AR077365A1 - IMIDAZOL DERIVATIVES FOR THE TREATMENT OF DISEASES MEDIATED BY THE INHIBITION OF ABETA FORMATION - Google Patents

IMIDAZOL DERIVATIVES FOR THE TREATMENT OF DISEASES MEDIATED BY THE INHIBITION OF ABETA FORMATION

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AR077365A1
AR077365A1 ARP100102352A ARP100102352A AR077365A1 AR 077365 A1 AR077365 A1 AR 077365A1 AR P100102352 A ARP100102352 A AR P100102352A AR P100102352 A ARP100102352 A AR P100102352A AR 077365 A1 AR077365 A1 AR 077365A1
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alkyl
alkynyl
alkenyl
alkylaryl
alkylheteroaryl
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ARP100102352A
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Spanish (es)
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Astrazeneca Ab
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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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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
    • C07D233/88—Nitrogen atoms, e.g. allantoin
    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • C07D403/10—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 carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—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
    • C07D405/02—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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond

Abstract

Derivados de imidazol y sus composiciones farmacéuticas. Asimismo, su uso para el tratamiento y/o la prevencion de patologías relacionadas con Abeta, tales como síndrome de Down, angiopatía beta-amiloide tal como, aunque no a modo de limitacion, angiopatía amiloide cerebral o hemorragia cerebral hereditaria, trastornos asociados con el deterioro cognitivo, tales como, aunque no a modo de limitacion, MCI (deterioro cognitivo leve), enfermedad de Alzheimer, pérdida de la memoria, síntomas de déficit de atencion asociados con la enfermedad de Alzheimer, neurodegeneracion asociada con enfermedades tales como la enfermedad de Alzheimer o demencia, incluyendo demencia de origen mixto vascular y degenerativo, demencia pre-senil, demencia senil y demencia asociada con enfermedad de Parkinson, parálisis supranuclear progresiva o degeneracion basal cortical. Reivindicacion 1: Un compuesto de acuerdo con la formula (1) donde A se selecciona de alquilo C1-6, alquenilo C2-6, alquinilo C2-6, alquilarilo C1-6, alquilheteroarilo C1-6, alquil C0-6-cicloalquilo C3-8, alquil C0-6-cicloalquenilo C3-6, alquil C0-6-cicloalquinilo C6 o alquil C0-6-heterociclilo C3-8, donde dicho A está opcionalmente sustituido con uno o varios R1; B es arilo o heteroarilo, donde dicho arilo o heteroarilo está opcionalmente sustituido con uno o varios R2; C se selecciona de hidrogeno, alquilo C1-6, alquenilo C2-6, alquinilo C2-6, alquil C0-6-cicloalquilo C3-6, alquil C0-6-cicloalquenilo C3-6, alquil C0-6-cicloalquinilo C6, alquilarilo C0-6, alquilheteroarilo C0-6, alquilheterociclilo C0-6, alquil C0-6OR4, alquil C0-6CO2R4, alquil C0-6N(R4)2, halogeno, alquil C0-6CN, alquil C0-6COR4, CHO, NO2, alquil C0-6CON(R4)2, O(CO)OR4, O(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, alquil C0-6NR4(CO)R4, NR4(CO)N(R4)2, NR4(CO)(CO)R4, NR4(CO)(CO)N(R4)2, alquil C0-6SR4, alquil C0-6OSO2R4, alquil C0-6SO3R4, alquil C0-6SO2R4, alquil C0-6SOR4, alquil