AR111375A1 - ANTAGONISTS OF THE ARILO HYDROCARBON RECEIVER AND ITS USES - Google Patents

ANTAGONISTS OF THE ARILO HYDROCARBON RECEIVER AND ITS USES

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Publication number
AR111375A1
AR111375A1 ARP180100921A ARP180100921A AR111375A1 AR 111375 A1 AR111375 A1 AR 111375A1 AR P180100921 A ARP180100921 A AR P180100921A AR P180100921 A ARP180100921 A AR P180100921A AR 111375 A1 AR111375 A1 AR 111375A1
Authority
AR
Argentina
Prior art keywords
optionally substituted
cr8ar8b
group
alkyl
aryl
Prior art date
Application number
ARP180100921A
Other languages
Spanish (es)
Inventor
Kevin A Goncalves
Arthur Romero
Original Assignee
Magenta Therapeutics Inc
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 Magenta Therapeutics Inc filed Critical Magenta Therapeutics Inc
Publication of AR111375A1 publication Critical patent/AR111375A1/en

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    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La divulgación se refiere a antagonistas del receptor de hidrocarburo de arilo, tales como imidazopiridinas e imidazopirazinas sustituidas, así como métodos de expansión de células madre hematopoyéticas por cultivo de células madre o progenitoras hematopoyéticas en presencia de estos agentes. Adicionalmente, la divulgación proporciona métodos de tratamiento de diversas patologías en un paciente por administración de células madre hematopoyéticas expandidas. La divulgación también proporciona métodos de síntesis de antagonistas del receptor de hidrocarburo de arilo, tales como imidazopiridinas e imidazopirazinas sustituidas, así como kits que contienen antagonistas del receptor de hidrocarburo de arilo que se pueden usar para la expansión de células madre hematopoyéticas. Reivindicación 1: Un compuesto representado por la fórmula (1), en donde L se selecciona del grupo que consiste en -NR⁷ᵃ(CR⁸ᵃR⁸ᵇ)ₙ-, -O(CR⁸ᵃR⁸ᵇ)ₙ-, -C(O)(CR⁸ᵃR⁸ᵇ)ₙ-, -C(S)(CR⁸ᵃR⁸ᵇ)ₙ-, -S(O)₀₋₂(CR⁸ᵃR⁸ᵇ)ₙ-, -(CR⁸ᵃR⁸ᵇ)ₙ-, -NR⁷ᵃC(O)(CR⁸ᵃR⁸ᵇ)ₙ-, -NR⁷ᵃC(S)(CR⁸ᵃR⁸ᵇ)ₙ-, -OC(O)(CR⁸ᵃR⁸ᵇ)ₙ-, -OC(S)(CR⁸ᵃR⁸ᵇ)ₙ-, -C(O)NR⁷ᵃ(CR⁸ᵃR⁸ᵇ)ₙ-, -C(S)NR⁷ᵃ(CR⁸ᵃR⁸ᵇ)ₙ-, -C(O)O(CR⁸ᵃR⁸ᵇ)ₙ-, -C(S)O(CR⁸ᵃR⁸ᵇ)ₙ-, -S(O)₂NR⁷ᵃ(CR⁸ᵃR⁸ᵇ)ₙ-, -NR⁷ᵃS(O)₂(CR⁸ᵃR⁸ᵇ)ₙ-, -NR⁷ᵃC(O)NR⁷ᵇ(CR⁸ᵃR⁸ᵇ)ₙ- y -NR⁷ᵃC(O)O(CR⁸ᵃR⁸ᵇ)ₙ-, en donde R⁷ᵃ, R⁷ᵇ, R⁸ᵃ y R⁸ᵇ se seleccionan cada uno, de modo independiente, del grupo que consiste en hidrógeno y alquilo C₁₋₄ opcionalmente sustituido y cada n es, de modo independiente, un número entero de 2 a 6; R¹ se selecciona del grupo que consiste en -S(O)₂NR⁹ᵃR⁹ᵇ, -NR⁹ᵃC(O)R⁹ᵇ, -NR⁹ᵃC(S)R⁹ᵇ, -NR⁹ᵃC(O)NR⁹ᵇR⁹ᶜ, -C(O)R⁹ᵃ, -C(S)R⁹ᵃ, -S(O)₀₋₂R⁹ᵃ, -C(O)OR⁹ᵃ, -C(S)OR⁹ᵃ, -C(O)NR⁹ᵃR⁹ᵇ, -C(S)NR⁹ᵃR⁹ᵇ, -NR⁹ᵃS(O)₂R⁹ᵇ, -NR⁹ᵃC(O)OR⁹ᵇ, -OC(O)CR⁹ᵃR⁹ᵇR⁹ᶜ, -OC(S)CR⁹ᵃR⁹ᵇR⁹ᶜ, arilo