a 7 átomos cíclicos y 1 ó 2 heteroátomos cíclicos seleccionados a partir de N, O ó S y heteroarilo de 5 ó 6 miembros, o dos sustituyentes R3a geminales, tomados en combinación forman un cicloalquilo o heterociclo espirocíclico de 3 a 6 miembros; R3b se selecciona independientemente en cada ocurrencia a partir de hidrógeno, alquilo C1-4, alcoxi C1-4alquilo C1-4 y alcanoilo C1-4, o N(R3b)2, tomados en combinación forman un heterociclo de 4 a 6 miembros con 0 ó 1 heteroátomos cíclicos adicionales seleccionados a partir de N, O ó S; X es O, N-L-R4 o CR5R6; L es un enlace, S(O)2 o C(O); R4 es alquilo C1-6 o cicloalquilo C3-7 cada uno de los cuales es sustituido por 0, 1 ó 2 hidroxilo y 0 ó 1 sustituyentes seleccionados a partir de ciano, S(O)2-alquilo C1-6, CO2H o NR4aR4b o fenilo; R4 es naftilo o fenilo, tal fenilo es sustituido por 0, 1, 2 ó 3 sustituyentes independientemente seleccionados a partir del grupo que consta de halógeno, ciano, alquilo C1-6, haloalquilo C1-6, alcoxilo C1-6, haloalcoxilo C1-6, amino, hidroxilo mono- y di-alquilamino C1-6, hidroxialquilo C1-4, aminoalquilo C1-4, alquilo C1-6-OC(O)NH-, alquilo C1-4-C(O)NH-, -C(O)NR4aR4b, fenilo, fenoxilo, heteroarilo con uno o dos átomos de nitrógeno cíclicos y que tiene 0, 1 ó 2 sustituyentes alquilo C1-4, o dos sustituyentes combinados para formar un anillo heterocíclico fusionado, tal heterociclo tiene 5, 6 ó 7 átomos cíclicos, 1 ó 2 heteroátomos cíclicos seleccionados a partir de N, O ó S y tal heterociclo es sustituido por 0, 1 ó 2 sustituyentes independientemente seleccionados a partir de alquilo C1-6, o R4 es un heteroarilo de 5 ó 6 miembros que tiene 1 a 3 heteroátomos seleccionados a partir de N, O ó S, tal heteroarilo es sustituido por 0, 1, ó 2 sustituyentes independientemente seleccionados del grupo que consta de halógeno, ciano, alquilo C1-6, haloalquilo C1-6, alcoxilo C1-6, haloalcoxilo C1-6, hidroxilo, NR4aR4b, hidroxialquilo C1-4, aminoalquilo C1-4, alquil C1-6-OC(O)NH-, cicloalquilo C3-7, cicloalquenilo C5-7, fenilo, heteroarilo de 5 ó 6 miembros que tiene 1 ó 2 heteroátomos cíclicos seleccionados a partir de N, O ó S, o un heterociclo monocíclico o bicíclico saturado o parcialmente no saturado tal heterociclo tiene 1 ó 2 átomos de N, O ó S cíclicos, de 5 a 7 átomos cíclicos en cada anillo y es sustituido por 0, 1 ó 2 sustituyentes independientemente seleccionados del grupo que consta de halógeno, alquilo C1-6, alcanoilo C1-6, alcoxilo C1-6C(O)N(H)-, alcoxilo C1-6C(O)N(H)CH2-, aminoalquilo C1-4, alcoxi C1-4alquilo C1-4 y NR4aR4b, y en donde el sustituyente fenilo o heteroarilo no es sustituido o es sustituido por 1 ó 2 sustituyentes independientemente seleccionados a partir de halógeno, CO2H, ciano, alquilo C1-4, alcoxilo C1-4, CH2NR4aR4b o C(O)NR4aR4b, o R4 es un heterociclo saturado que tiene un nitrógeno cíclico y cero o un heteroátomos cíclicos adicionales seleccionados a partir de N, O ó S, tal anillo heterocíclico es sustituido por 0, 1, ó 2 sustituyentes independientemente seleccionados del grupo que consta de alquilo C1-6, CO2-alquilo C1-6 o CO2-bencilo; R4a se selecciona independientemente en cada ocurrencia del grupo que consta de hidrógeno y alquilo C1-6, en donde el sustituyente alquilo no es sustituido o es sustituido por hidroxilo, alcoxilo C1-4, amino o mono- y di-alquilamino C1-4; R4b se selecciona