AR120811A1 - INHIBITORS OF MUTANT KRAS PROTEINS - Google Patents

INHIBITORS OF MUTANT KRAS PROTEINS

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AR120811A1
AR120811A1 ARP200103542A ARP200103542A AR120811A1 AR 120811 A1 AR120811 A1 AR 120811A1 AR P200103542 A ARP200103542 A AR P200103542A AR P200103542 A ARP200103542 A AR P200103542A AR 120811 A1 AR120811 A1 AR 120811A1
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Argentina
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alkyl
independently
nr5r6
occurrence
membered
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ARP200103542A
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Spanish (es)
Inventor
Amin Li
Sujing Li
Peng Wang
Chaojie Dang
Dan Liu
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Jacobio Pharmaceuticals Co Ltd
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Application filed by Jacobio Pharmaceuticals Co Ltd filed Critical Jacobio Pharmaceuticals Co Ltd
Publication of AR120811A1 publication Critical patent/AR120811A1/en

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Abstract

La presente se refiere a un inhibidor de la proteína KRAS mutante mostrado como fórmula (1), una composición que contiene el inhibidor y su uso. Reivindicación 1: Un compuesto de la fórmula (1), uno de sus estereoisómeros, uno de sus atropisómeros, una de sus sales farmacéuticamente aceptables, una sal farmacéuticamente aceptable de su estereoisómero o una sal farmacéuticamente aceptable de su atropisómero, en donde: R¹¹, R¹², R¹³, R¹⁴ o R¹⁵ está seleccionado, de modo independiente, de halógeno, -alquilo C₁₋₆, -alquenilo C₂₋₆, -alquinilo C₂₋₆, heteroalquilo C₂₋₆, -CN, -O-alquilo C₁₋₆, -S-alquilo C₁₋₆, -NR⁵R⁶, -C(=O)R⁵, -C(=O)OR⁵, -OC(=O)R⁵, -C(=O)NR⁵R⁶, -NR⁵C(=O)R⁶, -NR⁵SO₂R⁶, -SO₂R⁵, -S(=O)₂NR⁵R⁶, -POR⁵R⁶, -carbocíclico C₃₋₆, heterocíclico de 3 - 6 miembros, -arilo C₆₋₁₀ o heteroarilo de 5 - 10 miembros, cada hidrógeno en R¹¹, R¹², R¹³, R¹⁴ o R¹⁵ está opcionalmente sustituido, de modo independiente, con 1, 2, 3, 4, 5 ó 6 sustituyentes seleccionados de halógeno, -alquilo C₁₋₆, -alquenilo C₂₋₆, -alquinilo C₂₋₆, heteroalquilo C₂₋₆, -CN, oxo, -O-alquilo C₁₋₆, -S-alquilo C₁₋₆, -NR⁵R⁶, -C(=O)R⁵, -C(=O)OR⁵, -OC(=O)R⁵, -C(=O)NR⁵R⁶, -NR⁵C(=O)R⁶, -NR⁵SO₂R⁶, -SO₂R⁵, -S(=O)₂NR⁵R⁶, -POR⁵R⁶, -carbocíclico C₃₋₆, heterocíclico de 3 - 6 miembros, -arilo C₆₋₁₀ o heteroarilo de 5 - 10 miembros; cada heterocíclico o heteroarilo en cada aparición contiene, de modo independiente, 1, 2, 3 ó 4 heteroátomos seleccionados de N, O, S, S=O ó S(=O)₂; R²¹ o R²² está seleccionado, de modo independiente, de hidrógeno, halógeno, -alquilo C₁₋₆, -alquenilo C₂₋₆, -alquinilo C₂₋₆, heteroalquilo