WO2011021038A1 - Tricyclic heterocyclic compounds as phosphoinositide 3-kinase inhibitors - Google Patents

Tricyclic heterocyclic compounds as phosphoinositide 3-kinase inhibitors Download PDF

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WO2011021038A1
WO2011021038A1 PCT/GB2010/051370 GB2010051370W WO2011021038A1 WO 2011021038 A1 WO2011021038 A1 WO 2011021038A1 GB 2010051370 W GB2010051370 W GB 2010051370W WO 2011021038 A1 WO2011021038 A1 WO 2011021038A1
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Prior art keywords
compound
added
etoac
pyrido
vacuo
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PCT/GB2010/051370
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French (fr)
Inventor
Stephen Joseph Shuttleworth
Alexander Richard Liam Cecil
Thomas James Hill
Franck Alexandre Silva
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Karus Therapeutics Limited
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Priority claimed from GB0914594A external-priority patent/GB0914594D0/en
Priority claimed from GBGB1005584.6A external-priority patent/GB201005584D0/en
Priority to PL10747483T priority Critical patent/PL2467387T3/en
Priority to ES10747483.5T priority patent/ES2534326T3/en
Priority to MX2012002059A priority patent/MX2012002059A/en
Priority to BR112012003955A priority patent/BR112012003955A2/en
Priority to AU2010286168A priority patent/AU2010286168B2/en
Priority to US13/388,164 priority patent/US9200007B2/en
Priority to EP10747483.5A priority patent/EP2467387B1/en
Priority to CA2771594A priority patent/CA2771594C/en
Application filed by Karus Therapeutics Limited filed Critical Karus Therapeutics Limited
Priority to CN201080036402.7A priority patent/CN102498115B/en
Priority to JP2012525212A priority patent/JP5746172B2/en
Priority to IN1325DEN2012 priority patent/IN2012DN01325A/en
Priority to NZ597983A priority patent/NZ597983A/en
Publication of WO2011021038A1 publication Critical patent/WO2011021038A1/en
Priority to IL217903A priority patent/IL217903A/en
Priority to ZA2012/00910A priority patent/ZA201200910B/en
Priority to US14/920,410 priority patent/US9580442B2/en
Priority to US15/410,114 priority patent/US9938290B2/en
Priority to US15/909,011 priority patent/US10501478B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • aryl means a monocyclic, bicyclic, or tricyclic monovalent or divalent aromatic radical, such as phenyl, biphenyl, naphthyl, anthracenyl, which can be optionally substituted with up to five substituents preferably selected from the group of C 1 -C 6 alkyl, hydroxy, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, ammo, C 1 -C 3 mono alkylamino, C 1 -C 3 bis alkylamino, C 1 -C 3 acylamino, C 1 -C 3 aminoalkyl, mono (C 1 -C 3 alkyl) amino C 1 -C 3 alkyl, b ⁇ s(C 1 -C 3 alkyl) amino C 1 -C 3 alkyl, C 1 -C 3 -acylam ⁇ no, C 1 -C 3 alkyl sulf
  • a compound of the invention has the formula:
  • Y is N(R 3 ) 2 . More preferably, Y is a heteroaryl, such as an indolyl, or Y is a heterocycle.
  • a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base.
  • Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, salicylic, stearic, benzenesulphonic or p-toluenesulphonic acid.
  • Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines, aryl amines or heterocyclic amines.
  • the compounds of the invention can be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules.
  • Preferred pharmaceutical compositions of the invention are compositions suitable for oral administration, for example tablets and capsules.
  • the compounds of the invention may also be administered by inhalation.
  • a compound of the invention is used in combination with another chemotherapeutic or antineoplastic agent in the treatment of a cancer.
  • chemotherapeutic or antineoplastic agents include platinum complexes including cisplatin and carboplatin, mitoxantrone, vinca alkaloids for example vincristine and vinblastine, anthracycline antibiotics for example daunorubicin and doxorubicin, alkylating agents for example chlorambucil and melphalan, taxanes for example paclitaxel, antifolates for example methotrexate and tomudex, epipodophyllotoxins for example etoposide, camptothecins for example irinotecan and its active metabolite SN38 and DNA methylation inhibitors for example the DNA methylation inhibitors disclosed in WO02/085400.
  • the PI3K inhibitors of the present invention may also be used to treat abnormal cell proliferation due to insults to body tissue during surgery. These insults may arise as a result of a variety of surgical procedures such as joint surgery, bowel surgery, and cheloid scarring. Diseases that produce fibrotic tissue that may be treated using the PI3K inhibitors of the present invention include emphysema. Repetitive motion disorders that may be treated using the present invention include carpal tunnel syndrome. An example of a cell proliferative disorder that may be treated using the invention is a bone tumour.
  • Example D 4-MorphoIin-4-yI-2-(1H-pyrroIo[2,3-b]pyridin-4-yI)- pyrido[3',2':4,5]thieno[3,2-d]pyrimidine
  • Example O 8-(4-FIuoro-piperidin-1 -ylmethyl)-2-(1 H-indol-4-yl) ⁇ 4-morphoIin- 4-yI-pyrido[3',2':4,5]furo[3,2-d]pyrimidine

Abstract

Compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein: W is O, N-H, N-(C1-C10 alkyl) or S; each X is independently CH or N; R1 is a 5 to 7-membered saturated or unsaturated, optionally substituted heterocycle containing at least 1 heteroatom selected from N or O; R2 is (LQ)mY; and each R3 is independently H, C1-C10 alkyl, aryl or heteroaryl, are surprisingly found to be inhibitors of PI3K-p110δ, and therefore have utility in therapy.

Description

TRICYCLIC HETEROCYCLIC COMPOUNDS AS
PHOSPHOINOSITIDE 3-KINASE INHIBITORS
Field of the invention
The present invention relates to novel compounds which act as inhibitors of the class IA phosphoinositide 3-kinase enzyme, PI3K-p110δ, for the treatment of cancer, immune and inflammatory diseases.
Background of the Invention
The phosphoinositide 3-kinases (PI3Ks) constitute a family of lipid kinases involved in the regulation of a network of signal transduction pathways that control a range of cellular processes. PI3Ks are classified into three distinct subfamilies, named class I, II, and III based upon their substrate specificities. Class IA PI3Ks possess a p110α, p110β, or p1 10δ catalytic subunit complexed with one of three regulatory subunits, p85α, p85β or p55δ. Class IA PI3Ks are activated by receptor tyrosine kinases, antigen receptors, G-protein coupled receptors (GPCRs), and cytokine receptors. The class IA PI3Ks primarily generate phosphatidylinositol-3,4,5-triphosphate (PI(3,4,5)P3), a second messenger that activates the downstream target AKT. The consequences of biological activation of AKT include tumour cell progression, proliferation, survival and growth, and there is significant evidence suggesting that the PI3K/AKT pathway is dysregulated in many human cancers. Additionally, PI3K activity has been implicated in endocrinology, cardiovascular disease, immune disorders and inflammation. It has been established that PI3K-p1 10δ plays a critical role in the recruitment and activation of immune and inflammatory cells. PI3K-p110δ is also upregulated in a number of human tumours and plays a key role in tumour cell proliferation and survival.
Compounds which are able to modulate p110δ activity have important therapeutic potential in cancer and immune and inflammatory disorders.
WO2006/046035 describes fused pyrimidines, which have activity as inhibitors of PI3K. The compounds disclosed therein exhibit selectivity for class Ia PI3Ks, notably p1 10δ.
Summary of the Invention
The present invention is a compound of formula I:
Figure imgf000003_0001
or a pharmaceutically acceptable salt thereof, wherein:
W is O1 N-H, N-(C1-C10 alkyl) or S;
each X is independently CH or N;
R1 is a 5 to 7-membered saturated or unsaturated, optionally substituted heterocycle containing at least 1 heteroatom selected from N or O;
R2 is (LQ)mY;
each L is independently a direct bond, C1-C10 alkylene, C2-C10 alkenylene, C2-C10 alkynylene, arylene or C3-C10 cycloalkylene;
each Q is independently a direct bond, heteroarylene, a heterocycle linker, -O-, -NR3-, -C(O)-, -C(O)NR3-, -SO2-, -SO2-NR3-, -N-C(O)-NR3-, -N-SO2- NR3, halogen, -C(halogen)a(R3 (2^))-, -NR4R5-, -C(O)NR4R5, where R4 and R5 together with the nitrogen to which they are attached form a 5 to 7-membered heterocycle linker;
m is from O to 5;
Y is H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, C3- C10 cycloalkyl, heterocycle, heteroaryl, -OR3, -N(R3)2, -C(O)R3, -C(O)OR3, - C(O)N(R3)2> -N(R3)2, -SO2-R3, -SO2-N(R3)2, -N-C(O)-N(R3)2, -N-SO2-N(R3)2, halogen, -C(halogen)bR3 (3-b), -CN, -NR4R5-, -C(O)NR4R5, where R4 and R5 together with the nitrogen to which they are attached form a 5- to 7-membered heterocycle;
b is from 1 to 3;
a is 1 or 2; and
each R3 is independently H, C1-C10 alkyl, aryl or heteroaryl,
It has been surprisingly found that these compounds are inhibitors of
PI3K-p110δ. Some of the compounds disclosed herein may additionally inhibit PI3K-p1 10β. Description of the Preferred Embodiments
As used herein, alkyl means a C-I-C-IO alkyl group, which can be linear or branched Preferably, it is a C1-C6 alkyl moiety More preferably, it is a C1-C4 alkyl moiety Examples include methyl, ethyl, n-propyl and t-butyl It may be divalent, e g propylene
As used herein, cycloalkyl contains from 3 to 10 carbon atoms It may be monovalent or divalent
As used herein, alkenyl means a C2-C10 alkenyl group Preferably, it is a
C2-C6 alkenyl group More preferably, it is a C2-C4 alkenyl group The alkenyl radicals may be mono- or di-saturated, more preferably monosaturated Examples include vinyl, allyl, 1-propenyl, isopropenyl and 1-butenyl It may be divalent, e g propenylene
As used herein, alkynyl is a C2-C10 alkynyl group which can be linear or branched Preferably, it is a C2-C4 alkynyl group or moiety It may be divalent
Each of the C1-C10 alkyl, C2-C10 alkenyl and C2-C10 alkynyl groups may be optionally substituted with each other, 1 e C1-C10 alkyl optionally substituted with C2-C10 alkenyl They may also be optionally substituted with aryl, cycloalkyl (preferably C3-C10), aryl or heteroaryl
As used herein, aryl means a monocyclic, bicyclic, or tricyclic monovalent or divalent aromatic radical, such as phenyl, biphenyl, naphthyl, anthracenyl, which can be optionally substituted with up to five substituents preferably selected from the group of C1-C6 alkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, ammo, C1-C3 mono alkylamino, C1-C3 bis alkylamino, C1-C3 acylamino, C1-C3 aminoalkyl, mono (C1-C3 alkyl) amino C1-C3 alkyl, bιs(C1-C3 alkyl) amino C1-C3 alkyl, C1-C3-acylamιno, C1-C3 alkyl sulfonylamino, halo, nitro, cyano, tπfluoromethyl, carboxy, C1-C3 alkoxycarbonyl, aminocarbonyl, mono C1-C3 alkyl aminocarbonyl, bis C1-C3 alkyl aminocarbonyl, -SO3H, C1-C3 alkylsulfonyl, aminosulfonyl, mono C1-C3 alkyl aminosulfonyl and bis C1-C3-alkyl aminosulfonyl
As used herein, heteroaryl means a monocyclic, bicyclic or tricyclic monovalent aromatic radical containing up to four heteroatoms selected from oxygen, nitrogen and sulfur, such as thiazolyl, tetrazolyl, imidazolyl, oxazolyl, isoxazolyl, thienyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, said radical being optionally substituted with up to three substituents preferably selected from the group of C1-C6 alkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, amino, C1-C3 mono alkylamino, C1-C3 bis alkylamino, C1-C3 acylamino, C1-C3 aminoalkyl, mono (C1-C3 alkyl) amino C1-C3 alkyl , bis (C1-C3 alkyl) amino C1-C3 alkyl, C1-C3-acylamino, C1-C3 alkyl sulfonylamino, halo, nitro, cyano, trifluoromethyl, carboxy, C1-C3 alkoxycarbonyl, aminocarbonyl, mono C1-C3 alkyl aminocarbonyl, bis C1-C3 alkyl aminocarbonyl, -SO3H, C1-C3 alkylsulphonyl, aminosulfonyl, mono C1-C3 alkyl aminosulfonyl and bis d-C3-alkyl aminosulfonyl,
As used herein, heterocycle is a mono- or di-valent carbocyclic radical containing up to 4 heteroatoms selected from oxygen, nitrogen and sulphur. The word 'linker' has been used herein to mean di-valent. If the heterocycle is a divalent linker, the heterocycle may be attached to neighbouring groups through a carbon atom, or through on of the heteroatoms, e.g. a N.
The heterocyclic ring may be mono- or di-saturated. The radical may be optionally substituted with up to three substituents independently selected from C1-C6 alkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, amino, C1-C3 mono alkylamino, C1-C3 bis alkylamino, C1-C3 acylamino, C1-C3 aminoalkyl, mono (C1-C3 alkyl) amino C1-C3 alkyl , bis (C1-C3 alkyl) amino C1-C3 alkyl, C1-C3-acylamino, C1-C3 alkyl sulfonylamino, halo e.g. F, nitro, cyano, trifluoromethyl, carboxy, C1-C3 alkoxycarbonyl, aminocarbonyl, mono C1-C3 alkyl aminocarbonyl, bis C1-C3 alkyl aminocarbonyl, -SO3H, C1-C3 alkylsulphonyl, aminosulfonyl, mono C1-C3 alkyl aminosulfonyl and bis C1-C3-alkyl aminosulfonyl.
As used herein, the above groups can be followed by the suffix -ene. This means that the group is divalent, i.e. a linker group.
In a preferred embodiment R1 is represented by any of the following structures:
Figure imgf000005_0001
Preferably, W is S. More preferably, W is O. R may be attached to any suitable atom on the aryi group, as depicted in general formula I, Preferably, it is attached to atoms 2 or 3, as shown below:
Figure imgf000006_0001
It may also be attached to atoms 1 or 4.
