AR129707A1 - 4-ALCOXYPYRROLO[2,1-F][1,2,4]TRIAZINES AND THEIR PREPARATION AND USE - Google Patents

4-ALCOXYPYRROLO[2,1-F][1,2,4]TRIAZINES AND THEIR PREPARATION AND USE

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AR129707A1
AR129707A1 ARP230101623A ARP230101623A AR129707A1 AR 129707 A1 AR129707 A1 AR 129707A1 AR P230101623 A ARP230101623 A AR P230101623A AR P230101623 A ARP230101623 A AR P230101623A AR 129707 A1 AR129707 A1 AR 129707A1
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Argentina
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unsubstituted
group
optionally substituted
independently selected
5alkylene
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ARP230101623A
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Spanish (es)
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Gopi Kumar Mittapalli
Chi Ching Mak
Lewis Daniel Turner
Brian Joseph Hofilena
Ramkrishna Reddy Vakiti
Brian Walter Eastman
David Mark Wallace
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Biosplice Therapeutics Inc
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Publication of AR129707A1 publication Critical patent/AR129707A1/en

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Abstract

Se describen compuestos de 4-alcoxipirrolo[2,1-f][1,2,4]triazina para tratar diversas enfermedades y patologías. Más en particular, la presente descripción se refiere al uso de compuestos de 4-alcoxipirrolo[2,1-f][1,2,4]triazina o análogos de los mismos, en el tratamiento de trastornos caracterizados por sobreexpresión de DYRK1A (por ejemplo, cáncer, síndrome de Down, enfermedad de Alzheimer, diabetes, infecciones virales y osteoartritis). Reivindicación 1: Un compuesto o una de sus sales farmacéuticamente aceptables, de la fórmula (1) en donde: R¹ es heteroarilo opcionalmente sustituido con 1 - 10 R⁴; R² se selecciona del grupo que consiste en -(alquilo C₁₋₉) no sustituido, -(alquenilo C₂₋₉) no sustituido, -(alquinilo C₂₋₉) no sustituido, -(haloalquilo C₁₋₉) no sustituido, -(alquilen C₁₋₅)ₚOR⁵, -(alquilen C₁₋₅)CN, -(alquilen C₁₋₅)ₚheterociclilo opcionalmente sustituido con 1 - 10 R⁶, -(alquilen C₁₋₅)ₚarilo opcionalmente sustituido con 1 - 10 R²⁶, -(alquilen C₁₋₅)ₚheteroarilo opcionalmente sustituido con 1 - 10 R⁷ y -(alquilen C₁₋₅)ₚcarbociclilo opcionalmente sustituido con 1 - 12 R⁸, en donde cada -(alquilen C₁₋₅) está, de modo independiente, opcionalmente sustituido con 1 - 5 haluros y/o 1 - 3 -(alquilos C₁₋₃) no sustituidos; R³ se selecciona del grupo que consiste en H, -(alquilo C₁₋₉) no sustituido, -(alquenilo C₂₋₉) no sustituido, -(alquinilo C₂₋₉) no sustituido, -(haloalquilo C₁₋₉) no sustituido y heterociclilo opcionalmente sustituido con 1 - 10 R¹⁸; cada R⁴ se selecciona, de modo independiente, del grupo que consiste en haluro, -(alquilo C₁₋₉) no sustituido, -(alquenilo C₂₋₉) no sustituido, -(alquinilo C₂₋₉) no sustituido, -(haloalquilo C₁₋₉) no sustituido, -(haloalquenilo