C₂₋₆, -CN, -O-alquilo C₁₋₆, -S-alquilo C₁₋₆, -NR⁵R⁶, -C(=O)R⁵, -C(=O)OR⁵, -OC(=O)R⁵, -C(=O)NR⁵R⁶, -NR⁵C(=O)R⁶, -NR⁵SO₂R⁶, -SO₂R⁵, -S(=O)₂NR⁵R⁶, -POR⁵R⁶, -carbocíclico C₃₋₆, heterocíclico de 3 - 6 miembros, -arilo C₆₋₁₀ o heteroarilo de 5 - 10 miembros, cada hidrógeno en R²¹ o R²² está opcionalmente sustituido, de modo independiente, con 1, 2, 3, 4, 5 ó 6 sustituyentes seleccionados de halógeno, -alquilo C₁₋₆, -alquenilo C₂₋₆, -alquinilo C₂₋₆, heteroalquilo C₂₋₆, -CN, oxo, -O-alquilo C₁₋₆, -S-alquilo C₁₋₆, -NR⁵R⁶, -C(=O)R⁵, -C(=O)OR⁵, -OC(=O)R⁵, -C(=O)NR⁵R⁶, -NR⁵C(=O)R⁶, -S(=O)₂NR⁵R⁶, -POR⁵R⁶, -carbocíclico C₃₋₆, heterocíclico de 3 - 6 miembros, -arilo C₆₋₁₀ o heteroarilo de 5 - 10 miembros; cada heterocíclico o heteroarilo en cada aparición contiene, de modo independiente, 1, 2, 3 ó 4 heteroátomos seleccionados de N, O, S, S=O ó S(=O)₂; R³ está seleccionado de -alquilo C₁₋₁₄, -alquenilo C₂₋₁₄, -alquinilo C₂₋₁₄, -arilo C₆₋₁₀, heteroarilo de 5 - 10 miembros, heterocíclico de 3 - 14 miembros, -carbocíclico C₃₋₁₄, un resto de fórmula (2) o un resto de fórmula (3), cada anillo C en cada aparición está seleccionado, de modo independiente, de un anillo carbocíclico C₃₋₁₄ o heterocíclico de 3 - 14 miembros, cada anillo D en cada aparición está seleccionado, de modo independiente, de un anillo arilo C₆₋₁₀ o heteroarilo de 5 - 10 miembros, cada hidrógeno en R³ está opcionalmente sustituido, de modo independiente, con 1, 2, 3, 4, 5 ó 6 R³¹; cada heterocíclico o heteroarilo en cada aparición contiene, de modo independiente, 1, 2, 3 ó 4 heteroátomos seleccionados de N, O, S, S=O ó S(=O)₂; cada R³¹ en cada aparición está seleccionado, de modo independiente, de halógeno, -alquilo C₁₋₆, -alquenilo C₂₋₆, -alquinilo C₂₋₆, heteroalquilo C₂₋₆, -CN, -O-alquilo C₁₋₆, -S-alquilo C₁₋₆, -NR⁵R⁶, -C(=O)R⁵, -C(=O)OR⁵, -OC(=O)R⁵, -C(=O)NR⁵R⁶, -NR⁵C(=O)R⁶, -NR⁵SO₂R⁶, -SO₂R⁵, -S(=O)₂NR⁵R⁶, -POR⁵R⁶, -carbocíclico C₃₋₆, heterocíclico de 3 - 6 miembros, -arilo C₆₋₁₀ o heteroarilo de 5 - 10 miembros, cada hidrógeno en R³¹ está opcionalmente sustituido, de modo independiente, con 1, 2, 3, 4, 5 ó 6 sustituyentes seleccionados de halógeno, -alquilo C₁₋₆, -alquenilo C₂₋₆, -alquinilo C₂₋₆, heteroalquilo C₂₋₆, -CN, oxo, -O-alquilo C₁₋₆, -S-alquilo C₁₋₆, -NR⁵R⁶, -C(=O)R⁵, -C(=O)OR⁵, -OC(=O)R⁵, -C(=O)NR⁵R⁶, -NR⁵C(=O)R⁶, -S(=O)₂NR⁵R⁶, -POR⁵R⁶, -carbocíclico C₃₋₆, heterocíclico de 3 - 6 miembros, -arilo C₆₋₁₀ o heteroarilo de 5 - 10 miembros; cada heterocíclico o heteroarilo en cada aparición contiene, de modo independiente, 1, 2, 3 ó 4 heteroátomos seleccionados de N, O, S, S=O ó S(=O)₂; R⁴ está seleccionado de los compuestos del grupo de fórmula (4); cada G¹, G², G³ o G⁴ en cada