Preferably, a compound of the invention is of the structure:
Figure imgf000006_0002
As above, the placing of any of the R2 and R3 groups has no significance, other than the group must be attached to that particular aryl system. In other words, the R2 group has 4 possible bonding positions, the first R3 group has only 2 possible positions of attachment, and the other R3 group may be attached to one of 3 positions.
More preferably, a compound of the invention has the formula:
Figure imgf000007_0001
Preferably the 6,5-ring system in formula I is an indole. Alternatively, it may be a benzo-fused pyrrolo, a pyridyl-fused pyrrolo, a pyridazinyl-fused pyrrolo, a pyrazinyl-fused pyrrolo, or a pyrimidinyl-fused pyrrolo.
Preferably, both of the R3 groups that are attached to the 6,5 ring system in formula I are H.
Preferably, at least one Q is -C(O)-NR4R5, where R4 and R5 together with the nitrogen to which they are attached form a 5 to 7-membered heterocycle linker. More preferably, Q is
Figure imgf000007_0002
Preferably, at least one Q is -NR -
Preferably, at least one Q is a direct bond.
Preferably, at least one L is C1-C10 alkylene or at least one L is C2-C10 alkenylene, or at least one L is cyloalkylene.
Preferably Y is N(R3)2. More preferably, Y is a heteroaryl, such as an indolyl, or Y is a heterocycle.
Preferably R2 is H. Preferably R2 is -(C1-C10 alkylene)-N(R3)2. More preferably, R2 is -CH2-N(CH3)2. R2 may also be -(C2-C10 alkenylene)- C(O)-N(R4R5)-R3, where R4 and R5 together with the nitrogen to which they are attached form a 5- to 7-membered heterocycle. More preferably, R2 is
Figure imgf000008_0001
Still more preferably, R comprises -(C1-C10 alkylene)-NR4R5 or R2 comprises -(C1-C10 alkylene)-NR -(C1-C1O alkylene)-cycloakyl, wherein R2, R" and R5 are as defined above.
Preferably m is 0, 1 or 2.
Examples of structures embodying the invention are:
Figure imgf000009_0001
A pharmaceutical composition of the invention typically contains up to 85 wt% of a compound of the invention. More typically, it contains up to 50 wt% of a compound of the invention. Preferred pharmaceutical compositions are sterile and pyrogen-free. Further, the pharmaceutical compositions provided by the invention typically contain a compound of the invention which is a substantially pure optical isomer. Preferably, the pharmaceutical composition comprises a pharmaceutically acceptable salt form of a compound of the invention.
As used herein, a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, salicylic, stearic, benzenesulphonic or p-toluenesulphonic acid. Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines, aryl amines or heterocyclic amines.
For the avoidance of doubt, the present invention also embraces prodrugs which react in vivo to give a compound of the present invention.
The compounds of the invention may be prepared by synthetic routes that will be apparent to those skilled in the art, e.g. based on the Examples.
The compounds of the invention and compositions comprising them may be administered in a variety of dosage forms. In one embodiment, a pharmaceutical composition comprising a compound of the invention may be formulated in a format suitable for oral, rectal, parenteral, intranasal or transdermal administration or administration by inhalation or by suppository. Typical routes of administration are parenteral, intranasal or transdermal administration or administration by inhalation.
The compounds of the invention can be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules. Preferred pharmaceutical compositions of the invention are compositions suitable for oral administration, for example tablets and capsules.
The compounds of the invention may also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, transdermally or by infusion techniques. The compounds may also be administered as suppositories.
The compounds of the invention may also be administered by inhalation.
An advantage of inhaled medications is their direct delivery to the area of rich blood supply in comparison to many medications taken by oral route. Thus, the absorption is very rapid as the alveoli have an enormous surface area and rich blood supply and first pass metabolism is bypassed. A further advantage may be to treat diseases of the pulmonary system, such that delivering drugs by inhalation delivers them to the proximity of the cells which are required to be treated.
The present invention also provides an inhalation device containing such a pharmaceutical composition. Typically said device is a metered dose inhaler (MDI), which contains a pharmaceutically acceptable chemical propellant to push the medication out of the inhaler.
The compounds of the invention may also be administered by intranasal administration. The nasal cavity's highly permeable tissue is very receptive to medication and absorbs it quickly and efficiently, more so than drugs in tablet form. Nasal drug delivery is less painful and invasive than injections, generating less anxiety among patients. By this method absorption is very rapid and first pass metabolism is usually bypassed, thus reducing inter-patient variability. Further, the present invention also provides an intranasal device containing such a pharmaceutical composition.
The compounds of the invention may also be administered by transdermal administration. The present invention therefore also provides a transdermal patch containing a compound of the invention.
The compounds of the invention may also be administered by sublingual administration. The present invention therefore also provides a sub-lingual tablet comprising a compound of the invention.
A compound of the invention may also be formulated with an agent which reduces degradation of the substance by processes other than the normal metabolism of the patient, such as anti-bacterial agents, or inhibitors of protease enzymes which might be the present in the patient or in commensural or parasite organisms living on or within the patient, and which are capable of degrading the compound. Liquid dispersions for oral administration may be syrups, emulsions and suspensions.
Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. The suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
Solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.
The compounds of the present invention can be used in both the treatment and prevention of cancer and can be used in a monotherapy or in a combination therapy. When used in a combination therapy, the compounds of the present invention are typically used together with small chemical compounds such as platinum complexes, anti-metabolites, DNA topoisomerase inhibitors, radiation, antibody-based therapies (for example herceptin and rituximab), anticancer vaccination, gene therapy, cellular therapies, hormone therapies or cytokine therapy.
In one embodiment of the invention a compound of the invention is used in combination with another chemotherapeutic or antineoplastic agent in the treatment of a cancer. Examples of such other chemotherapeutic or antineoplastic agents include platinum complexes including cisplatin and carboplatin, mitoxantrone, vinca alkaloids for example vincristine and vinblastine, anthracycline antibiotics for example daunorubicin and doxorubicin, alkylating agents for example chlorambucil and melphalan, taxanes for example paclitaxel, antifolates for example methotrexate and tomudex, epipodophyllotoxins for example etoposide, camptothecins for example irinotecan and its active metabolite SN38 and DNA methylation inhibitors for example the DNA methylation inhibitors disclosed in WO02/085400.
According to the invention, therefore, products are provided which contain a compound of the invention and another chemotherapeutic or antineoplastic agent as a combined preparation for simultaneous, separate or sequential use in alleviating a cancer. Also provided according to the invention is the use of compound of the invention in the manufacture of a medicament for use in the alleviation of cancer by coadministration with another chemotherapeutic or antineoplastic agent. The compound of the invention and the said other agent may be administrated in any order. In both these cases the compound of the invention and the other agent may be administered together or, if separately, in any order as determined by a physician.
The PI3K inhibitors of the present invention may also be used to treat abnormal cell proliferation due to insults to body tissue during surgery. These insults may arise as a result of a variety of surgical procedures such as joint surgery, bowel surgery, and cheloid scarring. Diseases that produce fibrotic tissue that may be treated using the PI3K inhibitors of the present invention include emphysema. Repetitive motion disorders that may be treated using the present invention include carpal tunnel syndrome. An example of a cell proliferative disorder that may be treated using the invention is a bone tumour.
Proliferative responses associated with organ transplantation that may be treated using PI3K inhibitors of the invention include proliferative responses contributing to potential organ rejections or associated complications. Specifically, these proliferative responses may occur during transplantation of the heart, lung, liver, kidney, and other body organs or organ systems.
Abnormal angiogenesis that may be treated using this invention include those abnormal angiogenesis accompanying rheumatoid arthritis, ischemic- reperfusion related brain edema and injury, cortical ischemia, ovarian hyperplasia and hypervascularity, polycystic ovary syndrome, endometriosis, psoriasis, diabetic retinopathy, and other ocular angiogenic diseases such as retinopathy of prematurity (retrolental fibroplastic), macular degeneration, corneal graft rejection, neuroscular glaucoma and Oster Webber syndrome.
Examples of diseases associated with uncontrolled angiogenesis that may be treated according to the present invention include, but are not limited to retinal/choroidal neovascularisation and corneal neovascularisation. Examples of diseases which include some component of retinal/choroidal neovascularisation include, but are not limited to, Best's diseases, myopia, optic pits, Stargart's diseases, Paget's disease, vein occlusion, artery occlusion, sickle cell anaemia, sarcoid, syphilis, pseudoxanthoma elasticum carotid apo structive diseases, chronic uveitis/vitritis, mycobacterial infections, Lyme's disease, systemic lupus erythematosus, retinopathy of prematurity, Eale's disease, diabetic retinopathy, macular degeneration, Bechet's diseases, infections causing a retinitis or chroiditis, presumed ocular histoplasmosis, pars planitis, chronic retinal detachment, hyperviscosity syndromes, toxoplasmosis, trauma and post-laser complications, diseases associated with rubesis (neovascularisation of the angle) and diseases caused by the abnormal proliferation of fibrovascular or fibrous tissue including all forms of proliferative vitreoretinopathy. Examples of corneal neovascularisation include, but are not limited to, epidemic keratoconjunctivitis, Vitamin A deficiency, contact lens overwear, atopic keratitis, superior limbic keratitis, pterygium keratitis sicca, sjogrens, acne rosacea, phylectenulosis, diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, Mooren ulcer, Terrien's marginal degeneration, marginal keratolysis, polyarteritis, Wegener sarcoidosis, Scleritis, periphigoid radial keratotomy, neovascular glaucoma and retrolental fibroplasia, syphilis, Mycobacteria infections, lipid degeneration, chemical burns, bacterial ulcers, fungal ulcers, Herpes simplex infections, Herpes zoster infections, protozoan infections and Kaposi sarcoma.
Chronic inflammatory diseases associated with uncontrolled angiogenesis may also be treated using PI3K inhibitors of the present invention. Chronic inflammation depends on continuous formation of capillary sprouts to maintain an influx of inflammatory cells. The influx and presence of the inflammatory cells produce granulomas and thus maintains the chronic inflammatory state. Inhibition of angiogenesis using a PI3K inhibitor alone or in conjunction with other anti-inflammatory agents may prevent the formation of the granulosmas and thus alleviate the disease. Examples of chronic inflammatory diseases include, but are not limited to, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, psoriasis, sarcoidosis, and rheumatoid arthritis.
Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis are characterised by chronic inflammation and angiogenesis at various sites in the gastrointestinal tract. For example, Crohn's disease occurs as a chronic transmural inflammatory disease that most commonly affects the distal ileum and colon but may also occur in any part of the gastrointestinal tract from the mouth to the anus and perianal area. Patients with Crohn's disease generally have chronic diarrhoea associated with abdominal pain, fever, anorexia, weight loss and abdominal swelling Ulcerative colitis is also a chronic, nonspecific, inflammatory and ulcerative disease arising in the colonic mucosa and is characterised by the presence of bloody diarrhoea These inflammatory bowel diseases are generally caused by chronic granulomatous inflammation throughout the gastrointestinal tract, involving new capillary sprouts surrounded by a cylinder of inflammatory cells Inhibition of angiogenesis by these inhibitors should inhibit the formation of the sprouts and prevent the formation of granulomas Inflammatory bowel diseases also exhibit extra intestinal manifestations, such as skin lesions Such lesions are characterized by inflammation and angiogenesis and can occur at many sites other the gastrointestinal tract Inhibition of angiogenesis by PI3K inhibitors according to the present invention can reduce the influx of inflammatory cells and prevent lesion formation
Sarcoidosis, another chronic inflammatory disease, is characterized as a multisystem granulomatous disorder The granulomas of this disease can form anywhere in the body Thus, the symptoms depend on the site of the granulomas and whether the disease is active The granulomas are created by the angiogenic capillary sprouts providing a constant supply of inflammatory cells By using PI3K inhibitors according to the present invention to inhibit angiogenesis, such granulomas formation can be inhibited Psoriasis, also a chronic and recurrent inflammatory disease, is characterised by papules and plaques of various sizes Treatment using these inhibitors alone or in conjunction with other anti-inflammatory agents should prevent the formation of new blood vessels necessary to maintain the characteristic lesions and provide the patient relief from the symptoms
Rheumatoid arthritis (RA) is also a chronic inflammatory disease characterised by non-specific inflammation of the peripheral joints It is believed that the blood vessels in the synovial lining of the joints undergo angiogenesis In addition to forming new vascular networks, the endothelial cells release factors and reactive oxygen species that lead to pannus growth and cartilage destruction The factors involved in angiogenesis may actively contribute to, and help maintain, the chronically inflamed state of rheumatoid arthritis Treatment using PI3K inhibitors according to the present invention alone or in conjunction with other anti-RA agents may prevent the formation of new blood vessels necessary to maintain the chronic inflammation.
Preferably, the condition is cancer, notably leukaemias including chronic myelogenous leukaemia and acute myeloid leukaemia, lymphomas, solid tumours, and PTEN-negative tumours including PTEN-negative haematological, breast, lung, endometrial, skin, brain and prostrate cancers (where PTEN refers to "phosphatise and tensin homolog deleted on chromosome 10"). More preferably, the condition to be treated by a compound of the invention is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease (COPD), multiple sclerosis, psoriasis and other inflammatory skin disorders, systemic lupus erythematosus, inflammatory bowel disease, and organ transplant rejection. More preferably,
The invention will now be illustrated by the following Examples. Examples
Example A: 2-(1 H-lndol-4-yl)-morpholin-4-yl-pyrido[3',2' :4,5]thieno[3,2- d]pyrimidi3e
Figure imgf000016_0001
i. 3-Amino-thieno[2,3-b]pyridine-2-carboxylic acid ethyl ester, 2
Under Ar(g), 2-chloro-3-pyridinecarbonitrile, 1 , (3.026g, 21.8mmol) and sodium carbonate (2.51 "Ig, 23.7mmol) were dissolved in dry ethanol (11.5mL). Ethyl-2-meracaptacetate (3.1mL, 28.3mmol) was then added, and the reaction mixture was heated at reflux for 4h 35 min. The reaction was then cooled to rt; water (14OmL) was then added, at which point a precipitate formed, and the resulting reaction mixture was subsequently stirred for a further 30min. The precipitate was filtered, washed with water (2 x 15mL) and the resulting residue collected and dried under vacuum to furnish 2 (4.435g, 20mrnol, 92%) as an orange solid.
