DK2718290T3 - Sammensætninger og fremgangsmåde til modulering af en kinase - Google Patents

Sammensætninger og fremgangsmåde til modulering af en kinase Download PDF

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DK2718290T3
DK2718290T3 DK12780531.5T DK12780531T DK2718290T3 DK 2718290 T3 DK2718290 T3 DK 2718290T3 DK 12780531 T DK12780531 T DK 12780531T DK 2718290 T3 DK2718290 T3 DK 2718290T3
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compound
branched
linear
cancer
unsubstituted
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DK12780531.5T
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Oren M Becker
Itai Bloch
Efrat Ben-Zeev
Alina Shitrit
Avihai Yacovan
Sharon Gazal
Vered Behar
Alexander Konson
Nili Schutz
Sima Mirilashvili
Gali Golan
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Clevexel Pharma
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Claims (16)

1. Forbindelse med formlen I:
:o eller et farmaceutisk acceptabelt salt, solvat eller polymorf deraf, hvori: R1 er valgt fra gruppen bestående af en lineær eller forgrenet C^Ce alkyl, en lineær eller forgrenet C2-C6 alkenyl, en lineær eller forgrenet C2-C6 alkynyl, eller heteroalkyl, en C3-C8 cycloalkyl, en C3-C8 cycloalkenyl, en heterocycloalkyl, en amin, en aryl og en heteroaryl, hvori nævnte alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, amin eller heteroaryl er usubstitueret eller substitueret med en eller flere Ra, hvori Ra uafhængigt ved hver forekomst er valgt fra gruppen bestående af: a) en lineær eller forgrenet C^-Ce alkyl, b) en lineær eller forgrenet C2-C6 alkenyl, c) en lineær eller forgrenet C2-C6 alkynyl, d) en lineær eller forgrenet, mættet eller umættet C^Ce haloalkyl, e) en lineær eller forgrenet, mættet eller umættet C^Ce alkoxy eller aryloxy, f) en lineær eller forgrenet, mættet eller umættet C^Ce haloalkoxy, g) en lineær eller forgrenet, mættet eller umættet C^Ce alkylsulfonyl, h) en en lineær eller forgrenet, mættet eller umættet C^Ce thioalkyl eller thioaryl, hvori nævnte alkyl, alkenyl, alkynyl, og aryl i a)-h) er usubstitueret eller substitueret uafhængigt ved hver forekomst med en eller flere Rb, i) en C3-C8 cycloalkyl, hvori nævnte cycloalkyl er usubstitueret eller substitueret uafhængigt ved hver forekomst med en eller flere Rb, j) en C3-C8 cycloalkenyl, hvori nævnte cycloalkenyl er usubstitueret eller substitueret uafhængigt ved hver forekomst med en eller flere Rb, k) en aryl, hvori nævnte aryl er usubstitueret eller substitueret uafhængigt ved hver forekomst med en eller flere Rb, l) en heteroaryl, hvori nævnte heteroaryl er usubstitueret eller substitueret uafhængigt ved hver forekomst med en eller flere Rb, m) en heterocycloalkyl, hvori nævnte heterocycloalkyl er usubstitueret eller substitueret uafhængigt ved hver forekomst med en eller flere Rb, n) hydroxyl,; o) cyano, p) amino, q) nitro, r) halogen, s) CORb, t) COORb, u) CONRbR°, v) NHCORb, og w) NRbR° eller to Ra sammen med de atomer, til hvilke de er bundet, danner en fem- eller seks-elementers heterocycloalkyl, en aryl, eller heteroaromatisk ring; hvori hver Rb og Rc uafhængigt er brint eller en gruppe valgt blandt halogen, C(0)CH3, CF3, en lineær eller forgrenet C^Ce alkyl, en lineær eller forgrenet C2-C6 alkenyl, en lineær eller forgrenet C2-C6 alkynyl, en C3-C8 cycloalkyl, en C3-C8 cycloalkenyl, en heterocycloalkyl, en aryl og en heteroaryl; hvori nævnte alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl eller heteroaryl er usubstitueret eller substitueret med en eller flere Rd, hvori Rd er usubstitueret eller substitueret uafhængigt ved hver forekomst valgt fra gruppen bestående af en lineær eller forgrenet Ci-C6 alkyl, en lineær eller forgrenet C2-C6 akenyl, en lineær eller forgrenet C2-C6 alkynyl, en C3-C8 cycloalkyl, en C3-C8 cycloalkenyl, heterocycloalkyl, en aryl, en dialkylamin, en monoalkylamin, og en heteroaryl; eller