aparición está seleccionado, de modo independiente, de N o CH; cada n1, n2, n3, n4 o n5 en cada aparición está seleccionado, de modo independiente, de 0, 1, 2, 3, 4, 5 ó 6, siempre que n1 y n2 no sean 0 al mismo tiempo, n3 y n4 no sean 0 al mismo tiempo; cada hidrógeno en los restos del grupo de fórmulas (5) está opcionalmente sustituido, de modo independiente, con 1 R⁴², 2 R⁴², 3 R⁴², 4 R⁴², 5 R⁴² o 6 R⁴²; cada R⁴¹ en cada aparición está seleccionado, de modo independiente, de un compuesto de fórmula (6) o de fórmula (7); cada uno de Q en cada aparición está seleccionado, de modo independiente, de C(=O), NR⁵C(=O), S(=O)₂ o NR⁵S(=O)₂; ⁻ ⁻ ⁻ ⁻ ⁻ en el compuesto de fórmula (6) está seleccionado de ₌₌₌₌₌ o <sub>&The present relates to a mutant KRAS protein inhibitor shown as formula (1), a composition containing the inhibitor, and its use. Claim 1: A compound of formula (1), one of its stereoisomers, one of its atropisomers, one of its pharmaceutically acceptable salts, a pharmaceutically acceptable salt of its stereoisomer or a pharmaceutically acceptable salt of its atropisomer, where: R¹¹, R¹², R¹³, R¹⁴ or R¹⁵ is independently selected from halogen, -C₁₋₆ alkyl, -C₂₋₆ alkenyl, -C₂₋₆ alkynyl, C₂₋₆ heteroalkyl, -CN, -OC₁₋₆ alkyl , -S-C₁₋₆-alkyl, -NR⁵R⁶, -C(=O)R⁵, -C(=O)OR⁵, -OC(=O)R⁵, -C(=O)NR⁵R⁶, -NR⁵C(=O) R⁶, -NR⁵SO₂R⁶, -SO₂R⁵, -S(=O)₂NR⁵R⁶, -POR⁵R⁶, -C₃₋₆-carbocyclic, 3-6 membered heterocyclic, -C₆₋₁₀-aryl or 5-10 membered heteroaryl, each hydrogen at R¹¹, R¹², R¹³, R¹⁴ or R¹⁵ is optionally substituted, independently, with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C₁₋₆ alkyl, -C₂₋₆ alkenyl, -C₂₋₆ alkynyl, C₂₋₆ heteroalkyl, -CN, oxo, -O-C₁₋₆ alkyl, -S-C₁₋₆ alkyl, -NR⁵R⁶, -C(=O)R⁵, -C(=O)OR⁵, -OC(=O )R⁵, -C(=O)NR⁵R⁶, -N R⁵C(=O)R⁶, -NR⁵SO₂R⁶, -SO₂R⁵, -S(=O)₂NR⁵R⁶, -POR⁵R⁶, -C₃₋₆-carbocyclic, 3-6 membered heterocyclic, -C₆₋₁₀-aryl or 5-10 membered heteroaryl; each heterocyclic or heteroaryl at each occurrence independently contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, S=O or S(=O)₂; R²¹ or R²² is independently selected from hydrogen, halogen, -C₁₋₆ alkyl, -C₂₋₆ alkenyl, -C₂₋₆ alkynyl, C₂₋₆ heteroalkyl, -CN, -OC₁₋₆ alkyl, - S-C₁₋₆-alkyl, -NR⁵R⁶, -C(=O)R⁵, -C(=O)OR⁵, -OC(=O)R⁵, -C(=O)NR⁵R⁶, -NR⁵C(=O)R⁶, -NR⁵SO₂R⁶, -SO₂R⁵, -S(=O)₂NR⁵R⁶, -POR⁵R⁶, -C₃₋₆-carbocyclic, 3-6 membered heterocyclic, -C₆₋₁₀-aryl or 5-10 membered heteroaryl, each hydrogen in R²¹ or R²² is optionally substituted independently with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C₁₋₆ alkyl, -C₂₋₆ alkenyl, -C₂₋₆ alkynyl, C₂₋₆ heteroalkyl, -CN, oxo, -OC₁₋₆-alkyl, -S-C₁₋₆-alkyl, -NR⁵R⁶, -C(=O)R⁵, -C(=O)OR⁵, -OC(=O)R⁵, -C(=O )NR⁵R⁶, -NR⁵C(=O)R⁶, -S(=O)₂NR⁵R⁶, -POR⁵R⁶, -C₃₋₆-carbocyclic, 