1H NMR (400MHz, CDCI3) δH: 8.70 (dd, J=4.6, 1.44Hz, 1 H), 7.96 (dd, J=8.1 ,
1.57Hz, 1 H), 7.33 (dd, J=8.2, 4.6Hz, 1 H), 5.92 (br. s, 2H), 4.38 (q, J=7.1 Hz, 2H),
1.41 (t, J=7.2Hz, 3H).
MS (ES+) 223.0 (100%, [M+H]+). ii. I H-Pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4dione, 3
Under Ar(g), compound 2 (518mg, 2.33mmol) and urea (1.143g,
19.0mmol) were combined and heated to 190°C with stirring for 2.5h. The reaction mixture was then cooled, and 1 M NaOH (1OmL) was added while the mixture was warm; the resulting mixture was then stirred and filtered. The filtrate was acidified with 1 M HCI, and a precipitate formed; the mixture was then filtered and the solid collected dried under vacuum to furnish 3 as an orange/brown solid (125mg, 0.574mmol, 25%).
1H NMR (400MHz, DMSO-d6) δH: 12.40 (s, 1 H), 11.60 (s, 1 H), 8.80-8.73 (m,
2H), 7.63 (dd, J=8.2, 4.6Hz, 1 H).
MS (ES-) 217.9 (100%, [M-H]-). iii. 2,4-Dichloro-pyrido[3',2':4,5]thieno[3,2-d]pyrimidine, 4
To compound 3 (15.2mg, 0.070mmol) and PCI5 (592.2mg, 2.84mmol) under Ar(g) was added POCl3 (2mL), and the resulting reaction mixture was then heated at reflux for 26h. The POCI3 was then removed in vacuo to yield a solid residue which was slowly added to crushed ice (4g) with stirring. The aqueous phase was then extracted with CHCI3, the layers were separated and the organic phase was washed with water to remove all the remaining phosphoric acid. The organic layer was subsequently dried (MgSO4) and concentrated in vacuo to give 4 (3.8mg, 0.015mmol, 21%).
1H NMR (300MHz, CDCI3) δH: 8.93 (dd, J=4.7, 1.7Hz, 1 H), 8.78 (dd, J=7.9, 1.5Hz, 1 H), 7.61 (m, 1 H).
MS (ES+) 255.9 (100%, [M+H]+). iv. 2-Chloro-4-morpholin-4-yl-pyrido[3l,2I:4,5]thieno[3,2-d]pyrimidine, 5
To 4 (34.3mg, 0.14 mmol) in methanol (1.5mL) was added morpholine (25μL, 0.29mmol) dropwise, and the resulting reaction was stirred for 1 h at rt.
The mixture was then filtered, washed with water and then methanol, and the remaining solid was dissolved in CH2CI2 and concentrated in vacuo to furnish 5 as a pale brown solid (30.1 mg, 0.098mmol, 73%).
1H NMR (300MHz, CDCI3) δH: 8.83 (br. s, 1 H), 8.72 (dd, J=8.0, 1.51 Hz, 1 H), 7.53 (m, 1 H), 4.1 1-4.05 (m, 4H), 3.94-3.88 (m, 4H).
MS (ES+) 307.0 (100%, [M+H]+). v. 2-(1 H-lndol-4-yl)-4-morpholin-4-yl-pyrido[3',2':4,5]thieno[3>2-d]pyrimidine, A
Under Ar(g), to a mixture of compound 5 (14.97mg, 0.049mmol), indole-
4-boronic acid (8.70mg, 0.054mmol), dichloro-bis(triphenylphosphine)palladium (II) (1.81 mg, 0.0026mmol) and sodium hydrogen carbonate (12.50mg, 0.15mmol) was added ethanol (0.75mL) followed by toluene (1.25mL) and then water (0.35mL). The reaction was then heated in a microwave at 120°C (300W) for 1 h. The reaction mixture was then cooled to rt, and was partitioned between CH2CI2 and water, and the organic layer was then separated, dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 0:1-1 :99) MeOH/CH2CI2) furnished A (1 mg, 0.0026mol, 5%) as a white solid.
1H NMR (300MHz, CDCI3) δH: 8.91 (d, J=8.3Hz, 1 H) 8.82 (dd, J=4.7, 1.7Hz, 1 H) 8.40-8.33 (m, 2H), 7.72 (br. s, 1 H), 7.54 (d, J=1.1 Hz, 1 H), 7.54 (dd, J=12.8, 4.9Hz, 1 H), 7.42-7.32 (m, 2H), 4.19-4.11 (m, 4H)1 4.01-3.93 (m, 4H).
MS (ES+) 388.1 (100%, [M+H]+). Example B: 2-(1 H-lndol-4-yl)-4-morpholin-4-yl-pyrido[3',2':4,5]furo[3,2- d]pyrimidine
Figure imgf000019_0001
i. 3-Amino-furo[2,3-b]pyridine-2-carboxylic acid ethyl ester, 2
2-Chloro-3-pyridinecarbonitrile, 1 , (4.0Og, 28.9mmol), Cs2CO3 (28.2g, 86.6mmol) and ethyl glycolate (3mL, 31.7mmol) were placed in a flask under Ar(g). Dry NMP was added, and the suspension was heated at 75°C for 2Oh with vigorous stirring. The reaction mixture was cooled to rt, whereupon water (200 mL) and Et2θ (3 x 10OmL) were added. The organic layers were combined, washed with water (3 x 15mL) before being dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 15-40% EtOAc/Hex) gave 2 (2.41 g, 1 1 Jmmol, 40%) as a white solid.
1H NMR (400MHz, CDCI3) δH: 8.51 (dd, J=5.0, 2.0Hz, 1 H), 7.96 (dd, J=8.0, 2.0Hz, 1 H), 7.23-7.28 (m, 1 H), 4.44 (q, J=7.0Hz, 2H), 4.01 (br. s., 2H), 1.44 (t, J=7.0Hz, 3H).
MS (ES+) 229 (100%, [M+Na]+). ii. 1 H-Pyπdo[3',2':4,5]furo[3,2-d]pyrimidine-2,4-dione, 3
Under Ar(g), and at 0°C, to a solution of compound 2 (1.189g, 5.77mmol) in CH2CI2 (2OmL) was added dropwise chlorosulfonyl isocyanate (0.55mL, 6.34mmol). The reaction mixture was allowed to warm to rt and after 4h it was concentrated in vacuo. Water (2OmL) was added, and the suspension was stirred vigorously while heating to 70°C for 10min [MS analysis showed formation of the urea intermediate was complete]. The mixture was then cooled and filtered, washing with water. The resulting solid cake (0.87g) was subsequently suspended in water (61 mL) and NaOH (3.15g) was added. After 1 h stirring, LCMS analysis confirmed that the reaction had gone to completion. The mixture was then filtered, washing with water, to furnish 3 (460mg, 2.3mmol, 40%) as a white solid.
1H NMR (400MHz, DMSOd6) δH: 12.06 (br. s., 1 H), 1 1.49 (br. s., 1 H), 8.60 (dd, J=5.0, 1.5Hz, 1 H), 8.43 (dd, J=8.0, 2.0Hz, 1 H), 7.56 (dd, J=8.0, 5.0Hz, 1 H). MS (ES ) 202 (100%, [M-H]-). iii. 2,4-Dichloro-pyrido[3',2':4,5]furo[3,2-d]pyrimidine, 4
To compound 3 (0.14g, 0.70mmol) and PCI5 (2.4g, 2.84mmol) under
Ar(g) was added POCI3 (8mL), and the resulting reaction mixture was then heated at reflux for 2Oh. After the mixture had been cooled to rt it was poured onto crushed ice (20OmL) with vigorous stirring. The aqueous phase was then extracted with CH2CI2 (3 x 5OmL). The combined organic layers were subsequently dried (MgSO4) and concentrated in vacuo to give 4 (66mg,
0.28mmol, 40%) as an off-white solid.
1H NMR (400MHz, CDCI3) δH: 8.80 (dd, J=5.0, 1.5Hz, 1 H), 8.64 (dd, J=8.0,
2.0Hz, 1 H), 7.61 (dd, J=7.5, 5.0Hz, 1 H).
MS (ES+) 240 (100%, [M+H]+). iv. 2-Chloro-4-morpholin-4-yl-pyrido[3',2':4,5]furo[3,2-d]pyrimidine, 5
To a solution of 4 (64mg, 0.27mmol) in dry methanol (1 OmL) was added morpholine (55μL, 0.62mmol) dropwise, and the resulting reaction was stirred for 2h at rt. The resulting precipitate was then filtered, washed with water and then a mixture of 5:1 methanol/water, and the remaining solid was dried in vacuo to furnish 5 (50mg, 0.17mmol, 64%) as a white solid. 1H NMR (400MHz, CDCI3) δH: 8.63 (dd, J=5.0, 2.0Hz, 1 H), 8.52 (dd, J=7.5, 2.0Hz, 1 H), 7.48 (dd, J=7.5, 5.0Hz, 1 H), 4.10-4.23 (m, 4H), 3.86-3.91 (m, 4H). MS (ES+) 291 (100%, [M+H]+). v. 2-(1 H-lndol-4-yl)-4-morpholin-4-yI-pyrido[3',2':4,5]furo[3,2-d]pyπmidine, B
Under Ar(g), to a mixture of compound 5 (25mg, 0.086mmol), indole-4- boronic acid (15.2mg, 0,095mmol), dichloro-bis(triphenylphosphine)palladium (II)
(3mg, 0.004mmol) and sodium hydrogen carbonate (22mg, 0.26mmol) was added ethanol (1 mL) followed by toluene (1.6mL) and then water (0.5mL). The reaction mixture was then heated in a microwave at 120°C (300W) for 45min, and was subsequently cooled to rt; the mixture was then partitioned between CH2CI2 and water, and the organic layer was separated, dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 30-60% EtOAc/Hex) furnished B (24.5mg, 0.067mol, 77%) as an off- white solid.
1H NMR (400MHz, 19:1 CDCI3/CD3OD) δH: 8.94 (br. s., 1 H), 8.51 (dd, J=7.5, 2.0Hz, 1 H), 8.40 (dd, J=5.0, 2.0Hz, 1 H), 7.96 (d, J=7.5Hz, 1 H), 7.26-7.35 (m, 3H), 7.08-7.18 (m, 2H), 4.02-4.11 (m, 4H), 3.71-3.79 (m, 4H). 13C NMR (100MHz, 19:1 CDCI3/CD3OD) δc: 162.6, 161.7, 149.4, 148.9, 147.0, 137.0, 133.0, 132.3, 130.3, 126.6, 125.2, 121.6, 121.5, 120.4, 115.5, 113.2, 103.7, 67.0, 45.9.
MS (ES+) 372 (100%, [M+H]+).
Example C: 4-Morpholin-4-yl-2-(1 H-pyrrolo[2,3-b]pyridin-4-yl) - pyrido[3',2':4,5]thieno[3,2-d]pyrimidine
Figure imgf000022_0001
i. 3-Amino-thieno[2,3-b]pyridine-2-carboxylic acid ethyl ester, 2
2-Chloro-3-pyridinecarbonitrile, 1 , (3.026g, 21.8mmol) and sodium carbonate (2.51 1g, 23.7mmol) were dissolved in dry ethanol (1 1.5mL) under Ar(g). Ethyl-2-meracaptacetate (3.1 mL, 28.3mmol) was then added, and the reaction mixture was heated at reflux for 4.5h. The reaction mixture was then cooled to rt; water (14OmL) was added, at which point a precipitate formed, and the resulting reaction mixture was subsequently stirred for a further 30 min. The precipitate was filtered, washed with water (2 x 15ml_) and the resulting residue collected and dried under vacuum to furnish 2 (4.435g, 20mmol, 92%) as an orange solid.
1H NMR (400MHz, CDCI3) δH: 8.70 (dd, J=4.6, 1.44Hz, 1 H), 7.96 (dd, J=8.1 , 1.57Hz, 1 H), 7.33 (dd, J=8.2, 4.6Hz, 1 H), 5.92 (br. s, 2H), 4.38 (q, J=7.1 Hz, 2H), 1.41 (t, J=7.2Hz, 3H).
MS (ES+) 223.0 (100%, [M+H]+). ii. 1 H-Pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4-dione, 3
Compound 2 (518mg, 2.33mmol) and urea (1.143g, 19.0mmol) were combined and heated to 190°C with stirring for 2.5h. The reaction mixture was then cooled, and 1 M NaOH (1OmL) was added while the mixture was warm; the resulting mixture was then stirred and filtered. The aqueous layer was acidified with 1 M HCI, and a precipitate formed; the mixture was then filtered and the solid collected dried under vacuum to furnish 3 as an orange/brown solid (125mg, 0.574mmol, 25%).
1H NMR (400MHz, DMSO-d6) δH: 12.40 (s, 1 H), 1 1.60 (s, 1 H), 8.80-8.73 (m, 2H), 7.63 (dd, J=8.2, 4.6Hz, 1 H).
MS (ES-) 217.9 (100%, [M-Hf). iii. 2,4-Dichloro-pyrido[3',2':4,5]thieno[3,2-d]pyrimidine, 4
To compound 3 (15.2rng, 0.070mmol) and PCI5 (592mg, 2.84mmol) under Ar(g) was added POCb (2mL), and the resulting reaction mixture was then heated at reflux for 26h. The POCI3 was then removed in vacuo to furnish a solid residue, which was slowly added to crushed ice (5Og) with stirring. The aqueous phase was then extracted with CH2CI2, the layers were separated and the organic phase was washed with water to remove all the remaining phosphoric acid. The organic layer was subsequently dried (MgSO4) and concentrated in vacuo to give 4 (3.8mg, 0.015mmol, 21%).
1H NMR (300MHz, CDCI3) δH: 8.93 (dd, J=4.7, 1.7Hz, 1 H), 8.78 (dd, J=7.9, 1.5Hz, 1 H), 7.61 (m, 1 H).