opcionalmente sustituido, heteroarilo opcionalmente sustituido, cicloalquilo opcionalmente sustituido y heterocicloalquilo opcionalmente sustituido, en donde R⁹ᵃ, R⁹ᵇ y R⁹ᶜ se seleccionan cada uno, de modo independiente, del grupo que consiste en hidrógeno, arilo opcionalmente sustituido, heteroarilo opcionalmente sustituido, alquilo opcionalmente sustituido, heteroalquilo opcionalmente sustituido, cicloalquilo opcionalmente sustituido y heterocicloalquilo opcionalmente sustituido; R² se selecciona del grupo que consiste en hidrógeno y alquilo C₁₋₄ opcionalmente sustituido; R³ se selecciona del grupo que consiste en arilo opcionalmente sustituido, heteroarilo opcionalmente sustituido, cicloalquilo opcionalmente sustituido y heterocicloalquilo opcionalmente sustituido; R⁴ se selecciona del grupo que consiste en hidrógeno y alquilo C₁₋₄ opcionalmente sustituido; R⁵ se selecciona del grupo que consiste en arilo opcionalmente sustituido, heteroarilo opcionalmente sustituido, alquilo opcionalmente sustituido, heteroalquilo opcionalmente sustituido, cicloalquilo opcionalmente sustituido y heterocicloalquilo opcionalmente sustituido; y R⁶ se selecciona del grupo que consiste en hidrógeno, arilo opcionalmente sustituido, heteroarilo opcionalmente sustituido, alquilo opcionalmente sustituido, heteroalquilo opcionalmente sustituido, cicloalquilo opcionalmente sustituido y heterocicloalquilo opcionalmente sustituido; o una de sus sales. Reivindicación 37: Un compuesto representado por la fórmula (2), en donde L se selecciona del grupo que consiste en -NR⁷ᵃ(CR⁸ᵃR⁸ᵇ)ₙ-, -O(CR⁸ᵃR⁸ᵇ)ₙ-, -C(O)(CR⁸ᵃR⁸ᵇ)ₙ-, -C(S)(CR⁸ᵃR⁸ᵇ)ₙ-, -S(O)₀₋₂(CR⁸ᵃR⁸ᵇ)ₙ-, -(CR⁸ᵃR⁸ᵇ)ₙ-, -NR⁷ᵃC(O)(CR⁸ᵃR⁸ᵇ)ₙ-, -NR⁷ᵃC(S)(CR⁸ᵃR⁸ᵇ)ₙ-, -OC(O)(CR⁸ᵃR⁸ᵇ)ₙ-, -OC(S)(CR⁸ᵃR⁸ᵇ)ₙ-, -C(O)NR⁷ᵃ(CR⁸ᵃR⁸ᵇ)ₙ-, -C(S)NR⁷ᵃ(CR⁸ᵃR⁸ᵇ)ₙ-, -C(O)O(CR⁸ᵃR⁸ᵇ)ₙ-, -C(S)O(CR⁸ᵃR⁸ᵇ)ₙ-, -S(O)₂NR⁷ᵃ(CR⁸ᵃR⁸ᵇ)ₙ-, -NR⁷ᵃS(O)₂(CR⁸ᵃR⁸ᵇ)ₙ-, -NR⁷ᵃC(O)NR⁷ᵇ(CR⁸ᵃR⁸ᵇ)ₙ- y -NR⁷ᵃC(O)O(CR⁸ᵃR⁸ᵇ)ₙ-, en donde R⁷ᵃ, R⁷ᵇ, R⁸ᵃ y R⁸ᵇ se seleccionan cada uno, de modo independiente, del grupo que consiste en hidrógeno y alquilo C₁₋₄ opcionalmente sustituido y cada n es, de modo independiente, un numero entero de 2 a 6; R¹ se selecciona del grupo que consiste en -S(O)₂NR⁹ᵃR⁹ᵇ, -NR⁹ᵃC(O)R⁹ᵇ, -NR⁹ᵃC(S)R⁹ᵇ-, -NR⁹ᵃC(O)NR⁹ᵇR⁹ᶜ, -C(O)R⁹ᵃ, -C(S)R⁹ᵃ, -S(O)₀₋₂R⁹ᵃ, -C(O)OR⁹ᵃ, -C(S)OR⁹ᵃ, -C(O)NR⁹ᵃR⁹ᵇ, -C(S)NR⁹ᵃR⁹ᵇ, -NR⁹ᵃS(O)₂R⁹ᵇ, -NR⁹ᵃC(O)OR⁹ᵇ, -OC(O)CR⁹ᵃR⁹ᵇR⁹ᶜ, -OC(S)CR⁹ᵃR⁹ᵇR⁹ᶜ, arilo opcionalmente sustituido, heteroarilo opcionalmente sustituido, cicloalquilo opcionalmente sustituido y heterocicloalquilo opcionalmente sustituido, en donde R⁹ᵃ, R⁹ᵇ y R⁹ᶜ se seleccionan cada uno, de modo independiente, del