WO2011141713A1 - New bicyclic compounds as pi3-k and mtor inhibitors - Google Patents

New bicyclic compounds as pi3-k and mtor inhibitors Download PDF

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WO2011141713A1
WO2011141713A1 PCT/GB2011/000735 GB2011000735W WO2011141713A1 WO 2011141713 A1 WO2011141713 A1 WO 2011141713A1 GB 2011000735 W GB2011000735 W GB 2011000735W WO 2011141713 A1 WO2011141713 A1 WO 2011141713A1
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formula
compound
optionally substituted
alkyl
group
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PCT/GB2011/000735
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Joaquín PASTOR FERNÁNDEZ
Sonia MARTÍNEZ GONZÁLES
Antonio RODRIGUÉZ HERGUETA
Francisco Javier Ramos Lima
Rosa María ALVAREZ ESCOBAR
Ana Isabel HIGUERAS HERNÁNDEZ
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Centro Nacional De Investigaciones Oncologicas (Cnio)
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Priority to US13/697,499 priority Critical patent/US20130131057A1/en
Publication of WO2011141713A1 publication Critical patent/WO2011141713A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/10—Expectorants
    • A—HUMAN NECESSITIES
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • 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
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • This invention relates to novel pharmaceutically-useful compounds, which compounds are useful as inhibitors of protein or lipid kinases (such as inhibitors of the phosphoinositide 3 ⁇ kinase (PI3 kinase) family, particularly the PI3K class I sub-type.
  • the compounds may also be useful as inhibitors of the mammalian target of rapamycin (mTOR)).
  • mTOR mammalian target of rapamycin
  • the compounds are of potential utility in the treatment of diseases such as cancer.
  • the invention also relates to the use of such compounds as medicaments, to the use of such compounds for in vitro, in situ and in vivo diagnosis or treatment of mammalian cells (or associated pathological conditions), to pharmaceutical compositions containing them, and to synthetic routes for their production.
  • PKs protein kinases
  • a large share of the oncogenes and proto-oncogenes involved in human cancers code for PKs.
  • the enhanced activities of PKs are also implicated in many non-malignant diseases, such as benign prostate hyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis.
  • PKs are also implicated in inflammatory conditions and in the multiplication of viruses and parasites. PKs may also play a major role in the pathogenesis and development of neurodegenerative disorders.
  • Phosphatidylinositol 3-kinases are a family of lipid and serine/threonine kinases that catalyze the phosphorylation of the membrane lipid phosphatidylinositol (PI) on the 3'-OH of the inositol ring to produce phosphoinositol-3-phosphate (PIP), phosphoinositol-3,4-diphosphate (PIP 2 ) and phosphoinositol-3,4,5-triphosphate (PIP 3 ), which act as recruitment sites for various intracellular signalling proteins, which in turn form signalling complexes to relay extracellular signals to the cytoplasmic face of the plasma membrane.
  • PIP phosphoinositol-3-phosphate
  • PIP 2 phosphoinositol-3,4-diphosphate
  • PIP 3 phosphoinositol-3,4,5-triphosphate
  • 3'-phosphoinositide subtypes function as second messengers in intra- cellular signal transduction pathways (see e.g. Trends Biochem. Sci 22 87,267-72 (1997) by Vanhaesebroeck ef a/.; Chem. Rev. 101 (8), 2365-80 (2001) by Leslie et al (2001 ); Annu. Rev. Cell. Dev. Boil. 17, 615-75 (2001) by Katso et a/; and Cell. Mol. Life Sci. 59 (5), 761-79 (2002) by Toker et al).
  • PI3K isoforms categorized by their catalytic subunits, their regulation by corresponding regulatory subunits, expression patterns and signalling specific funtions ( ⁇ 1 10 ⁇ , ⁇ , ⁇ , ⁇ ) perform this enzymatic reaction (Exp. Cell. Res. 25 (1 ),. 239-54 (1999) by Vanhaesebroeck and Katso et al., 2001 , above).
  • the closely related isoforms p1 10oc and ⁇ are ubiquitously expressed, while ⁇ and ⁇ are more specifically expressed in the haematopoietic cell system, smooth muscle cells, myocytes and endothelial cells (see e.g. Trends Biochem. Sci. 22 (7),.
  • Class la includes ⁇ 3 ⁇ , ⁇ 3 ⁇ and PI3K5. All of the class la enzymes are heterodimeric complexes comprising a catalytic subunit ( ⁇ 1 10 ⁇ , ⁇ 110 ⁇ or p1 106) associated with an SH2 domain containing p85 adapter subunit. Class la PI3Ks are activated through tyrosine kinase signalling and are involved in cell proliferation and survival. PI3Ka and ⁇ 3 ⁇ have also been implicated in tumorigenesis in a variety of human cancers. Thus, pharmacological inhibitors of PI3Ka and ⁇ 3 ⁇ are useful for treating various types of cancer.
  • ⁇ 3 ⁇ the only member of the Class lb PI3Ks, consists of a catalytic subunit ⁇ 1 10 ⁇ , which is associated with a p110 regulatory subunit.
  • ⁇ 3 ⁇ is regulated by G protein coupled receptors (GPCRs) via association with ⁇ subunits of heterotrimeric G proteins.
  • GPCRs G protein coupled receptors
  • ⁇ 3 ⁇ is expressed primarily in hematopoietic cells and cardiomyocytes and is involved in inflammation and mast cell function.
  • pharmacological inhibitors of ⁇ 3 ⁇ are useful for treating a variety of inflammatory diseases, allergies and cardiovascular diseases.
  • mTOR The mammalian target of rapamycin (mTOR) also known as FK506 binding protein 12-rapamycin associated protein 1 (FRAP1 ) is a protein which in humans is encoded by the FRAP1 gene.
  • mTOR is a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription.
  • the inhibition of mTORs are believed to be useful for treating various diseases/conditions, such as cancer (for example, as described in Easton et al. (2006). "mTOR and cancer therapy”. Oncogene 25 (48): 6436-46).
  • targeted therapies are becoming more important. That is, therapy that has the effect of interfering with specific target molecules that are linked to tumor growth and/or carcinogenesis. Such therapy may be more effective than current treatments (e.g. chemotherapy) and less harmful to normal cells (e.g. because chemotherapy has the potential to kill normal cells as well as cancerous cells).
  • current treatments e.g. chemotherapy
  • targeted therapies may be selective (i.e. it may inhibit a certain targeted molecule more selectively as compared to other molecular targets, e.g. as described hereinafter), may have the benefit of reducing side effects and may also have the benefit that certain specific cancers can be treated (also selectively). The latter may in turn also reduce side effects.
  • German patent application DE 2424334 and US patent US 3,995,039 disclose various bicyclic compounds for use as medicaments (e.g. in the treatment of asthma and related diseases).
  • these documents do not mention that the compounds disclosed therein may be useful as kinase inhibitors, and do not primarily relate to 6,5-fused bicycles that are substituted with both an aromatic group and a morpholinyl group.
  • International patent application WO 03/044021 discloses various bicycles for use as mediators of pro-inflammatory cytokines, which may therefore be useful in the treatment of e.g. pain. There is no specific disclosure in this document of 6,5- fused bicycles that are substituted on the 6-membered ring with morpholinyl and only one other aromatic group.
  • International patent application WO 2010/1 19264 discloses various imidazopyrazines for use as kinase inhibitors, which imidazopyrazines may be substituted with an aromatic group and a morpholinyl group. However, this document only relates to imidazopyrazines.
  • AT represents N or C(R 1 );
  • a 4 represents N or C(R 1a );
  • a 4a represents N or C(R 1 b ); wherein at least one of A4 and A ⁇ does not represent N;
  • R 1 and R 2 independently represent hydrogen or a substituent selected from halo, -CN, -OR 10b , -N(R 10b )R 11 , -C(O)N(R 0b )R b , Ci. 12 (e.g. d. 6 ) alkyl and heterocycloalkyl (e.g.
  • R 3 represents:
  • any one of X ⁇ ,, X 2 , X 3 , X 4 and X 5 (e.g. X 3 ) represents C(R ), a second one of X 1 f X 2 , X 3 , X4 and X 5 represents C(R 2b ), and the remaining three independently represent C(R 2 ) or N; or any one, two or three of X 1 t X 2 , X3, X4 and X 5 may represent N and those remaining represent C(H);
  • each R 5a , R 5b , R 5c , R 5d , R 5e , R 5 '' R 59 , R 5h , R 5i , R 5j , R 5k , R 5m and R 5n independently represent hydrogen, d.i 2 (e.g. Ci -6 ) alkyl (optionally substituted by one or more halo (e.g. fluoro) atoms), heterocycloalkyi, aryl or heteroaryl (which latter three groups are optionally substituted by one or more substituents selected from halo and C,.
  • halo e.g. fluoro
  • a 4- to 20- (e.g. 4- to 12-) membered ring optionally containing one or more heteroatoms (for example, in addition to those that may already be present, e.g.
  • each E 1 , E 2 , E 3 , E 4 , E 4a , E 5 , E 6 , E 7 and E 8 independently represents, on each occasion when used herein:
  • R 60 , R 61 and R 62 independently represent hydrogen or C-,. e alkyl optionally substituted by one or more fluoro atoms; or a pharmaceutically acceptable ester, amide, solvate or salt thereof. which compounds, esters, amides, solvates and salts are referred to hereinafter as "the compounds of the invention".
  • salts include acid addition salts and base addition salts.
  • Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
  • esters and amides such as those defined herein may be mentioned, as well as pharmaceutically acceptable solvates or salts.
  • esters and amides of the compounds of the invention are also included within the scope of the invention.
  • Pharmaceutically acceptable esters and amides of compounds of the invention may be formed from corresponding compounds that have an appropriate group, for example an acid group, converted to the appropriate ester or amide.
  • pharmaceutically acceptable esters (of carboxylic acids of compounds of the invention) include optionally substituted C 6 alkyl, C 5 -i 0 aryl and/or C 5 . 10 aryl-C 1-6 alkyl- esters.
  • R z1 and R z2 independently represent optionally substituted Ci. 6 alkyl, C 5 . 10 aryl, or C 5 . 0 aryl-C ⁇ e alkylene-.
  • C 1 .6 alkyl groups that may be mentioned in the context of such pharmaceutically acceptable esters and amides are not cyclic, e.g. linear and/or branched.
  • prodrugs of compounds of the invention are also included within the scope of the invention.
  • the term "prodrug" of a relevant compound of the invention includes any compound that, following oral or parenteral administration, is metabolised in vivo to form that compound in an experimentally-detectable amount, and within a predetermined time (e.g. within a dosing interval of between 6 and 24 hours (i.e. once to four times daily)).
  • a predetermined time e.g. within a dosing interval of between 6 and 24 hours (i.e. once to four times daily).
  • parenteral administration includes all forms of administration other than oral administration.
  • Prodrugs of compounds of the invention may be prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, in vivo when such prodrug is administered to a mammalian subject. The modifications typically are achieved by synthesising the parent compound with a prodrug substituent.
  • Prodrugs include compounds of the invention wherein a hydroxyl, amino, sulfhydryl, carboxy or carbonyl group in a compound of the invention is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxy or carbonyl group, respectively.
  • prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, esters groups of carboxyl functional groups, N-acyl derivatives and N-Mannich bases. General information on prodrugs may be found e.g. in Bundegaard, H. "Design of Prodrugs” p. 1-92, Elesevier, New York-Oxford (1985).
  • Compounds of the invention may contain double bonds and may thus exist as E (entussi) and Z (zusammen) geometric isomers about each individual double bond. Positional isomers may also be embraced by the compounds of the invention. All such isomers (e.g. if a compound of the invention incorporates a double bond or a fused ring, the cis- and trans- forms, are embraced) and mixtures thereof are included within the scope of the invention (e.g. single positional isomers and mixtures of positional isomers may be included within the scope of the invention).
  • tautomer or tautomeric form
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganisation of some of the bonding electrons.
  • Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism.
  • Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation.
  • the various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques.
  • the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a 'chiral pool' method), by reaction of the appropriate starting material with a 'chiral auxiliary' which can subsequently be removed at a suitable stage, by derivatisation (i.e.
  • a resolution for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person.
  • stereoisomers including but not limited to diastereoisomers, enantiomers and atropisomers
  • mixtures thereof e.g. racemic mixtures
  • stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined.
  • the compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • the present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention.
  • Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2 H, 3 H, 1 C, 13 C, 14 C , 13 N, 15 0, 17 0, 18 0, 32 P, 33 P, 35 S, 18 F, 36 CI, 123 l, and 125 l.
  • Certain isotopically-labeled compounds of the present invention e.g., those labeled with 3 H and 1 C
  • Tritiated ( 3 H) and carbon-14 ( 4 C) isotopes are useful for their ease of preparation and detectability.
  • isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Scheme 1 and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non- isotopically labeled reagent.
  • d. q alkyl groups (where q is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two or three, as appropriate) of carbon atoms, be branched- chain, and/or cyclic (so forming a C 3 - q -cycloalkyl group).
  • Such cycloalkyl groups may be monocyclic or bicyclic and may further be bridged.
  • when there is a sufficient number (i.e. a minimum of four) of carbon atoms such groups may also be part cyclic.
  • Such alkyl groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated (forming, for example, a C 2 . q alkenyl or a C 2 . q alkynyl group).
  • C 1-q alkylene (where q is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number of carbon atoms, be saturated or unsaturated (so forming, for example, an alkenylene or alkynylene linker group).
  • C 3 .q cycloalkyl groups (where q is the upper limit of the range) that may be specifically mentioned may be monocyclic or bicyclic alkyl groups, which cycloalkyl groups may further be bridged (so forming, for example, fused ring systems such as three fused cycloalkyl groups).
  • Such cycloalkyl groups may be saturated or unsaturated containing one or more double bonds (forming for example a cycloalkenyl group). Substituents may be attached at any point on the cycloalkyl group. Further, where there is a sufficient number (i.e. a minimum of four) such cycloalkyl groups may also be part cyclic.
  • halo when used herein, preferably includes fluoro, chloro, bromo and iodo.
  • Heterocycloalkyl groups that may be mentioned include non-aromatic monocyclic and bicyclic heterocycloalkyl groups in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom), and in which the total number of atoms in the ring system is between 3 and 20 (e.g. between three and ten, e.g between 3 and 8, such as 5- to 8-). Such heterocycloalkyl groups may also be bridged. Further, such heterocycloalkyl groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C 2 .
  • q heterocycloalkenyl (where q is the upper limit of the range) group.
  • C 2 . q heterocycloalkyl groups that may be mentioned include 7- azabicyclo[2.2.1 ]heptanyl, 6-azabicyclo[3.1.1 jheptanyl, 6-azabicyclo[3.2.1 ]- octanyl, 8-azabicyclo-[3.2.1]octanyl, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1 ,3-dioxolanyl), dioxanyl (including 1 ,3-dioxanyl and 1 ,4-dioxanyl), dithianyl (including 1 ,4-dithianyl), dithiolanyl (including 1 ,3-dithiolanyl),
  • heterocycloalkyl groups may, where appropriate, be located on any atom in the ring system including a heteroatom.
  • the point of attachment of heterocycloalkyl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system.
  • Heterocycloalkyl groups may also be in the N- or S- oxidised form.
  • Heterocycloalkyl mentioned herein may be stated to be specifically monocyclic or bicyclic.
  • bicyclic refers to groups in which the second ring of a two-ring system is formed between two adjacent atoms of the first ring.
  • bridged e.g. when employed in the context of cycloalkyl or heterocycloalkyl groups refers to monocyclic or bicyclic groups in which two non-adjacent atoms are linked by either an alkylene or heteroalkylene chain (as appropriate).
  • Aryl groups that may be mentioned include C 6 -2o, such as C 6 .12 (e.g. C 6 . n0 ) aryl groups. Such groups may be monocyclic, bicyclic or tricyclic and have between 6 and 12 (e.g. 6 and 10) ring carbon atoms, in which at least one ring is aromatic.
  • C 6 -io aryl groups include phenyl, naphthyl and the like, such as 1 ,2,3,4-tetrahydro- naphthyl. The point of attachment of aryl groups may be via any atom of the ring system.
  • the point of attachment may be via any atom including an atom of a non-aromatic ring.
  • aryl groups are poiycyclic (e.g. bicyclic or tricyclic), they are preferably linked to the rest of the molecule via an aromatic ring.
  • heteroaryl when used herein refers to an aromatic group containing one or more heteroatom(s) (e.g. one to four heteroatoms) preferably selected from N, O and S.
  • Heteroaryl groups include those which have between 5 and 20 members (e.g. between 5 and 10) and may be monocyclic, bicyclic or tricyclic, provided that at least one of the rings is aromatic (so forming, for example, a mono-, bi-, or tricyclic heteroaromatic group).
  • the heteroaryl group is poiycyclic the point of attachment may be via atom including an atom of a non-aromatic ring.
  • heteroaryl groups are poiycyclic (e.g.