C₂₋₉) no sustituido, -(alquilen C₁₋₅)ₚOR⁹, -(alquilen C₁₋₅)ₚCN, -(alquilen C₁₋₅)ₚheterociclilo opcionalmente sustituido con 1 - 10 R¹⁰, -carbociclilo opcionalmente sustituido con 1 - 12 R¹¹, -(alquilen C₁₋₅)ₚheteroarilo opcionalmente sustituido con 1 - 10 R²⁰, -(alquilen C₁-₅)ₚC(=O)N(R¹²)₂ y -C(=O)R¹³, en donde cada -(alquilen C₁₋₅) está, de modo independiente, opcionalmente sustituido con 1 - 5 haluros y/o 1 - 3 -(alquilos C₁₋₃) no sustituidos; cada R⁵ se selecciona, de modo independiente, del grupo que consiste en H, -(alquilo C₁₋₉) no sustituido, -(alquenilo C₂₋₉) no sustituido, -(alquinilo C₂₋₉) no sustituido y -(haloalquilo C₁₋₉) no sustituido; cada R⁶ se selecciona, de modo independiente, del grupo que consiste en haluro, -(alquilo C₁₋₉) no sustituido, -(alquenilo C₂₋₉) no sustituido, -(alquinilo C₂₋₉) no sustituido, -(haloalquilo C₁₋₉) no sustituido, -heterociclilo opcionalmente sustituido con 1 - 10 R¹⁶, -carbociclilo opcionalmente sustituido con 1 - 12 R¹⁷, -(alquilen C₁₋₅)ₚOR²¹, -(alquilen C₁₋₅)CN, -SO₂R²³ y -C(=O)R²⁴, en donde el -(alquileno C₁₋₅) está opcionalmente sustituido con 1 - 5 haluros y/o 1 - 3 -(alquilos C₁₋₃) no sustituidos; alternativamente, dos R⁶ unidos al mismo átomo de carbono se toman juntos para formar un grupo carbonilo; cada R⁷ se selecciona, de modo independiente, del grupo que consiste en haluro, -(alquilo C₁₋₉) no sustituido, -(alquenilo C₂₋₉) no sustituido, -(alquinilo C₂₋₉) no sustituido, -(haloalquilo C₁₋₉) no sustituido y -OMe; cada R⁸ se selecciona, de modo independiente, del grupo que consiste en haluro, -(alquilo C₁₋₉) no sustituido, -(alquenilo C₂₋₉) no sustituido, -(alquinilo C₂₋₉) no sustituido, -(haloalquilo C₁₋₉) no sustituido, -N(R¹⁴)₂, -(alquilen C₁₋₅)ₚOR¹⁵, -CN, -(alquilen C₁₋₅)ₚheterociclilo opcionalmente sustituido con 1 - 10 R¹⁶, -C(=O)R²² y -NR¹⁴C(=O)R²³, en donde cada -(alquilen C₁₋₅) está, de modo independiente, opcionalmente sustituido con 1 - 5 haluros y/o 1 - 3 -(alquilos C₁₋₃) no sustituidos; cada R⁹ se selecciona, de modo independiente, del grupo que consiste en H, -(alquilo C₁₋₉) no sustituido, -(alquenilo C₂₋₉) no sustituido, -(alquinilo C₂₋₉) no sustituido y -(haloalquilo C₁₋₉) no sustituido; cada R¹⁰ se selecciona, de modo independiente, del grupo que consiste en haluro, -(alquilo C₁₋₉) no sustituido, -(alquenilo C₂₋₉) no sustituido, -(alquinilo C₂₋₉) no sustituido y -(haloalquilo C₁₋₉) no sustituido; cada R¹¹ se selecciona, de modo independiente, del grupo que consiste en haluro, -(alquilo C₁₋₉) no sustituido, -(alquenilo C₂₋₉) no sustituido, -(alquinilo C₂₋₉) no sustituido y -(haloalquilo C₁₋₉) no sustituido; cada R¹² se selecciona, de modo independiente, del grupo que consiste en H, -(alquilo C₁₋₉) no sustituido, -(alquenilo C₂₋₉) no sustituido, -(alquinilo C₂₋₉) no sustituido, -(haloalquilo C₁₋₉) no sustituido, -(alquilen C₁₋₅)ₚOR²¹, -(alquilen C₁₋₅)ₚcarbociclilo opcionalmente sustituido con 1 - 12 