C0-6(SO2)N(R4)2, alquil C0-6(SO)N(R4)2, alquil C0-6NR4(SO2)N(R4)2, alquil C0-6NR4(SO)R4, SF5 y OSF5, donde dicho alquilo C1-6, alquenilo C2-6, alquinilo C2-6, alquil C0-6-cicloalquilo C3-6, alquilarilo C0-6, alquilheteroarilo C0-6 o alquilheterociclilo C0-6 está opcionalmente sustituido con uno o varios R3; R1 se selecciona de alquilo C1-6, alquenilo C2-6, alquinilo C2-6, alquil C0-6-cicloalquilo C3-6, alquil C0-6-cicloalquenilo C3-6, alquil C0-6-cicloalquinilo C6, alquilarilo C0-6, alquilheteroarilo C0-6, alquilheterociclilo C0-6, alquil C0-6CO2R4, alquil C0-6N(R4)2, alquil C0-6OR4, halogeno, alquil C0-6CN, alquil C0-6COR4, CHO, NO2, alquil C0-6CON(R4)2, O(CO)OR4, O(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, alquil C0-6NR4(CO)R4, NR4(CO)N(R4)2, NR4(CO)(CO)R4, NR4(CO)(CO)N(R4)2, alquil C0-6SR4, alquil C0-6OSO2R4, alquil C0-6SO3R4, alquil C0-6SO2R4, alquil C0-6SOR4, alquil C0-6(SO2)N(R4)2, alquil C0-6(SO)N(R4)2, alquil C0-6NR4(SO2)N(R4)2, alquil C0-6NR4(SO)R4, SF5 y OSF5, donde dicho alquilo C1-6, alquenilo C2-6, alquinilo C2-6, alquil C0-6-cicloalquilo C3-6, alquilarilo C0-6, alquilheteroarilo C0-6 o alquilheterociclilo C0-6 está opcionalmente sustituido con uno o varios R3; o dos R1 pueden formar, junto con los átomos a los cuales están unidos, un anillo cíclico o heterocíclico opcionalmente sustituido con uno o varios R6; R2 se selecciona de alquilo C1-6, alquenilo C2-6, alquinilo C2-6, alquil C0-6-cicloalquilo C3-6, alquil C0-6-cicloalquenilo C3-6, alquil C0-6-cicloalquinilo C6, alquilarilo C0-6, alquilheteroarilo C0-6, alquilheterociclilo C0-6, alquil C0-6CO2R4, alquil C0-6N(R4)2, halogeno, alquil C0-6CN, alquil C0-6COR4, CHO, NO2, alquil C0-6CON(R4)2, O(CO)OR4, O(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, alquil C0-6NR4(CO)R4, NR4(CO)N(R4)2, NR4(CO)(CO)R4, NR4(CO)(CO)N(R4)2, alquil C0-6SR4, alquil C0-6OSO2R4, alquil C0-6SO3R4, alquil C0-6SO2R4, alquil C0-6SOR4, alquil C0-6(SO2)N(R4)2, alquil C0-6(SO)N(R4)2, alquil C0-6NR4(SO2)N(R4)2, alquil C0-6NR4(SO)R4, y alquil C0-6OR4, donde dicho alquilo C1-6, alquenilo C2-6, alquinilo C2-6, alquil C0-6-cicloalquilo C3-6, alquilarilo C0-6, alquilheteroarilo C0-6 o alquilheterociclilo C0-6 está opcionalmente sustituido con uno o varios R3; o dos R2 pueden formar, junto con los átomos a los cuales están unidos, un anillo cíclico o heterocíclico opcionalmente sustituido con uno o varios R6; R3 se selecciona de halogeno, NO2, CHO, alquil C0-6CN, alquil C0-6OR4, haloalquilo C1-6, alquil C0-6N(R4)2, NR4C(O)R4, alquil C0-6CO2R4, alquil C0-6CON(R4)2, alquil C0-6NR4(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, NR4(CO)N(R4)2, O(CO)OR4, O(CO)R4, alquil C0-6COR4, NR4(CO)(CO)R4, NR4(CO)(CO)N(R4)2, alquil C0-6SR4, alquil C0-6(SO2)N(R4)2, Oalquil C2-6NR4(SO2)R4, alquil C0-6(SO)N(R4)2, OSO2R4, SO3R4, alquil C0-6NR4(SO2)N(R4)2, alquil C0-6NR4(SO)R4, alquil C0-6SO2R4, alquil C0-6SOR4, alquilo C1-6, alquenilo C2-6, alquinilo C2-6, alquil C0-6-cicloalquilo C3-6, alquil C0-6-cicloalquenilo C3-6, alquil C0-6-cicloalquinilo C6, alquilarilo C0-6, alquilheteroarilo C0-6, y alquilheterociclilo C0-6, donde dicho alquilo C1-6, alquenilo C2-6, alquinilo C2-6, alquil C0-6-cicloalquilo C3-6, alquilarilo C0-6, alquilheteroarilo C0-6 o alquilheterociclilo C0-6 está opcionalmente sustituido con uno o varios R6; R4 se selecciona de hidrogeno, alquilo C1-6, haloalquilo C1-3, alquenilo