MS (ES+) 255.9 (100%, [M+H]+). iv. 2-Chloro-4-morpholin-4-yl-pyrido[3',2':4,5]thieno[3,2-d]pyrimidine, 5
To compound 4 (34.3mg, 0.14mmol) in dry methanol (1.5ml_) was added morpholine (25μL, 0.29mmol) in a dropwise fashion, and the resulting mixture was stirred for 1 h at rt. The mixture was then filtered, washed with water and then methanol, and the remaining solid was dissolved in CH2C^ and concentrated in vacuo to furnish 5 as a pale brown solid (30.1 mg, 0.098mmol, 73%). 1H NMR (300MHz, CDCI3) δH: 8.83 (br. s, 1 H), 8.72 (dd, J=8.0, 1.51 Hz, 1 H), 7.53 (m, 1 H), 4.11-4.05 (m, 4H), 3.94-3.88 (m, 4H).
MS (ES+) 307.0 (100%, [M+H]+). v. 4-Morpholin-4-yI-2-(1 H-pyrrolo[2,3-b]pyridin-4-yl)- pyrido[3',2':4,5]thieno[3,2-d]pyrimidine, C
To a mixture of compound 5 (16.0mg, 0.052mmol), 7-azaindole-4-boronic acid pinacol ester (14.3mg, 0.058mmoi), sodium hydrogen carbonate (13.5mg, 0.16mmol) and dichloro-bis(triphenylphosphine)palladium (II) (2.2mg, 0.0031 mmol) was added toluene (1.25mL) followed by ethanol (0.75ml_) and then distilled water (0.35mL). The reaction mixture was then heated in a microwave at 120°C (300W) for 1 h, and was subsequently cooled to rt; the mixture was then partitioned between CH2CI2 (4OmL) and water (4OmL), and the organic layer was separated, dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 70-90% EtOAc/Hex) furnished C (4.81 mg, 0.012mmol, 24%) as a pale green solid.
1H NMR (400MHz, 19:1 CDCI3/CD3OD) δH: 8.84 (dd, J=8.0, 1.5Hz, 1 H), 8.81 (dd, J=4.8, 1.8Hz, 1 H), 8.36 (d, J=5.5Hz, 1 H), 8.25 (d, J=5.0Hz, 1 H), 7.50-7.60 (m, 3H), 4.09-4.16 (m, 4H), 3.92-3.98 (m, 4H).
MS (ES+) 389 (100%, [M+H]+).
Example D: 4-MorphoIin-4-yI-2-(1H-pyrroIo[2,3-b]pyridin-4-yI)- pyrido[3',2':4,5]thieno[3,2-d]pyrimidine
Figure imgf000025_0001
i. 3-Amino-furo[2,3-b]pyridine-2-carboxylic acid ethyl ester, 2
2-Chloro-3-pyridinecarbonitrile, 1 , (4.0Og, 28.9mmol), Cs2CO3 (28.2g, 86.6mmol) and ethyl glycolate (3mL, 31.7mmol) were placed in a flask under Ar(g). Dry NMP was added, and the suspension was heated at 75°C for 2Oh with vigorous stirring. The reaction mixture was cooled to rt whereupon water (20OmL) and Et2O (3 x 10OmL) were added. The organic layers were combined, washed with water (3 x 15mL) before being dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 15-40% EtOAc/Hex) gave 2 (2.41 g, 1 1 Jmmol, 40%) as a white solid.
1H NMR (400MHz, CDCI3) δH: 8.51 (dd, ,7=5.0, 2.0Hz, 1 H), 7.96 (dd, J=8.0, 2.0Hz, 1 H), 7.23-7.28 (m, 1 H), 4.44 (q, J=7.0Hz, 2H), 4.01 (br. S., 2H), 1.44 (t, J=7.0Hz, 3H).
MS (ES+) 229 (100%, [M+Na]+).
1 H-Pyrido[3',2':4,5]furo[3,2-d]pyrimidine-2,4-dione, 3 Under Ar(g) and at 0°C to a solution of compound 2 (1 ,189g, 5.77mmol) in CH2CI2 (2OmL) was added dropwise chlorosulfonyl isocyanate (0.55mL,
6.34mmol). The reaction mixture was allowed to warm to rt, and after 4h it was concentrated in vacuo. Water (2OmL) was added, and the suspension was stirred vigorously while heating to 70°C for 10min. The mixture was then cooled and filtered, washing with water. The resulting solid cake (0.87g) was subsequently suspended in water (61 mL) and NaOH (3,15g) was added. After
1 h stirring, LCMS analysis confirmed that the reaction had gone to completion.
The mixture was then filtered, washing with water, to furnish 3 (460mg, 2.3mmol, 40%) as a white solid.
1H NMR (400MHz, DMSO-d6) δH: 12.06 (br. s., 1 H), 11.49 (br. s., 1 H), 8.60 (dd, J=5.0, 1.5Hz, 1 H), 8.43 (dd, J=8.0, 2.0Hz, 1 H), 7.56 (dd, J=8.0, 5.0Hz, 1 H). MS (ES-) 202 (100%, [M-H]I. iii. 2,4-Dichloro-pyrido[31,2':4,5]furo[3,2-d]pyrimidine, 4
To compound 3 (0.14g, OJOmmol) and PCI5 (2.4g, 2.84mmol) under
Ar(g) was added POCI3 (8mL), and the resulting reaction mixture was then heated at reflux for 2Oh. After the mixture had been cooled to rt it was poured onto crushed ice (20OmL) with vigorous stirring. The aqueous phase was then extracted with CH2CI2 (3 x 5OmL). The combined organic layers were subsequently dried (MgSO4) and concentrated in vacuo to give 4 (66mg,
0.28mmol, 40%) as an off-white solid.
1H NMR (400MHz, CDCI3) δH: 8.80 (dd, J=5.0, 1.5Hz, 1 H), 8.64 (dd, J=8.0,
2.0Hz, 1 H), 7.61 (dd, J=7.5, 5.0Hz, 1 H).
MS (ES+) 240 (100%, [M+H]+). iv. 2-Chloro-4-morpholin-4-yl-pyrido[3',2':4,5]furo[3,2-d]pyrimidine, 5
To a solution of 4 (64mg, 0.27mmol) in dry methanol (1 OmL) was added morpholine (55μL, 0.62mmol) dropwise, and the resulting reaction was stirred for 2h at rt. The resulting precipitate was then filtered, washed with water and then a mixture of 5:1 methanol/water, and the remaining solid was dried in vacuo to furnish 5 (50mg, 0.17mmol, 64%) as a white solid.
1H NMR (400MHz, CDCI3) δH: 8.63 (dd, J=5.0, 2.0Hz, 1 H), 8.52 (dd, J=7.5, 2.0Hz, 1 H), 7.48 (dd, J=7.5, 5.0Hz, 1 H), 4.10-4.23 (m, 4H), 3.86-3.91 (m, 4H). MS (ES+) 291 (100%, [M+H]+). v, 4-Morpholin-4-yl-2-(1 H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3',2':4,5]furo[3,2- djpyrimidine, D
Under Ar(g) to a mixture of compound 5 (20mg, 0.069mmol), 7- azaindole-4-boronic acid pinacol ester (18.5mg, 0.076mmol), dichloro- bis(triphenylphosphine)palladium (II) (2.4mg, 0.003mmol) and sodium hydrogen carbonate (17.4mg, 0.21 mmol) was added ethanol (1 mL) followed by toluene (1.6mL) and then water (0.5mL). The reaction mixture was then heated in a microwave at 120°C (300W) for 1 h, and was subsequently cooled to rt; the mixture was then partitioned between CH2CI2 and water, and the organic layer was separated, dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 30-90% EtOAc/Hex) furnished D (20mg, 0.054mol, 78%) as an off-white solid.
1H NMR (400MHz, 9:1 CDCI3/CD3OD) δH: 8.61 (dd, J=7.5, 1.5Hz, 1 H), 8.54 (dd, J=5.0, 1.5Hz, 1 H), 8.28 (d, J=5.0Hz, 1 H), 8.00 (d, J=5.0Hz, 1 H), 7.46 (dd, J=7.5, 5.0Hz1 1 H), 7.41 (d, J=3.5Hz, 1 H), 7.32 (d, J=3.5Hz, 1 H), 4.15-4.24 (m, 4H), 3.84-3.92 (m, 4H).
MS (ES+) 373 (100%, [M+H]+).
Example E: 2,8-Bis-(1H-indoI-4-yI)-4-morphoIin-4-yl- pyrido[3',2':4,5]furo[3,2-d]pyrimidine
Figure imgf000028_0001
i. 3-Amino-5-brorno-furo[2,3-b]pyridine-2-carboxylic acid ethyl ester, 2
5-Bromo-2-chloro-3-pyridinecarbonitrile, 1 , (4,802g, 22.08mmol), Cs2CO3 (21.6g, 66.2mmol) and ethyl glycolate (2.3ml_, 24.3mmol) were placed in a flask under Ar(g). Dry NMP (5OmL) was added, and the suspension was heated at 75°C for 2Oh with vigorous stirring. The reaction mixture was cooled to rt whereupon water (20OmL) and Et2O (3 x 10OmL) were added. The organic layers were combined, washed with water (3 x 15mL) before being dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 15-25% EtOAc/Hex) gave 2 (1.701g, 5.97mmol, 27%) as a yellow solid.
1H NMR (400MHz, CDCI3) δH: 8.53 (d, J=2.0Hz, 1 H), 8.07 (d, J=2.0Hz, 1 H), 5.00 (br. s., 2H), 4.44 (q, J=7.0Hz, 2H), 1.44 (t, J=7.0Hz, 3H).
MS (ES+) 309 (100%, [M+Na]+), 307 (100%, [M+Na]+).
8-Bromo-1 H-pyrido[3',2':4,5]thieno[3,2-d]pyrimidine , 3 Under Ar(g) and at 0°C to a solution of compound 2 (1.701g, 5.97mmol) in CH2CI2 (7OmL) was added dropwise chlorosulfonyl isocyanate (0.62mL,
7,16mmol). The reaction mixture was allowed to warm to rt and after 2.5h it was concentrated in vacuo. Water (14OmL) was added, and the suspension was stirred vigorously while heating to 70°C for 1 h [MS analysis showed formation of the urea intermediate was complete]. The mixture was then cooled to rt whereupon NaOH (5.6g [to give a 1 M solution]) was added. After 25 min a yellow/white precipitate had formed, 1 M HCI was added to the suspension till pH
5 was achieved whereupon the mixture was filtered, washing with water, to furnish 3 (1.418g, 5.03mmol, 84%) as a yellow solid.
1H NMR (400MHz, DMSO-d6) δH: 12.01 (br. s., 1 H)1 1 1.58 (br. s, 1 H), 8.72 (d,
J=2.0Hz, 1 H), 8.59 (d, J=2.0Hz, 1 H).
MS (ESl 282 (100%, [M-H]-), 280 (100%, [M-H]-). iii. 2,4-Dichloro-pyrido[3',2':4,5]furo[3,2-d]pyrimidine, 4
To compound 3 (0.615g, 2.18mmol) and PCI5 (7.2g, 34.6mmol) under Ar(g) was added POCI3 (24mL), and the resulting reaction mixture was then heated at reflux for 24h. After the mixture had been cooled to rt it was poured onto crushed ice (40OmL) with vigorous stirring. The aqueous phase was then extracted with CH2Cl2 (3 x 10OmL). The combined organic layers were subsequently dried (MgSO4) and concentrated in vacuo to give a 1 :1 mixture of 4 and an impurity (0.532g) as an off-white solid that was used directly in the next step.
1H NMR (400MHz, CDCI3) δH: 8.78 (d, J=2.5Hz, 1 H), 8.72 (d, J=2.5Hz, 1 H), 8.71 (d, J=2.5Hz, 1 H), 8.29 (d, J=2.5Hz, 1 H). iv. 8-Bromo-2-chloro-4-morpholin-4-yl-pyrido[3',2':4,5]furo[3,2-d]pyrimidine, 5 To a solution of 4 (532mg) in dry methanol (25mL) was added morpholine (321 μL, 3.7mmol) dropwise, and the resulting reaction was stirred for 1 h at rt. The resulting precipitate was then filtered, washed with water and dried in vacuo to furnish 5 (251 mg, 0.68mmol, 31%, 2 steps) as a white solid.
1H NMR (400MHz, CDCI3) δH: 8.66 (d, J=2.0Hz, 1 H), 8.62 (d, J=2.0Hz, 1 H), 4.07-4.21 (m, 4H), 3.85-3.91 (m, 4H).
MS (ES+) 393 (100%, [M+Na]+), 391 (80%, [M+Na]+). v. 2,8-Bis-(1 H-indol-4-yl)-4-morpholin-4-yl-pyrido[3',2':4,5]furo[3,2- d]pyrimidine, E
Under Ar(g) to a mixture of compound 5 (8mg, 0.022mmoi), indole-4- boronic acid (10.5mg, 0.065mmol), dichloro-bis(triphenylphosphine)palladium (II) (1.5mg, 0.002mmol) and sodium hydrogen carbonate (8mg, 0.097mmol) was added ethanol (1 mL) followed by toluene (1.6mL) and then water (0.5ml_). The reaction mixture was then heated in a microwave at 120°C (300W) for 1 h, and was subsequently cooled to rt; the mixture was then partitioned between CH2CI2 and water, and the organic layer was separated, dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 20-40% EtOAc/Hex) furnished E (2.7mg, O.OOSmol, 25%) as a yellow solid.
1H NMR (400MHz, 9:1 CDCI3/CD3OD) δH: 9.08 (s, 1 H)1 8.88 (d, J=1.5Hz, 1 H), 8.05 (d, J=7.5Hz, 1 H), 7.49 (d, J=8.0Hz, 1 H), 7.43 (d, J=7.5Hz, 1 H), 7.17-7.33 (m, 6H), 6.66 (d, J=3.0Hz, 1 H), 4.22-4.31 (m, J=4.5Hz, 4H), 3.85-3.95 (m, 4H). MS (ES+) 487 (100%, [M+H]+).