  • heteroaryl groups that may be mentioned include 3,4-dihydro-I H-isoquinolinyl, 1 ,3-dihydroisoindolyl, 1 ,3-dihydroisoindolyl (e.g. 3,4- dihydro-1 /-/-isoquinolin-2-yl, 1 ,3-dihydroisoindol-2-yl, 1 ,3-dihydroisoindol-2-yl; i.e.
  • heteroaryl groups that are linked via a non-aromatic ring or, preferably, acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including 1 ,3- benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiadiazolyl (including 2,1 ,3- benzothiadiazolyl), benzothiazolyl, benzoxadiazolyl (including 2,1 ,3- benzoxadiazolyl), benzoxazinyl (including 3,4-dihydro-2/-/-1 ,4-benzoxazinyl), benzoxazolyl, benzomorpholinyl, benzoselenadiazolyl (including 2,1 ,3-benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl,
  • heteroaryl groups may, where appropriate, be located on any atom in the ring system including a heteroatom.
  • the point of attachment of heteroaryl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system.
  • the heteroaryl group is monocyclic or bicyciic.
  • the heteroaryl may be consist of a five-, six- or seven-membered monocyclic ring (e.g. a monocyclic heteroaryl ring) fused with another a five-, six- or seven-membered ring (e.g. a monocyclic aryl or heteroaryl ring).
  • Heteroatoms that may be mentioned include phosphorus, silicon, boron and, preferably, oxygen, nitrogen and sulfur.
  • a group e.g. a CM 2 alkyl group
  • substituents e.g. selected from E 6
  • those substituents are independent of one another. That is, such groups may be substituted with the same substituent (e.g. defined by E 6 ) or different substituents (defined by E 6 ).
  • the bicyclic core of the compounds of the invention (containing A ! , A , A4 a and A 5 ) is aromatic. It is further stated herein that at least one of A4 and A 4a does not represent N, i.e. that at least one of C(R 1a ) or C(R 1b ) is present. Both C(R 1a ) and C(R 1 ) may also be present.
  • a 4a represents N) or, if present, then R 1 does not represent alkyl or heterocycloalkyl (both of which may be optionally substituted as defined herein).
  • R 1b preferably represents hydrogen (and Q 1 , in these instances, preferably represents halo, -CN or -N0 2 ).
  • R 10a and R 1 a are preferably not linked together.
  • Compounds of the invention include those as hereinbefore defined, but provided that when A 4 , A 4a and A 5 respectively represent C(R 1a ), C(R 1 ) and C(R 2 ), then A, does not represent N, i.e. the requisite bicycle (containing Ai, A4, A ⁇ and A 5 ) of formula I may not be the following:
  • R 2a represents CL I2 (e.g. C ⁇ ) alkyl, then that group is preferably substituted by at least one fluoro atom (e.g. it is a perfluoro group);
  • R 2 represents R 2a (e.g. as defined herein) or, preferably, hydrogen.
  • R 1A preferably does not represent Q 1 in which Q 1 represents -OR 0A (and R 10A represents H).
  • Preferred compounds of the invention include those in which either:
  • a ⁇ represents N
  • a 4 represents C(R 1a )
  • a 4a represents C(R 1 )
  • a 5 represents N;
  • a ! represents N
  • a 4 represents N
  • a 4a represents C(R 1b )
  • a 5 represents C(R 2 );
  • a ⁇ represents C(R 1 ), A4 represents N, A ⁇ represents C(R b ) and A 5 represents C(R 2 ),
  • R 1 , R 1a , R 1b , R 2 and R 3 are as hereinbefore defined and the squiggly line represents the point of attachment to the requisite (optionally substituted) morpholinyl moiety of the compound of formula I.
  • R 3 represents a fragment of formula IA or IB.
  • Exemplary embodiments of R 3 include, but are not limited to substituted phenyl, optionally substituted pyridyl (e.g.
  • R 3 when R 3 represents bicyclic aryl
  • R 3 when R 3 represents bicyclic heteroaryl
  • isatin groups, indolyl e.g.
  • indolin-2-one isoindolyl, 1 ,3- dihydro-indol-2-one-yl, indazolyl, 1-(indolin-1-yl)ethanone-yl, 1 H- benzo[d][1 ,2,3]triazolyl, 1 H-pyrazolo[3,4-b]pyridinyl, 1 H-pyrazolo[3,4- d]pyrimidinyl, 1 H-benzo[d]imidazolyl, 1 H-benzo[d]imidazol-2(3H)-one-yl, 1 H- pyrazolo[3,4-c]pyridinyl, 1 H-pyrazolo[4,3-d]pyrimidinyl, 5H-pyrrolo[3,2- d]pyrimidinyl, 2-amino-1 H-purin-6(9H)-one-yl, quinolinyl, quinazolinyl, quinoxalinyl, isoquino
  • R 3 groups include those of fragment IA, for instance phenyl, pyridyl and especially pyrimidinyl (e.g. 5-pyrimidinyl).
  • R 3 represents a bicyclic heteroaryl group, then it may represent any one of the following structures:
  • R 3 represents aryl (e.g. phenyl), then that group is substituted by one substituent (as defined herein by R a ) and optionally (a) further substituent(s) (e.g. by a further one or two substituents as defined herein by R 2b );
  • R 3 represents substituted aryl (e.g. phenyl)
  • the substituent may be situated at the 2-, 3-, 4-, 5- or 6- position of the phenyl ring (typically one substituent is situated at position 3 or 4, i.e. at the position corresponding to X 2) X 3 or X4; most preferably the substituent is situated at the 4-position, i.e. X 3 represents C(R 2a ) in which R 2a is a substituent as defined herein);
  • R 2a may represent (e.g. when attached to a phenyl ring) a -OH moiety, for instance the -OH group is typically situated at the 3- or 4- position of the phenyl ring, so forming a 3-hydroxyphenyl or 4-hydroxyphenyl group or an isostere thereof, which is unsubstituted or substituted; an isostere as used herein is a functional group which possesses binding properties which are the same as, or similar to, the 3-hydroxyphenyl or 4- hydroxyphenyl group in the context of the compounds of the invention; isosteres of 3-hydroxyphenyl and 4-hydroxyphenyl groups are encompassed within the definition of R 3 (and R 2a may also represent another moiety as defined herein); when R 3 represents heteroaryl, it is unsubstituted or substituted (when substituted, it may be substituted by one or more (e.g. one or two) substitutents selected from those listed in respect of R 2a and R 2b );
  • R 3 is a phenyl group typically the substituents are selected from -OR 5k (e.g. -OH) and, especially -N(R Sa )R 5 (e.g. NH 2 ).
  • Preferred compounds of the invention include those in which:
  • R 3 preferably represents a fragment of formula IA
  • any one of X X 2 , X 3 , X4 and X 5 (e.g. X 3 ) represents C(R 2a ), and the remaining groups (e.g. X 1 t X 2 , X4 and X 5 ) independently represent C(R 2b ), or X 2 and X 4 may alternatively and independently represent N;
  • R 2a represents alkyl substituted by one or more fluoro atoms, then it is preferably a perfluoro group (e.g. trifluoromethyl);
  • each R b independently represents halo or, preferably, hydrogen
  • each R 5a , R 5 , R 5c , R 5d , R 5e , R 5f ' R 5g , R 5h , R 5i , R 5j , R 5k , R 5m and R 5n e.g. R 5a , R 5b ,
  • R 5c and R 5d independently represent CM (e.g. Ci. 2 ) alkyl or, preferably, hydrogen;
  • any one or two of X 6 , X 7 , X 8 and X 9 represents a heteroatom selected from nitrogen, oxygen and sulfur and the other two or three independently represent C(R 2b );
  • E 1 , E 2 , E 3 , E 4 , E 4a , E 5 , E 6 , E 7 or E 8 groups may be linked together, but are preferably not linked together;
  • aryl e.g. phenyl; preferably unsubstituted, but which may be substituted by one to three J 5 groups
  • Ci. 6 e.g. C 1 .3
  • R 60 , R 6 and R 62 independently represent hydrogen or C 3 (e.g. CL 2 ) alkyl optionally substituted by one or more fluoro atoms.
  • Preferred optional substituents include:
  • halo e.g. fluoro, chloro or bromo
  • C 1 . 4 alkyl which alkyl group may be cyclic, part-cyclic, unsaturated or, preferably, linear or branched (e.g. C 1- alkyl (such as ethyl, n-propyl, isopropyl, f-butyl or, preferably, n-butyl or methyl), all of which are optionally substituted with one or more halo (e.g.
  • fluoro groups (so forming, for example, fluoromethyl, difluoromethyl or, preferably, trifluoromethyl) or substituted with an aryl, heteroaryl or heterocycloalkyi group (which themselves may be substituted with one or more -OR z1 , -C ⁇ R 22 , -C(0)OR z3 , -N(R z )R z5 , -S(0) 2 R z6 , -S(0) 2 N(R z7 )R z8 ;
  • each R z1 to R z12 independently represents, on each occasion when used herein, H or d. 4 alkyl (e.g. ethyl, n-propyl, f-butyl or, preferably, n-butyl, methyl, isopropyl or cyclopropylmethyl (i.e. a part cyclic alkyl group)) optionally substituted by one or more halo (e.g. fluoro) groups (so forming e.g. a trifluoromethyl group).
  • any two R z groups e.g. R z4 and R zS ), when attached to the same nitrogen heteroatom may also be linked together to form a ring such as one hereinbefore defined in respect of corresponding linkage of R 10a and R 1a or R 10b and R 11 groups.
  • Preferred compounds of the invention include those in which:
  • R 2 represents hydrogen or a substituent selected from -N(R 0 )R 1 b and, preferably, halo (e.g. chloro, bromo or iodo) and -CN (but R 2 most preferably represents hydrogen);
  • each J 1 , J 2 , J 3 , J 4 , J 5 and J 6 independently represent d-e alkyl (e.g. d 3 acyclic alkyl or C 3 . 5 cycloalkyl) optionally substituted by one or more substituents selected from Q 8 , or, J 1 to J 6 more preferably represent a substituent selected from Q 7 ;
  • each R 50 , R 51 , R 52 and R 53 independently represents hydrogen or d-e (e.g. d. ) alkyl optionally substituted by one or more fluoro atoms;
  • each R 60 , R 61 and R 62 independently represents hydrogen or d -2 alkyl (e.g. methyl).
  • More preferred compounds of the invention include those in which:
  • R 2 represents hydrogen, chloro, bromo, iodo or -CN;
  • each E 1 , E 2 , E 3 , E 4 , E 4a , E 5 , E 6 , E 7 and E 8 independently represent d -4 alkyl optionally substituted by one or more Q 5 substituents, or, each of these preferably represent a substituent selected from Q 4 ;
  • halo e.g. fluoro
  • R 22 represents alkyl or, preferably, hydrogen
  • each J 1 , J 2 , J 3 , J 4 , J 5 and J s independently represent a substituent selected from Q 7 , or J 1 to J 6 (e.g. J 4 ) represents C 1-6 alkyl (e.g. C 3 . 5 cycloalkyl);
  • each R 50 independently represents C 1-4 alkyl (e.g. fert-butyl or methyl).
  • R 3 groups of the compounds of the compounds of the invention include substituted phenyl, optionally substituted indazolyl (e.g. 4-indazolyl), pyrimidinyl (e.g. 5-pyrimidinyl), azaindolyl (e.g. azaindol-5-yl), indolyl (e.g. 5-indolyl or 4- indolyl) and pyridyl (e.g. 3-pyridyl).
  • Most preferred R 3 groups include optionally substituted (but preferably substituted by at least one substituent, e.g. as defined by R 2a ) pyrimidinyl (e.g. in which X 2 and X 4 represent N, X 3 represents C(R 2a ) and X 1 and X 5 independently represent C(R 2b )).
  • Preferred compounds of the invention include those in which:
  • R 2 represents hydrogen or halo (e.g. chloro);
  • R 3 represents substituted phenyl (as defined by fragment IA), optionally substituted 5- or 6-membered monocyclic heteroaryl (as defined by fragment IA or fragment IB) or a 9- or 10-membered bicyclic heteroaryl group (which heteroaryl groups may contain one to four, e.g. 3 or, preferably, 1 or 2, heteroatoms preferably selected from nitrogen, oxygen and sulfur) both of which heteroaryl moieties are optionally substituted by one or more (e.g. two, or, preferably, one) substituent(s) selected from R 2b (when it represents a substituent, i.e. it is other than hydrogen), R 2a and/or E 5 (e.g. -CF 3 , preferably, -OH, -OCH 3 and/or -N(R 5a )R 5b or -N(R 20 )R 21 as appropriate (e.g. -NH 2 ));
  • R 2a and/or E 5 e.g. -CF
  • E 1 to E 8 independently represent Ci_ 6 (e.g. C 1-3 , such as methyl) alkyl optionally substituted by one or more Q 5 substituents, or, preferably, Q 4 ;
  • Q 4 represents -OR 20 , -N(R 20 )R 21 , -S(0) 2 R 2 °, heterocycloalkyi (e.g. a 4- to 6- membered ring, containing preferably one or two heteroatoms selected from nitrogen and oxygen; which heterocycloalkyi group may be substituted but is preferably unsubstituted), aryl (e.g. phenyl; optionally substituted with two or, preferably, one substituent selected from J 3 ) or heteroaryl (e.g. a 5- or 6- membered monocyclic heteroaryl group preferably containing one or two heteroatoms preferably selected from nitrogen, oxygen and sulfur; which group may be substituted, but is preferably unsubstituted);
  • heterocycloalkyi e.g. a 4- to 6- membered ring, containing preferably one or two heteroatoms selected from nitrogen and oxygen; which heterocycloalkyi group may be substituted but is preferably unsubstituted
  • aryl
  • Q 5 represents halo (e.g. fluoro);
  • R 20 and R 21 independently represent hydrogen, C 1-3 alkyl (e.g. methyl or ethyl), which latter group is optionally substituted by one or more (e.g. one) substituent(s) selected from J 4 ;
  • R 20 and R 21 when there is a -N(R 20 )R 21 moiety present, then one of R 20 and R 21 represents hydrogen, and the other represents hydrogen or C 1-3 alkyl (e.g. methyl or ethyl), which latter group is optionally substituted by one or more (e.g. one) substituent(s) selected from J 4 ;
  • J 3 represents Q 7 ;
  • J 4 represents C-,. 6 alkyl, such as C 3 . 6 alkyl (especially C 3 . 6 cycloalkyl, such as cyclopropyl);
  • Q 7 represents -S(0) 2 R 50 ;
  • R 50 represents Ci. 3 alkyl (e.g. methyl).
  • Particularly preferred compounds of the invention include those in which:
  • R 2 represents hydrogen or chloro
  • R 3 represents pyrimidinyl (e.g. 5-pyrimidinyl, such as 2-amino-5-pyrimidinyl (such as 2-NH 2 -pyrimidin-5-yl);
  • B ⁇ B 1a , B 2 , B 2a , B 3 , B 3a , B 4 and B 4a independently represent hydrogen.
  • Particularly preferred compounds of the invention include those in which:
  • a ⁇ a represents C(R 1b );
  • A represents N
  • A4 represents C(R 1a ), represents C(R 1b ) and A 5 represents N;
  • A represents N, A represents N, A 4a represents C(R 1b ) and A 5 represents C(R 2 );
  • A represents C(R 1 ), A4 represents N, 4 3 represents C(R 1b ) and A 5 represents C(R 2 ),
  • Q 1 represents halo, -CN, -N0 2 , -N(R 10a )R a or -OR 0a (in which R 10a and R 11a preferably, and independently, represent hydrogen or C1.4 (e.g. C1.2) alkyl);
  • R 10a and R 11a independently represent hydrogen, C 1-4 (e.g. C 1-2 ) alkyl (optionally (and preferably) substituted by one or more (e.g. one) substituent(s) selected from E 5 ) or heterocycloalkyi (e.g. a 5- or, particularly, 6-membered heterocycloalkyi group containing one or two heteroatoms (e.g. one oxygen heteroatom, so forming e.g. a tetrahydropyranyl group, e.g. 4-tetrahydropyranyl); and which heterocycloalkyi group is preferably unsubstituted);
  • C 1-4 e.g. C 1-2 alkyl
  • heterocycloalkyi e.g. a 5- or, particularly, 6-membered heterocycloalkyi group containing one or two heteroatoms (e.g. one oxygen heteroatom, so forming e.g. a tetrahydropyranyl group, e.g. 4-
  • R 1a (when/if present) represents hydrogen
  • R 3 represents a fragment of formula IA (e.g. pyrimidinyl, such as 5-pyrimidinyl); X 2 and X" independently represent N;
  • X 1 and X 5 independently represent C(R 2 );
  • X 3 represents C(R 2a );
  • each R 2b independently represents halo or, preferably, hydrogen
  • R 2a represents -N(R 5a )R 5 ;
  • R 5a and R 5b independently represent hydrogen;
  • R 10a and R 11a independently represent hydrogen or (e.g. Ci_ 2 ) alkyl or heterocycloalkyl (e.g. a 5- or, preferably, 6-membered heterocycloalkyl group), which latter two groups are optionally (and preferably) substituted by one or more (e.g. one) substituent(s) selected from E 5 ;
  • At least one of R 10a and R 1 a (when attached to the same nitrogen atom) represents hydrogen
  • Q 4 represents -OR 20 ;
  • R 20 represents C 1-4 (e.g. Ci. 2 ) alkyl (e.g. methyl).
