AR077447A1 - BETA-SECRETASE INHIBITING COMPOUNDS, USEFUL FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES - Google Patents

BETA-SECRETASE INHIBITING COMPOUNDS, USEFUL FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES

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AR077447A1
AR077447A1 ARP100102351A ARP100102351A AR077447A1 AR 077447 A1 AR077447 A1 AR 077447A1 AR P100102351 A ARP100102351 A AR P100102351A AR P100102351 A ARP100102351 A AR P100102351A AR 077447 A1 AR077447 A1 AR 077447A1
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alkyl
alkynyl
alkenyl
alkylheteroaryl
alkylheterocyclyl
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ARP100102351A
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Spanish (es)
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Astrazeneca Ab
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    • 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
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    • 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
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    • 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
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    • C07D401/10—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 aromatic rings
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    • 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
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    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
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    • 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
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    • 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
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    • 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
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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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    • C07D405/00—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
    • C07D405/10—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 carbon chain containing aromatic rings
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    • C07D405/14—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 three or more hetero rings
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D471/00—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
    • 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
    • C07D471/04—Ortho-condensed systems

Abstract

Además la presente se refiere a métodos terapéuticos para el tratamiento y/o prevencion de patologías relacionadas con Abeta, tal como el síndrome de Down, angiopatía beta-amiloide tal como, pero sin limitarla a angiopatía amiloide cerebral o hemorragia cerebral hereditaria, trastornos asociados con trastornos asociados con disfuncion cognitiva, tal como, pero sin limitarlo a MCI (ôdisfuncion cognitiva leveö), enfermedad de Alzheimer, pérdida de memoria, síntomas de falta de atencion asociados con la enfermedad de Alzheimer; neurodegeneracion asociada con enfermedades tales como enfermedad de Alzheimer o demencia incluyendo demencia de origen mixto vascular y degenerativo, demencia pre-senil, demencia senil y demencia asociada con la enfermedad de Parkinson, parálisis supranuclear progresiva o degeneracion cortical basal. Reivindicacion 1: Un compuesto de acuerdo con la formula (1) en la cual A está seleccionado entre arilo y heteroarilo, donde dicho arilo o heteroarilo está