independientemente en cada ocurrencia del grupo que consta de hidrógeno, alquilo C1-6 y alcanoilo C1-4, en donde el sustituyente alquilo no es sustituido o es sustituido por hidroxilo, alcoxilo C1-4, amino o mono- y di-alquilamino C1-4, o NR4aR4b, tomados en combinación forman un anillo heterocíclico que tiene un átomo de nitrógeno cíclico y 0 ó 1 heteroátomo cíclico adicional seleccionado a partir de N, O y S, tal anillo heterocíclico es sustituido por 0, 1, 2 ó 3 sustituyentes independientemente seleccionados del grupo que consta de halógeno, hidroxilo, amino, alquilo C1-4, haloalquilo C1-4, hidroxialquilo C1-4, aminoalquilo C1-4, alcoxilo C1-4, alcoxi C1-4alquilo C1-4, y mono- y di-alquilamino C1-4; R5 está ausente o se selecciona del grupo que consta de hidrógeno y alquilo C1-6; R6 es oxo, hidrógeno, hidroxilo, amino, N(H)-J-R7; J es ausente, C(O) o S(O)2, y R7 es alquilo C1-6, fenilo o bencilo, cada uno es opcionalmente sustituido por alquilo C1-6, alcoxilo C1-6, halógeno, fenilo o fenoxilo.The present provides compounds of formula (1), a method for the preparation of the compounds of the present and their therapeutic uses. The present further provides a combination of pharmaceutically active agents and a pharmaceutical composition. These compounds are useful for the treatment of hepatitis C. Claim 1: A compound of the formula (1) or a salt thereof, wherein m is 0, 1 or 2; n is 0 or 1, where m + n is 1, 2 or 3; R1 is C3-10 alkynyl or phenyl, such phenyl is substituted by 0, 1, 2 or 3 substituents which are independently selected from the group consisting of halogen, hydroxyl, cyano, C1-4 alkyl, C1-4 haloalkyl and C1 alkoxy -4, and whose alkynyl is optionally substituted by a C3-7 cycloalkyl substituent, such cycloalkyl is optionally substituted by 1 or 2 independently selected C1-4 alkyl groups; R2 is CO2H, tetrazole or a carboxylic acid isoster; R3 is C3-7 cycloalkyl which is substituted by 0, 1, 2 or 3 halogen atoms; R3a represents 0, 1, 2, 3 or 4 residues independently selected at each occurrence from the group consisting of hydroxyl, amino, cyano, halogen, C1-6 alkyl, C1-6 alkoxy, wherein each alkyl or alkoxy substituent is substituted by 0, 1 or 2 substituents independently selected from hydroxyl, cyano, C1-4 alkoxy, C1-4 alkyl sulfone, N (R3b) 2, C (O) N (R3b), heterocycle with 4 to 7 cyclic atoms and 1 or 2 cyclic heteroatoms selected from N, O or S and 5- or 6-membered heteroaryl, or two R3a geminal substituents, taken in combination form a 3- to 6-membered cycloalkyl or heterocyclic heterocycle; R3b is independently selected at each occurrence from hydrogen, C1-4 alkyl, C1-4 alkoxy C1-4 alkyl and C1-4 alkanoyl, or N (R3b) 2, taken in combination form a 4- to 6-membered heterocycle with 0 or 1 additional cyclic heteroatoms selected from N, O or S; X is O, N-L-R4 or CR5R6; L is a bond, S (O) 2 or C (O); R4 is C1-6 alkyl or C3-7 cycloalkyl each of which is substituted by 0, 1 or 2 hydroxyl and 0 or 1 substituents selected from cyano, S (O) 2-C1-6 alkyl, CO2H or NR4aR4b or phenyl; R4 is naphthyl or phenyl, such phenyl is substituted by 0, 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1- haloalkoxy 6, amino, mono- and di- C 1-6 alkylamino hydroxy, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-6-OC (O) NH- alkyl, C 1-4 alkyl (O) NH-, - C (O) NR4aR4b, phenyl, phenoxy, heteroaryl with one or two cyclic nitrogen atoms and having 0, 1 or 2 C1-4 alkyl substituents, or two combined substituents to form a fused heterocyclic ring, such a heterocycle has 5, 6 or 7 cyclic atoms, 1 or 2 cyclic heteroatoms selected from N, O or S and such heterocycle is substituted by 0, 1 or 2 substituents independently selected from C1-6 alkyl, or R4 is a heteroaryl of 5 or 6 members having 1 to 3 heteroatoms selected from N, O or S, such heteroaryl is substituted by 0, 1, or 2 substituents independently Selected from the group consisting of halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, hydroxyl, NR4aR4b, C1-4 hydroxyalkyl, C1-4 aminoalkyl, C1-6 alkyl OC (O) NH-, C3-7 cycloalkyl, C5-7 cycloalkenyl, phenyl, 5- or 6-membered heteroaryl having 1 or 2 cyclic heteroatoms selected from N, O or S, or a saturated monocyclic or bicyclic heterocycle or partially unsaturated such a heterocycle has 1 or 2 cyclic N, O or S atoms, of 5 to 7 cyclic atoms in each ring and is substituted by 0, 1 or 2 substituents independently selected from the group consisting of halogen, C1-6 alkyl , C1-6 alkanoyl, C1-6C alkoxy (O) N (H) -, C1-6C alkoxy (O) N (H) CH2-, C1-4 aminoalkyl, C1-4 alkoxy C1-4alkyl and NR4aR4b, and in where the phenyl or heteroaryl substituent is not substituted or is substituted by 1 or 2 substituents independently selected from halogen, CO2H, cyano, C1-4 alkyl, C1-4 alkoxy, CH 2NR4aR4b or C (O) NR4aR4b, or R4 is a saturated heterocycle having a cyclic and zero nitrogen or an additional cyclic heteroatoms selected from N, O or S, such heterocyclic ring is substituted by 0, 1, or 2 substituents independently selected from the group consisting of C1-6 alkyl, CO2-C1-6 alkyl or CO2-benzyl; R4a is independently selected at each occurrence from the group consisting of hydrogen and C1-6 alkyl, wherein the alkyl substituent is not substituted or is substituted by hydroxyl, C1-4 alkoxy, amino or mono- and di-C1-4 alkylamino; R4b is independently selected at each occurrence from the group consisting of hydrogen, C1-6 alkyl and C1-4 alkanoyl, wherein the alkyl substituent is not substituted or is substituted by hydroxyl, C1-4 alkoxy, amino or mono- and di- C1-4 alkylamino, or NR4aR4b, taken in combination form a heterocyclic ring having a cyclic nitrogen atom and 0 or 1 additional cyclic heteroatom selected from N, O and S, such heterocyclic ring is substituted by 0, 1, 2 or 3 substituents independently selected from the group consisting of halogen, hydroxyl, amino, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 alkoxy, C 1-4 alkoxyC 1-4 alkyl, and mono- and di-C 1-4 alkylamino; R5 is absent or selected from the group consisting of hydrogen and C1-6 alkyl; R6 is oxo, hydrogen, hydroxyl, amino, N (H) -J-R7; J is absent, C (O) or S (O) 2, and R7 is C1-6 alkyl, phenyl or benzyl, each optionally substituted by C1-6 alkyl, C1-6 alkoxy, halogen, phenyl or phenoxy.

ARP120100004A 2011-07-21 2012-01-03 COMPOUNDS OF 2,3,5-THIOPHEN TRISUBSTITUIDOS AR084765A1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2011/062545 WO2012010663A1 (en) 2010-07-22 2011-07-21 2,3,5-trisubstituted thiophene compounds and uses thereof

Publications (1)

Publication Number Publication Date
AR084765A1 true AR084765A1 (en) 2013-06-26

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