grupo que consiste en hidrógeno, arilo opcionalmente sustituido, heteroarilo opcionalmente sustituido, alquilo opcionalmente sustituido, heteroalquilo opcionalmente sustituido, cicloalquilo opcionalmente sustituido y heterocicloalquilo opcionalmente sustituido; R³ se selecciona del grupo que consiste en arilo opcionalmente sustituido, heteroarilo opcionalmente sustituido, cicloalquilo opcionalmente sustituido y heterocicloalquilo opcionalmente sustituido; R⁴ se selecciona del grupo que consiste en hidrógeno y alquilo C₁₋₄ opcionalmente sustituido; R⁵ se selecciona del grupo que consiste en arilo opcionalmente sustituido, heteroarilo opcionalmente sustituido, alquilo opcionalmente sustituido, heteroalquilo opcionalmente sustituido, cicloalquilo opcionalmente sustituido y heterocicloalquilo opcionalmente sustituido; y R⁶ se selecciona del grupo que consiste en hidrógeno, arilo opcionalmente sustituido, heteroarilo opcionalmente sustituido, alquilo opcionalmente sustituido, heteroalquilo opcionalmente sustituido, cicloalquilo opcionalmente sustituido y heterocicloalquilo opcionalmente sustituido; o una de sus sales.The disclosure refers to aryl hydrocarbon receptor antagonists, such as imidazopyridines and substituted imidazopyrazines, as well as methods of expanding hematopoietic stem cells by culturing hematopoietic stem cells or progenitors in the presence of these agents. Additionally, the disclosure provides methods of treating various pathologies in a patient by administration of expanded hematopoietic stem cells. The disclosure also provides methods of synthesizing aryl hydrocarbon receptor antagonists, such as imidazopyridines and substituted imidazopyrazines, as well as kits containing aryl hydrocarbon receptor antagonists that can be used for hematopoietic stem cell expansion. Claim 1: A compound represented by the formula (1), wherein L is selected from the group consisting of -NR⁷ᵃ (CR⁸ᵃR⁸ᵇ) ₙ-, -O (CR⁸ᵃR⁸ᵇ) ₙ-, -C (O) (CR⁸ᵃR⁸ᵇ) ₙ-, -C (S) (CR⁸ᵃR⁸ᵇ) ₙ-, -S (O) ₀₋₂ (CR⁸ᵃR⁸ᵇ) ₙ-, - (CR⁸ᵃR⁸ᵇ) ₙ-, -NR⁷ᵃC (O) (CR⁸ᵃR⁸ᵇ) ₙ-, -NR⁷ᵃC (S) (CR⁸ᵃR⁸ᵇ ) ₙ-, -OC (O) (CR⁸ᵃR⁸ᵇ) ₙ-, -OC (S) (CR⁸ᵃR⁸ᵇ) ₙ-, -C (O) NR⁷ᵃ (CR⁸ᵃR⁸ᵇ) ₙ-, -C (S) NR⁷ᵃ (CR⁸ᵃR⁸ᵇ) ₙ-, -C (O) O (CR⁸ᵃR⁸ᵇ) ₙ-, -C (S) O (CR⁸ᵃR⁸ᵇ) ₙ-, -S (O) ₂NR⁷ᵃ (CR⁸ᵃR⁸ᵇ) ₙ-, -NR⁷ᵃS (O) ₂ (CR⁸ᵃR⁸ᵇ) ₙ-, -NR⁷ᵃC (O) NR⁷ᵇ (CR⁸ᵃR⁸ᵇ) ₙ- and -NR⁷ᵃC (O) O (CR⁸ᵃR⁸ᵇ) ₙ-, where R⁷ᵃ, R⁷ᵇ, R⁸ᵃ and R⁸ᵇ are each independently selected from the group consisting of hydrogen and C₁₋ alkyl ₄ optionally substituted and each n is, independently, an integer from 2 to 6; R¹ is selected from the group consisting of -S (O) ₂NR⁹ᵃR⁹ᵇ, -NR⁹ᵃC (O) R⁹ᵇ, -NR⁹ᵃC (S) R⁹ᵇ, -NR⁹ᵃC (O) NR⁹ᵇR⁹ᶜ, -C (O) R⁹ᵃ, -C (S) R⁹ᵃ, -S (O) ₀₋₂R⁹ᵃ, -C (O) OR⁹ᵃ, -C (S) OR⁹ᵃ, -C (O) NR⁹ᵃR⁹ᵇ, -C (S) NR⁹ᵃR⁹ᵇ, -NR⁹ᵃS (O) ₂R⁹ᵇ, -NR⁹ᵃC (O) OR⁹ᵇ , -OC (O) CR⁹ᵃR⁹ᵇR⁹ᶜ, -OC (S) CR⁹ᵃR⁹ᵇR⁹ᶜ, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, wherein R⁹ᵃ, R⁹ᵇ and R⁹ᶜ are each independently selected from the group that it consists of hydrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl; R² is selected from the group consisting of hydrogen and optionally substituted C₁₋₄ alkyl; R³ is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl; R⁴ is selected from the group consisting of hydrogen and optionally substituted C₁₋₄ alkyl; R⁵ is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl; and R⁶ is selected from the group consisting of hydrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl; or one of its salts. Claim 37: A compound represented by the formula (2), wherein L is selected from the group consisting of -NR⁷ᵃ (CR⁸ᵃR⁸ᵇ) ₙ-, -O (CR⁸ᵃR⁸ᵇ) ₙ-, -C (O) (CR⁸ᵃR⁸ᵇ) ₙ-, -C (S) (CR⁸ᵃR⁸ᵇ) ₙ-, -S (O) ₀₋₂ (CR⁸ᵃR⁸ᵇ) ₙ-, - (CR⁸ᵃR⁸ᵇ) ₙ-, -NR⁷ᵃC (O) (CR⁸ᵃR⁸ᵇ) ₙ-, -NR⁷ᵃC (S) (CR⁸ᵃR⁸ᵇ ) ₙ-, -OC (O) (CR⁸ᵃR⁸ᵇ) ₙ-, -OC (S) (CR⁸ᵃR⁸ᵇ) ₙ-, -C (O) NR⁷ᵃ (CR⁸ᵃR⁸ᵇ) ₙ-, -C (S) NR⁷ᵃ (CR⁸ᵃR⁸ᵇ) ₙ-, -C (O) O (CR⁸ᵃR⁸ᵇ) ₙ-, -C (S) O (CR⁸ᵃR⁸ᵇ) ₙ-, -S (O) ₂NR⁷ᵃ (CR⁸ᵃR⁸ᵇ) ₙ-, -NR⁷ᵃS (O) ₂ (CR⁸ᵃR⁸ᵇ) ₙ-, -NR⁷ᵃC (O) NR⁷ᵇ (CR⁸ᵃR⁸ᵇ) ₙ- and -NR⁷ᵃC (O) O (CR⁸ᵃR⁸ᵇ) ₙ-, where R⁷ᵃ, R⁷ᵇ, R⁸ᵃ and R⁸ᵇ are each independently selected from the group consisting of hydrogen and C₁₋ alkyl ₄ optionally substituted and each n is, independently, an integer from 2 to 6; R¹ is selected from the group consisting of -S (O) ₂NR⁹ᵃR⁹ᵇ, -NR⁹ᵃC (O) R⁹ᵇ, -NR⁹ᵃC (S) R⁹ᵇ-, -NR⁹ᵃC (O) NR⁹ᵇR⁹ᶜ, -C (O) R⁹ᵃ, -C (S) R⁹ᵃ , -S (O) ₀₋₂R⁹ᵃ, -C (O) OR⁹ᵃ, -C (S) OR⁹ᵃ, -C (O) NR⁹ᵃR⁹ᵇ, -C (S) NR⁹ᵃR⁹ᵇ, -NR⁹ᵃS (O) ₂R⁹ᵇ, -NR⁹ᵃC (O) OR⁹ᵇ, -OC (O) CR⁹ᵃR⁹ᵇR⁹ᶜ, -OC (S) CR⁹ᵃR⁹ᵇR⁹ᶜ, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, wherein R⁹ᵃ, R⁹ᵇ and R⁹ᶜ are each independently selected from the group consisting of hydrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl; R³ is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl; R⁴ is selected from the group consisting of hydrogen and optionally substituted C₁₋₄ alkyl; R⁵ is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl; and R⁶ is selected from the group consisting of hydrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl; or one of its salts.

ARP180100921A 2017-04-12 2018-04-12 ANTAGONISTS OF THE ARILO HYDROCARBON RECEIVER AND ITS USES AR111375A1 (en)

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US201762484692P 2017-04-12 2017-04-12

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AR111375A1 true AR111375A1 (en) 2019-07-03

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