  • R 10a and R 11a independently represent hydrogen, C ⁇ e (e.g. Ci_ 3 ) alkyl (optionally substituted by one or more (e.g. one) substituent(s) selected from E 5 ; and which alkyl group may be cyclic, e.g. a C 5 . 6 cycloalkyl group, also optionally substituted) or heterocycloalkyl (e.g. a 5- or, particularly, 6-membered heterocycloalkyl group containing one or two heteroatoms (e.g.
  • R 10a and R 1a may be linked together to form a 5- or 6- membered ring, preferably saturated and unsubstituted, e.g. a pyrrolidinyl;
  • R 10a and R 11a independently represent hydrogen or d. (e.g. C1. 2 ) alkyl or heterocycloalkyl (e.g. a 5- or, preferably, 6-membered heterocycloalkyl group), which latter two groups are optionally substituted by one or more (e.g. one) substituent(s) selected from E 5 , or, R 10a and R 11a are optionally linked as hereinbefore defined;
  • alkyl or heterocycloalkyl e.g. a 5- or, preferably, 6-membered heterocycloalkyl group
  • R 0a and R 1a when attached to the same nitrogen atom, and when R 10a and R 1a are not linked together) represents hydrogen
  • E 5 represents Q 4 ;
  • Q 4 represents -OR 20 or -N(R 20 )R 21 ;
  • R 20 represents hydrogen or C 1- (e.g. Ci -2 ) alkyl (e.g. methyl).
  • R 3 groups include 2-amino-5-pyrimidinyl (e.g. 2-N-[-CH 2 -(4- OCH 3 )phenyl] 2 -5-pyrimidinyl and, preferably, 2-NH 2 -5-pyrimidinyl).
  • Particularly preferred R 1a or R 1b (one of which is necessarily present, e.g. R 1b ) groups include -C(0)-NH 2 , -C(0)N(H)-CH 2 CH 2 -OCH 3 and -C(0)-N(H)-[4-tetrahydropyranyl].
  • Particularly preferred compounds of the invention include those of the examples described hereinafter. Compounds of the invention may be made in accordance with techniques that are well known to those skilled in the art, for example as described hereinafter.
  • L 1 represents a suitable leaving group, such as iodo, bromo, chloro, a sulfonate group (e.g. -OS(0) 2 CF 3 , -OS(0) 2 CH 3 or -OS(0) 2 PhMe), or a sulfide group (e.g. -S-C 6 alkyl, such as -SCH 3 ) and Ai, A4, A4 3 , A 5 , B ⁇ B 1a , B 2 , B 2a , B 3 , B 3a , B 4 and B 4a are as hereinbefore defined, with a compound of formula III,
  • a suitable leaving group such as iodo, bromo, chloro
  • a sulfonate group e.g. -OS(0) 2 CF 3 , -OS(0) 2 CH 3 or -OS(0) 2 PhMe
  • a sulfide group e.g. -S-C 6 alkyl, such as -SCH 3
  • L 2 represents a suitable group such as -B(OH) 2 , -B(OR W) ⁇ )2 or -Sn(R wx ) 3 , in which each R wx independently represents a C 1 .6 alkyl group, or, in the case of -BiOR ⁇ , the respective R wx groups may be linked together to form a 4- to 6- membered cyclic group (such as a 4,4,5, 5-tetramethyl-1 ,3,2-dioxaborolan-2-yl group), thereby forming e.g.
  • a pinacolato boronate ester group (or L 2 may represent iodo, bromo or chloro, provided that L and L 2 are mutually compatible) and R 3 is as hereinbefore defined.
  • the reaction may be performed, for example in the presence of a suitable catalyst system, e.g. a metal (or a salt or complex thereof) such as Pd, Cul, Pd/C, PdCI 2> Pd(OAc) 2 , Pd(Ph 3 P) 2 CI 2> Pd(Ph 3 P) 4 (i.e.
  • a suitable catalyst system e.g. a metal (or a salt or complex thereof) such as Pd, Cul, Pd/C, PdCI 2> Pd(OAc) 2 , Pd(Ph 3 P) 2 CI 2> Pd(Ph 3 P) 4 (i.e.
  • Pd 2 (dba) 3 and/or NiCI 2 palladium
  • Pd 2 (dba) 3 and/or NiCI 2 palladium
  • a ligand such as PdCI 2 (dppf).DCM, f-Bu 3 P, (C 6 Hn) 3 P, Ph 3 P, AsPh 3 , P(o-Tol) 3 , 1 ,2-bis(diphenylphosphino)ethane, 2,2'-bis(di-ferf-butyl- phosphjno)-1, 1'-biphenyl, 2,2'-bis(diphenylphosphino)-1, 1'-bi-naphthyl, 1 , 1'- bis(diphenyl-phosphino-ferrocene), 1 ,3-bis(diphenylphosphino)propane, xantphos, or a mixture thereof
  • PdCI 2 (dppf) Pdppf.DCM,
  • L 1 represents a sulfide (e.g. -SCH 3 )
  • an additive such as CuMeSal (copper(l) 3-methylsalicylate) or CuTC (copper(l)thiophene-2-carboxylate) may also be employed.
  • the reaction may be carried out for example at room temperature or above (e.g. at a high temperature such as at about the reflux temperature of the solvent system).
  • Alternative reaction conditions include microwave irradiation conditions, for example at elevated temperature, e.g. of about 130°C;
  • L 3 represents a suitable leaving group, such as one hereinbefore defined in respect of L or a sulfone (e.g. -S(0) 2 Ci -6 alkyl moiety, such as -S(0) 2 CH 3 ) or sulfide (e.g. -S-d.
  • a suitable leaving group such as one hereinbefore defined in respect of L or a sulfone (e.g. -S(0) 2 Ci -6 alkyl moiety, such as -S(0) 2 CH 3 ) or sulfide (e.g. -S-d.
  • the compound of formula IV (e.g. in which L 3 is chloro) may be prepared in situ, for example from a compound corresponding to a compound of formula IV, but in which L 3 represents -OC 1 -3 alkyl (e.g. methoxy) by reaction in the presence of e.g. a chlorinating agent (such as POCI 3 );
  • an electrophile that provides a source of iodide ions includes iodine, diiodoethane, diiodotetrachloroethane or, preferably, /V-iodosuccinimide
  • a source of bromide ions includes N- bromosuccinimide and bromine
  • a source of chloride ions includes N- chlorosuccinimide, chlorine and iodine monochloride, for instance in the presence of a suitable solvent, such as CHCI 3 or an alcohol (e.g. methanol), optionally in the presence of a suitable base, such as a weak inorganic base, e.g. sodium bicarbonate.
  • the reaction maybe performed by heating at a convenient temperature, either by conventional heating under reflux or under microwave irradiation;
  • R 2aa -L 7 VI wherein R 2aa represents R 2 as hereinbefore described provided that it does not represent hydrogen or halo, and L 7 represents a suitable leaving group such as one hereinbefore described in respect of L 1 or L 2 (see e.g. process step (i); reaction conditions such as those mentioned above may also be employed).
  • R 3 represents either L 1 as hereinbefore defined or R 3 as hereinbefore defined, and wherein either A 4 or A 4a represent C(R 1a ) or C(R 1b ) respectively, in which either R 1a or R 1b represents the relevant -COOR 0a moiety (i.e.
  • -COOR 10a is attached to a carbon atom at either the A or A 4a position), and the other one of A or A4a represents N or C(R 1a ) or C(R 1 ) (as appropriate) in which the other R 1a or R b group represents hydrogen or Q 1 as hereinbefore defined, and B 1 , B 1a , B 2 , B 2a , B 3 , B 3a , B 4 , B 4a , A,, A4, A4, R 3 and R 10a are as hereinbefore defined (R 10a is preferably hydrogen or optionally substituted alkyl), with a compound of formula VIB,
  • R 0a and R 1 a are as hereinbefore defined, under standard amide coupling reaction conditions, i.e. conditions that promote the formation of an amide from a carboxylic acid (or ester thereof), for example in the presence of a suitable coupling reagent (e.g. 1 ,1 '-carbonyldiimidazole, ⁇ , ⁇ 1 - dicyclohexylcarbodiimide, HBTU or the like) or, in the case when R 2 represents an ester (e.g. -C(0)OCH 3 or -C(0)OCH 2 CH 3 ), in the presence of e.g.
  • a suitable coupling reagent e.g. 1 ,1 '-carbonyldiimidazole, ⁇ , ⁇ 1 - dicyclohexylcarbodiimide, HBTU or the like
  • R 2 represents an ester (e.g. -C(0)OCH 3 or -C(0)OCH 2 CH 3 ), in the presence of
  • a -C(0)OH group may first be activated to the corresponding acyl halide (e.g -C(0)CI, by treatment with oxalyl chloride, thionyl chloride, phosphorous pentachloride, phosphorous oxychloride, or the like), and, in all cases, the relevant compound is reacted with a compound of formula VIB as defined above, under standard conditions known to those skilled in the art (e.g. optionally in the presence of a suitable solvent, suitable base and/or in an inert atmosphere).
  • a suitable solvent e.g. ammonia in alcoholic solution
  • the coupling reaction may take place in the presence of a suitable solvent (e.g.
  • R 1a and/or R 1b represents hydrogen
  • a suitable base such as an organometallic base (e.g. an organolithium base, such as t-, s- or n-butyllithium or, preferably a lithium amide base such as diisopropylamide; which deprotonates and/or lithiates at the relevant position), followed by reaction in the presence of an electrophile that is a source of halide ions (e.g. as described in respect of process step (iii)), or C0 2 (to form compounds of formula I in which R 1a and/or R 1b represent -COOH) or a compound of formula VII,
  • organometallic base e.g. an organolithium base, such as t-, s- or n-butyllithium or, preferably a lithium amide base such as diisopropylamide; which deprotonates and/or lithiates at the relevant position
  • an electrophile that is a source
  • L B -R 1 1 VII wherein L 8 represents a suitable leaving group, such as one hereinbefore defined in respect of L 1 (or another suitable leaving group), and R 1b represents -C(0)OR 1t)a (and R 10a is preferably not hydrogen), under standard reaction conditions, for example the deprotonation/lithiation may be performed in an inert atmosphere (e.g. under N 2 ) in the presence of an anhydrous polar aprotic solvent (such as THF, dimethoxyethane, ethyl ether and the like), which may be performed at below room temperature (e.g.
  • an anhydrous polar aprotic solvent such as THF, dimethoxyethane, ethyl ether and the like
  • reaction with the electrophile e.g. halide source or compound of formula VII
  • the subsequent 'quench' i.e. reaction with the electrophile (e.g. halide source or compound of formula VII) may also be performed at low temperatures (e.g. at the temperature of the deprotonation/lithiation), which temperature may be raised up to 0°C (or to rt) to ensure the complete reaction, before the mixture is worked up;
  • halo e.g. iodo, bromo or, preferably, chloro
  • L 1 R 3 represents either L 1 as hereinbefore defined or R 3 as hereinbefore defined
  • R 2 , B 1 , B 1a , B 2 , B 2a , B 3 , B 3a , B 4 and B 4a are as hereinbefore defined, with a compound of formula X,
  • a suitable base for instance a sterically hindered base, such as an amidine base, e.g. DBU
  • a suitable solvent e.g. dichloromethane
  • L 1 R 3 in the compound of formula IX represents L
  • this process step may be proceeded by process step (i) as defined above.
  • Corresponding reactions may also take place in which A 5 represents N (instead of C(R 2 ));
  • L 1 R 3 in the compound of formula XI represents L 1
  • this process step may be proceeded by process step (i) as defined above.
  • L , L 3 , A ⁇ , A 4a , A 5 and R 3 are as hereinbefore defined, with a compound of formula V, as hereinbefore defined, for example under reaction conditions such as those hereinbefore described in respect of preparation of compounds of formula I (process step (ii) above).
  • Compounds of formula IV (for example, in which ⁇ ⁇ represents C(R 1 ), A represents C(R 1a ), A 4a represents C(R 1b ) and A 5 represents C(R 2 )) in which L 3 represents e.g. chloro, bromo or iodo, may be prepared by reaction of a compound of formula XV,
  • Ai, A 4 , A 4a , A 5 and R 3 as hereinbefore defined (or its tautomer), in the presence of a suitable reagent that provides the source of the chloro, bromo or iodo e.g. POCI 3 may be employed, or, a reagent such as p-toluenesulfonyl chloride or the like) under reaction conditions known to the skilled person, for example at reflux (e.g. in the case of reaction with POCI 3 ) or, in the case of reaction with p-toluenesulfonyl chloride, in the presence of a base, such as an organic amine e.g.
  • the compound of formula I may be prepared directly form the intermediate compound IV that may be formed by reaction in the presence of a compound of formula V (which latter reaction need not follow the reaction conditions set out above in respect of process step (ii); for instance, the reaction mixture may simply be heated in the same pot, e.g. at elevated temperature such as at about 65°C.
  • R s2 represents Ci. 6 alkyl (e.g. methyl), and ⁇ ⁇ , A 4l A 4a , A 5 and R 3 are as hereinbefore defined, in the presence of an oxidising agent such as m- chloroperbenzoic acid and, if necessary, a suitable solvent (e.g. dichloromethane).
  • an oxidising agent such as m- chloroperbenzoic acid and, if necessary, a suitable solvent (e.g. dichloromethane).
  • L 15 represents a suitable leaving group, such as one hereinbefore defined by L 1 (e.g. halo, such as bromo), and R 1a and R 10a are as hereinbefore defined (but R 10a is preferably not hydrogen; e.g. it represents alkyl, such as ethyl), for instance the compound of formula XVIB may be ethyl bromopyruvate, under reaction conditions known to those skilled in the art, for instance in the presence of an acid (e.g. an organic acid such as para-toluenesulfonic acid) in the presence of a suitable solvent (e.g.
  • an acid e.g. an organic acid such as para-toluenesulfonic acid
  • a suitable solvent e.g.
  • reaction mixture may be heated at elevated temperature, e.g. at reflux.
  • This reaction may be followed by (if and as appropriate) conversion of the relevant -S-R 3 moieties to other suitable leaving groups (e.g. by oxidation to -S(0) 2 -R 3 ) and/or reaction with a compound of formula V or III as hereinbefore defined (and as appropriate).
  • the reaction of the compound of formula XVIB defined above may take place with a compound of formula XVIA but in which the respective -S-R 3 groups are replaced with a -L -R 3 and an optionally substituted morpholinyl moiety, as appropriate.
  • R 2 , L 1 R 3 , B 1 , B 1a , B 2 , B 2a , B 3 , B 3a , B 4 and B 4a are as hereinbefore defined, with o- (mesitylsulfonyl)hydroxylamine (or the like; i.e. another suitable source of -NH 2 ), under standard reaction conditions known to those skilled in the art, e.g. in the presence of a suitable solvent (e.g. dichloromethane).
  • a suitable solvent e.g. dichloromethane
  • L 1 , R 2 , L 1 R 3 , B 1 , B 1a , B 2 , B 2a , B 3 , B 3a , B 4 and B 4a are as hereinbefore defined, with hydrazine (or a derivative thereof, e.g. hydrazine hydrate), under standard conditions.
  • R s3 represents Ci -6 alkyl (preferably methyl), with a compound of formula XXI,
  • L 15 -C(H)(R 1a )-C(0)-R 1 b XXI wherein L 15 represents a suitable leaving group, such as one hereinbefore defiend by L 1 (e.g. halo, such as bromo) and R 1a and R 1b are as hereinbefore defined, and R 1a preferably represents hydrogen (or a protected derivative thereof; e.g. the compound of formula XXI may be bromoacetaldehyde diethyl acetal, or, when R 1b represents -C(0)Oethyl, the compound of formula XXI may be ethyl bromopyruvate), for example in the presence of an acid catalyst (e.g. p- toluenesulfonic acid or the like), which reaction may be performed at room temperature or preferably at elevated temperature e.g. at about 65°C. Corresponding reactions may also take place in which A 5 represents C(R 2 ).
  • L 1 e.g. halo
  • a ⁇ A 4 , A 4a , A 5 and R are as hereinbefore defined (and R represents a group defined by R s2 and is preferably methyl), under halogenation reaction conditions such as those described herein, e.g. in the presence POCI 3 .
  • L 1 , A 1 t A ⁇ , A ⁇ and A 5 are as hereinbefore defined, for example, in the presence of a base such as a metal hydroxide (e.g. KOH), in the presence of solvent (e.g. an alcohol such as methanol), followed by isolation of any intermediate product and then reaction under conditions such as those hereinbefore described in respect of preparation of compounds of formula IV (e.g. the conditions deployed in the reaction of a compound of formula XV in the presence of POCI 3 , which reaction mixture may be heated at reflux for an appropriate period of time).