Example F: (E)-1 -(4-Methyl-piperazin-1 -yI)-3-[4-morpholin-4-yI-2-(1 H- pyrrolo[2,3-b]pyridin-4-yl)--pyrid[3',2':4,5]furo([,2-d]pyrimidin-8-yl]- propenone
Figure imgf000031_0001
i, 1-(4-Methyl-piperazin-1-yl)-propenone, 6
At 0°C to a solution of N-methylpiperazine (3mL, 27mmol) in CH2CI2
(15ml_) was added acryloyl chloride (879mL, 10.8mmol) dropwise under Ar(g).
After 2h water (2OmL) was added. The organic layer was separated and washed with water (2 x 1 OmL), dried (MgSO4), before being concentrated in vacuo to give 6 (463mg, 3mmol, 28%) as a pale yellow oil that required no further purification.
1H NMR (400MHz, CDCI3) δH: 6.56 (dd, J=16.6, 10.5Hz, 1 H), 6.28 (dd, J=16.6,
2.0Hz, 1 H), 5.61-5.75 (m, 1 H), 3.54-3.79 (m, 4H), 2.38-2.49 (m, 4H), 2.33 (s, 3H).
MS (ES+) 155 (100%, [M+H]+). ii. (E)-3-(2-Chloro-4-morpholin-4-yl-pyrido[3',21:4,5]furo[3,2-d]pyrimidin-8-yl)- 1 -(4-methyl-piperazin-1 -yl)-propenone, 7
To a sealed tube was added 5 (as per Example E above, 50mg,
0.14mmol), 6 (20.9mg, 0.14mmol), dichloro-bis(triphenylphosphine)palladium (II) (2.9mg, 0.004mmol), XPhos (3.9mg, 0.008mmol) and NaOAc (33mg, 0.41 mmol) followed by anhydrous DMF (4mL) under Ar(g). The lid was sealed and the tube was heated to 110°C for 16h whereupon it was cooled to rt and diluted with EtOAc (4OmL). The organic layer was washed with water (2 x 2OmL); the combined aqueous layers were then extracted with CH2CI2 (3 x 6OmL). The combined organic layers were then dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 2-6% MeOH/CH2CI2) furnished 7 (44mg, O.IOmol, 71%) as a white solid.
1H NMR (400MHz1 CDCI3) δH: 8.62-8.76 (m, 2H), 7.82 (d, J=15.6Hz, 1 H), 7.05 (d, J=15.6Hz, 1 H), 4.07-4.23 (m, 4H), 3.85-3.92 (m, 4H), 3.68-3.84 (m, 4H), 2.47-2.61 (m, 4H), 2.39 (s, 3H).
MS (ES+) 443 (100%, [M+H]+). iii. (E)-1 -(4-Methyl-piperazin-1 -yl)-3-[4-morpholin-4-yl-2-(1 H-pyrrolo[2,3- b]pyridin-4-yl)-pyrido[3',2':4,5]furo[3,2-d]pyrimidin-8-yl]-propenone, F
To a sealed tube was added 7 (20mg, 0.045mmol), indole-4-boronic acid
(18mg, O.H mmol), dichloro-bis(triphenylphosphine)palladium (II) (6.3mg, 0.009mmol) and Na2CO3 (9.6mg, 0.09mmol) followed by dioxane (2m L) and water (0.8mL) under Ar(g). The lid was sealed and the tube was heated to 88°C for 2Oh whereupon it was cooled to rt and diluted with EtOAc (3OmL) and 50% brine (5mL). The organic layer was separated and the aqueous layer extracted with EtOAc (3 x 15mL). The combined organic layers were then dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 2-5% MeOH/CH2CI2) furnished F (6.8mg, 0.013mol, 29%) as a white solid.
1H NMR (400MHz, 5:1 CDCI3/CD3OD) δH: 8.74 (d, J=2.0Hz, 1 H), 8.54 (d, J=2.0Hz, 1 H), 7.89 (d, J=7.5Hz, 1 H), 7.65 (d, J=15.1 Hz, 1 H), 7.40 (d, J=8.0Hz, 1 H), 7.18-7.25 (m, 2H), 7.14 (t, J=7.7Hz, 1 H), 7.05 (d, J=15.1 Hz, 1 H), 4.08-4.13 (m, 4H), 3.75-3.82 (m, 4H), 3.61-3.73 (m, 4H), 2.37-2.55 (m, 4H), 2.27 (s, 3H). MS (ES+) 524 (100%, [M+H]+).
Example G: (E)-3-[2-(1 H-lndoI-4-yi)-4-morpholin-4-yl- pyridoP'^'^.Slfurop.a-dlpyrimidin-S-yO-N^-dimethylacrylamide
Figure imgf000033_0001
i. (E)-3-(2-Chloro-4-morpholin-4-yl-pyrido[31,2':4,5]furo[3,2-d]pyrimidin-8-yl)-
N,N-dimethylacrylamide, 7
To a sealed tube was added 5 (as per Example E above, 50mg, 0.14mmol), dimethylacrylamide (6, 14mL, 0.14mmol), dichloro- bis(triphenylphosphine)palladium (II) (2.8mg, 0.004mmol), XPhos (3.9mg, 0.008mmol) and NaOAc (33mg, 0.41 mmol) followed by anhydrous DMF (3.5mL) under Ar(g). The lid was sealed and the tube was heated to 110°C for 16h whereupon it was cooled to rt and diluted with EtOAc (4OmL). The organic layer was washed with 50% brine (3 x 1OmL) then dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 50-100% EtOAc/Hex then 1 % MeOH) furnished 7 (44mg, 0.11 mol, 84%) as a white solid. 1H NMR (400MHz, CDCI3) δH: 8.70 (s, 2H), 7.82 (d, J=15.6Hz, 1 H), 7.07 (d, J=15.6Hz, 1 H), 4.1 1-4.19 (m, 4H), 3.85-3.93 (m, 4H), 3.22 (s, 3H), 3.11 (s, 3H). MS (ES+) 388 (100%, [M+H]+). ii. (E)-3-[2-(1 H-lndol-4-yl)-4-morpholin-4-yl-pyrido[3',2':4,5]furo[3,2- d]pyrimidin-8-yl]-N,N-dimethylacrylamide, G
To a sealed tube was added 7 (30mg, 0.077mmol), indole-4-boronic acid (31mg, 0.19mmol), dichloro-bis(triphenylphosphine)palladium (II) (13.6mg, 0.02mmol) and Na2CO3 (24.4mg, 0.23mmol) followed by dioxane (3mL) and water (1.2mL) under Ar(g). The lid was sealed and the tube was heated to 88°C for 2Oh whereupon it was cooled to rt and diluted with EtOAc (3OmL) and 50% brine (3mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2 x 5mL). The combined organic layers were then dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 1-3% MeOH/CH2CI2) furnished G (6.9mg, 0.015mol, 19%) as an off white solid.
1H NMR (400MHz, 5:1 CDCI3/CD3OD) δH: 8.77 (d, J=2.0Hz, 1 H), 8.55 (d, J=2.0Hz, 1 H), 7.88 (dd, J=7.5, 1.0Hz, 1 H), 7.61 (d, J=15.6Hz, 1 H), 7.40 (d, J=8.0Hz, 1 H), 7.21 (d, J=3.0Hz, 1 H), 7.10-7.17 (m, 2H), 7.04 (d, J=15.6Hz, 1 H), 4.09 (s, 4H), 3.74-3.82 (m, 4H), 3.1 1 (s, 3H), 2.94 (s, 3H).
MS (ES+) 469 (100%, [M+H]+).
Example H: [2-(1 H-Indol-4-yl)-4-morpholin-4-yl-pyrido[3',2':4,5]furo[3,2- d]pyrimidin-8-yImethyI]-dimethyl-amine
Figure imgf000035_0001
i. 2-Chloro-4-morpholin-4-yl-pyrido[3',2':4,5]furo[3,2-d]pynmidine-8- carbaldehyde, 8
To a solution of (E)-3-(2-chloro-4-morpholin-4-yl-pyrido[3',2':4,5]furo[3,2- d]pyrimidin-8-yl)-N,N-dimethylacrylamide (7, as per Example G above) (13mg, 0.034mmol) in THF (1.5ml_) was added H2O (0.5mL) followed by NaIO4 (22mg, 0.10mmol) and a solution of OsO4 (2.5% wt/v in fBu0H, 9mL, 0.0009mmol) under Ar(g). After stirring for 2 days at rt, EtOAc (25mL) and sodium thiosulfate (0.1 M, 5mL) were added. The organic layer was separated and washed with brine (3mL) before being dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 5-20% EtOAc/CH2CI2) furnished 8 (8mg, 0.025mmol, 74%) as a white solid.
1H NMR (9:1 CDCI3/CD3OD) δH: 10.13 (s, 1 H), 9.04 (d, J=2.0Hz, 1 H), 8.91 (d,
J=2.0Hz, 1 H), 3.99-4.13 (m, 4H), 3.73-3.84 (m, 4H).
LCMS (ES+) 351 (100%, [M+MeOH+H]+), 319 (40%, [M+H]+). ii. (2-Chloro-4-morpholin-4-yl-pyrido[3',2':4,5]furo[3,2-d]pyrimidin-8- ylmethyl)-dimethyl-amine, 9
To a suspension of 8 (7.8mg, 0.024mmol) in dry DMF (2.5mL) was added a solution of dimethylamine (2M in MeOH, 24ml_, 0.049mmol) followed by
NaBH(OAc)3 (8mg, 0.037mmol) under Ar(g). After stirring at rt for 23h, a further quantity of dimethylamine (2M in MeOH, 35mL, 0.071 mmol) and NaBH(OAc)3
(6mg, 0.028mmol) were added. After 3 days the reaction was concentrated in vacuo. EtOAc (4OmL) and 50% saturated brine (5mL) were added and the organic layer separated, re-extracting the aqueous with EtOAc (2 x 15mL). The combined organic layers were then dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 1-6% MeOH/CH2CI2) furnished 9 (5mg, 0.014mmol, 60%) as a white solid.
1H NMR (CDCI3) δH: 8.65 (d, J=2.0Hz, 1 H), 8.50 (d, J=2.0Hz, 1 H), 4.08-4.23 (m, 4H), 3.82-3.93 (m, 4H), 3.75 (br. s., 2H), 2.38 (s, 6H).
MS (ES+) 348 (100%, [M+H]+). iii. [2-(1 H-lndol-4-yl)-4-morpholin-4-yl-pyrido[3',2':4,5]furo[3,2-d]pyrimidin-8- ylmethyl]-dimethyl-amine, H
To a sealed tube was added 9 (5mg, 0.014mmol), indole-4-boronic acid (5.8mg, 0.036mmol), dichloro-bis(triphenylphosphine)palladium (II) (2.0mg, 0.0029mmol) and Na2CO3 (3.1 mg, 0.029mmol) followed by dioxane (2mL) and water (O.δmL) under Ar(g). The lid was sealed and the tube was heated to 88°C for 18h whereupon it was cooled to rt and diluted with EtOAc (35ml_) and 50% saturated brine (5ml_). The organic layer was separated and the aqueous layer extracted with EtOAc (2 x 1 OmL). The combined organic layers were then dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 2-5% MeOH/CH2CI2) furnished H (2mg, 0.005mmol, 32%) as an off-white solid.
1H NMR (400MHz, 9:1 CDCI3/CD3OD) δH: 9.79 (br. s., 1 H), 8.57 (br. s, 1 H), 8.53 (br. s., 1 H), 7.98 (d, J=7.5Hz, 1 H), 7.45 (d, J=8.0Hz, 1 H), 7.24-7.32 (m, 2H), 7.19 (t, J=8.0Hz, 1 H), 4.13-4.19 (m, 4H), 3.81-3.87 (m, 4H), 3.78 (br. s, 2H), 2.36 (s, 6H),
MS (ES+) 429 (100%, [M+H]+).
Example I: 2-(1 H-Indol-4-yl)-4-morpholin-4-yI-8-piperidin-1-ylmethyl- pyrido[3',2':4,5]furo[3,2d]pyrimidine
Figure imgf000037_0001
i. 2-Chloro-4-morpholin-4-yl-8-pipeπdin-1-ylmethyl-pyrido[3',2':4,5]furo[3,2- d]pyrimidine, 10
To compound 8 (as per Example H above) (19.7mg, 0,062mmol) in dry DMF (6.3mL) was added piperidine (12.2μL, 0.14mmol) followed by NaBH(OAc)3 (20.05mg, 0.095mmol) and the reaction was stirred for 5h. After which time NaBH3CN (5.8mg, 0.092mmol) was added and the reaction was stirred for a further 48h. The DMF was removed in vacuo, EtOAc (5OmL) was added along with 50% saturated brine (5OmL), the layers separated, extracted with EtOAc (2 x 3OmL), dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 0:1-6:94) MeOH/CHaCI2) furnished 10 (12.9mg, 0.033mmol, 54%) as a white solid.
1H NMR (400MHz, CDCI3) δH: 8.55 (d, J=2.0Hz, 1 H), 8.49 (d, J=2.0Hz, 1 H), 4.15 (br. s., 4H), 3.84-3.90 (m, 4H), 3.65 (s, 2H), 2.42 (m, 4H), 1.59 (quin, J=5.5Hz, 4H), 1.41-1.49 (m, 2H).
MS (ES+) 388.2 (100%, [M+H]+). ii. 2-(1 H-lndol-4-yl)-4-morpholin-4-yl-8-piperidin-1-ylmethyl- pyrido[3',2':4,5]furo [3,2d]pyrimidine, i
To indole-4-boronic acid (13.4mg, 0.083mmol), dichloro- bis(triphenylphosphine)palladium (II) (4.60mg, 0.0065mmol) and sodium carbonate (7.22 mg, 0.068mmol) was added compound 10 (12.9mg, 0.033mmol) dissolved in dioxane/water (2mL/0.8mL). The reaction was then heated in a sealed tube at 88°C for 16h. The reaction was cooled to rt where the reaction was partitioned between EtOAc/water (30mL/5mL) and the layers were separated, extracted with EtOAc (3 x 1OmL), dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 0:1-6:94) MeOH/CH2CI2) give I (4mg, 0.0085mol, 26%) as a white solid.