C2-6, alquinilo C2-6, alquil C0-6-cicloalquilo C3-6, alquil C0-6-cicloalquenilo C3-6, alquil C0-6-cicloalquinilo C6, alquilarilo C0-6, alquilheteroarilo C0-6, alquilheterociclilo C0-6, alquil C1-6OR5 y alquil C1-6N(R5)2, donde dicho alquilo C1-6, alquenilo C2-6, alquinilo C2-6, alquil C0-6-cicloalquilo C3-6, alquilarilo C0-6, alquilheteroarilo C0-6 o alquilheterociclilo C0-6 está opcionalmente sustituido con uno o varios R6; o dos R4 pueden formar juntos un anillo heterocíclico de 4 a 6 miembros que contiene uno o varios heteroátomos seleccionados de N, O o S, donde dicho anillo heterocíclico está opcionalmente sustituido con uno o varios R6; R5 se selecciona de hidrogeno, alquilo C1-6, alquenilo C2-6, alquinilo C2-6, alquil C0-6-cicloalquilo C3-6, alquil C0-6-cicloalquenilo C3-6, alquil C0-6-cicloalquinilo C3-6, alquilarilo C0-6, alquilheterociclilo C0-6 y alquilheteroarilo C0-6, donde dicho alquilo C1-6, alquenilo C2-6, alquinilo C2-6, alquil C0-6-cicloalquilo C3-6, alquilarilo C0-6, alquilheteroarilo C0-6 o alquilheterociclilo C0-6 está opcionalmente sustituido con uno o varios R6; o dos R5 pueden formar juntos un anillo heterocíclico de 4 a 6 miembros que contiene uno o varios heteroátomos seleccionados de N, O o S, donde dicho anillo heterocíclico está opcionalmente sustituido con uno o varios R6; R6 se selecciona de oxo, halogeno, nitro, CN, OR7, alquilo C1-6, alquenilo C2-6, alquinilo C2-6, alquilarilo C0-6, alquilheteroarilo C0-6, alquil C0-6-cicloalquilo C3-6, alquilheterociclilo C0-6, haloalquilo C1-6, Oalquil C2-6N(R7)2, N(R7)2, CON(R7)2, NR7(CO)R7, O(CO)alquilo C1-6, (CO)Oalquilo C1-6, COR7, SON(R7)2, (SO2)N(R7)2, NR7SO2R7, NR7SOR7, SO2R7, SOR7, (CO)alquil C1-6N(R7)2, (SO2)alquil C1-6N(R7)2, OSO2R7 y SO3R7, donde dicho alquilo C1-6, alquenilo C2-6, alquinilo C2-6, alquilarilo C0-6, alquilheteroarilo C0-6, alquilheterociclilo C0-6 o alquil C0-6-cicloalquilo C3-6 está opcionalmente sustituido con uno o varios sustituyentes seleccionados independientemente de halo, nitro, ciano, OR7, alquilo C1-6 o haloalquilo C1-6; R7 se selecciona de hidrogeno, alquilo C1-6, haloalquilo C1-3, alquenilo C2-6, alquinilo C2-6, cicloalquilo C3-6, cicloalquenilo C3-6, cicloalquinilo C6, arilo, heteroarilo y heterociclilo, donde dicho alquilo C1-6, alquenilo C2-6, alquinilo C2-6, cicloalquilo C3-6 arilo, heteroarilo o heterociclilo está opcionalmente sustituido con uno a tres sustituyentes seleccionados independientemente de hidroxi, ciano, halogeno y Oalquilo C1-3; o dos R7 pueden formar juntos un anillo heterocíclico de 4 a 6 miembros que contiene uno o varios heteroátomos seleccionados de N, O o S, donde dicho anillo heterocíclico está opcionalmente sustituido con uno o varios sustituyentes seleccionados independientemente de hidroxi, Oalquilo C1-3, ciano y halogeno; en forma de base libre o de una sal farmacéuticamente aceptable de dicho compuesto.Imidazole derivatives and their pharmaceutical compositions. Also, its use for the treatment and / or prevention of diseases related to Abeta, such as Down syndrome, beta-amyloid angiopathy such as, but not limited to, cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment, such as, but not limited to, MCI (mild cognitive impairment), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as disease of Alzheimer's or dementia, including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear paralysis or cortical basal degeneration. Claim 1: A compound according to formula (1) wherein A is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylaryl, C1-6 alkylheteroaryl, C0-6 alkylC3 alkyl -8, C0-6 alkyl C3-6 alkyl, C0-6 alkyl C6- or C0-6 alkyl heterocyclyl C3-8, wherein said A is optionally substituted with one or more R1; B is aryl or heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R2; C is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C0-6 alkyl C3-6 alkyl, C0-6 alkyl C3-6 cycloalkenyl, C0-6 alkyl C6- cycloalkynyl, alkylaryl C0-6, C0-6 alkylheteroaryl, C0-6 alkylheterocyclyl, C0-6OR4 alkyl, C0-6CO2R4 alkyl, C0-6N (R4) 2 alkyl, halogen, C0-6CN alkyl, C0-6COR4 alkyl, CHO, NO2, alkyl C0-6CON (R4) 2, O (CO) OR4, O (CO) R4, O (CO) N (R4) 2, NR4 (CO) OR4, alkyl C0-6NR4 (CO) R4, NR4 (CO) N (R4) 2, NR4 (CO) (CO) R4, NR4 (CO) (CO) N (R4) 2, C0-6SR4 alkyl, C0-6OSO2R4 alkyl, C0-6SO3R4 alkyl, C0-6SO2R4 alkyl, C0- alkyl 6SOR4, C0-6 (SO2) alkyl N (R4) 2, C0-6 (SO) alkyl N (R4) 2, C0-6NR4 (SO2) alkyl N (R4) 2, C0-6NR4 (SO) alkyl R4, SF5 and OSF5, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C0-6 alkyl C3-6 cycloalkyl, C0-6 alkylaryl, C0-6 alkylheteroaryl or C0-6 alkylheterocyclyl optionally is substituted with one or several R3; R1 is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C0-6 alkyl C3-6 alkyl, C0-6 alkyl C3-6 cycloalkenyl, C0-6 alkyl C6- alkylaryl, C0- alkylaryl 6, C0-6 alkylheteroaryl, C0-6 alkylheterocyclyl, C0-6CO2R4 alkyl, C0-6N (R4) alkyl 2, C0-6OR4 alkyl, halogen, C0-6CN alkyl, C0-6COR4 alkyl, CHO, NO2, C0- alkyl 6CON (R4) 2, O (CO) OR4, O (CO) R4, O (CO) N (R4) 2, NR4 (CO) OR4, alkyl C0-6NR4 (CO) R4, NR4 (CO) N (R4 ) 2, NR4 (CO) (CO) R4, NR4 (CO) (CO) N (R4) 2, C0-6SR4 alkyl, C0-6OSO2R4 alkyl, C0-6SO3R4 alkyl, C0-6SO2R4 alkyl, C0-6SOR4 alkyl, C0-6 (SO2) N (R4) 2 alkyl, C0-6 (SO) alkyl N (R4) 2, C0-6NR4 (SO2) alkyl N (R4) 2, C0-6NR4 (SO) R4, SF5 alkyl OSF5, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C0-6 alkyl C3-6 cycloalkyl, C0-6 alkylaryl, C0-6 alkylheteroaryl or C0-6 alkylheterocyclyl optionally is substituted with one or more R3; or two R1 can form, together with the atoms to which they are attached, a cyclic or heterocyclic ring optionally substituted with one or several R6; R2 is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C0-6 alkyl C3-6 alkyl, C0-6 alkyl C3-6 cycloalkenyl, C0-6 alkyl C6- alkylaryl, C0- alkylaryl 6, C0-6 alkylheteroaryl, C0-6 alkylheterocyclyl, C0-6CO2R4 alkyl, C0-6N (R4) alkyl 2, halogen, C0-6CN alkyl, C0-6COR4 alkyl, CHO, NO2, C0-6CON (R4) 2 alkyl , O (CO) OR4, O (CO) R4, O (CO) N (R4) 2, NR4 (CO) OR4, alkyl C0-6NR4 (CO) R4, NR4 (CO) N (R4) 2, NR4 ( CO) (CO) R4, NR4 (CO) (CO) N (R4) 2, C0-6SR4 alkyl, C0-6OSO2R4 alkyl, C0-6SO3R4 alkyl, C0-6SO2R4 alkyl, C0-6SOR4 alkyl, C0-6 alkyl SO2) N (R4) 2, C0-6 alkyl (SO) N (R4) 2, C0-6NR4 (SO2) alkyl N (R4) 2, C0-6NR4 (SO) R4 alkyl, and C0-6OR4 alkyl, where said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C0-6 alkyl C3-6 cycloalkyl, C0-6 alkylaryl, C0-6 alkylheteroaryl or C0-6 alkylheterocyclyl optionally is substituted with one or more R3; or two R2 may form, together with the atoms to which they are attached, a cyclic or heterocyclic ring optionally substituted with one or more R6; R3 is selected from halogen, NO2, CHO, C0-6CN alkyl, C0-6OR4 alkyl, C1-6 haloalkyl, C0-6N alkyl (R4) 2, NR4C (O) R4, C0-6CO2R4 alkyl, C0-6CON alkyl ( R4) 2, alkyl C0-6NR4 (CO) R4, O (CO) N (R4) 2, NR4 (CO) OR4, NR4 (CO) N (R4) 2, O (CO) OR4, O (CO) R4 , C0-6COR4 alkyl, NR4 (CO) (CO) R4, NR4 (CO) (CO) N (R4) 2, C0-6SR4 alkyl, C0-6 (SO2) N (R4) 2 alkyl, C2-6NR4 alkyl (SO2) R4, C0-6 alkyl (SO) N (R4) 2, OSO2R4, SO3R4, C0-6NR4 (SO2) alkyl N (R4) 2, C0-6NR4 (SO) R4 alkyl, C0-6SO2R4 alkyl, alkyl C0-6SOR4, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C0-6 alkyl C3-6 alkyl, C0-6 alkyl C3-6 cycloalkenyl, C0-6 alkyl C6- cycloalkynyl, C0 alkylaryl 6, C0-6 alkylheteroaryl, and C0-6 alkylheterocyclyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C0-6 alkyl C3-6 cycloalkyl, C0-6 alkylaryl, C0-6 alkylheteroaryl or C0-6 alkylheterocyclyl is optionally substituted with one or more R6; R4 is selected from hydrogen, C1-6 alkyl, C1-3 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C0-6 alkyl C3-6 alkyl, C0-6 alkyl C3-6 alkyl, C0-6 alkyl -C6 cycloalkynyl, C0-6 alkylaryl, C0-6 alkylheteroaryl, C0-6 alkylheterocyclyl, C1-6OR5 alkyl and C1-6N alkyl (R5) 2, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C0-6 alkyl C3-6 cycloalkyl, C0-6 alkylaryl, C0-6 alkylheteroaryl or C0-6 alkylheterocyclyl is optionally substituted with one or more R6; or two R4 may together form a 4- to 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, wherein said heterocyclic ring is optionally substituted with one or more R6; R5 is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C0-6 alkyl C3-6 alkyl, C0-6 alkyl C3-6 cycloalkenyl, C0-6 alkyl C3-6 cycloalkynyl , C0-6 alkylaryl, C0-6 alkylheterocyclyl and C0-6 alkylheteroaryl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C0-6 alkyl C3-6 alkyl, C0-6 alkylaryl, C0 alkylheteroaryl -6 or C0-6 alkylheterocyclyl is optionally substituted with one or more R6; or two R5 may together form a 4- to 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, wherein said heterocyclic ring is optionally substituted with one or more R6; R6 is selected from oxo, halogen, nitro, CN, OR7, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C0-6 alkylaryl, C0-6 alkylheteroaryl, C0-6 alkylC3-6 alkyl, alkylheterocyclyl C0-6, C1-6 haloalkyl, C2-6N alkyl (R7) 2, N (R7) 2, CON (R7) 2, NR7 (CO) R7, O (CO) C1-6 alkyl, (CO) C1 alkyl -6, COR7, SON (R7) 2, (SO2) N (R7) 2, NR7SO2R7, NR7SOR7, SO2R7, SOR7, (CO) C1-6N alkyl (R7) 2, (SO2) C1-6N alkyl (R7) 2, OSO2R7 and SO3R7, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C0-6 alkynyl, C0-6 alkylheteroaryl, C0-6 alkylheterocyclyl or C0-6 alkyl C3-6 alkyl is optionally substituted with one or more substituents independently selected from halo, nitro, cyano, OR7, C1-6 alkyl or C1-6 haloalkyl; R7 is selected from hydrogen, C1-6 alkyl, C1-3 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, C6 cycloalkynyl, aryl, heteroaryl and heterocyclyl, wherein said C1- alkyl 6, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl aryl, heteroaryl or heterocyclyl is optionally substituted with one to three substituents independently selected from hydroxy, cyano, halogen and C1-3alkyl; or two R7 may together form a 4- to 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O or S, wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, C1-3alkyl, cyano and halogen; in the form of a free base or a pharmaceutically acceptable salt of said compound.

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