  • a base such as a metal hydroxide (e.g. KOH)
  • solvent e.g. an alcohol such as methanol
  • a ! , A 4 , A 4A , A 5 and R 3 as hereinbefore defined in the presence of a suitable reagent for the replacement of the -O- moiety with a -N(H)- moiety, for example ammonia or a source thereof (e.g. ammonium acetate), under standard reaction conditions, for instance optionally in the presence of a suitable solvent (e.g. acetic acid), at elevated temperature (e.g. at about 160°C under microwave irradiation reaction conditions).
  • a suitable reagent for the replacement of the -O- moiety with a -N(H)- moiety for example ammonia or a source thereof (e.g. ammonium acetate)
  • a suitable solvent e.g. acetic acid
  • elevated temperature e.g. at about 160°C under microwave irradiation reaction conditions.
  • a ⁇ may represent -C(R 1 ), in which R 1b represents -C(O)OR 10a and R 10a is preferably ethyl
  • Ai, A , A 4a and R 3 are as hereinbefore defined (but, preferably, Ai represents C(R 1 ), Ai represents N and A a represents C(R 1 ), in which R 1 may represent -C(O)OR 10a ), with a source of ammonia, such as ammonium acetate, for example under reaction conditions such as those described herein (e.g. above), or in the presence of an alcoholic solvent (e.g.
  • Compounds of formula XV, or protected derivatives thereof (which includes salts, e.g. a bromide salt), in which A 5 represents C(R 2 ) (and, preferably, A, a represents N and/or, preferably, ⁇ represents C(R 1 ) and A 4 represents C(R 1a )) may be prepared by reaction of a compound of formula XXVI,
  • A- ! to A4 a -containing ring represents an imidazole ring (i.e. A 4a represents N, and the other ring members are C, then the N at A a may be protected, e.g. by a methyl group, so forming for example 1-methyl-1 H-imidazole- 4-carboxamide) and wherein ⁇ , A4 and A 4a are as hereinbefore defined, with a compound of formula XXVII,
  • L 12 represents a suitable leaving group, such as one hereinbefore defined in respect of L 1 (e.g. halo, preferably, bromo), and R 2 and R 3 are as hereinbefore defined (and R 2 is preferably hydrogen), for example at elevated temperature (e.g at reflux) in the presence of an appropriate solvent (e.g. acetonitrile, dimethylformamide, and the like, or mixtures thereof).
  • an appropriate solvent e.g. acetonitrile, dimethylformamide, and the like, or mixtures thereof.
  • a 5 represents N
  • a ⁇ A4 and A 4a respectively represent C(R 1 ), C(R 1a ) and C(R 1b ) and A 5 represents N
  • A4 represents C(R 1a ) and A4 a and A 5 both represent N
  • a base for instance an aqueous basic solution such as ammonium hydroxide, or a metal alkyl-oxide (e.g. potassium terf-butoxide) in an alcoholic solution (e.g. butanol), for instance at elevated temperature e.g. at about 120°C under microwave irradiation reaction conditions.
  • a base for instance an aqueous basic solution such as ammonium hydroxide, or a metal alkyl-oxide (e.g. potassium terf-butoxide) in an alcoholic solution (e.g. butanol), for instance at elevated temperature e.g. at about 120°C under microwave irradiation reaction conditions.
  • a base for
  • amido-compounds may be prepared by coupling of the corresponding carboxylic acid with ammonia (or a suitable source thereof, e.g. NH 4 CI in NH 3 / eOH).
  • L 3 represents a suitable leaving group (such as halo, e.g. iodo) and R s2 is as hereinbefore defined (e.g. methyl iodide), for example in the presence of aqueous NaOH solution and an alocoholic solvent (e.g. methanol).
  • R s2 is as hereinbefore defined (e.g. methyl iodide), for example in the presence of aqueous NaOH solution and an alocoholic solvent (e.g. methanol).
  • L 17 represents a suitable leaving group (e.g. halo, such as chloro), Ai is preferably N, A 4 is C(R a ) and A 5 is C(R 1b ), for example in the presence of base at elevated temperature, followed by standard modification and/or introduction of functional groups.
  • a suitable leaving group e.g. halo, such as chloro
  • L 18 represents a suitable leaving group, such as one hereinbefore defined by L 1 (and preferably bromo, chloro or especially iodo), for instance in the presence of a base (e.g. an organic amine, such as DIPEA or the like) and a suitable solvent (e.g. DCM).
  • a base e.g. an organic amine, such as DIPEA or the like
  • a suitable solvent e.g. DCM
  • a suitable aminating agent for instance a hydroxylamine compound (e.g. a sulfonyl-hydroxylamine, such as o-(meistylsulfonyl)hydroxylamine), under standard reaction conditions.
  • a suitable aminating agent for instance a hydroxylamine compound (e.g. a sulfonyl-hydroxylamine, such as o-(meistylsulfonyl)hydroxylamine), under standard reaction conditions.
  • A,, ) and A 4a are as hereinbefore defined (but, preferably, ⁇ represents C(R 1a ), A 4a represents C(R b ) and A, represents N), in the presence of a compound of formula XXXI as hereinbefore defined but in which R s2 represents R 53 .
  • L 9 represents a suitable leaving group, for example one hereinbefore defined in respect of L 1 (e.g. halo, and preferably, bromo), under standard reaction conditions, for example, optionally in the presence of a suitable base (preferably an inorganic base, such as NaH, K 3 P0 4 , Cs 2 C0 3 , f-BuONa, f-BuOK, and, more preferably an inorganic carbonate such as Na 2 C0 3 and, preferably, K 2 C0 3 ) and a suitable solvent (e.g. an aprotic solvent such as dichloromethane or, preferably, acetone).
  • a suitable base preferably an inorganic base, such as NaH, K 3 P0 4 , Cs 2 C0 3 , f-BuONa, f-BuOK, and, more preferably an inorganic carbonate such as Na 2 C0 3 and, preferably, K 2 C0 3
  • a suitable solvent e.g. an aprotic solvent such as dich
  • XXXVIII or a derivative thereof (e.g. ester such as ethyl ester), wherein A A4 and fi ⁇ a are as hereinbefore defined, with a compound of formula XXXIX,
  • L 10 represents a suitable leaving group, such as one hereinbefore defined in respect of L 1 (e.g. halo, such as bromo), and R 3 is as hereinbefore defined, under standard reaction conditions, for example optionally in the presence of a suitable base and solvent (such as those hereinbefore described in respect of preparation of compounds of formula XXIV (by reaction of a compound of formula XXXVI and XXXVII), e.g. K 2 C0 3 in acetone).
  • a suitable base and solvent such as those hereinbefore described in respect of preparation of compounds of formula XXIV (by reaction of a compound of formula XXXVI and XXXVII), e.g. K 2 C0 3 in acetone.
  • Compounds of formula XXVI may be prepared by reaction of a compound of formula XXXVIII as hereinbefore defined, or a derivative thereof (e.g. an ester, such as an ethyl ester), with ammonia or a suitable source thereof (e.g. NH 4 CI in a solution of NH 3 in an alcohol such as methanol).
  • a compound of formula XXXVIII as hereinbefore defined, or a derivative thereof (e.g. an ester, such as an ethyl ester), with ammonia or a suitable source thereof (e.g. NH 4 CI in a solution of NH 3 in an alcohol such as methanol).
  • L 11 represents a suitable leaving group such as one hereinbefore defined by L 1 (e.g. halo, such as chloro) or -OH (or an ester, thereof) under standard acylation or amide coupling reaction conditions, e.g. in the case of acylation, the presence of an appropriate base (e.g. an organic amine base such as triethylamine) and an appropriate solvent (e.g. pyridine, dichloromethane, dioxane, etc, or mixtures thereof), or, in the case of amide couplings, under conditions described hereinafter (or e.g. in the presence of polyphosphoric acid, which advantageously may form a compound of formula XXVIII in situ, which may undergo subsequent reaction to provide the compound of formula XV isoquinolinone directly).
  • L 1 e.g. halo, such as chloro
  • -OH or an ester, thereof
  • a ⁇ , and A a are as hereinbefore defined, under standard hydrolysis reaction conditions, e.g. in the presence of an aqueous hydroxide base (e.g. potassium hydroxide) in a suitable solvent such as tetrahydrofuran.
  • aqueous hydroxide base e.g. potassium hydroxide
  • suitable solvent such as tetrahydrofuran.
  • Compounds of formula XXIX (or the corresponding carboxylic acid or ester) may also be prepared by amination of a compound of formula XXVI as hereinbefore defined, or compounds of formula XLI may also be prepared by amination of a compound of formula XLII,
  • Ai, A 4 and A 4a are as hereinbefore defined, under reaction conditions such as those described hereinafter, e.g. in the presence of sodium hydride, followed by o-(diphenylphosphinyl)hydroxylamine.
  • XLIIA In the presence of a suitable reagent for the conversion of a carbonyl group to a thiocarbonyl group, for instance in the presence of Lawesson's reagent or phosphorous pentasulfide, in the presence of a suitable solvent (e.g. dry pyridine), which reaction mixture may be heated at elevated temperature, for instance at reflux.
  • a suitable solvent e.g. dry pyridine
  • Compounds of formula XXXIX in which L 10 represents halo may be prepared by reaction of a compound corresponding to a compound of formula XXXIX but in which L 0 represents hydrogen, with a source of halide ions (e.g. such as one hereinbefore described in respect of preparation of compounds of formula I; process step (iii) above), such as N- chlorosuccinimide or /V-bromosuccinimide, under standard reaction conditions e.g. in the presence of a suitable base (such as an organic base e.g. triethylamine or the like) and trimethylsilylfluoromethanesulfonate, or the like.
  • a source of halide ions e.g. such as one hereinbefore described in respect of preparation of compounds of formula I; process step (iii) above
  • a source of halide ions e.g. such as one hereinbefore described in respect of preparation of compounds of formula I; process step (iii
  • L 11 represents a suitable leaving group, such as one hereinbefore defined in respect of L 1 (e.g. halo, such as chloro or, preferably bromo), with a compound that allows the introduction of the -C(0)CH 3 moiety, such as tributyl(1- ethoxyvinyl)tin in the presence of a precious metal catalyst/ligand (e.g. dichlorobis(triphenyl-phosphine)palladium (II)) and a suitable solvent (e.g. dimethylformamide, or the like).
  • a precious metal catalyst/ligand e.g. dichlorobis(triphenyl-phosphine)palladium (II)
  • a suitable solvent e.g. dimethylformamide, or the like.
  • Compounds of formula XLI may be prepared by reaction of a compound of formula XLII as hereinbefore defined, for example by reaction in the presence of base (e.g.
  • a metal hydride such as sodium hydride
  • an appropriate reagent for the introduction of the amino group e.g. o-(diphenylphosphinyl)- hydroxylamine, or another reagent suitable for electrophilic aminations, under reaction conditions such as those described hereinafter.
  • Ai, A 4 and A a are as hereinbefore defined, in the presence of hydroxylamine (e.g. the hydrochloride thereof), followed by dehydration (in the presence of a suitable dehydrating agent, such as phthalic anhydride).
  • hydroxylamine e.g. the hydrochloride thereof
  • dehydration in the presence of a suitable dehydrating agent, such as phthalic anhydride.
  • a suitable dehydrating agent such as phthalic anhydride
  • L 19 represents a suitable leaving group such as one hereinbefore defined by L 1 (e.g. bromo), in the presence of a source of ammonia (e.g. liquid ammonia), for instance under coupling reaction conditions e.g. in the presence of a metal catalyst e.g. copper.
  • a source of ammonia e.g. liquid ammonia
  • amide coupling reactions i.e. the formation of an amide from a carboxylic acid (or ester thereof), for example when R 2 represents -C(0)OH (or an ester thereof), it may be converted to a -C(O)N(R 10 )R 11b group (in which R 10b and R 11b are as hereinbefore defined, and may be linked together, e.g. as defined above), and which reaction may (e.g. when R 2 represents -C(O)OH) be performed in the presence of a suitable coupling reagent (e.g.
  • R 2 represents an ester (e.g. -C(0)OCH 3 or -C(0)OCH 2 CH 3 ), in the presence of e.g.
  • the -C(0)OH group may first be activated to the corresponding acyl halide (e.g -C(0)CI, by treatment with oxalyl chloride, thionyl chloride, phosphorous pentachloride, phosphorous oxychloride, or the like), and, in all cases, the relevant compound is reacted with a compound of formula HN(R 10a )R 11a (in which R 10a and R 11a are as hereinbefore defined), under standard conditions known to those skilled in the art (e.g. optionally in the presence of a suitable solvent, suitable base and/or in an inert atmosphere);
  • acyl halide e.g -C(0)CI, by treatment with oxalyl chloride, thionyl chloride, phosphorous pentachloride, phosphorous oxychloride, or the like
  • nucleophilic substitution reactions where any nucleophile replaces a leaving group, e.g. methylsulfonylpiperazine may replace a chloro leaving group, or, aromatic nucleophilic substitution reactions such as the substitution of ammonia (or a protected derivative thereof, e.g. a dibenzyl derivative) onto an aromatic group bearing a leaving group (e.g. onto a 2-chloropyrimidinyl moiety);
  • a leaving group e.g. methylsulfonylpiperazine may replace a chloro leaving group
  • aromatic nucleophilic substitution reactions such as the substitution of ammonia (or a protected derivative thereof, e.g. a dibenzyl derivative) onto an aromatic group bearing a leaving group (e.g. onto a 2-chloropyrimidinyl moiety);
  • the substituents R 3 , B 1 , B a , B 2 , B a , B 3 , B 3a , B 4 , B 4a , A,, A 2 , A 3 , A 4 , A 4a and A 5 in final compounds of the invention or relevant intermediates may be modified one or more times, after or during the processes described above by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions, oxidations, alkylations, acylations, hydrolyses, esterifications, etherifications, halogenations or nitrations. Such reactions may result in the formation of a symmetric or asymmetric final compound of the invention or intermediate.
  • the precursor groups can be changed to a different such group, or to the groups defined in formula I, at any time during the reaction sequence.
  • substituents in the compounds of the invention e.g. represented by R 3 , B 1 , B 1a , B 2 , B 2a , B 3 , B 3a , B 4 , B a , Ai, A 2 , A 3 , A4, A4 3 and A 5
  • substituents in the compounds of the invention e.g. represented by R 3 , B 1 , B 1a , B 2 , B 2a , B 3 , B 3a , B 4 , B a , Ai, A 2 , A 3 , A4, A4 3 and A 5
  • these groups can be further derivatized to other fragments described (e.g. by those integers mentioned above) in compounds of the invention, following synthetic protocols very well know to the person skilled in the art and/or according to the experimental part described in the patent.
  • transformation steps include: the reduction of a nitro or azido group to an amino group; the hydrolysis of a nitrile group to a carboxylic acid group; and standard nucleophilic aromatic substitution reactions, for example in which an iodo-, preferably, fluoro- or bromo-phenyl group is converted into a cyanophenyl group by employing a source of cyanide ions (e.g. by reaction with a compound which is a source of cyano anions, e.g.
  • a palladium catalyst preferably iodo or bromo
  • a suitable coupling catalyst e.g. a palladium and/or a copper based catalyst
  • a suitable base e.g. a tri-(Ci.
  • 6 alkyl)amine such as triethylamine, tributylamine or ethyldiisopropylamine
  • introduction of amino groups and hydroxy groups in accordance with standard conditions using reagents known to those skilled in the art; the conversion of an amino group to a halo, azido or a cyano group, for example via diazotisation (e.g. generated in situ by reaction with NaN0 2 and a strong acid, such as HCI or H 2 S0 , at low temperature such as at 0°C or below, e.g. at about -5°C) followed by reaction with the appropriate nucleophile e.g.
  • diazotisation e.g. generated in situ by reaction with NaN0 2 and a strong acid, such as HCI or H 2 S0 , at low temperature such as at 0°C or below, e.g. at about -5°C
  • reaction with the appropriate nucleophile e.g.
  • a source of the relevant anions for example by reaction in the presence of a halogen gas (e.g. bromine, iodine or chlorine), or a reagent that is a source of azido or cyanide anions, such as NaN 3 or NaCN; the conversion of -C(0)OH to a -NH 2 group, under Schmidt reaction conditions, or variants thereof, for example in the presence of HN 3 (which may be formed in by contacting NaN 3 with a strong acid such as H 2 S0 4 ), or, for variants, by reaction with diphenyl phosphoryl azide ((PhO) 2 P(0)N 3 ) in the presence of an alcohol, such as ferf-butanol, which may result in the formation of a carbamate intermediate; the conversion of -C(0)NH 2 to -NH 2 , for example under Hofmann rearrangement reaction conditions, for example in the presence of NaOBr (which may be formed by contacting NaOH and Br 2 ) which may result in the formation of a
  • Compounds of the invention bearing a carboxyester functional group may be converted into a variety of derivatives according to methods well known in the art to convert carboxyester groups into carboxamides, N-substituted carboxamides, ⁇ , ⁇ -disubstituted carboxamides, carboxylic acids, and the like.
