Bicyclic heterocycle compounds and their uses in therapy

Patent metadata

Field	Value
Publication number	US-10618895-B2
Application number	US-201715675052-A
Country	US
Kind code	B2
Filing date	Aug 11, 2017
Priority date	Dec 20, 2013
Publication date	Apr 14, 2020
Grant date	Apr 14, 2020

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 process for preparing a compound of formula (I):

or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof;
wherein
X is CR 4 , N or NR 3 ;
wherein
when X is CR 4 , then U represents nitrogen and R 6 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 1 and R 2 independently represent hydrogen or methyl;
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; and
R x and R z independently represent hydrogen or methyl,

said process comprising:
(a) (i) reacting a compound of formula (II):

wherein L 1 represents a suitable leaving group, and P 1 represents hydrogen or a suitable protecting group, with a compound of formula (III):

or an optionally protected derivative thereof, followed by a deprotection reaction suitable to remove the P 1 protecting group and any other protecting groups as necessary; or
(ii) reacting a compound of formula (IV):

wherein L 2 represents a suitable leaving group, with a compound of formula (V):

or an optionally protected derivative thereof, wherein P 2 represents hydrogen or a suitable protecting group, followed by a deprotection reaction suitable to remove the P 2 protecting group and any other protecting groups as necessary; and/or

(b) deprotecting a protected derivative of a compound of formula (I); and/or
(c) interconverting a compound of formula (I) or protected derivative thereof to a further compound of formula (I) or protected derivative thereof; and
(d) optionally forming a pharmaceutically acceptable salt of a compound of formula (I).

2. The process according to claim 1 , comprising the process (a)(ii) of reacting a compound of formula (IV) with a compound of formula (V), wherein L 2 is halogen.

3. The process according to claim 2 , wherein P 2 is a tert-butyloxycarbonyl (tBoc) group.

4. The process according to claim 2 , wherein (a)(ii) comprises reacting a compound of formula (IV) with a compound of formula (V), in the presence of a suitable additive and a suitable base in a suitable solvent.

5. The process according to claim 2 , wherein (a)(ii) comprises reacting a compound of formula (IV) with a compound of formula (V) in the presence of potassium iodide, potassium carbonate, and acetonitrile.

6. The process according to claim 2 , wherein the compound of formula (V) is:

7. The process according to claim 6 , wherein P 2 is a tert-butyloxycarbonyl (tBoc) group.

8. The process according to claim 2 , comprising preparing the compound of formula (IV), wherein said preparing comprises reacting a compound of formula (XV):

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

9. The process according to claim 8 , wherein the haloacetyl halide is chloroacetyl chloride.

10. The process according to claim 2 , comprising preparing the compound of formula (IV), wherein said preparing comprises:
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 isobutyronitrile 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
a borane-tetrahydrofuran complex in the presence of a suitable solvent; or
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.

11. The process according to claim 10 , wherein L 3 and L 4 are both fluorine.

12. The process according to claim 10 , wherein L 5 is chlorine and/or L 6 is bromine.

13. The process according to claim 10 , wherein the compound of formula (IV) is a compound of formula (IV) a :

14. The process according to claim 1 comprising (b) deprotecting a protected derivative of a compound of formula (I), wherein said deprotecting comprises using a suitable acid in a suitable solve

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

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P21/00

  Drugs for disorders of the muscular or neuromuscular system · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61P31/22

  for herpes viruses · CPC title