opcionalmente sustituido con uno o más R1; B está seleccionado entre arilo y heteroarilo, donde dicho arilo o heteroarilo está opcionalmente sustituido con uno o más R2; C está seleccionado entre hidrogeno, alquilo C1-6, alquenilo C2-6, alquinilo C2-6, alquilo C0-6-cicloalquilo C3-6, alquilo C0-6-cicloalquenilo C3-6, alquilo C0-6-cicloalquinilo C6, alquilarilo C0-6, alquilheteroarilo C0-6, alquilheterociclilo C0-6, alquilo C0-6OR4, alquilo C0-6CO2R4, alquilo C0-6N(R4)2, halogeno, alquilo C0-6CN, alquilo C0-6COR4, CHO, NO2, alquilo C0-6CON(R4)2, O(CO)OR4, O(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, alquilo C0-6NR4(CO)R4, NR4(CO)N(R4)2, NR4(CO)(CO)R4, NR4(CO)(CO)N(R4)2, alquilo C0-6SR4, alquilo C0-6OSO2R4, alquilo C0-6SO3R4, alquilo C0-6SO2R4, alquilo C0-6SOR4, alquilo C0-6(SO2)N(R4)2, alquilo C0-6(SO)N(R4)2, alquilo C0-6NR4(SO2)N(R4)2, alquilo C0-6NR4(SO)R4, SF5 y OSF5, donde dicho alquilo C1-6, alquenilo C2-6, alquinilo C2-6, alquilo C0-6-cicloalquilo C3-6, alquilarilo C0-6, alquilheteroarilo C0-6, o alquilheterociclilo C0-6, están opcionalmente sustituidos con uno o más R3; R1 está seleccionado entre alquilo C1-6, alquenilo C2-6, alquinilo C2-6, alquilo C0-6-cicloalquilo C3-6, alquilo C0-6cicloalquenilo C3-6, alquilo C0-6-cicloalquinilo C6, alquilarilo C0-6, alquilheteroarilo C0-6, alquilheterociclilo C0-6, alquilo C0-6CO2R4, alquilo C0-6N(R4)2, alquilo C0-6OR4, halogeno, alquilo C0-6CN, alquilo C0-6COR4, CHO, NO2, alquilo C0-6CON(R4)2, O(CO)OR4, O(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, alquilo C0-6NR4(CO)R4, NR4(CO)N(R4)2, NR4(CO)(CO)R4, NR4(CO)(CO)N(R4)2, alquilo C0-6SR4, alquilo C0-6OSO2R4, alquilo C0-6SO3R4, alquilo C0-6SO2R4, alquilo C0-6SOR4, alquilo C0-6(SO2)N(R4)2, alquilo C0-6(SO)N(R4)2, alquilo C0-6NR4(SO2)N(R4)2, alquilo C0-6NR4(SO)R4, SF5, y OSF5, donde dicho alquilo C1-6, alquenilo C2-6, alquinilo C2-6, alquilo C0-6-cicloalquilo C3-6, alquilarilo C0-6, alquilheteroarilo C0-6 o alquilheterociclilo C0-6 están opcionalmente sustituidos con uno o más R3; o dos R1 pueden formar conjuntamente con los átomos de carbono a los cuales están unidos un anillo cíclico o heterocíclico opcionalmente sustituido con uno o más R6; R2 está seleccionado entre alquilo C1-6, alquenilo C2-6, alquinilo C2-6, alquilo C0-6-cicloalquilo C3-6, alquilo C0-6-cicloalquenilo C3-6, alquilo C0-6-cicloalquinilo C6, alquilarilo C0-6, alquilheteroarilo C0-6, alquilheterociclilo C0-6, alquilo C0-6CO2R4, alquilo C0-6N(R4)2, halogeno, alquilo C0-6CN, alquilo C0-6COR4, CHO, NO2, alquilo C0-6CON(R4)2, O(CO)OR4, O(CO)R4, O(CO)N(R4)2, R4(CO)OR4, alquilo C0-6NR4(CO)R4, NR4(CO)N(R4)2, NR4(CO)(CO)R4, NR4(CO)(CO)N(R4)2, alquilo C0-6SR4, alquilo C0-6OSO2R4, alquilo C0-6SO3R4, alquilo C0-6SO2R4, alquilo C0-6SOR4, alquilo C0-6(SO2)N(R4)2, alquilo C0-6(SO)N(R4)2, alquilo C0-6R4(SO2)N(R4)2, alquilo C0-6NR4(SO)R4 y alquilo C0-6OR4, donde dichos alquilo C1-6, alquenilo C2-6, alquinilo C2-6, alquilo C0-6-cicloalquilo C3-6, alquilarilo C0-6, alquilheteroarilo C0-6 o alquilheterociclilo C0-6 están opcionalmente sustituidos con uno o más R3; o dos R2 pueden formar conjuntamente con los átomos a los cuales están unidos un anillo cíclico o heterocíclico opcionalmente sustituido con uno o más R6; R3 está seleccionado entre halogeno, NO2, CHO, alquilo C0-6CN, alquilo C0-6OR4, haloalquilo C1-6, alquilo C0-6N(R4)2, NR4C(O)R4, alquilo C0-6CO2R4, alquilo C0-6CON(R4)2, alquilo C0-6NR4(CO)R4, O(CO)N(R4)2, NR4(CO)OR4, NR4(CO)N(R4)2, O(CO)OR4, O(CO)R4, alquilo C0-6COR4, NR4(CO)(CO)R4, NR4(CO)(CO)N(R4)2, alquilo C0-6SR4, alquilo C0-6(SO2)N(R4)2, Oalquilo