R¹⁷, -heterociclilo opcionalmente sustituido con 1 - 10 R¹⁸ y -heteroarilo opcionalmente sustituido con 1 - 10 R¹⁹, en donde el -(alquileno C₁₋₅) está opcionalmente sustituido con 1 - 5 haluros y/o 1 - 3 -(alquilos C₁₋₃) no sustituidos; cada R¹³ es -heterociclilo opcionalmente sustituido con 1 - 10 R¹⁸; cada R¹⁴ se selecciona, de modo independiente, del grupo que consiste en H, -(alquilo C₁₋₉) no sustituido, -(alquenilo C₂₋₉) no sustituido, -(alquinilo C₂₋₉) no sustituido y -(haloalquilo C₁₋₉) no sustituido; cada R¹⁵ se selecciona, de modo independiente, del grupo que consiste en H, -(alquilo C₁₋₉) no sustituido, -(alquenilo C₂₋₉) no sustituido, -(alquinilo C₂₋₉) no sustituido, -(haloalquilo C₁₋₉) no sustituido y -(alquilen C₁₋₅)ₚOR²¹; cada R¹⁶ se selecciona, de modo independiente, del grupo que consiste en haluro, -CN, -(alquilo C₁₋₉) no sustituido, -(alquenilo C₂₋₉) no sustituido, -(alquinilo C₂₋₉) no sustituido, -(haloalquilo C₁₋₉) no sustituido y -carbociclilo opcionalmente sustituido con 1 - 12 R²⁷; alternativamente, dos R¹⁶ unidos al mismo átomo de carbono se toman juntos para formar un grupo carbonilo; cada R¹⁷ se selecciona, de modo independiente, del grupo que consiste en haluro, -OMe, -(alquilo C₁₋₉) no sustituido, -(alquenilo C₂₋₉) no sustituido, -(alquinilo C₂₋₉) no sustituido y -(haloalquilo C₁₋₉) no sustituido; cada R¹⁸ se selecciona, de modo independiente, del grupo que consiste en haluro, -(alquilo C₁₋₉) no sustituido, -(alquenilo C₂₋₉) no sustituido, -(alquinilo C₂₋₉) no sustituido y -(haloalquilo C₁₋₉) no sustituido; cada R¹⁹ se selecciona, de modo independiente, del grupo que consiste en haluro, -(alquilo C₁₋₉) no sustituido, -(alquenilo C₂₋₉) no sustituido, -(alquinilo C₂₋₉) no sustituido y -(haloalquilo C₁₋₉) no sustituido; cada R²⁰ se selecciona, de modo independiente, del grupo que consiste en haluro, -(alquilo C₁₋₉) no sustituido, -(alquenilo C₂₋₉) no sustituido, -(alquinilo C₂₋₉) no sustituido y -(haloalquilo C₁₋₉) no sustituido; cada R²¹ se selecciona, de modo independiente, del grupo que consiste en H, -(alquilo C₁₋₉) no sustituido, -(alquenilo C₂₋₉) no sustituido, -(alquinilo C₂₋₉) no sustituido y -(haloalquilo C₁₋₉) no sustituido; cada R²² se selecciona, de modo independiente, del grupo que consiste en -heterociclilo opcionalmente sustituido con 1 - 10 R¹⁸, -N(R¹²)₂ y -OR²¹; cada R²³ se selecciona, de modo independiente, del grupo que consiste en -(alquilo C₁₋₉) no sustituido, -(alquenilo C₂₋₉) no sustituido, -(alquinilo C₂₋₉) no sustituido, -(haloalquilo C₁₋₉) no sustituido, -(alquilen C₁₋₅)ₚOR²¹ y -carbociclilo opcionalmente sustituido con 1 - 12 R²⁵; cada R²⁴ se selecciona, de modo independiente, del grupo que consiste en -(alquilo C₁₋₉) no sustituido, -(alquenilo C₂₋₉) no sustituido, -(alquinilo C₂₋₉) no sustituido, -(haloalquilo C₁₋₉) no sustituido, -OR²¹ y -carbociclilo opcionalmente sustituido con 1 - 12 R²⁵; cada R²⁵ se selecciona, de modo