AR098145A1 - COMPOUNDS DERIVED FROM BICYCLIC PIRIDYL FUSED AS INHIBITORS OF FGFR4 - Google Patents

COMPOUNDS DERIVED FROM BICYCLIC PIRIDYL FUSED AS INHIBITORS OF FGFR4

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Publication number
AR098145A1
AR098145A1 ARP140103960A ARP140103960A AR098145A1 AR 098145 A1 AR098145 A1 AR 098145A1 AR P140103960 A ARP140103960 A AR P140103960A AR P140103960 A ARP140103960 A AR P140103960A AR 098145 A1 AR098145 A1 AR 098145A1
Authority
AR
Argentina
Prior art keywords
alkyl
ring
substituted
alkoxy
saturated
Prior art date
Application number
ARP140103960A
Other languages
Spanish (es)
Inventor
Buschmann Nicole
Alec Fairhurst Robin
Furet Pascal
Knpfel Thomas
Leblanc Catherine
Liao Lv
Mah Robert
Nimsgern Pierre
Ripoche Sebastien
Xiong Jing
Original Assignee
Novartis Ag
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 Novartis Ag filed Critical Novartis Ag
Publication of AR098145A1 publication Critical patent/AR098145A1/en

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Abstract

Un método para fabricar los compuestos, y sus usos terapéuticos. Además proporciona una combinación de agentes farmacológicamente activos y una composición farmacéutica. Útiles en el tratamiento de cáncer, en particular cáncer hepático. Reivindicación 1: Un compuesto de la fórmula (1), o una sal farmacéuticamente aceptable del mismo, en donde V se selecciona a partir de CH₂, O, CH(OH); W se selecciona a partir de CH₂, CH₂CH₂; X es C(RX) o N; Y es C(RY) o N; Z es CH o N; en donde cuando X es N, Y y Z no son N; en donde cuando Y es N, X y Z no son N; en donde cuando Z es N, X e Y no son N; RX se selecciona a partir de hidrógeno, halógeno, haloalquilo C₁₋₃, ciano, alquilo C₁₋₆, hidroxialquilo C₁₋₆; RY se selecciona a partir de hidrógeno, halógeno, alquilo C₁₋₆, alcoxilo C₁₋₆, hidroxialcoxilo C₁₋₃, NRY¹RY², ciano, alcoxilo C₁₋₃alcoxilo C₁₋₃, alcoxilo C₁₋₃-haloalcoxilo C₁₋₃, di(alquilo C₁₋₃)amino-alcoxilo C₁₋₆, O-(CH₂)₀₋₁-RY³, CRY⁶RY⁷, haloalcoxilo C₁₋₃ opcionalmente sustituido por hidroxilo; o RX y RY junto con el anillo al cual están fijados forman un sistema de anillo aromático bicíclico que comprende además opcionalmente uno o dos heteroátomos seleccionados a partir de N, O, o S, tal sistema de anillo es opcionalmente sustituido por alquilo C₁₋₃; RY¹ es hidrógeno y RY² es alquilo C₁₋₆, hidroxialquilo C₁₋₆, haloalquilo C₁₋₆ opcionalmente sustituido por hidroxilo, alcoxilo C₁₋₃alquilo C₁₋₆, (CH₂)₀₋₁-RY⁴, di(alquilo C₁₋₃)aminoalquilo C₁₋₆ sustituido por hidroxilo, biciclo[2.2.1]heptanilo sustituido por hidroxialquilo C₁₋₃, fenilo sustituido por S(O)₂-CH(CH₃)₂; o RY¹ y RY² junto con el átomo N al cual están fijados forman un anillo heterocíclico de 6 miembros no aromático saturado o no saturado que puede contener un átomo O, tal anillo puede ser sustituido una o dos veces por RY⁵; RY³ se selecciona a partir de quinuclidinilo, un anillo heterocíclico de 4-, 5- ó 6- miembros saturado que comprende al menos un heteroátomo seleccionado a partir de N, O ó S, tal anillo es opcionalmente sustituido por alquilo C₁₋₃; RY⁴ es un anillo heterocíclico de 4-, 5- ó 6- miembros saturado que comprende al menos un heteroátomo seleccionado a partir de N, O, o S, tal anillo es opcionalmente sustituido por alquilo C₁₋₃; RY⁵ es independientemente seleccionado a partir de alquilo C₁₋₃, hidroxilo, di(alquilo C₁₋₃)aminoalquilo C₁₋₃, o dos RY⁵ fijadas al mismo átomo de carbono forman junto