C2-6NR4(SO2)R4, alquilo C0-6(SO)N(R4)2, OSO2R4, SO3R4, alquilo C0-6NR4(SO2)N(R4)2, alquilo C0-6NR4(SO)R4, alquilo C0-6SO2R4, alquilo C0-6SOR4, alquilo C1-6, alquenilo C2-6, alquinilo C2-6, alquilo C0-6-cicloalquilo C3-6, alquilo C0-6-cicloalquenilo C3-6, alquilo C0-6cicloalquinilo C6, alquilarilo C0-6, alquilheteroarilo C0-6 y alquilheterociclilo C0-6, donde dicho alquilo C1-6, alquenilo C2-6, alquinilo C2-6, alquilo C0-6-cicloalquilo C3-6, alquilarilo C0-6, alquilheteroarilo C0-6 o alquilheterociclilo C0-6 está opcionalmente sustituido con uno o más R6; R4 está seleccionado entre hidrogeno, alquilo C1-6, haloalquilo C1-3, alquenilo C2-6, alquinilo C2-6, alquilo C0-6-cicloalquilo C3-6, alquilo C0-6-cicloalquenilo C3-6, alquilo C0-6-cicloalquinilo C6, alquilarilo C0-6, alquilheteroarilo C0-6, alquilheterociclilo C0-6, alquilo C1-6OR5 y alquilo C1-6N(R5)2, donde dichos alquilo C1-6, alquenilo C2-6, alquinilo C2-6, alquilo C0-6-cicloalquilo C3-6, alquilarilo C0-6, alquilheteroarilo C0-6 o alquilheterociclilo C0-6 están opcionalmente sustituidos con uno o más R6; o dos R4 pueden formar conjuntamente un anillo heterocíclico de 4 a 6 miembros que contiene uno o más heteroátomos seleccionados entre N, O o S, donde dicho anillo heterocíclico está sustituido con uno o más R6; R5 está seleccionado entre hidrogeno, alquilo C1-6, alquenilo C2-6, alquinilo C2-6, alquilo C0-6-cicloalquilo C3-6, alquilo C0-6-cicloalquenilo C3-6, alquilo C0-6-cicloalquinilo C6, alquilarilo C0-6, alquilheterociclilo C0-6 y alquilheteroarilo C0-6, donde dichos alquilo C1-6, alquenilo C2-6, alquinilo C2-6, alquilo C0-6-cicloalquilo C3-6, alquilarilo C0-6, alquilheteroarilo C0-6 o alquilheterociclilo C0-6 están opcionalmente sustituidos con uno o más R6; o dos R5 pueden formar conjuntamente un anillo heterocíclico de 4 a 6 miembros que contiene uno o más heteroátomos seleccionados entre N, O o S, donde dicho anillo heterocíclico está opcionalmente sustituido con uno o más R6; R6 está seleccionado entre oxo, halogeno, nitro, CN, OR7, alquilo C1-6, alquenilo C2-6, alquinilo C2-6, alquilarilo C0-6, alquilheteroarilo C0-6, alquilo C0-6-cicloalquilo C3-6, alquilheterociclilo C0-6, haloalquilo C1-6, Oalquilo 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)alquilo C1-6N(R7)2, (SO2)alquilo 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 alquilo C0-6-cicloalquilo C3-6 están opcionalmente sustituidos con uno o más sustituyentes independientemente seleccionados entre halo, nitro, ciano, OR7, alquilo C1-6, haloalquilo C1-3, o haloalquilo OC1-3; R7 está seleccionado entre 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 dichos alquilo C1-6, alquenilo C2-6, alquinilo C2-6, cicloalquilo C3-6, arilo, heteroarilo o heterociclilo están opcionalmente sustituidos con uno, dos o tres hidroxi, ciano, halogeno u Oalquilo C1-3; o dos R7 pueden formar conjuntamente un anillo heterocíclico de 4 a 6 miembros que contiene uno o más heteroátomos seleccionados entre N, O o S, donde dicho anillo heterocíclico está opcionalmente sustituido con uno o más sustituyentes independientemente seleccionados entre hidroxi, Oalquilo C1-3, ciano o halogeno; como base libre o una sal farmacéuticamente aceptable del mismo.In addition, this refers to therapeutic methods 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 disorders associated with cognitive dysfunction, such as, but not limited to MCI ("mild cognitive dysfunction"), Alzheimer's disease, memory loss, symptoms of lack of attention associated with Alzheimer's disease; neurodegeneration associated with diseases