  • the operative conditions are those widely known in the art and may comprise, for instance in the conversion of a carboxyester group into a carboxamide group, the reaction with ammonia or ammonium hydroxide in the presence of a suitable solvent such as a lower alcohol, dimethylformamide or a mixture thereof; preferably the reaction is carried out with ammonium hydroxide in a methanol/dimethyl- formamide mixture, at a temperature ranging from about 50°C to about 100°C.
  • Analogous operative conditions apply in the preparation of N-substituted or N,N- disubstituted carboxamides wherein a suitable primary or secondary amine is used in place of ammonia or ammonium hydroxide.
  • carboxyester groups may be converted into carboxylic acid derivatives through basic or acidic hydrolysis conditions, widely known in the art.
  • amino derivatives of compounds of the invention may easily be converted into the corresponding carbamate, carboxamido or ureido derivatives.
  • Compounds of the invention may be isolated from their reaction mixtures using conventional techniques (e.g. recrystallisations). It will be appreciated by those skilled in the art that, in the processes described above and hereinafter, the functional groups of intermediate compounds may need to be protected by protecting groups.
  • Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), 9-fluorenylmethyleneoxycarbonyl (Fmoc) and 2,4,4-trimethylpentan-2-yl (which may be deprotected by reaction in the presence of an acid, e.g. HCI in water/alcohol (e.g. MeOH)) or the like.
  • an acid e.g. HCI in water/alcohol (e.g. MeOH)
  • the protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes.
  • Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter. For example, protected compounds/intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques.
  • Compounds of the invention may inhibit protein or lipid kinases, such as a PI3 kinase (especially a class I PI3K), for example as may be shown in the tests described below (for example, the test for PI3Koc inhibition described below) and/or in tests known to the skilled person.
  • the compounds of the invention may also inhibit mTOR.
  • the compounds of the invention may be useful in the treatment of those disorders in an individual in which the inhibition of such protein or lipid kinases (e.g. PI3K, particularly class I PI3K, and/or mTOR) is desired and/or required (for instance compounds of the invention may inhibit PI3K, particularly class I PI3K and, optionally, may also inhibit mTOR).
  • inhibitor may refer to any measurable reduction and/or prevention of catalytic kinase (e.g. PI3K, particularly class I PI3K, and/or mTOR) activity.
  • the reduction and/or prevention of kinase activity may be measured by comparing the kinase activity in a sample containing a compound of the invention and an equivalent sample of kinase (e.g. PI3K, particularly class I PI3K, and/or mTOR) in the absence of a compound of the invention, as would be apparent to those skilled in the art.
  • the measurable change may be objective (e.g.
  • test or marker for example in an in vitro or in vivo assay or test, such as one described hereinafter, or otherwise another suitable assay or test known to those skilled in the art) or subjective (e.g. the subject gives an indication of or feels an effect).
  • Compounds of the invention may be found to exhibit 50% inhibition of a protein or lipid kinase (e.g. PI3K, such as class I PI3K, and/or mTOR) at a concentration of 100 ⁇ or below (for example at a concentration of below 50 ⁇ , or even below 10 ⁇ , such as below 1 ⁇ ), when tested in an assay (or other test), for example as described hereinafter, or otherwise another suitable assay or test known to the skilled person.
  • PI3K protein or lipid kinase
  • assay or other test
  • a protein or lipid kinase e.g. PI3K, such as class I PI3K, and/or mTOR
  • PI3K protein or lipid kinase
  • mTOR a protein or lipid kinase
  • compounds of the invention are expected to be useful in the treatment of a disease/disorder arising from abnormal cell growth, function or behaviour associated with the protein or lipid kinase (e.g. PI3K, such as class I PI3K, and/or mTOR).
  • Such conditions/disorders include cancer, immune disorders, cardiovascular diseases, viral infections, inflammation, metabolism/endocrine function disorders and neurological disorders.
  • the disorders/conditions that the compounds of the invention may be useful in treating hence includes cancer (such as lymphomas, solid tumours or a cancer as described hereinafter), obstructive airways diseases, allergic diseases, inflammatory diseases (such as asthma, allergy and Chrohn's disease), immunosuppression (such as transplantation rejection and autoimmune diseases), disorders commonly connected with organ transplantation, AIDS- related diseases and other associated diseases.
  • Other associated diseases that may be mentioned (particularly due to the key role of kinases in the regulation of cellular proliferation) include other cell proliferative disorders and/or non- malignant diseases, such as benign prostate hyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis, psoriasis, bone disorders, atherosclerosis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis.
  • non- malignant diseases such as benign prostate hyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis, psoriasis, bone disorders, atherosclerosis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis.
  • cardiovascular disease cardiovascular disease, stroke, diabetes, hepatomegaly, Alzheimer's disease, cystic fibrosis, hormone- related diseases, immunodeficiency disorders, destructive bone disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukaemia, liver disease, pathologic immune conditions involving T cell activation and CNS disorders.
  • cardiovascular disease stroke, diabetes, hepatomegaly, Alzheimer's disease, cystic fibrosis, hormone- related diseases, immunodeficiency disorders, destructive bone disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukaemia, liver disease, pathologic immune conditions involving T cell activation and CNS disorders.
  • the compounds of the invention may be useful in the treatment of cancer.
  • the compounds of the invention may therefore be useful in the treatment of a variety of cancer including, but not limited to: carcinoma such as cancer of the bladder, breast, colon, kidney, liver, lung (including non-small cell cancer and small cell lung cancer), esophagus, gall- bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, skin, squamous cell carcinoma, testis, genitourinary tract, larynx, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, small cell lung carcinoma, lung adenocarcinoma, bone, adenoma, adenocarcinoma, follicular carcinoma, undifferentiated carcinoma, papilliary carcinoma, seminona, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, hairy cells
  • carcinoma
  • protein or lipid kinases may also be implicated in the multiplication of viruses and parasites. They may also play a major role in the pathogenesis and development of neurodegenerative disorders. Hence, compounds of the invention may also be useful in the treatment of viral conditions, parasitic conditions, as well as neurodegenerative disorders.
  • a method of treatment of a disease which is associated with the inhibition of protein or lipid kinase (e.g. PI3K, such as class I PI3K, and/or mTOR), i.e. where such inhibition is desired and/or required (for example, a method of treatment of a disease/disorder arising from abnormal cell growth, function or behaviour associated with protein or lipid kinases, e.g. PI3K, such as class I PI3K, and/or mTOR), which method comprises administration of a therapeutically effective amount of a compound of the invention, as hereinbefore defined, to a patient suffering from, or susceptible to, such a condition.
  • PI3K protein or lipid kinase
  • “Patients” include mammalian (including human) patients. Hence, the method of treatment discussed above may include the treatment of a human or animal body.
  • the term "effective amount” refers to an amount of a compound, which confers a therapeutic effect on the treated patient. The effect may be objective (e.g. measurable by some test or marker) or subjective (e.g. the subject gives an indication of or feels an effect).
  • Compounds of the invention may be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, sublingually, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form.
  • Compounds of the invention may be administered alone, but are preferably administered by way of known pharmaceutical formulations, including tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.
  • the type of pharmaceutical formulation may be selected with due regard to the intended route of administration and standard pharmaceutical practice.
  • Such pharmaceutically acceptable carriers may be chemically inert to the active compounds and may have no detrimental side effects or toxicity under the conditions of use.
  • Such formulations may be prepared in accordance with standard and/or accepted pharmaceutical practice. Otherwise, the preparation of suitable formulations may be achieved non-inventively by the skilled person using routine techniques and/or in accordance with standard and/or accepted pharmaceutical practice.
  • a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier.
  • pharmaceutical formulations that may be mentioned include those in which the active ingredient is present in at least 1 % (or at least 10%, at least 30% or at least 50%) by weight. That is, the ratio of active ingredient to the other components (i.e. the addition of adjuvant, diluent and carrier) of the pharmaceutical composition is at least 1 :99 (or at least 10:90, at least 30:70 or at least 50:50) by weight.
  • the amount of compound of the invention in the formulation will depend on the severity of the condition, and on the patient, to be treated, as well as the compound(s) which is/are employed, but may be determined non-inventively by the skilled person.
  • the invention further provides a process for the preparation of a pharmaceutical formulation, as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, or a pharmaceutically acceptable ester, amide, solvate or salt thereof with a pharmaceutically-acceptable adjuvant, diluent or carrier.
  • Compounds of the invention may also be combined with other therapeutic agents that are inhibitors of protein or lipid kinases (e.g. PI3K, such as class I PI3K, a PI family kinase (e.g. PIM-1 , PIM-2- and/or PI -3) and/or mTOR) and/or useful in the treatment of a cancer and/or a proliferative disease.
  • PI3K protein or lipid kinases
  • a combination product comprising:
  • each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
  • Such combination products provide for the administration of a compound of the invention in conjunction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises a compound of the invention, and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including a compound of the invention and the other therapeutic agent).
  • a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, another therapeutic agent that is useful in the treatment of cancer and/or a proliferative disease, and a pharmaceutically-acceptable adjuvant, diluent or carrier; and
  • a pharmaceutical formulation including another therapeutic agent that is useful in the treatment of cancer and/or a proliferative disease in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.
  • the invention further provides a process for the preparation of a combination product as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, or a pharmaceutically acceptable ester, amide, solvate or salt thereof with the other therapeutic agent that is useful in the treatment of cancer and/or a proliferative disease, and at least one pharmaceutically-acceptable adjuvant, diluent or carrier.
  • kits of parts By “bringing into association”, we mean that the two components are rendered suitable for administration in conjunction with each other.
  • the two components of the kit of parts may be:
  • compounds of the invention may be administered at varying therapeutically effective doses to a patient in need thereof.
  • the dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the mammal over a reasonable timeframe.
  • the selection of the exact dose and composition and the most appropriate delivery regimen will also be influenced by inter alia the pharmacological properties of the formulation, the nature and severity of the condition being treated, and the physical condition and mental acuity of the recipient, as well as the potency of the specific compound, the age, condition, body weight, sex and response of the patient to be treated, and the stage/severity of the disease.
  • Administration may be continuous or intermittent (e.g. by bolus injection).
  • the dosage may also be determined by the timing and frequency of administration.
  • the dosage can vary from about 0.01 mg to about 1000 mg per day of a compound of the invention.
  • the medical practitioner or other skilled person, will be able to determine routinely the actual dosage, which will be most suitable for an individual patient.
  • the above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • Compounds of the invention may have the advantage that they are effective inhibitors of protein or lipid kinases (e.g. PI3K, such as class I PI3K, and/or mTOR).
  • compounds of the invention may inhibit (e.g. selectively) certain protein or lipid kinases (e.g. PI3K, such as class I PI3K), without exhibiting inhibition (or significant inhibition) of other protein or lipid kinases.
  • the compounds of the invention may selectively inhibit only one protein or lipid kinase (e.g. PI3K, such as class I PI3K).
  • Compounds of the invention may also have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the above- stated indications or otherwise.
  • pharmacokinetic profile e.g. higher oral bioavailability and/or lower clearance
  • Compounds of the invention may be beneficial as they are medicaments with targeted therapy, i.e. which target a particular molecular entity by inferring or inhibiting it (e.g. in this case by inhibiting one or more protein or lipid kinases as hereinbefore described). Compounds of the invention may therefore also have the benefit that they have a new effect (for instance as compared to known compounds in the prior art), for instance, the new effect may be a particular mode of action or another effect resultant of the targeted therapy.
  • Targeted therapies may be beneficial as they may have the desired effect (e.g. reduce cancer, by reducing tumor growth or carcinogenisis) but may also have the advantage of reducing side effects (e.g. by preventing the killing of normal cells, as may occur using e.g. chemotherapy).
  • compounds of the invention may selectively target particular protein or lipid kinases (e.g. the ones described herein) compared to other known protein or lipid kinases (as may be shown experimentally hereinafter; see Table 4 for example). Accordingly, compounds of the invention may have the advantage that certain, specific, cancers may be treated selectively, which selective treatment may also have the effect of reducing side effects.
  • PI3 kinase activity of compounds of the invention is possible by a number of direct and indirect detection methods.
  • Certain exemplary compounds described herein were prepared, characterized, and tested for their PI3K binding activity and in vitro activity against tumor cells.
  • the range of PI3K binding activities was less than 1 nM to about 10 ⁇ (i.e. certain compounds of the examples/invention had PI3K binding activity IC S0 values of less than 10 nM).
  • Compounds of the examples/invention had tumor cell-based activity IC 50 values less than 100 nM (see Table(s) below).
  • the kinase activity was measured by using the commercial ADP HunterTM Plus assay available from DiscoveR x (#33-016), which is a homogeneous assay to measure the accumulation of ADP, a universal product of kinase activity.
  • the enzyme, PI3K ( ⁇ 1 10 ⁇ / ⁇ 85 ⁇ was purchased from Carna Biosciences (#07CBS- 0402A).
  • the assay was done following the manufacturer recommendations with slight modifications: Mainly the kinase buffer was replace by 50 mM HEPES, pH 7.5, 3 mM MgCI 2 , 100 mM NaCI, 1 mM EGTA, 0.04% CHAPS, 2 mM TCEP and 0.01 mg/ml BGG.
  • the PI3K was assayed in a titration experiment to determine the optimal protein concentration for the inhibition assay.
  • serial 1 :5 dilutions of the compounds were added to the enzyme at a fixed concentration (2.5 ⁇ g/ml.
  • the enzyme was preincubated with the inhibitor and 30 ⁇ PIP 2 substrate (P9763, Sigma) for 5 min and then ATP was added to a final 50 ⁇ concentration. Reaction was carried out for 1 hour at 25°C. Reagent A and B were sequentially added to the wells and plates were incubated for 30 min at 37 °C.
  • the cell lines were obtained from the American Type Culture Collection (ATCC). U20S (human osteosarcoma) was cultured in Dulbecco's modified Eagle's medium (DMEM). PC3 (human prostate carcinoma), MCF7 (human breast cardinoma), HCT1 16 (human colon carcinoma), 768-0 (human neuroblastoma), U251 (human glyoblastoma) were grown in RPMI. All media were supplemented with 10% fetal bovine serum (FBS) (Sigma) and antibiotics- antimycotics. Cell were maintained in a humidified incubator at 37°C with 5% C0 2 and passaged when confluent using trypsin/EDTA.
  • FBS fetal bovine serum
  • U2foxRELOC and U2nesRELOC assay The U2nesRELOC assay and the U2foxRELOC assay have been described previously (1 , 2). Briefly, cells were seeded at a density of 1.0*10 5 cells/ml into black-wall clear-bottom 96-well microplates (BD Biosciences) After incubation at 37°C with 5% C0 2 for 12 hours, 2 ⁇ of each test compound were transferred from the mother plates to the assay plates. Cells were incubated in the presence of the compounds for one hour. Then cells were fixed and the nucleus stained with DAPI (Invitrogen). Finally the plates were washed with 1X PBS twice and stored at 4°C before analysis. Compounds of the invention have a range of in vitro cell potency activities from about 1 nM to about 10 ⁇ .
  • Image acquirement and processing Assay plates were read on the BD PathwayTM 855 Bioimager equipped with a 488/10 nm EGFP excitation filter, a 380/10 nm DAPI excitation filter, a 515LP nm EGFP emission filter and a 435LP nm DAPI emission filter. Images were acquired in the DAPI and GFP channels of each well using 10x dry objective. The plates were exposed 0.066 ms (Gain 31) to acquire DAPI images and 0.55 ms (Gain 30) for GFP images.
  • the BD Pathway Bioimager outputs its data in standard text files. Data were imported into the data analysis software BD Image Data Explorer.
  • the nuclear/cytoplasmic (Nuc/Cyt) ratios of fluorescence intensity were determined by dividing the fluorescence intensity of the nucleus by the cytoplasmic.
  • a threshold ratio of greater than 1.8 was employed to define nuclear accumulation of fluorescent signal for each cell. Based on this procedure we calculated the percentage of cells per well displaying nuclear translocation or inhibition of nuclear export. Compounds that induced a nuclear accumulation of the fluorescent signal greater than 60% of that obtained from wells treated with 4n LMB were considered as hits.
  • AKT phosphorylation Inhibition was incubated under different conditions and washed twice with TBS prior to lysis. Lysis buffer was added containing 50 mM Tris HCI, 150 mM NaCI, 1 % NP- 40, 2mM Na 3 V0 4 , 100 mM NaF, 20 mM Na P 2 0 7 and protease inhibitor cocktail (Roche Molecular Biochemicals). The proteins were resolved on 10% SDS-PAGE and transferred to nitrocellulose membrane (Schleicher & Schuell, Dassel, Germany).
  • the membranes were incubated overnight at 4°C with antibodies specific for Akt, phospho-Ser-473-Akt (Cell Signaling Technology) and a-tubulin (Sigma), they were washed and then incubated with IRDye800 conjugated anti- mouse and Alexa Fluor 680 goat anti-rabbit IgG secondary antibodies.