independiente, del grupo que consiste en haluro, -(alquilo C₁₋₉) no sustituido, -(alquenilo C₂₋₉) no sustituido, -(alquinilo C₂₋₉) no sustituido, -(haloalquilo C₁₋₉) no sustituido y -CN; cada R²⁶ se selecciona, de modo independiente, del grupo que consiste en haluro, -(alquilo C₁₋₉) no sustituido, -(alquenilo C₂₋₉) no sustituido, -(alquinilo C₂₋₉) no sustituido y -(haloalquilo C₁₋₉) no sustituido; cada R²⁷ se selecciona, de modo independiente, del grupo que consiste en haluro, -(alquilo C₁₋₉) no sustituido, -(alquenilo C₂₋₉) no sustituido, -(alquinilo C₂₋₉) no sustituido y -(haloalquilo C₁₋₉) no sustituido; R²⁸ se selecciona, de modo independiente, del grupo que consiste en H y haluro; y cada p es, modo independiente, 0 o 1; en donde cada átomo de H está opcionalmente reemplazado, de modo opcional, por ²H (D) (deuterio).4-Alkoxypyrrolo[2,1-f][1,2,4]triazine compounds are described for treating various diseases and pathologies. More particularly, the present disclosure relates to the use of 4-alkoxypyrrolo[2,1-f][1,2,4]triazine compounds or analogues thereof, in the treatment of disorders characterized by overexpression of DYRK1A (e.g., cancer, Down syndrome, Alzheimer's disease, diabetes, viral infections and osteoarthritis). Claim 1: A compound or a pharmaceutically acceptable salt thereof, of the formula (1) wherein: R¹ is heteroaryl optionally substituted with 1 - 10 R⁴; R² is selected from the group consisting of unsubstituted -(C₁₋₉alkyl), unsubstituted -(C₂₋₉alkenyl), unsubstituted -(C₂₋₉alkynyl), unsubstituted -(C₁₋₉haloalkyl), -(C₁₋₅alkylene)ₚOR⁵, -(C₁₋₅alkylene)CN, -(C₁₋₅alkylene)ₚheterocyclyl optionally substituted with 1 - 10 R⁶, -(C₁₋₅alkylene)ₚaryl optionally substituted with 1 - 10 R²⁶, -(C₁₋₅alkylene)ₚheteroaryl optionally substituted with 1 - 10 R⁷ and -(C₁₋₅ alkylene)ₚcarbocyclyl optionally substituted with 1 - 12 R⁸, wherein each -(C₁₋₅ alkylene) is independently optionally substituted with 1 - 5 halides and/or 1 - 3 unsubstituted -(C₁₋₃ alkyls); R³ is selected from the group consisting of H, unsubstituted -(C₁₋₉ alkyl), unsubstituted -(C₂₋₉ alkenyl), unsubstituted -(C₂₋₉ alkynyl, unsubstituted -(C₁₋₉ haloalkyl), and heterocyclyl optionally substituted with 1 - 10 R¹⁸; each R⁴ is independently selected from the group consisting of halide, unsubstituted -(C₁₋₉alkyl), unsubstituted -(C₂₋₉alkenyl), unsubstituted -(C₂₋₉alkynyl), unsubstituted -(C₁₋₉haloalkyl), unsubstituted -(C₂₋₉haloalkenyl), -(C₁₋₅alkylene)ₚOR⁹, -(C₁₋₅alkylene)ₚCN, -(C₁₋₅alkylene)ₚheterocyclyl optionally substituted with 1 - 10 R¹⁰, -carbocyclyl optionally substituted with 1 - 12 R¹¹, -(C₁₋₅alkylene)ₚ C₁₋₅)ₚheteroaryl optionally substituted with 1 - 10 R²⁰, -(C₁-₅ alkylene)ₚC(=O)N(R¹²)₂ and -C(=O)R¹³, wherein each -(C₁₋₅ alkylene) is independently optionally substituted with 1 - 5 halides and/or 1 - 3 unsubstituted -(C₁₋₃ alkyls); each R⁵ is independently selected from the group consisting of H, unsubstituted -(C₁₋₉ alkyl), unsubstituted -(C₂₋₉ alkenyl), unsubstituted -(C₂₋₉ alkynyl) and unsubstituted -(C₁₋₉ haloalkyl); each R⁶ is independently selected from the group consisting of halide, unsubstituted -(C₁₋₉alkyl), unsubstituted -(C₂₋₉alkenyl), unsubstituted -(C₂₋₉alkynyl), unsubstituted -(C₁₋₉haloalkyl), -heterocyclyl optionally substituted with 1 - 10 R¹⁶, -carbocyclyl optionally substituted with 1 - 12 R¹⁷, -(C₁₋₅alkylene)ₚOR²¹, -(C₁₋₅alkylene)CN, -SO₂R²³, and -C(=O)R²⁴, wherein the -(C₁₋₅alkylene) is optionally substituted with 1 - 5 halides and/or 1 - 3 unsubstituted -(C₁₋₃ alkyls); alternatively, two R⁶ attached to the same carbon atom are taken together to form a carbonyl group; each R⁷ is independently selected from the group consisting of halide, unsubstituted -(C₁₋₉ alkyl), unsubstituted -(C₂₋₉ alkenyl), unsubstituted -(C₂₋₉ alkynyl), unsubstituted -(C₁₋₉ haloalkyl) and -OMe; each R⁸ is independently selected from the group consisting of halide, unsubstituted -(C₁₋₉alkyl), unsubstituted -(C₂₋₉alkenyl), unsubstituted -(C₂₋₉alkynyl), unsubstituted -(C₁₋₉haloalkyl), -N(R¹⁴)₂, -(C₁₋₅alkylene)ₚOR¹⁵, -CN, -(C₁₋₅alkylene)ₚheterocyclyl optionally substituted with 1 - 10 R¹⁶, -C(=O)R²², and -NR¹⁴C(=O)R²³, wherein each -(C₁₋₅alkylene) is independently optionally substituted with 1-5 halides and/or 1-3 unsubstituted -(C₁₋₃)alkyls; each R⁹ is independently selected from the group consisting of H, unsubstituted -(C₁₋₉)alkyl, unsubstituted -(C₂₋₉alkenyl), unsubstituted -(C₂₋₉alkynyl), and unsubstituted -(C₁₋₉haloalkyl); each R¹⁰ is independently selected from the group consisting of halide, unsubstituted -(C₁₋₉)alkyl, unsubstituted -(C₂₋₉alkenyl), unsubstituted -(C₂₋₉alkynyl), and unsubstituted -(C₁₋₉haloalkyl; each R¹¹ is independently selected from the group consisting of halide, unsubstituted -(C₁₋₉alkyl), unsubstituted -(C₂₋₉alkenyl), unsubstituted -(C₂₋₉alkynyl), and unsubstituted -(C₁₋₉haloalkyl); each R¹² is independently selected from the group consisting of H, unsubstituted -(C₁₋₉alkyl), unsubstituted -(C₂₋₉alkenyl), unsubstituted -(C₂₋₉alkynyl), unsubstituted -(C₁₋₉haloalkyl), -(C₁₋₅alkylene)ₚOR²¹, -(C₁₋₅alkylene)ₚcarbocyclyl optionally substituted with 1 - 12 R¹⁷, -heterocyclyl optionally substituted with 1 - 10 R¹⁸, and -heteroaryl optionally substituted with 1 - 10 R¹⁹, wherein the -(C₁₋₅alkylene) is optionally substituted with 1 - 5 halides and/or 1 - 3 unsubstituted -(C₁₋₃)alkyls; each R¹³ is -heterocyclyl optionally substituted with 1 - 10 R¹⁸; each R¹⁴ is independently selected from the group consisting of H, unsubstituted -(C₁₋₉)alkyl, unsubstituted -(C₂₋₉alkenyl), unsubstituted -(C₂₋₉alkynyl), and unsubstituted -(C₁₋₉haloalkyl); each R¹⁵ is independently selected from the group consisting of H, unsubstituted -(C₁₋₉alkyl), unsubstituted -(C₂₋₉alkenyl), unsubstituted -(C₂₋₉alkynyl), unsubstituted -(C₁₋₉haloalkyl), and -(C₁₋₅alkylene)ₚOR²¹; each R¹⁶ is independently