to Rb sammen med de atomer, til hvilke de er bundet, danner en fem- eller seks-elementers heterocycloalkyl ring; hvor R2 og R3 enten (i) uafhængigt hver er valgt fra gruppen bestående af brint, en lineær eller forgrenet C^Ce alkyl, en lineær eller forgrenet C2-C6 alkenyl, en lineær eller forgrenet C2-C6 alkynyl, en C3-C8 cycloalkyl, en C3-C8 cycloalkenyl, og en heterocycloalkyl, eller (ii) sammen med det kvælstofatom, til hvilket de er bundet, danner en fem-, seks- eller syvelementers heterocykloalkyl eller heteroaromatisk ring, hvori ringen er usubstitueret; og hvori aryl betyder fenyl og naftyl, heterocycloalkyl betyder enhver stabil monocyklisk, bicyklisk eller tricyklisk ring, som er mættet og omfatter kulstofatomer og et eller flere ringheteroatomer uafhængigt valgt fra gruppen bestående af kvælstof, ilt og svovl, og heteroaryl betyder en stabil 5-, 6-, eller 7-elementers monocyklisk eller bicyklisk aromatisk heterocyklisk ring, eller bicyklisk aromatisk heterocyklisk ring, der består af kulstofatomer og et eller flere heteroatomer uafhængigt valgt fra gruppen bestående af kvælstof, ilt og svovl; til anvendelse som et farmaceutisk middel.
2. Forbindelse til anvendelse som farmaceutisk middel ifølge krav 1 med formlen II:
(Π) eller et farmaceutisk acceptabelt salt, solvat eller polymorf deraf, hvori Ra1, Ra2, Ra3, Ra4 og Ra5 hver er uafhængigt udvalgt fra gruppen bestående af: a) en lineær eller forgrenet C^Ce alkyl, b) en lineær eller forgrenet C2-C6 alkenyl, c) en lineær eller forgrenet C2-C6 alkynyl, d) en lineær eller forgrenet, mættet eller umættet C^Ce haloalkyl, e) en lineær eller forgrenet, mættet eller umættet C^Ce alkoxy eller aryloxy, f) en lineær eller forgrenet, mættet eller umættet C^Ce haloalkoxy, g) en lineær eller forgrenet, mættet eller umættet C^Ce alkylsulfonyl, h) en en lineær eller forgrenet, mættet eller umættet C^Ce thioalkyl eller thioaryl, hvori nævnte alkyl, alkenyl, alkynyl, og aryl i a)-h) er usubstitueret eller substitueret uafhængigt ved hver forekomst med en eller flere Rb, i) en C3-C8 cycloalkyl, hvori nævnte cycloalkyl er usubstitueret eller substitueret uafhængigt ved hver forekomst med en eller flere Rb, j) en C3-C8 cycloalkyl, hvori nævnte cycloalkyl er usubstitueret eller substitueret uafhængigt ved hver forekomst med en eller flere Rb, k) en aryl, hvori nævnte aryl er usubstitueret eller substitueret uafhængigt ved hver forekomst med en eller flere Rb, l) en heteroaryl, hvori nævnte heteroaryl er usubstitueret eller substitueret uafhængigt ved hver forekomst med en eller flere Rb, m) en heterocycloalkyl, hvori nævnte heterocycloalkyl er usubstitueret eller substitueret uafhængigt ved hver forekomst med en eller flere Rb, n) hydroxyl,; o) cyano, p) amino, q) nitro, r) halogen, s) CORb, t) COORb, u) CONRbR°, v) NHCORb, w) NRbR°, og x) brint, eller to Ra1, Ra2, Ra3, Ra4 and Ra5 sammen med de atomer, til hvilke de er bundet, danner en fem- eller seks-elementers heterocycloalkyl, en aryl, eller heteroaromatisk ring; hvori hver Rb og R° uafhængigt er brint eller en gruppe valgt blandt halogen, C(0)CH3, CF3i en lineær eller forgrenet C^Ce alkyl, en lineær eller forgrenet C2-C6 alkenyl, en lineær eller forgrenet C2-C6 alkynyl, en C3-C8 cycloalkyl, en C3-C8 cycloalkenyl, en heterocycloalkyl, en aryl og en heteroaryl; hvori nævnte alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl eller heteroaryl er usubstitueret eller substitueret med en eller flere Rd, hvori Rd er uafhængigt ved hver forekomst valgt fra gruppen bestående af en lineær eller forgrenet Ci-C6 alkyl, en lineær eller forgrenet C2-C6 akenyl, en lineær eller forgrenet C2-C6 alkynyl, en C3-C8 cycloalkyl, en C3-C8 cycloalkenyl, heterocycloalkyl, en aryl, en dialkylamin, en monoalkylamin, og en heteroaryl; to Rb sammen med de atomer, til hvilke de er bundet, danner en fem- eller seks-elementers heterocycloalkyl ring.