con el átomo de carbono al cual están fijadas un anillo heterocíclico de 5- miembros saturado que comprende al menos un heteroátomo seleccionado a partir de N, O ó S, tal anillo es sustituido por alquilo C₁₋₃; RY⁶ y RY⁷ junto con el átomo de carbono al cual están fijados forman un anillo heterocíclico no aromático de 6- miembros saturado o no saturado que comprende un heteroátomo seleccionado a partir de N, O ó S; R¹ se selecciona a partir de hidrógeno, halógeno, alquilo C₁₋₃, haloalquilo C₁₋₃, hidroxialquilo C₁₋₃, cicloalquilo C₃₋₆, CH₂NR²R³, CH(CH₃)NR²R³, alcoxilo C₁₋₃alquilo C₁₋₃, CH₂CO₂H, C(O)H; R² se selecciona a partir de alquilo C₁₋₃, di(alquilo C₁₋₃)aminoalquilo C₁₋₃; R³ se selecciona a partir de alquilo C₁₋₃, C₍O₎ₐₗqᵘⁱₗₒ C₁₋₃, C₍O₎₋CH₂-OH, C(O)-CH₂-O-CH₃, C(O)-CH₂-N(CH₃)₂, S(O)₂CH₃; o R² y R³ junto con el átomo N al cual están fijados forman un anillo saturado de 5- ó 6- miembros que comprende opcionalmente un heteroátomo adicional seleccionado a partir de N, O ó S, tal anillo puede ser sustituido una o más de una vez por R⁴; R⁴ es independientemente seleccionado a partir de alquilo C₁₋₃, di(alquilo C₁₋₃)amino, C(O)CH₃, hidroxilo; o dos R⁴ fijados al mismo átomo de carbono forman junto con el átomo de carbono al cual están fijados un anillo heterocíclico no aromático de de 4-, 5- ó 6- miembros que comprende al menos un heteroátomo seleccionado a partir de N, O ó S; o dos R⁴ fijadas al mismo átomo de carbono forman un grupo oxo; R⁵ se selecciona a partir de hidrógeno o alquilo C₁₋₃. Reivindicación 15: Un compuesto de la fórmula (2), o una sal farmacéuticamente aceptable del mismo, en donde V se selecciona a partir de CH₂, O, CH(OH); W se selecciona a partir de CH₂, CH₂CH₂; R¹ se selecciona a partir de halógeno, alquilo C₁₋₃, haloalquilo C₁₋₃, hidroxialquilo C₁₋₃, cicloalquilo C₃₋₆, CH₂NR²R³, CH(CH₃)NR²R³, alcoxi C₁₋₃alquilo C₁₋₃, CH₂CO₂H, C(O)H; R⁵ se selecciona a partir de hidrógeno o alquilo C₁₋₃.A method to manufacture the compounds, and their therapeutic uses. It also provides a combination of pharmacologically active agents and a pharmaceutical composition. Useful in the treatment of cancer, in particular liver cancer. Claim 1: A compound of the formula (1), or a pharmaceutically acceptable salt thereof, wherein V is selected from CH₂, O, CH (OH); W is selected from CH₂, CH₂CH₂; X is C (RX) or N; Y is C (RY) or N; Z is CH or N; where when X is N, Y and Z are not N; where when Y is N, X and Z are not N; where when Z is N, X and Y are not N; RX is selected from hydrogen, halogen, C₁₋₃ haloalkyl, cyano, C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl; RY is selected from hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₃ hydroxyalkoxy, NRY¹RY², cyano, C₁₋₃alkoxy C alco alkoxy, C₁₋₃-haloalkoxy C₁₋₃ alkoxy, di (alkyl C₁₋₃) C-amino-alkoxy, O- (CH₂) ₀₋₁-RY³, CRY⁶RY⁷, C₁₋₃ haloalkoxy optionally substituted by hydroxyl; or RX and RY together with the ring to which they are attached form a bicyclic aromatic ring system that optionally further comprises one or two heteroatoms selected from N, O, or S, such a ring system is optionally substituted by C₁₋₃ alkyl ; RY¹ is hydrogen and RY² is C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ haloalkyl optionally substituted by hydroxyl, C₁₋₃ alkoxy C₁₋₆, (CH₂) ₀₋₁-RY⁴, di (C₁₋₃ alkyl) aminoalkyl C₁₋₆ substituted by hydroxyl, bicyclo [2.2.1] heptanyl substituted by hydroxyalkyl C₁₋₃, phenyl substituted by S (O) ₂-CH (CH₃) ₂; or RY¹ and RY² together with the N atom to which they are attached form a saturated or unsaturated non-aromatic 6-membered heterocyclic ring that may contain an O atom, such a ring may be substituted once or twice by RY⁵; RY³ is selected from quinuclidinyl, a saturated 4-, 5- or 6- membered heterocyclic ring comprising at least one heteroatom selected from N, O or S, such ring is optionally substituted by C₁₋₃ alkyl; RY⁴ is a saturated 4-, 5- or 6- membered heterocyclic ring comprising at least one heteroatom selected from N, O, or S, such ring is optionally substituted by C₁₋₃ alkyl; RY⁵ is independently selected from C₁₋₃ alkyl, hydroxyl, di (C₁₋₃ alkyl) C₁₋₃ aminoalkyl, or two RY⁵ attached to the same carbon atom together with the carbon atom to which a heterocyclic ring of 5- saturated members comprising at least one heteroatom selected from N, O or S, such a ring is substituted by C₁₋₃ alkyl; RY⁶ and RY⁷ together with the carbon atom to which they are attached form a saturated or unsaturated 6- aromatic non-aromatic heterocyclic ring comprising a heteroatom selected from N, O or S; R¹ is selected from hydrogen, halogen, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ hydroxyalkyl, C₃₋₆ cycloalkyl, CH₂NR²R³, CH (CH₃) NR²R³, C₁₋₃alkyl Cx alkyl, CH₂CO₂H, C ( O) H; R² is selected from C₁₋₃ alkyl, di (C₁₋₃ alkyl) C₁₋₃ aminoalkyl; R³ is selected from alkyl C₁₋₃, C₍O₎ₐₗqᵘⁱₗₒ C₁₋₃, C₍O₎₋CH₂-OH, C (O) -CH₂-O-CH₃, C (O) -CH₂-N (CH₃ ) ₂, S (O) ₂CH₃; or R² and R³ together with the N atom to which they are attached form a saturated 5- or 6- membered ring optionally comprising an additional heteroatom selected from N, O or S, such ring can be substituted one or more than one once for R⁴; R⁴ is independently selected from C₁₋₃ alkyl, di (C₁₋₃ alkyl) amino, C (O) CH₃, hydroxyl; or two R⁴ attached to the same carbon atom together with the carbon atom to which a non-aromatic 4-, 5- or 6--membered heterocyclic ring comprising at least one heteroatom selected from N, O or S; or two R⁴ attached to the same carbon atom form an oxo group; R⁵ is selected from hydrogen or C₁₋₃ alkyl. Claim 15: A compound of the formula (2), or a pharmaceutically acceptable salt thereof, wherein V is selected from CH₂, O, CH (OH); W is selected from CH₂, CH₂CH₂; R¹ is selected from halogen, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ hydroxyalkyl, C₃₋₆ cycloalkyl, CH₂NR²R³, CH (CH₃) NR²R³, C₁₋₃alkyl alkoxy, CH₂CO₂H, C (O) H; R⁵ is selected from hydrogen or C₁₋₃ alkyl.

ARP140103960A 2013-10-25 2014-10-22 COMPOUNDS DERIVED FROM BICYCLIC PIRIDYL FUSED AS INHIBITORS OF FGFR4 AR098145A1 (en)

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CN2013086003 2013-10-25

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AR098145A1 true AR098145A1 (en) 2016-05-04

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AR (1) AR098145A1 (en)
MA (1) MA39054B1 (en)
TW (2) TWI673268B (en)
UY (1) UY35792A (en)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0906472D0 (en) * 2009-04-15 2009-05-20 Astex Therapeutics Ltd New compounds
GB201118656D0 (en) * 2011-10-28 2011-12-07 Astex Therapeutics Ltd New compounds

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MA39054A1 (en) 2018-02-28
TWI690528B (en) 2020-04-11
TW201605853A (en) 2016-02-16
MA39054B1 (en) 2018-09-28
TW201938560A (en) 2019-10-01
TWI673268B (en) 2019-10-01
UY35792A (en) 2015-05-29

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