1H NMR (400MHz, 9.5:0.5 CDCI3/CD3OD) δH: 8.59 (d, J=2.0Hz, 1 H), 8.50 (d, J=2.5Hz, 1 H), 8.12 (d, J=7.5Hz, 1 H), 7.49 (d, J=8.0Hz, 1 H), 7.45-7.47 (m, 1 H), 7.33 (d, J=3.0Hz, 1 H), 7.25-7.30 (m, 2H), 4.22 (t, J=4.9Hz, 4H), 3.87-3.92 (m, 4H), 3.67 (s, 2H), 2.44 (m, 4H), 1.54-1.62 (m, 4H), 1.39-1.46 (m, 2H).
MS (ES+) 469.2 (100%, [M+H]+).
Example J: 2-(1 H-IndoI-4-yI)-8-(4-methyI-piperazin-1 -ylmethyl)-4-morphoIin- 4-yl-pyrido[3l,2':4,5]furo[3,2-d]pyrimidine
Figure imgf000039_0001
i. 2-Chloro-8-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl- pyrido[3',2':4,5]furo[3,2-d]pyrimicline, 11
To compound 8 (as per Example H above) (19.13mg, 0.060mmol) in dry CH2CI2 (6.6mL) was added N-methylpiperazine (13.3μL, 0.12mmol) followed by NaBH3CN (4.6mg, 0.073mmol) and the reaction mixture was stirred for 21 h. NaBH(OAc)3 (11.3mg, 0.053mmol) was then added and the reaction mixture was stirred for a further 6.5h. EtOAc (5OmL) was added along with 50% saturated brine (5OmL); the layers were separated, extracted with EtOAc (2 x 3OmL), dried over MgSO4, and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 0:1-1 :9 MeOH/CH2CI2) furnished 11 (8.48mg, 0.021 mmol, 35%) as a white solid.
1H NMR (400MHz, 9:1 CDCI3/CD3OD) δH: 8.49 (d, J=2.5Hz, 1 H), 8.45 (d, J=2.0Hz, 1 H), 4.10 (br. s., 4H), 3.82 (t, J=4.8Hz, 4H), 3.65 (s, 2H), 2.49 (br. s., 8H), 2.27 (s, 3H). MS (ES+) 403.1 (100%, [M+H]+). ii. 2-(1 H-lndol-4-yl)-8-(4-methyl-piperazin-1~ylmethyl)-4-morpholin-4-yl- pyπdo[3',2':4,5]furo[3,2-d]pyrimidine, J
To indoIe-4-boronic acid (14.1 mg, 0.088mmol), dichloro- bis(triphenylphosphine)palladium (II) (4.77mg, 0.0068mmol) and sodium carbonate (7.47mg, 0.070mmol) was added compound 11 (13.1 mg, 0.032mmol) dissolved in dioxane/water (2mL/0.8mL). The resulting reaction mixture was then heated in a sealed tube at 88°C for 16h. The mixture was then cooled to rt, and was partitioned between EtOAc/water (30mL/5mL); the layers were subsequently separated, extracted with EtOAc (2 x 1OmL), dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica
(eluant 0:1-1 :9) MeOH/CH2CI2) furnished compound J (3.97mg, 0.0082mol,
25%) as a white solid.
1H NMR (400MHz, 9:1 CDCI3/CD3OD) δH.: 8.59 (d, J=2.0Hz, 1 H), 8.48 (d,
J=2.0Hz, 1 H), 8.06-8.12 (m, 1 H), 7.48 (d, J=8.0Hz, 1 H), 7.42 (d, J=3.0Hz, 1 H), 7.32 (d, J=3.0Hz, 1 H), 7.25 (s, 1 H), 4.20 (t, J=4.8Hz, 4H), 3.88 (m, J=4.8Hz,
4H), 3.67 (s, 2H), 2.51 (br. s., 8H), 2.25 (s, 3H).
MS (ES+) 484.2 (100%, [M+H]+).
Example K: 2-(1 H-lndol-4-yl)-4-morpholin-4-yl-8-morphoIin-4-ylmethyI- pyrido[3',2':4,5]thieno[3,2-d]pyrimidine
Figure imgf000041_0001
i. 2-Chloro-4-morpholin-4-yl-8-morpholin-4-ylmethyl- pyrido[3',2':4,5]furo[3,2-d]pyrimidine, 12
To compound 8 (as per Example H above) (19.7mg, 0.062mmol) in dry DMF (3mL) was added morpholine (11 μl_, 0.13mmol) followed by NaBH(OAc)3 (20mg, 0.095mmol) under Ar(g) and the reaction mixture was stirred for 3 days. NaBH3CN (5mg, 0.07mmol) was then added, and the reaction mixture was stirred for a further 5h. The DMF was then removed in vacuo, and EtOAc (4OmL) was added along with 50% saturated brine (5mL); the resulting layers were separated, extracted with EtOAc (2 x 15ml_), dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 1-2.5% MeOH/CH2CI2) furnished 12 (15mg, 0.038mmol, 61 %) as a white solid.
1H NMR (CDCI3) δH: 8.56 (s, 1 H), 8.53 (s, 1 H), 4.08-4.21 (m, 4H), 3.83-3.91 (m, 4H), 3.65-3.79 (m, 6H), 2.43-2.59 (m, 4H).
MS (ES+) 390 (100%, [M+H]+). ii. 2-(1 H-lndol-4-yl)-4-morpholin-4-yl-8-morpholin-4-ylmethyl- pyrido[3',2':4,5]furo[3,2-d]pyrimidine, K
To a sealed tube was added compound 12 (15mg, 0.038mmol), indole-4- boronic acid (15.5mg, O.i mmol), dichloro-bis(triphenylphosphine)palladium (II) (5.4mg, 0.008mmol) and Na2CO3 (8.2IDg1 0.077mmol), followed by dioxane (2mL) and water (0.8mL) under Ar(g). The tube was heated to 88°C for 18h whereupon it was cooled to rt, and diluted with EtOAc (35mL) and 50% saturated brine (5mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2 x 1 OmL). The combined organic layers were then dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 1-3% MeOH/CH2Cl2) furnished K (6.7mg, 0.014mmol, 37%) as an off-white solid.
1H NMR (400MHz, CDCI3) δH: 8.63 (d, J=2.0Hz, 1 H), 8.58 (br. s., 1 H), 8.39 (br. s., 1 H), 8.24 (dd, J=7.5, 1.0Hz, 1 H), 7.58-7.67 (m, 1 H), 7.53 (d, J=8.0Hz, 1 H), 7.38 (t, J=2.5Hz, 1 H), 7.34 (t, J=8.0Hz, 1 H), 4.19-4.33 (m, 4H), 3.90-4.01 (m, 4H), 3.67-3.84 (m, 6H), 2.45-2.67 (m, 4H).
MS (ES+) 471 (100%, [M+H]+).
Example L: [2-(1H-lndol-4-yl)-4-morpholin-4-yI-pyrido[3',2':4,5]furo[3,2- d]pyrimidin-8-yImethyl]-(2-methoxy-ethyl)-methyl-amine
Figure imgf000043_0001
i. (2-Chloro-4-morpholin-4-yI-pyrido[3',2':4)5]furo[3,2-d]pyrimidin-8- ylmethyl)-(2-methoxy-ethyl)-methyl-amine, 13
To compound 8 (as per Example H above) (23mg, 0.072mmol) in dry CH2CI2 (5mL), MeOH (2mL) was added 3A molecular sieves, (2- methoxyethyl)methylamine (12μL, O.H mmol) followed by NaBH(0Ac)3 (46mg,0.22mmol) and NaBH3CN (4.5mg, 0.07mmol) under Ar(g). After 18h, the reaction mixture was filtered, washing through with CH2CI2 (3OmL). 50% saturated brine (5mL) was then added to the filtrate and the layers were separated, extracting with CH2CI2 followed by EtOAc, dried (MgSO4) and concentrated in vacuo. Purification by first flash column chromatography on silica (eluant 1-4% MeOH/CH2CI2) followed by ion exchange column chromatography (SCX-3, MeOH-0.5M NH3 in MeOH) furnished 13 (1 1 mg, 0.028mmol, 39%) as a white solid.
1H NMR (400MHz, CDCI3) δH: 8.60 (d, J=2.0Hz, 1 H), 8.49 (d, J=2.0Hz, 1 H), 4.10-4.19 (m, 4H), 3.84-3.90 (m, 4H), 3.80 (br. s., 2H), 3.57 (t, J=5.5Hz, 2H), 3.37 (s, 3H), 2.71 (t, J=5.5Hz, 2H), 2.31 (s, 3H).
MS (ES+) 392 (100%, [M+H]+). ii. [2-(1 H-lndol-4-yl)-4-morpholin-4-yl-pyrido[3',2':4,5]furo[3,2-d]pyrinnidin-8- ylmethyl]-(2-methoxy-ethyl)-methyl-amine, L
To a sealed tube was added compound 13 (11 mg, 0.028mmol), indole-4- boronic acid (11.3mg, 0.07mmol), dichloro-bis(triphenylphosphine)palladium (II) (4mg, 0.006mmol) and Na2CO3 (6mg, 0.056mmol) followed by dioxane (2mL) and water (O.δmL) under Ar(g). The tube was heated to 88°C for 18h whereupon it was cooled to rt and diluted with EtOAc (35mL) and 50% saturated brine (5mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2 x 1OmL). The combined organic layers were then dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 1-3% MeOH/CH2CI2) furnished L (4.5mg, 0.01 mmol, 34%) as an off- white solid.
1H NMR (400MHz, 9:1 CDCI3/CD3OD) δH: 9.80 (br. s., 1 H), 8.56 (s, 1 H), 8.49 (br. s., 1 H), 7.98 (d, J=7.5Hz, 1 H), 7.44 (d, J=8.0Hz, 1 H), 7.31 (br. s., 1 H), 7.24-7.28 (m, 1 H), 7.18 (t, J=7.5Hz, 1 H), 4.10-4.20 (m, 4H), 3.76-3.87 (m, 4H), 3.51 (t, J=5.0Hz, 2H), 3.27 (s, 3H), 3.22-3.26 (m, 2H), 2.59-2.75 (m, 2H), 2.29 (s, 3H). MS (ES+) 473 (100%, [M+H]+).
Example M: 2-(1 H-lndoM-ylH.S-di-morpholin^-yl-pyridoIS^'^.δlfurotS.a- djpyrimidine
Figure imgf000045_0001
i. 2-Chloro-4,8-di-morphoIin-4-yl-pyriclo[3',2':4,5]furo[3,2-d]pyrimidine, 14
To a sealed tube was added compound 5 (as per Example E above, 20mg, 0.054mmol), Pd2(dba)3 (1.5mg, 0.0016mmol), ±BINAP (2mg, 0,0032mmol) and Cs2CO3 (26mg, 0.081 mmol) followed by dry toluene (2m L) and morpholine (5.7mL, 0.065mmol) under Ar(g). The tube was heated at 90°C for 18h. After cooling to rt, EtOAc (35mL) and 50% saturated brine (5mL) were added. The organic layer was separated and the aqueous layer extracted with EtOAc (2 x 1OmL). The combined organic layers were then dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 0.5-2% MeO H/C H2C I2) furnished 14 (10mg, 0.027mmol, 49%) as a yellow solid.
1H NMR (400MHz, CDCI3) δH: 8.34 (d, J=3.0Hz, 1 H), 7.94 (d, J=3.0Hz, 1 H), 4.07-4.23 (m, 4H), 3.90-3.97 (m, 4H)1 3.81-3.89 (m, 4H), 3.18-3.28 (m, 4H). MS (ES+) 376 (100%, [M+H]+). ii. 2-(1 H-lndoM-yO^.δ-di-morpholin^-yl-pyridoP'^'^.δJfurop^- djpyrimidine, M
To a sealed tube was added compound 14 (10mg, 0.027mmol), indole-4- boronic acid (10.9mg, 0.068mmol), dichloro-bis(triphenylphosphine)palladium (II) (3.7mg, 0.005mmol) and Na2COs (5.7mg, 0.054mmol) followed by dioxane (2mL) and water (0.8mL) under Ar(g). The tube was heated to 88°C for 18h whereupon it was cooled to rt and diluted with EtOAc (35mL) and 50% saturated brine (5m L). The organic layer was separated and the aqueous layer extracted with EtOAc (2 x 1OmL). The combined organic layers were then dried (MgSO4) and concentrated in vacuo. Purification by first flash column chromatography on silica (eluant 0.5-1.5% MeOH/CH2CI2) followed by ion exchange column chromatography (SCX-3, MeOH-0.5M NH3 in MeOH) furnished M (3.2mg, 0.007mmol, 26%) as a white solid.
1H NMR (400MHz, CDCI3) δH: 8.39 (br. s., 1 H), 8.35 (d, J=2.5Hz, 1 H), 8.21 (d, J=7.5Hz, 1 H), 7.33-7.58 (m, 3H), 7.19-7.31 (m, 2H), 4.19-4.37 (m, 4H), 3.85- 4.02 (m, 8H), 3.25-3.37 (m, 4H).
LCMS (ES+) 457 (100%, [M+H]+).
Example N: 2-(1H-lndol-4-yl)-7-methyI-4-morpholin-4-yI- pyrido[3',2':4,5]furoJ[3,2-d]pyrimidine
Figure imgf000047_0001
i. 3-Amino-6-methyl-furo[2,3-b]pyridine-2-carboxylic acid ethyl ester, 16
To a suspension of 2-chloro-3-cyano-6-methylpyridine, 15 (2.Og, 13.1 mmol, 1eq) and cesium carbonate (12.8g, 39.3mmol, 3eq) in anhydrous NMP (2OmL) was added at rt ethyl glycolate (1.36ml_, 14.4mmol, 1.1eq) under Ar(g). The reaction mixture was heated up at 75°C overnight; once cooled down, it was partitioned with H2O (20OmL) and extracted with EtOAc (3 x 7OmL). The combined organics were thoroughly washed with H2O (3 x 75mL), then dried over MgSO4 and the solvent was removed in vacuo. The residue was further purified by silica gel column chromatography with hexane/EtOAc (4:1-1 :3) to yield 16 as a pale yellow solid (1.30 g, 45%).
1H NMR (400MHz, CDCI3) δH: 7.84 (d, J=8.0Hz, 1 H), 7.12 (d, J=8.0Hz, 1 H), 4.41 (q, J=7.0Hz, 2H), 4.26 (br. s., 2H), 2.66 (s, 3H), 1.42 (t, J=7.0Hz, 3H).