3. Forbindelse til anvendelse som farmaceutisk middel ifølge krav 1 eller 2, hvori R2 og R3 er hver uafhængigt valgt blandt en lineær eller forgrenet CrC6 alkyl, brint og C3-C8 C3-C8 cycloalkyl, eller R2 og R3 sammen med kvælstofatomet, til hvilket de er bundet, danner en fem-, seks-, eller syvelementers heterocycloalkyl.
4. Forbindelse til anvendelse som farmaceutisk middel ifølge krav 3, hvori R2 og R3 sammen med nitrogenatomet, til hvilket de er bundet, danner en pyrrolidin-eller piperidinring.
5. Forbindelse til anvendelse som farmaceutisk middel ifølge krav 4, hvori R2 og R3 sammen med nitrogenatomet, til hvilket de er bundet, danner en pyrrolidinring.
6. Forbindelse til anvendelse som farmaceutisk middel ifølge ethvert af krav 2 til 6, hvori Ra1’ Ra2, Ra3, Ra4 og Ra5 er hver uafhængigt valgt blandt brint, NHCORb, CrCe alkoxy, halogen, hydroxyl, Ο,-Οβ alkyl, CF3 og NRbRc.
7. Forbindelse til anvendelse som farmaceutisk middel ifølge krav 6, hvori et af Ra1 Ra2, Ra3, Ra4 og Ra5 er NHCORb, og de resterende Ra1’ Ra2, Ra3, Ra4 og Ra5 er brint.
8. Forbindelse til anvendelse som farmaceutisk middel ifølge krav 7, hvori Ra4 ikke er brint.
9. Forbindelse til anvendelse som farmaceutisk middel ifølge krav 8, hvori Ra4 er valgt blandt brint, NHCORb, methoxy, metyl, og klorin.
10. Forbindelse til anvendelse som farmaceutisk middel ifølge ethvert af krav 1 til 9, hvori Rb er valgt blandt en lineær eller forgrenet C^Ce alkyl, unsubstitueret C3-C8 cycloalkyl, unsubstitueret aryl og unsubstitueret heterocycloalkyl, hvori nævnte (VC6 alkyl er unsubstitueret eller substitueret med et eller flere Rd.
11. Forbindelse til anvendelse som farmaceutisk middel ifølge krav 10, hvori Rb er -CH2Rd.
12. Forbindelse til anvendelse som farmaceutisk middel ifølge krav 11, hvori Rd er morfolin.
13. Forbindelse til anvendelse som farmaceutisk middel ifølge krav 1, som er 2- morfolin-N-(3-(4-(5-(pyrrolidin-1 -karbonyl)-1 H-pyrrol-3-y l)thiazol-2-yl)fenyl)acetamid med formlen:
14. Forbindelse til anvendelse som farmaceutisk middel ifølge krav 1, som er N- (3-(4-(5-(pyrrolidin-1 - karbon y I)-1 H-pyrrol-3-yl)thiazol-2-yl)fenyl)acetamid med fnrm Ιρπ
15. Forbindelse ifølge ethvert af krav 1 til 14 til anvendelse som tyrosinkinaseadgangsvejhæmmer til forebyggelse eller behandling af en kræftform og/eller en celleproliferativ lidelse.
16. Forbindelse ifølge krav 15 til anvendelse ved forebyggelse eller behandling af leukæmi, såsom myelofibrosis eller akut myeloid leukæmi (AML), lymfom, polycythaemia vera (erythremia), thrombocytæmi, lungekræft, tyktarmskræft, bugspytkirtelkræft, prostatakræft, hudkræft, æggestokkræft, brystkræft, autoimmune sygdomme såsom transplantafstødning, rheumatoid arthritis, psoriatisk arthritis, amyotrofisk lateral sklerose, psoriasis, ulcerativ colitis, Crohns sygdom, ankylosisk spondylitis og tørre-øjne-sygdom.
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