selected from the group consisting of halide, -CN, unsubstituted -(C₁₋₉ alkyl), unsubstituted -(C₂₋₉ alkenyl), unsubstituted -(C₂₋₉ alkynyl), unsubstituted -(C₁₋₉ haloalkyl), and -carbocyclyl optionally substituted with 1 - 12 R²⁷; alternatively, two R¹⁶ attached to the same carbon atom are taken together to form a carbonyl group; each R¹⁷ is independently selected from the group consisting of halide, -OMe, unsubstituted -(C₁₋₉alkyl), unsubstituted -(C₂₋₉alkenyl), unsubstituted -(C₂₋₉alkynyl), and unsubstituted -(C₁₋₉haloalkyl); each R¹⁸ is independently selected from the group consisting of halide, unsubstituted -(C₁₋₉alkyl), unsubstituted -(C₂₋₉alkenyl), unsubstituted -(C₂₋₉alkynyl), and unsubstituted -(C₁₋₉haloalkyl; each R¹⁹ is independently selected from the group consisting of halide, unsubstituted -(C₁₋₉ alkyl), unsubstituted -(C₂₋₉ alkenyl), unsubstituted -(C₂₋₉ alkynyl), and unsubstituted -(C₁₋₉ haloalkyl; each R²⁰ is independently selected from the group consisting of halide, unsubstituted -(C₁₋₉ alkyl), unsubstituted -(C₂₋₉ alkenyl), unsubstituted -(C₂₋₉ alkynyl), and unsubstituted -(C₁₋₉ haloalkyl; each R²¹ is independently selected from the group consisting of H, unsubstituted -(C₁₋₉ alkyl), unsubstituted -(C₂₋₉ alkenyl), unsubstituted -(C₂₋₉ alkynyl), and unsubstituted -(C₁₋₉ haloalkyl); each R²² is independently selected from the group consisting of -heterocyclyl optionally substituted with 1 - 10 R¹⁸, -N(R¹²)₂, and -OR²¹; each R²³ is independently selected from the group consisting of unsubstituted -(C₁₋₉ alkyl), unsubstituted -(C₂₋₉ alkenyl), unsubstituted -(C₂₋₉ alkynyl), unsubstituted -(C₁₋₉ haloalkyl), -(C₁₋₅ alkylene)ₚOR²¹, and -carbocyclyl optionally substituted with 1 - 12 R²⁵; each R²⁴ is independently selected from the group consisting of unsubstituted -(C₁₋₉ alkyl), unsubstituted -(C₂₋₉ alkenyl), unsubstituted -(C₂₋₉ alkynyl), unsubstituted -(C₁₋₉ haloalkyl), -OR²¹, and -carbocyclyl optionally substituted with 1 - 12 R²⁵; each R²⁵ is independently selected from the group consisting of halide, unsubstituted -(C₁₋₉ alkyl), unsubstituted -(C₂₋₉ alkenyl), unsubstituted -(C₂₋₉ alkynyl), unsubstituted -(C₁₋₉ haloalkyl) and -CN; each R²⁶ is independently selected from the group consisting of halide, unsubstituted -(C₁₋₉ alkyl), unsubstituted -(C₂₋₉ alkenyl), unsubstituted -(C₂₋₉ alkynyl), and unsubstituted -(C₁₋₉ haloalkyl); each R²⁷ is independently selected from the group consisting of halide, unsubstituted -(C₁₋₉ alkyl), unsubstituted -(C₂₋₉ alkenyl), unsubstituted -(C₂₋₉ alkynyl), and unsubstituted -(C₁₋₉ haloalkyl); R²⁸ is independently selected from the group consisting of H and halide; and each p is independently 0 or 1; where each H atom is optionally replaced by ²H(D) (deuterium).

ARP230101623A 2020-04-12 2023-06-23 4-ALCOXYPYRROLO[2,1-F][1,2,4]TRIAZINES AND THEIR PREPARATION AND USE AR129707A1 (en)

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