MS (ES+) 221.0 (50%, [M+H]+), 243.0 (50%, [M+Na]+). ii. 7-Methyl-1 H-pyrido[3l,2l:4,5]furo[3,2-d]pyrimidine-2,4-dione, 17 A round-bottomed flask was loaded up with 3-amino-6-methyl-furo[2,3- b]pyridine-2-carboxylic acid ethyl ester, 16 (926mg, 4.20mmol, 1eq) and urea (2.52g, 42.0mmol, 10eq). The mixture was heated up at 190°C for 3h until no more ammonia release was observed. H2O (1OmL) was added, and the reaction mixture was stirred for 30 min vigorously; it was then filtered, and the solid was washed with H2O (3 x 1OmL) before drying to furnish the product as a pale brown solid (1.60 g, quant.)
1H NMR (400MHz, DMSO-Cf6) δH: 8.24 (d, J=7.5Hz, 1 H), 7.40 (d, J=8.0Hz, 1 H), 7.16 (br. s., 1 H), 5.41 (br. s., 1 H), 2.61 (s, 3H).
MS (ES+) 240.0 (100%, [M+Na]+). iii. 2-Chloro-7-methyl-4-morpholin-4-yl-pyrido[31,2':4,5]furo[3,2-d]pyrimidine, 18
To a mixture of 7-methyl-1 H-pyrido[3r,2':4,5]furo[3,2-d]pyrimidine-2,4- dione (1.6g, 4.20 mmol, 1eq) 17, and PCI5 (10.5 g, 50 mmol, 12eq) was added at rt POCI3 (33.5mL, 357mmol, 85eq) under Ar(g). The reaction mixture was refluxed at 1 15°C overnight. Once cooled down to rt, the mixture was poured dropwise very slowly onto stirred crushed ice over 2h, then warmed up to rt for 1 h. The resulting aqueous was extracted with EtOAc (3 x 10OmL) and CH2CI2 (4 x 10OmL). The combined organics were dried over MgSO4 and the solvent was removed in vacuo. To this residue in dry MeOH (50 mL) was added at rt morpholine (0.92mL, 10.5mmol, 2.5eq) under Ar(g). The reaction mixture was stirred for 3h, then the solvent was removed in vacuo. The residue was further purified by silica gel column chromatography with hexane/EtOAc (1 :1-0:1) to yield the product as a pale brown solid (384mg, 30%).
1H NMR (400MHz, CDCI3) δH: 8.38 (d, J=8.0Hz, 1 H), 7.34 (d, J=8.0Hz, 1 H), 4.10-4.19 (m, 4H), 3.84-3.89 (m, 4H), 2.74 (s, 3H).
MS (ES+) 305.0 (90%, [M+H]+). iv. 2-(1 H-lndol-4-yl)-7-methyl-4-morpholin-4-yl-pyπdo[3',2':4,5]furo[3,2- d]pyrimidine, N
To a solution of 2-chloro-7-methyl-4-morpholin-4-yl- pyrido[3',2':4,5]furo[3,2-d]pyrimidine, 18 (27mg, 0.09mmol, 1eq), indole-4- boronic acid (43mg, 0.27mmol, 3eq) and PdCI2(PPh3)2 (12.4mg, 0.02mmol, 20mol%) in a mixture of dioxane (2mL) and H2O (1 ,OmL) was added Na2CO3 (19mg, 0,18mmol, 2eq) under Ar(g). The reaction mixture was then heated in a pressure tube for 18h at 90°C. Once cooled down, the mixture was partitioned with H2O (1 OmL) and extracted with CH2CI2 (2 x 1 OmL) and EtOAc (2 x 1 OmL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was further purified by SCX-3 cartridge eluting with CH2CI2/Me0H (1 :0-0:1 then + 1 M NH3) followed by silica gel column chromatography with hexane/EtOAc (3:1-0:1 ) to yield N as a pale brown solid (5.4 mg, 16%).
1H NMR (400MHz, CDCI3 + 10% MeOD) δH: 8.38 (d, J=8.0Hz, 1 H), 7.82 (d, J=7.5Hz, 1 H), 7.35 (d, J=8.0Hz, 1 H), 7.19 (d, J=7.5Hz, 1 H), 7.16 (d, J=3.0Hz, 1 H), 7.12 (m, J=LOHz, 1 H), 7.08 (t, J=7.5Hz, 1 H), 4.03-4.09 (m, 4H), 3.70-3.76 (m, 4H), 2.54 (s, 3H).
MS (ES+) 386.1 (100%, [M+H]+).
Example O: 8-(4-FIuoro-piperidin-1 -ylmethyl)-2-(1 H-indol-4-yl)~4-morphoIin- 4-yI-pyrido[3',2':4,5]furo[3,2-d]pyrimidine
Figure imgf000050_0001
i. 2-Chloro-8-(4-fluoro-piperidin-1-ylmethyl)-4-morpholin-4-yl- pyrido[3',2':4,5]furo[3,2-d]pyrimidine, 19
To compound 8 (as per Example H above) (80mg, 0.25mmol) in dry DMF (12mL) was added 4-fluoropiperidine hydrochloride (70 mg, O.δmmol) and NaOAc (41 mg, O.δmmol) under Ar(g). After 20 minutes NaBH(OAc)3 (106mg, O.δmmol) and NaBHsCN (16mg, 0.25mmol) were added and the suspension was stirred for 16h. The DMF was then removed in vacuo, EtOAc (45mL) was added along with 50% saturated brine (7mL), the layers separated, extracted with EtOAc (2 x 15mL), dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 1-2% MeOH/CH2CI2) furnished 9 (58mg, 0.014mmol, 57%) as a white solid.
1H NMR (300MHz, CDCI3) δH: 8.55 (d, J=1.8Hz, 1 H), 8.51 (d, J=1.8Hz, 1 H), 4.58-4.86 (m, 1 H), 4.06-4.23 (m, 4H), 3.82-3.92 (m, 4H)1 3.69 (s, 2H), 2.54-2.68 (m, 2H), 2.38-2.52 (m, 2H), 1.81-2.00 (m, 4H).
LCMS (ES+) 406 (100%, [M+H]+). ii. 8-(4-Fluoro-piperidin-1-ylmethyl)-2-(1 H-indol-4-yl)-4-morpholin-4-yl- pyrido[3',2':4,5]furo[3,2-d]pyrimidine, O
To a sealed tube was added 19 (55mg, 0.136mmol), indole-4-boronic acid (55mg, 0.34mmol), dichloro-bis(triphenylphosphine)palladium (II) (19mg, 0.027mmol) and Na2CO3 (29mg, 0,27mmol) followed by dioxane (3.5ml_) and water (1.4mL) under Ar(g). The tube was heated to 88°C for 18h whereupon it was cooled to rt and diluted with EtOAc (45ml_) and 50% saturated brine (7mL),
The organic layer was separated and the aqueous layer extracted with EtOAc (2 x 1OmL). The combined organic layers were then dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica
(eluant 1-3% MeO H/C H2CI2) furnished O (30mg, O.Oβmmol, 45%) as a brown solid,
1H NMR (300MHz, CDCI3) δH: 8.62 (d, J=2.2Hz, 1 H), 8.55 (d, J=2.2Hz, 1 H), 8.34
(br. S., 1 H), 8.24 (d, J=7.0Hz, 1 H), 7.59-7.68 (m, 1 H), 7.54 (d, .7=8.1 Hz1 1 H), 7.31-7.41 (m, 2H), 4.57-4.88 (m, 1 H), 4.20-4.34 (m, 4H), 3.89-4.00 (m, 4H), 3.72
(s, 2H), 2.57-2.74 (m, 2H), 2.39-2.54 (m, 2H), 1.81-2.04 (m, 4H).
LCMS (ES+) 487 (100%, [M+H]+).
Example P: 8-(4,4-DifIuoro-piperidin-1 -ylmethyl)-2-(1 H-indoI-4-yI)-4- morpholin-4-yl-pyrido[3',2':4,5]furo[3,2-d]pyrimidine
Figure imgf000052_0001
i. 8-(4,4-Difluoro-piperidin-1 -ylmethyl)-2-(1 H-indol-4-yl)-4-morpholin-4-yl- pyrido[3',2':4,5]furo[3,2-d]pyrimidine, 20
To compound 8 (as per Example H above) (80mg, 0.25mmol) in dry DMF (12mL) was added 4,4-difluoropiperidine hydrochloride (79mg, O.Smmol) and NaOAc (41 mg, O.δmmol) under Ar(g). After 20 minutes NaBH(OAc)3 (106mg, O.δmmol) and NaBH3CN (16mg, 0.25mmol) were added and the suspension was stirred for 16h. The DMF was then removed in vacuo, EtOAc (45ml_) was added along with 50% saturated brine (7mL), the layers separated, extracted with EtOAc (2 x 15mL), dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 1-2% MeOH/CH2Cl2) furnished 20 (41 mg, 0.097mmol, 39%) as a white solid.
1H NMR (300MHz, CDCI3) δH: 8.55 (d, J=2.0Hz, 1 H), 8.51 (d, J=2.0Hz, 1 H), 4.08-4.23 (m, 4H), 3.82-3.93 (m, 4H), 3.74 (s, 2H), 2.54-2.66 (m, 4H), 1.92-2.12 (m, 4H).
LCMS (ES+) 424 (100%, [M+H]+). ii. [2-(1 H-indol-4-yl)-4-morpholin-4-yl-pyrido[3',2':4,5]furo[3,2-d]pyrimidin-8- ylmethyl]-(2-methoxy-ethyl)-methyl-amine, N
To a sealed tube was added 20 (41 mg, 0.097mmol), indole-4-boronic acid (39mg, 0.24mmol), dichloro-bis(triphenylphosphine)palladium (II) (13.6mg, 0.02mmol) and Na2CO3 (21mg, 0.19mmol) followed by dioxane (3.5mL) and water (1.4mL) under Ar(g). The tube was heated to 88°C for 18h, and the reaction mixture was then cooled to rt, and diluted with EtOAc (45ml_) and 50% saturated brine (7mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2 x 1 OmL). The combined organic layers were then dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 0.5-2% MeOH/CHaCIa) furnished P (7.4mg, 0.015mmol, 15%) as a white solid.
1H NMR (300MHz, CDCI3) δH: 8.61 (d, J=2.3Hz, 1 H), 8.54 (d, J=2.3Hz, 1 H), 8.38 (br. s., 1 H), 8.24 (dd, J=7.5, 0.8Hz, 1 H), 7.58-7.65 (m, 1 H), 7.53 (d, J=7.9Hz, 1 H), 7.37-7.40 (m, 1 H), 7.34 (t, J=7.9Hz, 1 H), 4.21-4.32 (m, 4H), 3.91-3.99 (m, 4H), 3.76 (s, 2H), 2.56-2.70 (m, 4H), 1.95-2.14 (m, 4H).
LCMS (ES+) 505 (100%, [M+H]+).
Example Q: 2-(1 H-Indol-4-yI)-8-[4-(2-methoxy-ethyl)-piperazin-1 -ylmethyl]-4- morphoIin-4-yI-pyrido[3",2':4,5]furo[3,2-d]pyrimidine
Figure imgf000054_0001
i. 2-Chloro-8-[4-(2-methoxy-ethyl)-piperazin-1-ylmethyl]-4-morpholin-4-yl- pyrido[3',2':4,5]furo[3,2-d]pyrimidine, 21
To compound 8 (as per Example H above) (22.2mg, 0.070mmol) in dry CH2CI2/MeOH (5mL/2mL) was added 1 -(2-methoxyethyl) piperazine (13μL, 0.093mmol) and the reaction was stirred for 1 h. NaBH(OAc)3 (45.8mg, 0.022mmol) was then added, followed by NaBH3CN (4.4mg, 0.070mmol), and the reaction mixture was stirred for 48h. EtOAc (30 ml_) was added along with water/saturated brine (10ml_/5mL); the layers were separated, extracted with EtOAc (2 x 3OmL), dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 2:98-6:94 MeOH/CH2CI2) furnished 21 (10mg, 0.022mrnol, 32%) as a white solid. 1H NMR (300MHz, 9.5:0.5 CDCI3/CD3OD) δH 8.53 (d, J=1.9Hz, 1 H), 8.47-8.52 (m, 1 H), 4.14 (br. s., 4H), 3.83-3.93 (m, 4H), 3.68 (s, 2H), 3.48-3.57 (m, 2H), 3.34 (s, 3H), 2.47-2.66 (m, 10H). MS (ES+) 447.2 (100%, [M+H]+). ii. 2-(1 H-lndol-4-yl)-8-[4-(2-methoxy-ethyl)-piperazin-1-ylmethyl]-4-morph olin-4-yl-pyrido[3',2':4,5]furo[3,2-d]pyrimidine, Q
To indole-4-boronic acid (8.6mg, 0.053mmol), dichloro- bis(triphenylphosphine)palladium (II) (3.0mg, 0.0043mmol) and sodium carbonate (4.7 mg, 0.045mmol) was added compound 21 (10.0mg, 0.022mmol) dissolved in dioxane/water (2mL/0.8mL). The reaction was then heated in a sealed tube at 88°C for 16h, and was subsequently cooled to rt; it was then partitioned between EtOAc/water (30mL/5mL), the layers separated, extracted with EtOAc (2 x 3OmL), dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 0:1-2:98 MeOH/CH2CI2) furnished Q (1.09mg, 0.0021 mol, 9%) as a white solid.
LCMS (ES+) 528.3 (100%, [M+H]+).
