AR099464A1 - BENZIMIDAZOL-2-AMINAS AS MIDH1 INHIBITORS - Google Patents

BENZIMIDAZOL-2-AMINAS AS MIDH1 INHIBITORS

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Publication number
AR099464A1
AR099464A1 ARP150100401A ARP150100401A AR099464A1 AR 099464 A1 AR099464 A1 AR 099464A1 AR P150100401 A ARP150100401 A AR P150100401A AR P150100401 A ARP150100401 A AR P150100401A AR 099464 A1 AR099464 A1 AR 099464A1
Authority
AR
Argentina
Prior art keywords
alkyl
alkoxy
haloalkyl
cycloalkyl
aryl
Prior art date
Application number
ARP150100401A
Other languages
Spanish (es)
Inventor
Dr Bauser Marcus
Dr Panknin Olaf
Dr Zimmermann Katja
Dr Siebeneicher Holger
Dr Nguyen Duy
Dr Kaulfuss Stefan
Dr Neuhaus Roland
Dr Rehwinkel Hartmut
Ring Sven
Anlauf Sonja
Dr Schwede Wolfgang
Matthew Dr Blaney Paul
Original Assignee
Bayer Pharma AG
Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts
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
Application filed by Bayer Pharma AG, Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts filed Critical Bayer Pharma AG
Publication of AR099464A1 publication Critical patent/AR099464A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Métodos para elaborarlos. Compuestos intermediarios útiles su elaboración. Composiciones y combinaciones farmacéuticas que los componen. Su uso en la manufactura de composiciones farmacéuticas útiles en la profilaxis o el tratamiento de diversas enfermedades, particularmente de los neoplasmas, en forma de agentes individuales o en combinación con otros ingredientes activos. Reivindicación 1: Un compuesto caracterizado porque es de fórmula (1) en donde: R¹ representa un átomo de halógeno o un grupo seleccionado entre: C₁₋₆-alquilo, C₃₋₆-cicloalquilo, C₁₋₆-alcoxi, C₃₋₆-cicloalquiloxi, C₁₋₆-haloalquilo, C₁₋₆-haloalcoxi, (C₁₋₃-alcoxi)-(C₁₋₆-alquilo)-, ciano, nitro, (C₁₋₆-alquil)-S-, (C₁₋₆-alquil)-S(=O)-, (C₁₋₆-alquil)-S(=O)₂-, (C₁₋₆-haloalquil)-S-, (C₁₋₆-haloalquil)-S(=O)-, (C₁₋₆-haloalquil)-S(=O)₂-, -C(=O)OR¹³, -C(=O)N(R¹⁴)R¹⁵, -N(R¹⁴)R¹⁵, -N(R¹⁴)C(=O)R¹⁶, aril-O-, aril-(C₁₋₃-alquilo)-, heteroaril-O-, y heteroaril-(C₁₋₃-alquilo)-; donde los grupos arilo y heteroarilo están opcionalmente sustituidos con uno o dos sustituyentes, que se seleccionan en forma independiente entre sí entre: C₁₋₃-alquilo, C₁₋₃-alcoxi, C₃₋₆-cicloalquilo, C₃₋₆-cicloalquiloxi, C₁₋₃-haloalquilo, C₁₋₃-haloalcoxi, halógeno, ciano, -C(=O)OR¹³, y -C(=O)N(R¹⁴)R¹⁵; R² representa un átomo de hidrógeno; R³ representa un átomo de hidrógeno; R⁴ representa un átomo de hidrógeno o un átomo de halógeno; R⁵ representa un grupo seleccionado entre: R¹³OC(=O)-(C₁₋₆-alquilo)-, R¹³OC(=O)-(C₂₋₆-alquenilo)-, -R¹³OC(=O)-(C₁₋₆-alcoxi)-, R¹⁴(R¹⁵)NC(=O)-(C₁₋₆-alquilo)-, -R¹⁴(R¹⁵)NC(=O)-(C₂₋₆-alquenilo)-, R¹⁴(R¹⁵)NC(=O)-(C₁₋₆-alcoxi)-; R⁶ representa un átomo de hidrógeno o un átomo de halógeno o un grupo seleccionado entre: C₁₋₆-alquilo, C₁₋₆-alcoxi, (C₁₋₃-alcoxi)-(C₁₋₃-alquilo)-, C₃₋₆-cicloalquilo, C₃₋₆-cicloalquiloxi, C₁₋₆-haloalquilo, C₁₋₆-haloalcoxi, ciano, nitro, (C₁₋₆-alquil)-S-, (C₁₋₆-alquil)-S(=O)-, (C₁₋₆-alquil)-S(=O)₂-, (C₁₋₆-haloalquil)-S-, -N(R¹⁴)R¹⁵, y -N(R¹⁴)C(=O)R¹⁶; R⁷ representa un átomo de hidrógeno; R⁸ representa un grupo C₁₋₃-alquilo; R⁹, R¹⁰, y R¹¹ se seleccionan en forma independiente entre sí entre: hidrógeno