Bicyclic heterocycle compounds and their uses in therapy

Patent metadata

Field	Value
Publication number	US-11225476-B2
Application number	US-202016795117-A
Country	US
Kind code	B2
Filing date	Feb 19, 2020
Priority date	Dec 20, 2013
Publication date	Jan 18, 2022
Grant date	Jan 18, 2022

Abstract

The invention relates to new bicyclic heterocycle compounds, to pharmaceutical compositions comprising the compounds and to the use of the compounds in the treatment of diseases, e.g. cancer.

First claim

The invention claimed is:

1. A compound of formula (IV):

wherein
X is CR 4 , N or NR 3 ;
wherein
when X is CR 4 , then U represents nitrogen and R 5 represents oxo; or
when X is N, then U represents carbon and R 6 represents hydroxymethyl or —CH(OR x )CH 2 OR z , or
when X is NR 3 , then U represents carbon and R 6 represents oxo;

dashed bond ( ) represents a single or double bond wherein at least two of said dashed bonds represent a double bond;
R 3 represents hydrogen, methyl or —NH 2 ,
R 4 represents hydrogen, methyl, hydroxymethyl, —NH 2 or fluorine;
R 5 represents unsubstituted n-butyl or benzyl substituted on the phenyl group by one or two fluorines;
R x and R z independently represent hydrogen or methyl; and
L 2 represents a suitable leaving group.

2. The compound of formula (IV) according to claim 1 , wherein L 2 is a chlorine atom.

3. A compound of formula (IV) a :

wherein
R 5 represents unsubstituted n-butyl or benzyl substituted on the phenyl group by one or two fluorines; and
L 2 represents a suitable leaving group.

4. A process for the preparation of a compound of formula (IV) a as recited in claim 3 , the process comprising reacting a compound of formula (XV):

with a haloacetyl halide in MeCN followed by addition of potassium carbonate in methanol.

5. A process according to claim 4 wherein the haloacetyl halide is chloroacetyl chloride.

6. A process for the preparation of a compound of formula (IV) a as recited in claim 3 , the process comprising:
reacting a compound of formula (VIII):

wherein L 3 , L 4 , and L 5 each individually represent fluorine, bromine or chlorine, with a base in the presence of tetrahydrofuran and isobutronitrile in a suitable solvent; and/or
reacting a compound of formula (IX):

wherein L 4 and L 5 each individually represent fluorine, bromine or chlorine, with
(I) a borane-tetrahydrofuran complex in the presence of a suitable solvent; or
(II) nickel(II) chloride hexahydrate followed by addition of sodium borohydride; and/or

performing cyclization of a compound of formula (X):

wherein L 4 and L 5 each individually represent fluorine, bromine or chlorine, using a suitable base and an appropriate solvent; and/or
reacting a compound of formula (XI):

wherein L 5 represents fluorine, bromine or chlorine, with a compound of formula R 5 -M, wherein M represents the residue of an organometallic species such that R 5 -M represents a nucleophilic organometallic reagent, said reacting comprising using lithium bromide, a catalyst, and a suitable solvent system; and/or
performing halogenation of a compound of formula (XII):

thereby forming a compound of formula (XIII):

wherein L 6 represents fluorine, bromine or chlorine; and/or
replacing L 6 in a compound of formula (XIII),

wherein L 6 represents fluorine, bromine or chlorine; with a formyl group by performing lithiation and reaction of the compound of formula (XIII) with a suitable electrophile; and/or
reducing the formyl group of compound (XIV):

with a suitable reducing agent; and/or
reacting a compound of formula (XV):

with a haloacetyl halide.

7. The process according to claim 6 , wherein L 3 and L 4 are both fluorine.

8. The process according to claim 6 , wherein L 5 is chlorine and/or L 6 is bromine.

9. The process according to claim 6 , comprising:
reacting a compound of formula (VIII):

wherein L 3 , L 4 , and L 5 each individually represent fluorine, bromine or chlorine, with sodium bis(trimethylsilyl)amide in the presence of tetrahydrofuran and isobutronitrile in toluene; and/or
reacting a compound of formula (IX):

wherein L 4 and L 5 each individually represent fluorine, bromine or chlorine, with
(III) a borane-tetrahydrofuran complex in the presence of tetrahydrofuran; or
(IV) nickel(II) chloride hexahydrate followed by addition of sodium borohydride; and/or

performing cyclization of a compound of formula (X):

wherein L 4 and L 5 each individually represent fluorine, bromine or chlorine, using potassium carbonate and NMP; and/or
reacting a compound of formula (XI):

wherein L 5 represents fluorine, bromine or chlorine, with a compound of formula R 5 -M, wherein M represents the residue of an organometallic species such that R 5 -M represents a nucleophilic organometallic reagent that is an organozinc halide, said reacting comprising using lithium bromide, [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride as a catalyst, and a suitable solvent system comprising tetrahydrofuran and NMP; and/or
performing halogenation of a compound of formula (XII):

using N-bromosuccinimide in dimethylformamide, thereby forming a compound of formula (XIII):

wherein L 6 represents bromine; and/or
replacing L 6 in a compound of formula (XIII),

wherein L 6 represents fluorine, bromine or chlorine; with a formyl group by reacting the compound (XIII) with MeLi in THF followed by addition of tBuLi in hexane followed by addition of dimethylformamide; and/or
reducing the formyl group of compound (XIV):

by reacting the compound of formula (XIV) with sodium borohydride in methanol; and/or
reacting a compound of formula (XV):

with chloroacet

Assignees

• Astex Therapeutics Ltd

Inventors

• Chessari Gianni
• Johnson Christopher Norbert
• Howard Steven
• Day James Edward Harvey
• Buck Ildiko Maria
• Griffiths-Jones Charlotte Mary
• Saxty Gordon
• Tamanini Emiliano
• Wilsher Nicola Elizabeth

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• A61P31/22

  for herpes viruses · CPC title