1370
55
Example R: 3-{4-[2-(1 H-lndol-4-yI)-4-morphorm-4-yl-pyrido[3',2':4,5]furo[3,2- d]pyrimidin-8-ylmethyl]-piperazin-1-yl}-propionitrile
Figure imgf000056_0001
i 3-[4-(2-Chloro-4-morpholin-4-yl-pynclo[31,2I 4,5]furo[3,2-d]pynm[din-8- ylmethyl)-pιperazιn-1 -yl]-propionιtπle, 22
To compound 8 (as per Example H above) (24 2mg, 0 076mmol) in dry CH2CI2/Me0H (5mL/2ml_) was added 3-(1-pιperazιnyl) propionitπie (15μL, 0 11mmol) and the reaction mixture was stirred for 15 mins NaBH(OAc)3 (47 8mg, 0 023mmol) was then added, and the resulting mixture was stirred for 17h NaBH3CN (4 8mg, 0 076mmol) was added, and following additional stirring for a further 5h, the reaction mixture was partitioned between EtOAc/water/saturated brine (30mL/10ml_/5mL), the layers separated, extracted with EtOAc (2 x 3OmL), dried (MgSO4) and concentrated in vacuo Purification using an SCX-2 column with MeOH/CH2CI2 (1 9-1 1-1 1 + O 2 M NH3 in MeOH) followed by flash column chromatography on silica (eluant 1 :9 MeOH/CHaCI2) furnished 22 (15.1 mg, 0.034mmol, 45%) as a white solid.
1H NMR (400MHz, 9:1 CDCI3/CD3OD) δH 8,43 (d, J=2.0Hz, 1 H), 8.38 (d, J=2.0Hz, 1 H), 4.04 (br. s., 4H), 3.76 (t, 4H, J=5.0Hz), 3.60 (s, 2H)1 2.57-2.64 (m, 2H), 2.40-2,51 (m, 10H).
MS (ES+) 442.1 (100%, [M+H]+). ii.3-{4-[2-(1 H-lndol-4-yl)-4-morpholin-4-yl-pyrido[3',2l:4,5]furo[3)2- d]pyrimidin-8-ylmethyl]-piperazin-1 -yl}-propionitrile, R
To indole-4-boronic acid (14,6mg, 0.091 mmol), dichloro- bis(triphenylphosphine)palladium (II) (4.7mg, 0.0066mmol) and sodium carbonate (7,5mg, 0.071 mmol) was added 22 (15.1mg, 0.034mmol) dissolved in dioxane/water (2mL/0.8ml_). The reaction mixture was heated in a sealed tube at 88°C for 16h, was subsequently cooled to rt, and was then partitioned between EtOAc/water (30mL/5mL). The layers were separated, extracted with EtOAc (2 x 3OmL), dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 2:98-4:96-6:94) MeOH/CH2CI2) furnished R (6.8mg, 0.013mol, 38%) as a white solid.
1H NMR (400MHz, CDCI3) δH 8.60 (s, 1 H), 8.54 (s, 1 H), 8.40 (br. s., 1 H), 8.24 (dd, J=7.5, 1.0Hz, 1 H), 7.60-7.63 (m, 1 H), 7.53 (d, J=8.0Hz, 1 H), 7.38 (br. s., 1 H), 7.34 (t, J=7.8Hz, 1 H), 4.26 (t, J=4.3Hz, 4H), 3.94 (t, J=4.5Hz, 4H), 3.72 (s, 2H), 2.69-2.75 (m, 2H), 2.48-2.65 (m, 10H).
MS (ES+) 523.2 (100%, [M+H]+).
Example S: CycIopropyI-[2-(1H-indol-4-yI)-4-morphoIin-4-yl- pyrido[3',2':4,5]furo[3,2-d]pyrimidin-8-yImethyl]-methyI-arnine
Figure imgf000058_0001
i. 2-(1 H-lndol-4-yl)-4-morpholin-4-yl-pyrido[3l,2l;4,5]furo[3,2-d]pyrimidine- 8-carbaldehyde, 23
To compound 8 (as per Example H above) (40mg, 0.13mmol, 1eq), indole-4-boronic acid (61 mg, 0.38mmol, 3eq) and PdCI2(PPh3)2 (18.0mg, 0.03mmol, 20mol%) in a mixture of toluene (2.5mL), ethanol (1.5ml_) and H2O (O.δmL) was added NaHCO3 (32mg, 0.38mmol, 3eq) under Ar(g). The reaction mixture was heated in a microwave for 1 h at 120°C. Once cooled down, the mixture was partitioned with H2O (1 OmL) and extracted with CH2CI2 (2 x 1OmL) and EtOAc (2 x 1 OmL), The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuo. The resulting residue was further purified by silica gel column chromatography with CH2CI2/Me0H (1 :0-19:1 ) to yield the product, 23, as a pale yellow solid (33.0mg, 65%), 1H NMR (300MHz, DMSO-d6) δH: 11.27 (br. s, 1 H), 10.26 (s, 1 H), 9.16 (d, J=2.3Hz, 1 H), 9.1 1 (d, J=2.3Hz, 1 H), 8.18 (d, J=7.5Hz, 1 H)1 7.58-7.67 (m, 2H), 7.49 (t, J=2.8Hz, 1 H), 7.23 (t, J=7.7Hz, 1 H), 4.08-4.16 (m, 4H), 3.83-3.90 (m, 4H).
MS (ES+) 432.0 (100%, [M+H+MeOH]+). ii. Cyclopropyl-[2-(1 H-indol-4-yl)-4-morpholin-4-yl-pyrido[3',2':4,5]furo[3,2- d]pyrimidin-8-ylmethyl]-methyl-amine, S
To a solution of compound 23 (19mg, 0.048mmol, 1eq), NaBH3CN (6.0mg, 0.096mmol. 2eq), NaBH(OAc)3 (31 mg, 0.144mmol, 3eq) in a mixture of anhydrous CH2CI2 (2ml_), MeOH (2mL) and DMF (0.5mL) was added cyclopropyl-methyl-amine (19μL, 0.19mmol, 4eq) under Ar(g). The reaction mixture was stirred at rt overnight, and the solvents were removed in vacuo. The resulting residue was then partitioned with H2O (1OmL) and extracted with CH2CI2 (3 x 1 OmL) and EtOAc (2 x 1OmL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was further purified by silica gel column chromatography with CH2CI2/Me0H (1 :0- 24:1) to furnish the product, S, as a white solid (9.56mg, 44%).
1H NMR (300MHz, CDCI3) δH: 8.55 (d, J=2.3Hz, 1 H), 8.50 (d, J=2.3Hz, 1 H), 8.33 (br. s., 1 H), 8.23 (dd, J=7.5, 0.8Hz, 1 H), 7.58-7.63 (m, 1 H), 7.50-7.56 (m, 1 H), 7.37-7.40 (m, 1 H), 7.30-7.37 (m, 1H), 4.22-4.30 (m, 4H), 3.91-3.98 (m, 4H), 3.89 (s, 2H), 2.33 (s, 2H), 1.76-1.84 (m, 1 H), 0.43-0.58 (m, 4H).
MS (ES+) 455.1 (100%, [M+H]+).
Example T: Cyelopropyimethyl-[2-(1 H-indol-4-yl)-4-morpholin-4-yl- pyrido[3',2':4,5]furo[3,2-d]pyrimidin-8-ylmethyl]-methyI-amine
Figure imgf000060_0001
To a solution of compound 23 (as per Example S above) (19mg, 0.048mmol, 1eq), NaBH3CN (6.0mg, 0.096mmol. 2eq), NaBH(OAc)3 (31 mg, 0,i44mmol, 3eq), NaOAc (15.7mg, 0.19mmol, 4eq) in a mixture of anhydrous CH2CI2 (2mL), MeOH (2mL) and DMF (0.5mL) was added cyclopropylmethyl- methyl-amine hydrochloride (23mg, 0.19mmol, 4eq) under Ar(g). The reaction mixture was stirred at rt overnight. Solvents were removed in vacuo. Then, the residue was partitioned with H2O (1OmL) and extracted with CH2CI2 (3 x 1OmL) and EtOAc (2 x 1 OmL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was further purified by silica gel column chromatography with CH2CI2/Me0H (1 :0-47:3) to yield the product, T, as a white solid (8.35mg, 37%).
1H NMR (300MHz1 CDCI3 + 10% CD3OD) δH: 8.57 (d, J=2.3Hz, 1 H), 8.49 (d, J=2.3Hz, 1 H), 8.05 (dd, J=7.5, 1.1 Hz, 1 H), 7.47 (d, J=8.3Hz, 1 H), 7.37 (dd, J=3.4, 0.8Hz, 1 H), 7.30 (d, J=3.4Hz, 1 H), 7.19-7.26 (m, 1 H), 4.16-4.22 (m, 4H), 3.84-3.90 (m, 4H), 3.75 (s, 2H), 2.32 (d, J=6.8Hz, 2H)1 2.29 (s, 3H), 0.46-0.54 (m, 2H), 0.04-0.12 (m, 2H).
MS (ES+) 469.1 (100%, [M+H]+). Example U: 8-Azetidin-1-ylmethyl-2-(1H-indoI-4-yl)-4-morphoIin-4-yl- pyrido[3',2':4,5]furo[3,2-d]pyrimidine
Figure imgf000061_0001
To compound 23 (as per Example S above) (17mg, 0.04mmol) in a mixture of dry DMF (2mL), CH2CI2 (O.δmL) and MeOH (0.2mL) was added azetidine hydrochloride (16mg, 0.17mmol) and NaOAc (14mg, 0.17mmol) under Ar(g), After 5 minutes NaBH(OAc)3 (27mg, 0.13mmol) and NaBH3CN (5.4mg, 0.09mmol) were added and the reaction mixture was stirred for 16h. EtOAc (45mL) was added along with 50% saturated brine (5mL); the layers were separated, extracted with EtOAc (3 x 1OmL), dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 2-8% MeOH/CH2CI2) furnished U (5.4mg, 0.012mmol, 28%) as an off-white solid.
1H NMR (300MHz, 9:1 CDCI3/CD3OD) δH: 8.52 (d, J=2.3Hz, 1 H), 8.43 (d, J=2.3Hz, 1 H), 8.02 (dd, J=7.5, 1.1 Hz, 1 H), 7.47 (d, J=7.9Hz, 1 H), 7.34 (dd, J=3.4, 0.8Hz, 1 H), 7.29 (d, J=3.0Hz, 1 H), 7.22 (t, J=7.8Hz, 1 H), 4.15-4.21 (m, 4H), 3.83-3.89 (m, 4H), 3.73 (s, 2H), 3.20-3.33 (m, 4H), 2.01-2.15 (m, 2H).
LCMS (ES+) 441 (100%, [M+H]+).
Biological Data
1) PI3K lsoform Biochemical Data
Figure imgf000062_0001
2) Anti-Inflammatory Activity: Inhibition of the Production of Pro-Inflammatory Cytokines from Stimulated Human Peripheral Blood Mononuclear Cells
(hPBMCs)
Compounds were tested at a concentration of 1 uM for cytokine release inhibition in hPBMCs stimulated with LPS (TNFa)1 PHA (IFNγ) and anti-CD3 (IL-17A, IL- 17F, IL-21 , IL-23):
Figure imgf000062_0002
Figure imgf000063_0001
3) In Vitro Inhibition of Rheumatoid Arthritis Synovial Fibroblast (RASF) Proliferation
Figure imgf000063_0002
4) In Vitro Inhibition of Tumour Cell Proliferation
Figure imgf000063_0003

Claims

1. A compound of formula
Figure imgf000064_0001
or a pharmaceutically acceptable salt thereof, wherein:
W is O, N-H, N-(C1-C10 alkyl) or S;
each X is independently CH or N;
R1 is a 5 to 7-membered saturated or unsaturated, optionally substituted heterocycle containing at least 1 heteroatom selected from N or O;
R2 is (LQ)mY;
each L is independently a direct bond, C1-C10 alkylene, C2-C10 alkenylene, C2-C10 alkynylene, arylene or 03-C10 cycloalkylene;
each Q is independently a direct bond, heteroarylene, a heterocycle linker, -O-, -NR3-, -C(O)-, -C(O)NR3-, -SO2-, -SO2-NR3-, -N-C(O)-NR3-, -N-SO2-
NR3, halogen, -C(halogen)a(R3(2-a))-, -NR4R5-, -C(O)NR4R5, where R4 and R5 together with the nitrogen to which they are attached form a 5 to 7-membered heterocycle linker;
m is from O to 5;
Y is H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, C3- C10 cycloalkyl, heterocycle, heteroaryl, -OR3, -N(R3)2, -C(O)R3, -C(O)OR3, - C(O)N(R3)2, -N(R3)2, -SO2-R3, -SO2-N(R3)2, -N-C(O)-N(R3)2, -N-SO2-N(R3)2, halogen, -C(halogen)bR3 (3-b). -CN, -NR4R5-, -C(O)NR4R5, where R4 and R5 together with the nitrogen to which they are attached form a 5- to 7-membered heterocycle;
b is from 1 to 3;
a is 1 or 2; and
each R3 is independently H, C1-C10 alkyl, aryl or heteroaryl.
2. A compound according to claim 1 , wherein R1 is represented by any of the following structures:
Figure imgf000065_0001
3. A compound according to claim 1 or claim 2, with the structure
Figure imgf000065_0002
4. A compound according to any preceding claim, wherein W is O,
5. A compound according to any of claims 1 to 3, wherein W is S.
6. A compound according to any preceding claim, wherein both of the R3 groups that are attached to the 6,5-ring system in formula I are H.
7. A compound according to any preceding claim, wherein R2 comprises -(C1-C10 alkylene)-NR4R5 or R2 comprises -(C1-C10 alkylene)-NR3-(CrC10 alkylene)-cycloakyl, wherein R2, R4 and R5 are as defined in claim 1.
8. A compound according to any preceding claim, wherein m is 0, 1 or 2.
9. A compound according to any preceding claim, which is of any of the structures shown below:
Figure imgf000066_0001
10. A pharmaceutical composition comprising a compound according to any preceding claim, and a pharmaceutically acceptable excipient.
11. A compound or composition according to any preceding claim, for use in therapy.
12. A compound or composition according to claim 11 , wherein the therapy is of cancer, an immune disorder or an inflammatory disorder.
13. A compound or composition according to claim 12, wherein the cancer is a leukaemia or a PTEN-negative solid tumour.
14. A compound according to claim 11 or claim 12, wherein the therapy is of rheumatoid arthritis.
15. A compound or composition according to claim 11 , for use in anti- rejection therapy following an organ transplant.
16. Use of a compound or composition as defined in any of claims 1 to 10, for the manufacture of a medicament for use in therapy.
17. Use according to claim 16, wherein the therapy is as defined in any of claims 12 to 14.
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