  • the bands were visualized using an Odyssey infrared imaging system (Li-Cor Biosciences).
  • Compounds of the invention have a range of in vitro cell potency activities from about 1 nM to about 10 ⁇ .
  • the compounds were tested on 96-well trays. Cells growing in a flask were harvested just before they became confluent, counted using a haemocytometer and diluted down with media adjusting the concentration to the required number of cells per 0.2 ml (volume for each well). Cells were then seeded in 96-well trays at a density between 1000 and 4000 cells/well, depending of the cell size. Cells were left to plate down and grow for 24 hours before adding the drugs. Drugs were weighed out and diluted with DMSO to get them into solution to a concentration of 10mM. From here a "mother plate" with serial dilutions was prepared at 200X the final concentration in the culture.
  • the final concentration of DMSO in the tissue culture media should not exceed 0.5%.
  • the appropriate volume of the compound solution (usually 2 microlitres) was added automatically (Beckman FX 96 tip) to media to make it up to the final concentration for each drug.
  • the medium was removed from the cells and replaced with 0.2 ml of medium dosed with drug.
  • Each concentration was assayed in triplicate.
  • Two sets of control wells were left on each plate, containing either medium without drug or medium with the same concentration of DMSO.
  • a third control set was obtained with the cells untreated just before adding the drugs (seeding control, number of cells starting the culture). Cells were exposed to the drugs for 72 hours and then processed for MTT colorimetric read-out.
  • Compounds of the invention have a range of in vitro cell potency activities from about 1 nM to about 10 ⁇ .
  • Mammalian target of rapamycin was assayed by monitoring phosphorylation of GFP-4EBP using a homogeneous time-resolved fluorescence resonante energy transfer format and assay reagents from Invitrogen.
  • mTOR phosphorylation of GFP-4EBP
  • a homogeneous time-resolved fluorescence resonante energy transfer format and assay reagents from Invitrogen In the presence of 10 ⁇ ATP, 50 mM Hepes (pH 7.5), 0.01 % (v/v) Polysorbate 20, 10 mM MnCI 2 , 1 rnM EGTA, and 2.5 mM DTT, the mTOR-mediated phosphorylation of 200 nM GFP-4E-BP1 was measured under initial rate conditions.
  • the HPLC measurement was performed using a HP 1 100 from Agilent Technologies comprising a pump (binary) with degasser, an autosampler, a column oven, a diode-array detector (DAD) and a column as specified in the respective methods below.
  • Flow from the column was split to a MS spectrometer.
  • the MS detector was configured with an electrospray ionization source or API/APCI. Nitrogen was used as the nebulizer gas.
  • the source temperature was maintained at 150 °C.
  • Data acquisition was performed with ChemStation LC/MSD quad, software.
  • Reversed phase HPLC was carried out on a Gemini-NX C18 (100 x 2.0 mm; 5 urn), Solvent A: water with 0.1 % formic acid; Solvent B: acetonitrile with 0.1 % formic acid. Gradient: 5% of B to 100% of B within 8 min at 50 °C, DAD.
  • Reversed phase HPLC was carried out on a Gemini-NX C18 (100 x 2.0 mm; 5 urn), Solvent A: water with 0.1 % formic acid; Solvent B: acetonitrile with 0.1 % formic acid. Gradient: 5% of B to 40% of B within 8 min at 50 °C, DAD.
  • Table 1 Analytical data and PI3Ka activity - R t means retention time (in minutes), [M+H] + means the protonated mass of the compound, method refers to the method used for (LC)MS.

Abstract

There is provided compounds of formula (I), wherein A1, A4, A4a, A5, B1, B1a, B2, B2a, B3, B3a, B4, B4a and R3 have meanings given in the description, and pharmaceutically-acceptable esters, amides, solvates or salts thereof, which compounds are useful in the treatment of diseases in which inhibition of a protein or lipid kinase (e.g. a PI3-K and/or mTOR) is desired and/or required, and particularly in the treatment of cancer or a proliferative disease.

Description

NEW BICYCLIC COMPOUNDS AS PI3-K AND MTOR INHIBITORS
Field of the Invention This invention relates to novel pharmaceutically-useful compounds, which compounds are useful as inhibitors of protein or lipid kinases (such as inhibitors of the phosphoinositide 3ΌΗ kinase (PI3 kinase) family, particularly the PI3K class I sub-type. The compounds may also be useful as inhibitors of the mammalian target of rapamycin (mTOR)). The compounds are of potential utility in the treatment of diseases such as cancer. The invention also relates to the use of such compounds as medicaments, to the use of such compounds for in vitro, in situ and in vivo diagnosis or treatment of mammalian cells (or associated pathological conditions), to pharmaceutical compositions containing them, and to synthetic routes for their production.
Background of the Invention
The malfunctioning of protein kinases (PKs) is the hallmark of numerous diseases. A large share of the oncogenes and proto-oncogenes involved in human cancers code for PKs. The enhanced activities of PKs are also implicated in many non-malignant diseases, such as benign prostate hyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis. PKs are also implicated in inflammatory conditions and in the multiplication of viruses and parasites. PKs may also play a major role in the pathogenesis and development of neurodegenerative disorders.
For a general reference to PKs malfunctioning or disregulation see, for instance, Current Opinion in Chemical Biology 1999, 3, 459 - 465.
Phosphatidylinositol 3-kinases (PI3Ks) are a family of lipid and serine/threonine kinases that catalyze the phosphorylation of the membrane lipid phosphatidylinositol (PI) on the 3'-OH of the inositol ring to produce phosphoinositol-3-phosphate (PIP), phosphoinositol-3,4-diphosphate (PIP2) and phosphoinositol-3,4,5-triphosphate (PIP3), which act as recruitment sites for various intracellular signalling proteins, which in turn form signalling complexes to relay extracellular signals to the cytoplasmic face of the plasma membrane. These 3'-phosphoinositide subtypes function as second messengers in intra- cellular signal transduction pathways (see e.g. Trends Biochem. Sci 22 87,267-72 (1997) by Vanhaesebroeck ef a/.; Chem. Rev. 101 (8), 2365-80 (2001) by Leslie et al (2001 ); Annu. Rev. Cell. Dev. Boil. 17, 615-75 (2001) by Katso et a/; and Cell. Mol. Life Sci. 59 (5), 761-79 (2002) by Toker et al). Multiple PI3K isoforms categorized by their catalytic subunits, their regulation by corresponding regulatory subunits, expression patterns and signalling specific funtions (ρ1 10α, β, δ, γ) perform this enzymatic reaction (Exp. Cell. Res. 25 (1 ),. 239-54 (1999) by Vanhaesebroeck and Katso et al., 2001 , above). The closely related isoforms p1 10oc and β are ubiquitously expressed, while δ and γ are more specifically expressed in the haematopoietic cell system, smooth muscle cells, myocytes and endothelial cells (see e.g. Trends Biochem. Sci. 22 (7),. 267-72 (1997) by Vanhaesebroeck et al). Their expression might also be regulated in an inducible manner depending on the cellular, tissue type and stimuli as well as disease context. Inductibility of protein expression includes synthesis of protein as well as protein stabilization that is in part regulated by association with regulatory subunits.
Eight mammalian PI3Ks have been identified so far, including four class I PI3Ks. Class la includes ΡΙ3Κα, ΡΙ3Κβ and PI3K5. All of the class la enzymes are heterodimeric complexes comprising a catalytic subunit (ρ1 10α, ρ110β or p1 106) associated with an SH2 domain containing p85 adapter subunit. Class la PI3Ks are activated through tyrosine kinase signalling and are involved in cell proliferation and survival. PI3Ka and ΡΙ3Κβ have also been implicated in tumorigenesis in a variety of human cancers. Thus, pharmacological inhibitors of PI3Ka and ΡΙ3Κβ are useful for treating various types of cancer.
ΡΙ3Κγ, the only member of the Class lb PI3Ks, consists of a catalytic subunit ρ1 10γ, which is associated with a p110 regulatory subunit. ΡΙ3Κγ is regulated by G protein coupled receptors (GPCRs) via association with βγ subunits of heterotrimeric G proteins. ΡΙ3Κγ is expressed primarily in hematopoietic cells and cardiomyocytes and is involved in inflammation and mast cell function. Thus, pharmacological inhibitors of ΡΙ3Κγ are useful for treating a variety of inflammatory diseases, allergies and cardiovascular diseases.
These observations show that deregulation of phosphoinositol-3-kinase and the upstream and downstream components of this signalling pathway is one of the most common deregulations associated with human cancers and proliferative diseases (see e.g. Parsons et al., Nature 436:792 (2005); Hennessey et al., Nature Rev. Drug Discovery 4: 988-1004 (2005).
The mammalian target of rapamycin (mTOR) also known as FK506 binding protein 12-rapamycin associated protein 1 (FRAP1 ) is a protein which in humans is encoded by the FRAP1 gene. mTOR is a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription. The inhibition of mTORs are believed to be useful for treating various diseases/conditions, such as cancer (for example, as described in Easton et al. (2006). "mTOR and cancer therapy". Oncogene 25 (48): 6436-46).
For the treatment of cancer, targeted therapies are becoming more important. That is, therapy that has the effect of interfering with specific target molecules that are linked to tumor growth and/or carcinogenesis. Such therapy may be more effective than current treatments (e.g. chemotherapy) and less harmful to normal cells (e.g. because chemotherapy has the potential to kill normal cells as well as cancerous cells). This, and also the fact that targeted therapies may be selective (i.e. it may inhibit a certain targeted molecule more selectively as compared to other molecular targets, e.g. as described hereinafter), may have the benefit of reducing side effects and may also have the benefit that certain specific cancers can be treated (also selectively). The latter may in turn also reduce side effects.
Hence, it is a clear goal of current oncologists to develop targeted therapies (e.g. ones that are selective). In this respect, it should be pointed out that several different molecular targets may exist that are linked to certain diseases (e.g. cancer). However, one simply cannot predict if a therapy (e.g. a small molecule as a therapeutic) that interferes with or inhibits one target molecule could inhibit a different molecular target (be it one that will ultimately have the effect of treating the same disease or a different one).
The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge. US patent application US 2009/0163489 and international patent application WO 2009/085230 both disclose various molecules containing a 6,5-fused bicyclic core, which may be useful as inhibitors of PI3 kinase (PI3-K). However, these documents do not relate to 6,5-bicyclic compounds that are substituted on the 6- membered ring with at least two substituents, an aromatic group and a morpholinyl group.
International patent applications WO 2007/127175 and WO 2006/046040 both disclose various thienopyrimidines and furopyrimidines, of potential use as PI3-K inhibitors. However, these documents do not disclose or suggest any other 6,5- fused bicyclic compounds.
International patent application WO 2004/092177 discloses various triazolopyrazines for use in modulating the A2a adenosine receptor signalling pathways. International patent applications WO 2006/027346, WO 2007/032936, WO 2005/042537, WO 2007/088168, WO 2008/131050, WO 03/000693, WO 2004/005290 and WO 2004/005291 and US patent application US 2006/0084650 (and international patent application WO 2006/044687) disclose various bicyclic compounds that may be useful for treating diseases/disorders such as cancer, pain, neurodegenerative disorders and/or that may be useful as kinase inhibitors. However, these documents do not relate to such bicycles that are directly substituted with both an aromatic group and a morpholinyl group.
International patent applications WO 2008/113469 and WO 2009/007029 disclose various compounds including bicyclic compounds, for use in treating diseases such as haematological diseases. However, these documents do not relate to bicycles that are substituted with a morpholinyl group.
Journal article Chorvat et al., J. Med. Chem. 1999, 42, 833 discloses various bicyclic compounds that may possess biological activity. However, there is no disclosure of 6,5-fused bicycles in which the 6-membered ring is directly substituted with an aromatic group.
International patent application WO 2005/035532 discloses various triazolopyrazinones that may be useful in the treatment of asthma or another glycogen synthase kinase mediated condition. However, this document only discloses 6,5-bicyclic compounds in which there is a carbonyl group attached to the 5-membered ring. US patent application (and equivalent application WO 2007/038314) as well as international patent application WO 2008/116064 both disclose various compounds, including bicycles, which may be useful in the treatment of inflammatory and immune diseases. However, these documents do not predominantly relate to 6,5-fused bicyclic compounds that are substituted with both an aromatic group and a morpholinyl group.
German patent application DE 2424334 and US patent US 3,995,039 disclose various bicyclic compounds for use as medicaments (e.g. in the treatment of asthma and related diseases). However, these documents do not mention that the compounds disclosed therein may be useful as kinase inhibitors, and do not primarily relate to 6,5-fused bicycles that are substituted with both an aromatic group and a morpholinyl group.
International patent application WO 03/044021 discloses various bicycles for use as mediators of pro-inflammatory cytokines, which may therefore be useful in the treatment of e.g. pain. There is no specific disclosure in this document of 6,5- fused bicycles that are substituted on the 6-membered ring with morpholinyl and only one other aromatic group. International patent application WO 2010/1 19264 discloses various imidazopyrazines for use as kinase inhibitors, which imidazopyrazines may be substituted with an aromatic group and a morpholinyl group. However, this document only relates to imidazopyrazines.
International patent application WO 2009/085230 and US patent application US 2009/085230 disclose various 6,5-fused bicyclic compounds. However, this application does not predominantly relate to bicycles in which the 6-membered ring is substituted with two certain substituents.