y C₁₋₃-alquilo; R¹² representa un átomo de hidrógeno; R¹³ representa un átomo de hidrógeno o un grupo seleccionado entre: C₁₋₆-alquilo, C₃₋₆-cicloalquilo, HO-(C₂₋₆-alquilo)-, y (C₁₋₃-alcoxi)-(C₁₋₆-alquilo)-; R¹⁴ y R¹⁵ se seleccionan en forma independiente entre sí entre: hidrógeno, C₁₋₆-alquilo, C₃₋₆-cicloalquilo, HO-(C₂₋₆-alquilo)-, (C₁₋₃-alcoxi)-(C₂₋₆-alquilo)-, C₁₋₆-haloalquilo, H₂N-(C₂₋₆-alquilo)-, (C₁₋₃-alquil)N(H)(C₂₋₆-alquilo), (C₁₋₃-alquil)₂N(C₂₋₆-alquilo)-, R¹³OC(=O)-(C₁₋₆-alquilo)-, heterocicloalquilo de entre 4 y 6 miembros, arilo, heteroarilo, aril-(C₁₋₆-alquilo)-, y heteroaril-(C₁₋₆-alquilo)-, donde los grupos arilo y heteroarilo están opcionalmente sustituidos con uno o dos sustituyentes, que se seleccionan en forma independiente entre sí entre: C₁₋₃-alquilo, C₃₋₆-cicloalquilo, C₁₋₃-alcoxi, C₃₋₆-cicloalquiloxi, C₁₋₃-haloalquilo, C₁₋₃-haloalcoxi, halógeno, ciano, -C(=O)OR¹³, y -C(=O)NH₂; o R¹⁴ y R¹⁵ junto con el átomo de nitrógeno al cual están unidos forman un heterocicloalquilo de entre 4 y 6 miembros; donde dicho heterocicloalquilo de entre 4 y 6 miembros está opcionalmente sustituido con un sustituyente seleccionado entre: C₁₋₃-alquilo, C₁₋₃-haloalquilo, C₁₋₃-alcoxi, C₁₋₃-haloalcoxi, C₃₋₆-cicloalquilo, C₃₋₆-cicloalquiloxi, amino, hidroxi, halógeno, y ciano; o donde dicho heterocicloalquilo de entre 4 y 6 miembros está opcionalmente sustituido con dos átomos de halógeno; R¹⁶ representa un átomo de hidrógeno o un grupo seleccionado entre: C₁₋₆-alquilo, HO-(C₁₋₆-alquilo)-, C₃₋₆-cicloalquilo, HO-(C₃₋₆-cicloalquilo)-, C₁₋₆-haloalquilo, (C₁₋₃-alcoxi)-(C₁₋₆-alquilo)-, arilo, heteroarilo, y heterocicloalquilo de entre 4 y 6 miembros; donde los grupos arilo y heteroarilo están opcionalmente sustituidos con uno o dos sustituyentes, que se seleccionan en forma independiente entre sí entre: C₁₋₃-alquilo, C₃₋₆-cicloalquilo, C₁₋₃-alcoxi, C₃₋₆-cicloalquiloxi, C₁₋₃-haloalquilo, C₁₋₃-haloalcoxi, halógeno, ciano, -C(=O)OR¹³, y -C(=O)N(R¹⁴)R¹⁵; o un estereoisómero, un tautómero, un N-óxido, un hidrato, un solvato, o una sal de los mismos, o una mezcla de los mismos.Methods to elaborate them. Intermediate compounds useful for its elaboration. Compositions and pharmaceutical combinations that compose them. Its use in the manufacture of pharmaceutical compositions useful in the prophylaxis or treatment of various diseases, particularly neoplasms, in the form of individual agents or in combination with other active ingredients. Claim 1: A compound characterized in that it is of formula (1) wherein: R¹ represents a halogen atom or a group selected from: C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₁₋₆-alkoxy, C₃₋₆- cycloalkyloxy, C₁₋₆-haloalkyl, C₁₋₆-haloalkoxy, (C₁₋₃-alkoxy) - (C₁₋₆-alkyl) -, cyano, nitro, (C₁₋₆-alkyl) -S-, (C₁₋₆ -alkyl) -S (= O) -, (C₁₋₆-alkyl) -S (= O) ₂-, (C₁₋₆-haloalkyl) -S-, (C₁₋₆-haloalkyl) -S (= O ) -, (C₁₋₆-haloalkyl) -S (= O) ₂-, -C (= O) OR¹³, -C (= O) N (R¹⁴) R¹⁵, -N (R¹⁴) R¹⁵, -N (R¹⁴ ) C (= O) R¹⁶, aryl-O-, aryl- (C₁₋₃-alkyl) -, heteroaryl-O-, and heteroaryl- (C₁₋₃-alkyl) -; where the aryl and heteroaryl groups are optionally substituted with one or two substituents, which are independently selected from each other from: C₁₋₃-alkyl, C₁₋₃-alkoxy, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyloxy, C₁ ₋₃-haloalkyl, C₁₋₃-haloalkoxy, halogen, cyano, -C (= O) OR¹³, and -C (= O) N (R¹⁴) R¹⁵; R² represents a hydrogen atom; R³ represents a hydrogen atom; R⁴ represents a hydrogen atom or a halogen atom; R⁵ represents a group selected from: R¹³OC (= O) - (C₁₋₆-alkyl) -, R¹³OC (= O) - (C₂₋₆-alkenyl) -, -R¹³OC (= O) - (C₁₋₆-alkoxy ) -, R¹⁴ (R¹⁵) NC (= O) - (C₁₋₆-alkyl) -, -R¹⁴ (R¹⁵) NC (= O) - (C₂₋₆-alkenyl) -, R¹⁴ (R¹⁵) NC (= O ) - (C₁₋₆-alkoxy) -; R⁶ represents a hydrogen atom or a halogen atom or a group selected from: C₁₋₆-alkyl, C₁₋₆-alkoxy, (C₁₋₃-alkoxy) - (C₁₋₃-alkyl) -, C₃₋₆- cycloalkyl, C₃₋₆-cycloalkyloxy, C₁₋₆-haloalkyl, C₁₋₆-haloalkoxy, cyano, nitro, (C₁₋₆-alkyl) -S-, (C₁₋₆-alkyl) -S (= O) -, (C₁₋₆-alkyl) -S (= O) ₂-, (C₁₋₆-haloalkyl) -S-, -N (R¹⁴) R¹⁵, and -N (R¹⁴) C (= O) R¹⁶; R⁷ represents a hydrogen atom; R⁸ represents a C₁₋₃-alkyl group; R⁹, R¹⁰, and R¹¹ are independently selected from each other from: hydrogen and C₁₋₃-alkyl; R² represents a hydrogen atom; R¹³ represents a hydrogen atom or a group selected from: C₁₋₆-alkyl, C₃₋₆-cycloalkyl, HO- (C₂₋₆-alkyl) -, and (C₁₋₃-alkoxy) - (C₁₋₆-alkyl ) -; R¹⁴ and R¹⁵ are independently selected from each other from: hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, HO- (C₂₋₆-alkyl) -, (C₁₋₃-alkoxy) - (C₂₋₆- alkyl) -, C₁₋₆-haloalkyl, H₂N- (C₂₋₆-alkyl) -, (C₁₋₃-alkyl) N (H) (C₂₋₆-alkyl), (C₁₋₃-alkyl) ₂N (C₂ ₋₆-alkyl) -, R¹³OC (= O) - (C₁₋₆-alkyl) -, 4-6 membered heterocycloalkyl, aryl, heteroaryl, aryl- (C₁₋₆-alkyl) -, and heteroaryl- (C₁ ₋₆-alkyl) -, where the aryl and heteroaryl groups are optionally substituted with one or two substituents, which are independently selected from each other from: C₁₋₃-alkyl, C₃₋₆-cycloalkyl, C₁₋₃-alkoxy, C₃₋₆-cycloalkyloxy, C₁₋₃-haloalkyl, C₁₋₃-haloalkoxy, halogen, cyano, -C (= O) OR¹³, and -C (= O) NH₂; or R¹⁴ and R¹⁵ together with the nitrogen atom to which they are attached form a 4-6 membered heterocycloalkyl; wherein said 4- to 6-membered heterocycloalkyl is optionally substituted with a substituent selected from: C₁₋₃-alkyl, C₁₋₃-haloalkyl, C₁₋₃-alkoxy, C₁₋₃-haloalkoxy, C₃₋₆-cycloalkyl, C₃₋ ₆-cycloalkyloxy, amino, hydroxy, halogen, and cyano; or wherein said 4- to 6-membered heterocycloalkyl is optionally substituted with two halogen atoms; R¹⁶ represents a hydrogen atom or a group selected from: C₁₋₆-alkyl, HO- (C₁₋₆-alkyl) -, C₃₋₆-cycloalkyl, HO- (C₃₋₆-cycloalkyl) -, C₁₋₆- haloalkyl, (C₁₋₃-alkoxy) - (C₁₋₆-alkyl) -, aryl, heteroaryl, and 4-6 membered heterocycloalkyl; where the aryl and heteroaryl groups are optionally substituted with one or two substituents, which are independently selected from each other from: C₁₋₃-alkyl, C₃₋₆-cycloalkyl, C₁₋₃-alkoxy, C₃₋₆-cycloalkyloxy, C₁ ₋₃-haloalkyl, C₁₋₃-haloalkoxy, halogen, cyano, -C (= O) OR¹³, and -C (= O) N (R¹⁴) R¹⁵; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture thereof.

ARP150100401A 2014-02-11 2015-02-11 BENZIMIDAZOL-2-AMINAS AS MIDH1 INHIBITORS AR099464A1 (en)

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EP14154680 2014-02-11

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AR099464A1 true AR099464A1 (en) 2016-07-27

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MA (1) MA39256A1 (en)

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