3-6 membered heterocyclic, -C₆₋₁₀-aryl or 5-10 membered heteroaryl; each heterocyclic or heteroaryl at each occurrence independently contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, S=O or S(=O)₂; R³ is selected from -C₁₋₁₄ alkyl, -C₂₋₁₄ alkenyl, -C₂₋₁₄ alkynyl, -C₆₋₁₀ aryl, 5-10 membered heteroaryl, 3-14 membered heterocyclic, -C₃₋₁₄ carbocyclic, a moiety of formula (2) or a moiety of formula (3), each C ring at each occurrence is independently selected from a 3-14 membered C₃₋₁₄ carbocyclic or heterocyclic ring, each D ring at each occurrence is selected independently of a 5-10 membered C₆₋₁₀ aryl or heteroaryl ring, each hydrogen in R³ is independently optionally substituted with 1, 2, 3, 4, 5 or 6 R³¹; each heterocyclic or heteroaryl at each occurrence independently contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, S=O or S(=O)₂; each R³¹ at each occurrence is independently selected from halogen, -C₁₋₆ alkyl, -C₂₋₆ alkenyl, -C₂₋₆ alkynyl, C₂₋₆ heteroalkyl, -CN, -OC₁₋₆ alkyl, - S-C₁₋₆-alkyl, -NR⁵R⁶, -C(=O)R⁵, -C(=O)OR⁵, -OC(=O)R⁵, -C(=O)NR⁵R⁶, -NR⁵C(=O)R⁶, -NR⁵SO₂R⁶, -SO₂R⁵, -S(=O)₂NR⁵R⁶, -POR⁵R⁶, -C₃₋₆ carbocyclic, 3-6 membered heterocyclic, -C₆₋₁₀ aryl or 5-10 membered heteroaryl, each hydrogen in R³¹ is optionally substituted , independently, with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C₁₋₆ alkyl, -C₂₋₆ alkenyl, -C₂₋₆ alkynyl, C₂₋₆ heteroalkyl, -CN, oxo, -OC₁₋₆-alkyl, -S-C₁₋₆-alkyl, -NR⁵R⁶, -C(=O)R⁵, -C(=O)OR⁵, -OC(=O)R⁵, -C(=O)NR⁵R⁶ , -NR⁵C(=O)R⁶, -S(=O)₂NR⁵R⁶, -POR⁵R⁶, -C₃₋₆ carbocyclic, 3-6 membered heterocyclic, -C₆₋₁₀ aryl or 5-10 membered heteroaryl; each heterocyclic or heteroaryl at each occurrence independently contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, S=O or S(=O)₂; R⁴ is selected from the compounds of the group of formula (4); each G¹, G², G³ or G⁴ at each occurrence is independently selected from N or CH; each n1, n2, n3, n4, or n5 in each occurrence is independently selected from 0, 1, 2, 3, 4, 5, or 6, provided that n1 and n2 are not 0 at the same time, n3 and n4 are not 0 at the same time; each hydrogen in the moieties of the group of formulas (5) is optionally substituted, independently, with 1 R⁴², 2 R⁴², 3 R⁴², 4 R⁴², 5 R⁴² or 6 R⁴²; each R⁴¹ at each occurrence is independently selected from a compound of formula (6) or formula (7); each Q at each occurrence is independently selected from C(=O), NR⁵C(=O), S(=O)₂, or NR⁵S(=O)₂; ⁻ ⁻ ⁻ ⁻ ⁻ in the compound of formula (6) is selected from ₌₌₌₌₌ or <sub>&

ARP200103542A 2019-12-19 2020-12-18 INHIBITORS OF MUTANT KRAS PROTEINS AR120811A1 (en)

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