such as Alzheimer's disease 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 basal cortical degeneration. Claim 1: A compound according to formula (1) in which A is selected from aryl and heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more R1; B is selected from aryl and 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 alkynyl, 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) N (R4) 2 alkyl, C0-6 (SO) alkyl N (R4) 2, C0-6NR4 (SO2) alkyl N (R4) 2, C0-6NR4 (SO) R4 alkyl, 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 are optionally substituted with one or more 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- cycloalkynyl, C0-6 alkylaryl, C0-6 alkylheteroaryl, C0-6 alkylheterocyclyl, C0-6CO2R4 alkyl, C0-6N (R4) 2 alkyl, C0-6OR4 alkyl, halogen, C0-6CN alkyl, C0-6COR4 alkyl, CHO, NO2, C0-6CON alkyl ( R4) 2, O (CO) OR4, O (CO) R4, O (CO) N (R4) 2, NR4 (CO) OR4, C0-6NR4 alkyl (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 alkyl -6 (SO2) N (R4) 2, C0-6 (SO) N (R4) 2 alkyl, C0-6NR4 (SO2) N (R4) 2 alkyl, C0-6NR4 (SO) R4, SF5, and OSF5 alkyl , 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 carbon atoms to which a cyclic or heterocyclic ring optionally substituted with one or more R6 is attached; 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- cycloalkynyl, C0 alkylaryl 6, C0-6 alkylheteroaryl, C0-6 alkylheterocyclyl, C0-6CO2R4 alkyl, C0-6N (R4) 2 alkyl, halogen, C0-6CN alkyl, C0-6COR4 alkyl, CHO, NO2, C0-6CON (R4) alkyl 2 , O (CO) OR4, O (CO) R4, O (CO) N (R4) 2, R4 (CO) OR4, 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 (SO) N (R4) 2 alkyl, C0-6R4 (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 are optionally substituted with one or more R3; or two R2 may form together with the atoms to which a cyclic or heterocyclic ring optionally substituted with one or more R6 is attached; R3 is selected from halogen, NO2, CHO, C0-6CN alkyl, C0-6OR4 alkyl, C1-6 haloalkyl, C0-6N (R4) alkyl 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, NR4 (CO) (CO) R4, NR4 (CO) (CO) N (R4) 2 alkyl, C0-6SR4 alkyl, C0-6 (SO2) alkyl N (R4) 2, C2-6NR4 alkyl (SO2) R4, C0-6 alkyl (SO) N (R4) 2, OSO2R4, SO3R4, C0-6NR4 (SO2) N (R4) 2 alkyl, 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 C6-6 alkynyl, C0-6 alkylaryl, 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- alkylheterocyclyl 6 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-C3-6 cycloalkenyl alkyl, C0-6 alkyl -C6 cycloalkynyl, C0-6 alkylaryl, C0-6 alkylheteroaryl, C0-6 alkylheterocyclyl, C1-6OR5 alkyl and C1-6N (R5) 2 alkyl, 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 are 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 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 C6 alkynyl, alkylaryl C0-6, C0-6 alkylheterocyclyl and C0-6 alkylheteroaryl, 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 are 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, C2-6Nalkyl (R7) 2, N (R7) 2, CON (R7) 2, NR7 (CO) R7, O (CO) C1-6 alkyl, (CO) C1alkyl -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 alkylaryl, C0-6 alkylheteroaryl, C0-6 alkylheterocyclyl or C0-6 alkyl C3-6 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, nitro, cyano, OR7, C1-6 alkyl, C1-3 haloalkyl, or OC1-3 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 are optionally substituted with one, two or three hydroxy, cyano, halogen or 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 or halogen; as a free base or a pharmaceutically acceptable salt thereof.

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