Disclosure of the Invention
According to the invention, there is now provided a compound of formula I,
Figure imgf000007_0001
AT represents N or C(R1); A4 represents N or C(R1a);
A4a represents N or C(R1 b); wherein at least one of A4 and A^ does not represent N;
A5 represents N or C(R2); each B1, B1a, B2, B2a, B3, B3a, B4 and B4a independently represent hydrogen or a substituent selected from halo, -C(=Y)-R10a, -C(=Y)-OR10a, -C(=Y)N(R10a)R11a, -S(O)2N(R 0a)R11a, Cn.i2 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0 and E1), aryl and/or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E2); or any two B1, B1a, B2, B a, B3, B3a, B4 and B4a substituents that are attached to the same carbon atom (i.e. B1 and B a; B2 and B2a; B3 and B3a; and/or B4 and B a) may together form a =0 group; or, any two B1, B a, B2, B a, B3, B3a, B4 and B4a substituents may be linked together to form a further 3- to 12- membered (e.g. 3- to 6-membered) ring, optionally containing (in addition to the atom(s) of the morpholine ring) one or more (e.g. two or, preferably, one) heteroatom(s) (preferably selected from sulfur, oxygen and nitrogen), which ring optionally contains one or more (e.g. one to three) double bonds, and which ring is itself optionally substituted by one or more substituents selected from halo, =0 and Ci_3 alkyl optionally substituted by one or more fluoro atoms;
R1 and R2 (when present) independently represent hydrogen or a substituent selected from halo, -CN, -OR10b, -N(R10b)R11 , -C(O)N(R 0b)R b, Ci.12 (e.g. d.6) alkyl and heterocycloalkyl (e.g. a 3- to 7-membered heterocycloalkyl), which latter two groups are optionally substituted by one or more substituents selected from E3 and =0; one of R1a and R b is present and represents -C(=Y)N(R10a)R11a or -C(=Y)-R10a and the other (when/if present) independently represents hydrogen or Q1;
Q1 represents:
halo, -CN, -N02, -N(R10a)R11a, -OR 0a, -C(=Y)-R10a, -C(=Y)-OR10a, -C(=Y)N(R10a)R1 a, -OC(=Y)-R10a, -OC(=Y)-OR10a, -OC(=Y)N(RlDa)R11a, -OS(O)2OR10a, -OP(=Y)(OR10a)(OR1 a), -OP(OR10a)(OR11a), -N(R1 a)C(=Y)R11a, -N(R12a)C(=Y)OR11a, -N(R12a)C(=Y)N(R10a)R11a, -NR 2aS(O)2R 0a,
-NR12aS(O)2N(R10a)R11a, -S(O)2N(R10a)R11a, -SC(=Y)R10a, -S(O)2R10a, -SR10a, -S(O)R10a, alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0 and E4), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E a);
R3 represents:
(i) a bicyclic aryl or heteroaryl group (both of which are optionally substituted by one or more substituents selected from E5); or
(ii) a fragment of formula IA or IB,
Figure imgf000009_0001
IA IB wherein any one of X·,, X2, X3, X4 and X5 (e.g. X3) represents C(R ), a second one of X1 f X2, X3, X4 and X5 represents C(R2b), and the remaining three independently represent C(R2 ) or N; or any one, two or three of X1 t X2, X3, X4 and X5 may represent N and those remaining represent C(H); X6, X7l X8 and X9 independently represent C(R2 ), N, O or S; each R2b independently represents hydrogen, halo, -CN or R a; each R2a independently represents, on each occasion when used herein, -N(R5a)R5b, -N(R5c)-C(=Y)-R5d, -N(R5e)-C(=Y)-N(R5f), -N(R5g)-C(0)-OR5h, -N(R5i)-OR5i, -OR*, -N(R5m)-S(0)2-R5n or C,.12 (e.g. C1-6) alkyl optionally substituted by one or more halo (e.g. fluoro) atoms; each R5a, R5b, R5c, R5d, R5e, R5'' R59, R5h, R5i, R5j, R5k, R5m and R5n independently represent hydrogen, d.i2 (e.g. Ci-6) alkyl (optionally substituted by one or more halo (e.g. fluoro) atoms), heterocycloalkyi, aryl or heteroaryl (which latter three groups are optionally substituted by one or more substituents selected from halo and C,.4 alkyl); each R10a, R11a, R10&, R11b and R12a independently represent, on each occasion when used herein, hydrogen, CM2 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0, =S, =N(R20) and E6), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E7); or any relevant pair of R10a and R11a or R10b and R11b (for example, when attached to the same atom, adjacent atom (i.e. 1 ,2-relationship) or to atoms that are two atoms apart, i.e. in a 1 ,3-relationship) may be linked together to form (e.g. along with the requisite nitrogen atom to which they may be attached) a 4- to 20- (e.g. 4- to 12-) membered ring, optionally containing one or more heteroatoms (for example, in addition to those that may already be present, e.g. (a) heteroatom(s) selected from oxygen, nitrogen and sulfur), optionally containing one or more unsaturations (preferably, double bonds), and which ring is optionally substituted by one or more substituents selected from =0, =S, =N(R20) and E8; each E1, E2, E3, E4, E4a, E5, E6, E7 and E8 independently represents, on each occasion when used herein:
(i) Q";
(ii) C1.12 alkyl optionally substituted by one or more substituents selected from =0 and Q5; or any two E1, E2, E3, E4, E4a, E5, E6, E7 and E8 groups, for example on C1-12 alkyl groups, e.g. when they are attached to the same or adjacent carbon atoms, or on adjacent atoms of an aryl group, may be linked together to form a 3- to 12- membered ring, optionally containing one or more (e.g. one to three) unsaturations (preferably, double bonds), and which ring is optionally substituted by one or more substituents selected from =0 and J1; each Q4 and Q5 independently represent, on each occasion when used herein: halo, -CN, -NO2, -N(R20)R21, -OR20, -C(=Y)-R20, -C(=Y)-OR20, -C(=Y)N(R20)R21, -OC(=Y)-R20, -OC(=Y)-OR20, -OC(=Y)N(R20)R21, -OS(0)2OR20, -OP(=Y)(OR20)(OR21), -OP(OR20)(OR21), -N(R22)C(=Y)R21 , -N(R22)C(=Y)OR21, -N(R22)C(=Y)N(R20)R21, -NR22S(0)2R20, -NR22S(O)2N(R20)R21, -S(O)2N(R20)R21 , -SC(=Y)R20, -S(0)2R20, -SR20, -S(0)R20, d.6 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0 and J2), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from J3); each Y independently represents, on each occasion when used herein, =0, =S, =NR23 or =N-CN; each R20, R21 , R22 and R23 independently represent, on each occasion when used herein, hydrogen, Ci-6 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from J4 and =0), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from J5); or any relevant pair of R20, R2 and R22, may (for example, when attached to the same atom, adjacent atom (i.e. 1 ,2-relationship) or to atoms that are two atoms apart, i.e. in a 1 ,3-relationship) be linked together to form (e.g. along with the requisite nitrogen atom to which they may be attached) a 4- to 20- (e.g. 4- to 12-) membered ring, optionally containing one or more heteroatoms (for example, in addition to those that may already be present, e.g. (a) heteroatom(s) selected from oxygen, nitrogen and sulfur), optionally containing one or more unsaturations (preferably, double bonds), and which ring is optionally substituted by one or more substituents selected from J6 and =0; each J1 , J2, J3, J4, J5 and J6 independently represents, on each occasion when used herein:
(0 Q7;
(ii) C1-6 alkyl or heterocycloalkyl, both of which are optionally substituted by one or more substituents selected from =0 and Q8; each Q7 and Q8 independently represents, on each occasion when used herein: halo, -CN, -N(R50)R51, -OR50, -C(=Ya)-R50, -C(=Ya)-OR50, -C(=Ya)N(R50)R51, -N(R52)C(=Y3)R51, -NR52S(0)2R50, -S(0)2R50, -SR50, -S(0)R50 or d.6 alkyl optionally substituted by one or more fluoro atoms; each Ya independently represents, on each occasion when used herein, =0, =S, =NR53 or =N-CN; each R50, R5 , R5Z and R53 independently represents, on each occasion when used herein, hydrogen or C1-6 alkyl optionally substituted by one or more substituents selected from fluoro, -OR60 and -N(R61)R62; or
any relevant pair of R50, R51 and R52 may (for example when attached to the same or adjacent atoms) be linked together to form, a 3- to 8-membered ring, optionally containing one or more heteroatoms (for example, in addition to those that may already be present, heteroatoms selected from oxygen, nitrogen and sulfur), optionally containing one or more unsaturations (preferably, double bonds), and which ring is optionally substituted by one or more substituents selected from =0 and Ci.3 alkyl;
R60, R61 and R62 independently represent hydrogen or C-,.e alkyl optionally substituted by one or more fluoro atoms; or a pharmaceutically acceptable ester, amide, solvate or salt thereof. which compounds, esters, amides, solvates and salts are referred to hereinafter as "the compounds of the invention".
Pharmaceutically-acceptable salts include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
I I By "pharmaceutically acceptable ester, amide, solvate or salt thereof, we include salts of pharmaceutically acceptable esters or amides, and solvates of pharmaceutically acceptable esters, amides or salts. For instance, pharmaceutically acceptable esters and amides such as those defined herein may be mentioned, as well as pharmaceutically acceptable solvates or salts.
Pharmaceutically acceptable esters and amides of the compounds of the invention are also included within the scope of the invention. Pharmaceutically acceptable esters and amides of compounds of the invention may be formed from corresponding compounds that have an appropriate group, for example an acid group, converted to the appropriate ester or amide. For example, pharmaceutically acceptable esters (of carboxylic acids of compounds of the invention) that may be mentioned include optionally substituted C 6 alkyl, C5-i0 aryl and/or C5.10 aryl-C1-6 alkyl- esters. Pharmaceutically acceptable amides (of carboxylic acids of compounds of the invention) that may be mentioned include those of the formula -C(0)N(Rz1)Rz2, in which Rz1 and Rz2 independently represent optionally substituted Ci.6 alkyl, C5.10 aryl, or C5. 0 aryl-C^e alkylene-. Preferably, C1.6 alkyl groups that may be mentioned in the context of such pharmaceutically acceptable esters and amides are not cyclic, e.g. linear and/or branched.
Further compounds of the invention that may be mentioned include carbamate, carboxamido or ureido derivatives, e.g. such derivatives of existing amino functional groups.
For the purposes of this invention, therefore, prodrugs of compounds of the invention are also included within the scope of the invention. The term "prodrug" of a relevant compound of the invention includes any compound that, following oral or parenteral administration, is metabolised in vivo to form that compound in an experimentally-detectable amount, and within a predetermined time (e.g. within a dosing interval of between 6 and 24 hours (i.e. once to four times daily)). For the avoidance of doubt, the term "parenteral" administration includes all forms of administration other than oral administration. Prodrugs of compounds of the invention may be prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, in vivo when such prodrug is administered to a mammalian subject. The modifications typically are achieved by synthesising the parent compound with a prodrug substituent. Prodrugs include compounds of the invention wherein a hydroxyl, amino, sulfhydryl, carboxy or carbonyl group in a compound of the invention is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxy or carbonyl group, respectively.
Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, esters groups of carboxyl functional groups, N-acyl derivatives and N-Mannich bases. General information on prodrugs may be found e.g. in Bundegaard, H. "Design of Prodrugs" p. 1-92, Elesevier, New York-Oxford (1985).
Compounds of the invention may contain double bonds and may thus exist as E (entgegen) and Z (zusammen) geometric isomers about each individual double bond. Positional isomers may also be embraced by the compounds of the invention. All such isomers (e.g. if a compound of the invention incorporates a double bond or a fused ring, the cis- and trans- forms, are embraced) and mixtures thereof are included within the scope of the invention (e.g. single positional isomers and mixtures of positional isomers may be included within the scope of the invention).
Compounds of the invention may also exhibit tautomerism. All tautomeric forms (or tautomers) and mixtures thereof are included within the scope of the invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerisations. Valence tautomers include interconversions by reorganisation of some of the bonding electrons. Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a 'chiral pool' method), by reaction of the appropriate starting material with a 'chiral auxiliary' which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person.
All stereoisomers (including but not limited to diastereoisomers, enantiomers and atropisomers) and mixtures thereof (e.g. racemic mixtures) are included within the scope of the invention.
In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined.
The compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
The present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2H, 3H, 1 C, 13C, 14C , 13N, 150, 170, 180, 32P, 33P, 35S, 18F, 36CI, 123l, and 125l. Certain isotopically-labeled compounds of the present invention (e.g., those labeled with 3H and 1 C) are useful in compound and for substrate tissue distribution assays. Tritiated (3H) and carbon-14 ( 4C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron emitting isotopes such as 150, 13N, 11C and 18F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Scheme 1 and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non- isotopically labeled reagent.
Unless otherwise specified, d.q alkyl groups (where q is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two or three, as appropriate) of carbon atoms, be branched- chain, and/or cyclic (so forming a C3-q-cycloalkyl group). Such cycloalkyl groups may be monocyclic or bicyclic and may further be bridged. Further, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic. Such alkyl groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated (forming, for example, a C2.q alkenyl or a C2.q alkynyl group).
Unless otherwise stated, the term C1-q alkylene (where q is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number of carbon atoms, be saturated or unsaturated (so forming, for example, an alkenylene or alkynylene linker group). C3.q cycloalkyl groups (where q is the upper limit of the range) that may be specifically mentioned may be monocyclic or bicyclic alkyl groups, which cycloalkyl groups may further be bridged (so forming, for example, fused ring systems such as three fused cycloalkyl groups). Such cycloalkyl groups may be saturated or unsaturated containing one or more double bonds (forming for example a cycloalkenyl group). Substituents may be attached at any point on the cycloalkyl group. Further, where there is a sufficient number (i.e. a minimum of four) such cycloalkyl groups may also be part cyclic. The term "halo", when used herein, preferably includes fluoro, chloro, bromo and iodo.
Heterocycloalkyl groups that may be mentioned include non-aromatic monocyclic and bicyclic heterocycloalkyl groups in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom), and in which the total number of atoms in the ring system is between 3 and 20 (e.g. between three and ten, e.g between 3 and 8, such as 5- to 8-). Such heterocycloalkyl groups may also be bridged. Further, such heterocycloalkyl groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C2.q heterocycloalkenyl (where q is the upper limit of the range) group. C2.q heterocycloalkyl groups that may be mentioned include 7- azabicyclo[2.2.1 ]heptanyl, 6-azabicyclo[3.1.1 jheptanyl, 6-azabicyclo[3.2.1 ]- octanyl, 8-azabicyclo-[3.2.1]octanyl, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1 ,3-dioxolanyl), dioxanyl (including 1 ,3-dioxanyl and 1 ,4-dioxanyl), dithianyl (including 1 ,4-dithianyl), dithiolanyl (including 1 ,3-dithiolanyl), imidazolidinyl, imidazolinyl, morpholinyl, 7-oxabicyclo[2.2.1]heptanyl, 6- oxabicyclo-[3.2.1]octanyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3- sulfolenyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridyl (such as 1 ,2,3,4-tetrahydropyridyl and 1 ,2,3,6-tetrahydropyridyl), thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including 1 ,3,5-trithianyl), tropanyl and the like. Substituents on heterocycloalkyl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of heterocycloalkyl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heterocycloalkyl groups may also be in the N- or S- oxidised form. Heterocycloalkyl mentioned herein may be stated to be specifically monocyclic or bicyclic.
For the avoidance of doubt, the term "bicyclic" (e.g. when employed in the context of heterocycloalkyl groups) refers to groups in which the second ring of a two-ring system is formed between two adjacent atoms of the first ring. The term "bridged" (e.g. when employed in the context of cycloalkyl or heterocycloalkyl groups) refers to monocyclic or bicyclic groups in which two non-adjacent atoms are linked by either an alkylene or heteroalkylene chain (as appropriate).
Aryl groups that may be mentioned include C6-2o, such as C6.12 (e.g. C6.n0) aryl groups. Such groups may be monocyclic, bicyclic or tricyclic and have between 6 and 12 (e.g. 6 and 10) ring carbon atoms, in which at least one ring is aromatic. C6-io aryl groups include phenyl, naphthyl and the like, such as 1 ,2,3,4-tetrahydro- naphthyl. The point of attachment of aryl groups may be via any atom of the ring system. For example, when the aryl group is poiycyclic the point of attachment may be via any atom including an atom of a non-aromatic ring. However, when aryl groups are poiycyclic (e.g. bicyclic or tricyclic), they are preferably linked to the rest of the molecule via an aromatic ring. When aryl groups are polyyclic in which there is a non-aromatic ring present, then that non-aromatic ring may be substituted by one or more =0 group.
Unless otherwise specified, the term "heteroaryl" when used herein refers to an aromatic group containing one or more heteroatom(s) (e.g. one to four heteroatoms) preferably selected from N, O and S. Heteroaryl groups include those which have between 5 and 20 members (e.g. between 5 and 10) and may be monocyclic, bicyclic or tricyclic, provided that at least one of the rings is aromatic (so forming, for example, a mono-, bi-, or tricyclic heteroaromatic group). When the heteroaryl group is poiycyclic the point of attachment may be via atom including an atom of a non-aromatic ring. However, when heteroaryl groups are poiycyclic (e.g. bicyclic or tricyclic), they are preferably linked to the rest of the molecule via an aromatic ring. Heteroaryl groups that may be mentioned include 3,4-dihydro-I H-isoquinolinyl, 1 ,3-dihydroisoindolyl, 1 ,3-dihydroisoindolyl (e.g. 3,4- dihydro-1 /-/-isoquinolin-2-yl, 1 ,3-dihydroisoindol-2-yl, 1 ,3-dihydroisoindol-2-yl; i.e. heteroaryl groups that are linked via a non-aromatic ring), or, preferably, acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including 1 ,3- benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiadiazolyl (including 2,1 ,3- benzothiadiazolyl), benzothiazolyl, benzoxadiazolyl (including 2,1 ,3- benzoxadiazolyl), benzoxazinyl (including 3,4-dihydro-2/-/-1 ,4-benzoxazinyl), benzoxazolyl, benzomorpholinyl, benzoselenadiazolyl (including 2,1 ,3-benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl, imidazo[1 ,2-a]pyridyl, indazolyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiaziolyl, isothiochromanyl, isoxazolyl, naphthyridinyl (including 1 ,6-naphthyridinyl or, preferably, 1 ,5-naphthyridinyl and 1 ,8-naphthyridinyl), oxadiazolyl (including
1.2.3- oxadiazolyl, 1 ,2,4-oxadiazolyl and 1 ,3,4-oxadiazolyl), oxazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl (including 1 ,2,3,4-tetrahydroisoquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinolinyl (including 1 ,2,3,4- tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl), tetrazolyl, thiadiazolyl (including 1 ,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl and 1 ,3,4-thiadiazolyl), thiazolyl, thiochromanyl, thiophenetyl, thienyl, triazolyl (including 1 ,2,3-triazolyl,
1.2.4- triazolyl and 1 ,3,4-triazolyl) and the like. Substituents on heteroaryl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of heteroaryl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heteroaryl groups may also be in the N- or S- oxidised form. Heteroaryl groups mentioned herein may be stated to be specifically monocyclic or bicyciic. When heteroaryl groups are polycyclic in which there is a non- aromatic ring present, then that non-aromatic ring may be substituted by one or more =0 group.
It may be specifically stated that the heteroaryl group is monocyclic or bicyciic. In the case where it is specified that the heteroaryl is bicyciic, then it may be consist of a five-, six- or seven-membered monocyclic ring (e.g. a monocyclic heteroaryl ring) fused with another a five-, six- or seven-membered ring (e.g. a monocyclic aryl or heteroaryl ring).
Heteroatoms that may be mentioned include phosphorus, silicon, boron and, preferably, oxygen, nitrogen and sulfur.
For the avoidance of doubt, where it is stated herein that a group (e.g. a CM2 alkyl group) may be substituted by one or more substituents (e.g. selected from E6), then those substituents (e.g. defined by E6) are independent of one another. That is, such groups may be substituted with the same substituent (e.g. defined by E6) or different substituents (defined by E6).
For the avoidance of doubt, in cases in which the identity of two or more substituents in a compound of the invention may be the same, the actual identities of the respective substituents are not in any way interdependent. For example, in the situation in which there is more than one e.g. B to B4 or E1 to E8 (such as E5) substituent present, then those B1 to B4 or E to E8 (e.g. E5) substituents may be the same or different. Further, in the case where there are e.g. B1 to B4 or E1 to E8 (such as E5) substituents present, in which one represents -C(=Y)OR10a (or e.g. -OR20, as appropriate) and the other represents -C(O)R10a (or e.g. -C(0)2R2°, as appropriate), then those R 0a or R20 groups are not to be regarded as being interdependent. Also, when e.g. there are two -OR10a substituents present, then those -OR10a groups may be the same or different (i.e. each R10a group may be the same or different). Further, each of the integers mentioned (e.g. each E4) are independent of one another.
For the avoidance of doubt, when a term such as "£' to E8" is employed herein, this will be understood by the skilled person to mean E , E2, E3, E4, E4a, E5, E6, E7 and E8, inclusively. Similarly, the term "S1 to B4" as employed herein will be understood to mean B\ B1a, B2, B2a, B3, B3a, B4 and B4a, inclusively.
All individual features (e.g. preferred features) mentioned herein may be taken in isolation or in combination with any other feature (including preferred feature) mentioned herein (hence, preferred features may be taken in conjunction with other preferred features, or independently of them). The skilled person will appreciate that compounds of the invention that are the subject of this invention include those that are stable. That is, compounds of the invention include those that are sufficiently robust to survive isolation from e.g. a reaction mixture to a useful degree of purity.
In a further embodiment of the invention:
Q1 may represent: -C(=Y)N(R10a)-OR11c, in which R10a is as hereinbefore defined, and R1 c represents d.12 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0, =S, =N(R20) and E6), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E7);
Q4 and Q5 may represent -C(=Y)N(R20)-R21a, in which R20 is as hereinbefore defined, and R21a represents Ci-6 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from J4 and =0), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from J5);
each Q7 and Q8 independently represents, on each occasion when used herein: halo, -CN, -N(R50)R51 , -OR50, -C(=Ya)-R50, -C(=Ya)-OR50, -C(=Ya)N(R50)R51, -N(R52)C(=Ya)R51, -NR52S(0)2R50, -S(O)2N(R50)R51 , -N(R52)-C(=Ya)-N(R50)R51, -S(0)2R50, -SR50, -S(0)R50, CL6 alkyl (optionally substituted by one or more fluoro atoms), heterocyclalkyl, aryl or heteroaryl (which latter three groups are optionally substituted by one or more substituents selected from halo, -OR60 and -N(R61)R62), in which R60, R61 and R62 are as hereinbefore defined;
alkyl groups or heterocycloalkyl groups mentioned herein may also be (additionally) substituted by =S or =N-R10a (although they are preferably not), in which R 0a is as hereinbefore defined.
The skilled person will appreciate that the bicyclic core of the compounds of the invention (containing A! , A , A4a and A5) is aromatic. It is further stated herein that at least one of A4 and A4a does not represent N, i.e. that at least one of C(R1a) or C(R1b) is present. Both C(R1a) and C(R1 ) may also be present.
Compounds of the invention that may be mentioned include those in which either: (i) R b is present (i.e. ^ reprsents C(R1b)) and represents -C(=Y)N(R'0a)R11a or -C(=Y)-R10a and R a (if present) represents hydrogen or Q as hereinbefore defined (this is the preferred option); or
(ii) R1a is present (i.e. A., reprsents C(R1a)) represents -C(=Y)N(R 0a)R11a or -C(=Y)-R10a and either R1b is not present (i.e. A4a represents N) or, preferably, R1b is present (i.e. A4 represents C(R1b)) and represents hydrogen or Q1, in which Q1 represents halo, -CN, -N02, -N(R10a)R11a, -OR 0a, -C(=Y)-R 0a, -C(=Y)-OR10a, -C(=Y)N(R10a)R11a, -OC(=Y)-R10a, -OC(=Y)-OR 0a, -OC(=Y)N(R10a)R11a, -OS(O)2OR10a, -OP(=Y)(OR10a)(OR11a), -OP(OR10a)(OR1 la), -N(R12a)C(=Y)Rl1a, -N(R12a)C(=Y)OR11a, -N(Rl2a)C(=Y)N(R10a)R11a, -NR 2aS(O)2R10a,
-NR12aS(O)2N(R 0a)R1 la, -S(O)2N(R10a)R11a, -SC(=Y)R10a, -S(O)2R10a, -SR 0a, -S(O)R10a, aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E4a). It is preferred that when R1a is present and represents -C(=Y)N(Rl0a)R1 a or -C(=Y)-R10a, then R1b is either not present (i.e. A4a represents N) or, if present, then R1 does not represent alkyl or heterocycloalkyl (both of which may be optionally substituted as defined herein). In this instance, R1 (when present) preferably represents hydrogen or Q in which Q preferably represents halo, -CN, -N02, -N(R10a)R 1a, -OR10a, -C(=Y)-R10a, -C(=Y)-OR10a, -C(=Y)N(R10a)R11a, -N(R1 a)C(=Y)R11a, -N(R12a)C(=Y)OR11a, -N(R12a)C(=Y)N(R 03)R1 a,
-NR12aS(O)2R10a, -NR1 aS(O)2N(R10a)R11a or -S(O)2N(R 0a)R a.
It is also preferred that when R1b is present and represents -C(=Y)N(R10a)R 1a or -C(=Y)-R10a, then R1a (if present) represents hydrogen or Q1, in which Q1 preferably represents halo, -CN, -N02, -N(R10a)R11a, -OR10a, -C(=Y)-R10a, -C(=Y)-OR 0a, -C(=Y)N(R10a)R11a, -N(R12a)C(=Y)R11a, -N(R12a)C(=Y)N(R 0a)R11a, -NR12aS(O)2R10a, -NR12aS(O)2N(R10a)R1 a or -S(O)2N(R 0a)R1 1a. Preferably, when R1a is present that represents the requisite -C(=Y)N(R10a)R 1a or -C(=Y)-R10a moiety, then R1b is either not present (i.e. A4a represents N) or R1 is present (i.e. A4a represents C(R b)) and preferably represents hydrogen or Q1 (e.g. halo, -CN, -N02, -N(R10a)R11a, -OR10a, -C(=Y)-R10a, -C(=Y)-OR10a, -C(=Y)N(R10a)R 1a, -N(R 2a)C(=Y)R11a, -N(R12a)C(=Y)N(R10a)R11a, -NR12aS(O)2R 0a, -NR12aS(O)2N(R10a)R11a and -S(O)2N(R10a)R11a, in which R10a, R1 a and R12a are as hereinbefore defined, provided that they are not linked together). In this instance, R1b preferably represents hydrogen (and Q1, in these instances, preferably represents halo, -CN or -N02). Preferably, it is R1b that is present and represents the requisite -C(=Y)N(R10a)R1 a or -C(=Y)-R 0a moiety, and either R1a is not present or represents hydrogen or a substituent selected from halo, -CN, -N02, -N(R10a)R 1a, -OR103, -C(=Y)-R10a, -C(=Y)-OR 0a, -C(=Y)N(R 0a)R1 a, -N(R12a)C(=Y)R11a, -N(R12a)C(=Y)N(R10a)R11a, -NR12aS(O)2R 0a, -NR12aS(O)2N(R10a)R 1a and -S(O)2N(R10a)R11a (in which R10a and R1'3 are preferably not linked together).
Other preferred compounds of the invention that may be mentioned include those in which:
Q1 represents:
halo, -CN, -N02, -N(R10a)R11a, -OR10a, -C(=Y)-R10a, -C(=Y)-OR1°a, -C(=Y)N(Rl0a)R 1a, -OC(=Y)-R10a, -OC(=Y)-OR10a, -OC(=Y)N(R10a)R1 a, -OS(O)2OR10a, -OP(=Y)(OR10a)(OR11a), -OP(OR10a)(OR1 a), -N(R12a)C(=Y)R11a, -N(R a)C(=Y)OR 1a, -N(R12a)C(=Y)N(R10a)Rl 1a, -NR 2aS(O)2R10a,
-NR12aS(O)2N(R10a)R11a, -S(O)2N(R10a)R11a, -SC(=Y)R10a, -S(O)2R10a, -SR10a, -S(O)R10a, aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E4a); or, more preferably,
halo, -CN, -N02, -N(R 0a)R11a, -OR10a, -C(=Y)-R 0a, -C(=Y)-OR 0a, -C(=Y)N(R 0a)R11a, -N(R12a)C(=Y)R11a or -NR12aS(O)2R10a (e.g. halo, -CN, -N02, -N(R 0a)R11a or -OR103);
R10a and R1 a are preferably not linked together.
Compounds of the invention include those as hereinbefore defined, but provided that when A4, A4a and A5 respectively represent C(R1a), C(R1 ) and C(R2), then A, does not represent N, i.e. the requisite bicycle (containing Ai, A4, A^ and A5) of formula I may not be the following:
Figure imgf000024_0001
Other compounds of the invention that may be mentioned include those in which: when R2a represents CLI2 (e.g. C^) alkyl, then that group is preferably substituted by at least one fluoro atom (e.g. it is a perfluoro group);
R2a represents -N(R5a)R5b, -N(R5C)-C(=Y)-R5d, -N(R5E)-C(=Y)-N(R5f), -N(R5G)-C(0)-OR5h, -N(R5i)-OR5j or d.12 (e.g. C1-5) alkyl optionally substituted by one or more halo (e.g. fluoro) atoms);
R2a represents -N(R5a)R5b, -N(R5C)-C(=Y)-R5d, -N(R5E)-C(=Y)-N(R5f), -N(R59)-C(0)-OR5h or -N(R5i)-OR5j; and/or
R2 represents R2a (e.g. as defined herein) or, preferably, hydrogen.
Compounds of the invention that may be mentioned include those in which, for example when AT and A4A represent N, A5 represents C(R2) and A4 represents C(R1A), then R1A preferably does not represent Q1 in which Q1 represents -OR 0A (and R10A represents H).
Preferred compounds of the invention include those in which either:
(i) A^ represents N, A4 represents C(R1a), A4a represents C(R1 ) and A5 represents N;
(ii) A! represents N, A4 represents N, A4a represents C(R1b) and A5 represents C(R2);
(iii) A^ represents C(R1), A4 represents N, A^ represents C(R b) and A5 represents C(R2),
i.e. the requisite Ai, A4, A43 and A5-containing bicycle of formula I represents one of the following structures:
Figure imgf000025_0001
in which R1, R1a, R1b, R2 and R3 are as hereinbefore defined and the squiggly line represents the point of attachment to the requisite (optionally substituted) morpholinyl moiety of the compound of formula I.
The attachment site of the R3 group to the relevant carbon atom of the requisite bicyclic Α,, Α,, Λ,3 and A5-containing ring of formula I may preferably be via any carbon of the R3 group (carbon-linked). It is preferred that R3 represents a fragment of formula IA or IB. Exemplary embodiments of R3 (when R3 represents a fragment of formula IA or IB) include, but are not limited to substituted phenyl, optionally substituted pyridyl (e.g. pyridine-2-one or pyridine-3-ol), pyrimidinyl, triazinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridazinyl, imidazolyl and pyraztnyl. Exemplary embodiments of R3 (when R3 represents bicyclic aryl) include naphthyl. Exemplary embodiments of R3 (when R3 represents bicyclic heteroaryl) include isatin groups, indolyl (e.g. indolin-2-one), isoindolyl, 1 ,3- dihydro-indol-2-one-yl, indazolyl, 1-(indolin-1-yl)ethanone-yl, 1 H- benzo[d][1 ,2,3]triazolyl, 1 H-pyrazolo[3,4-b]pyridinyl, 1 H-pyrazolo[3,4- d]pyrimidinyl, 1 H-benzo[d]imidazolyl, 1 H-benzo[d]imidazol-2(3H)-one-yl, 1 H- pyrazolo[3,4-c]pyridinyl, 1 H-pyrazolo[4,3-d]pyrimidinyl, 5H-pyrrolo[3,2- d]pyrimidinyl, 2-amino-1 H-purin-6(9H)-one-yl, quinolinyl, quinazolinyl, quinoxalinyl, isoquinolinyl, isoquinolin-1 (2H)-one-yl, 3,4-dihydroisoquinolin-1 (2H)- one-yl, 3,4-dihydroquinolin-2(1 H)-one-yl, quinazolin-2(1 H)-one-yl, quinoxalin- 2(1 H)-one-yl, 1 ,8-naphthyridinyl, pyrido[3,4-d]pyrimidinyl, pyrido[3,2-b]pyrazinyl, 1 ,3-dihydro benzimidazolone-yl, benzimidazolyl, benzothiazolyl and benzothiadiazolyl. Most preferred R3 groups include those of fragment IA, for instance phenyl, pyridyl and especially pyrimidinyl (e.g. 5-pyrimidinyl). When R3 represents a bicyclic heteroaryl group, then it may represent any one of the following structures:
Figure imgf000026_0001
Figure imgf000026_0002
25
Figure imgf000027_0001
Compounds of the invention that are preferred include those in which:
when R3 represents aryl (e.g. phenyl), then that group is substituted by one substituent (as defined herein by R a) and optionally (a) further substituent(s) (e.g. by a further one or two substituents as defined herein by R2b);
when R3 represents substituted aryl (e.g. phenyl), then the substituent may be situated at the 2-, 3-, 4-, 5- or 6- position of the phenyl ring (typically one substituent is situated at position 3 or 4, i.e. at the position corresponding to X2) X3 or X4; most preferably the substituent is situated at the 4-position, i.e. X3 represents C(R2a) in which R2a is a substituent as defined herein);
R2a may represent (e.g. when attached to a phenyl ring) a -OH moiety, for instance the -OH group is typically situated at the 3- or 4- position of the phenyl ring, so forming a 3-hydroxyphenyl or 4-hydroxyphenyl group or an isostere thereof, which is unsubstituted or substituted; an isostere as used herein is a functional group which possesses binding properties which are the same as, or similar to, the 3-hydroxyphenyl or 4- hydroxyphenyl group in the context of the compounds of the invention; isosteres of 3-hydroxyphenyl and 4-hydroxyphenyl groups are encompassed within the definition of R3 (and R2a may also represent another moiety as defined herein); when R3 represents heteroaryl, it is unsubstituted or substituted (when substituted, it may be substituted by one or more (e.g. one or two) substitutents selected from those listed in respect of R2a and R2b);
when R3 is a phenyl group typically the substituents are selected from -OR5k (e.g. -OH) and, especially -N(RSa)R5 (e.g. NH2).
Preferred compounds of the invention include those in which:
R3 preferably represents a fragment of formula IA;
any one of X X2, X3, X4 and X5 (e.g. X3) represents C(R2a), and the remaining groups (e.g. X1 t X2, X4 and X5) independently represent C(R2b), or X2 and X4 may alternatively and independently represent N;
R2a represents d.4 (e.g. C1-2) alkyl substituted by one or more fluoro atoms or R2a represents -N(R5c)-C(=Y)-R5d or, preferably, -N(R5a)R5b;
when R2a represents alkyl substituted by one or more fluoro atoms, then it is preferably a perfluoro group (e.g. trifluoromethyl);
each R b independently represents halo or, preferably, hydrogen;
each R5a, R5 , R5c, R5d, R5e, R5f' R5g, R5h, R5i, R5j, R5k, R5m and R5n (e.g. R5a, R5b,
R5c and R5d) independently represent CM (e.g. Ci.2) alkyl or, preferably, hydrogen;
when R3 represents a fragment of formula IB, then any one or two of X6, X7, X8 and X9 represents a heteroatom selected from nitrogen, oxygen and sulfur and the other two or three independently represent C(R2b);
when R3 represents bicyclic heteroaryl (e.g. a 8-, 9- or 10-membered heteroaryl group), then that group preferably consists of a 5- or 6-membered ring fused to another 5- or 6-membered ring (in which either one of those rings may contain one or more (e.g. four, or, preferably one to three) heteroatoms), in which the total number of heteroatoms is preferably one to four, and which ring is optionally substituted by one or more (e.g. two or, preferably, one) substituent(s) selected from E5 (and, if there is a non-aromatic ring present in the bicyclic heteroaryl group, then such a group may also be substituted by one or more (e.g. one) =0 groups).
Further preferred compounds of the invention include those in which: each R 0a, R11a, R10 , R11b and R12a independently represent, on each occasion when used herein, hydrogen or Ci.12 (e.g. Ci_6) alkyl (which latter group is optionally substituted by one or more substituents selected from =0 and E6); or any relevant pair of R10a and R11a and/or R10b and Rm may, when attached to the same nitrogen atom, be linked together to form (along with the requisite nitrogen atom to which they are attached) a 3- to 12- (e.g. 4- to 12-) membered ring, optionally containing one or more (e.g. one to three) double bonds, and which ring is optionally substituted by one or more substituents selected from E8 and =0;
each of E1, E2, E3, E4, E4a, E5, E6, E7 and E8 independently represents, on each occasion when used herein, Q4 or d.6 alkyl (e.g. d.3) alkyl optionally substituted by one or more substituents selected from =0 and Q5;
each Q4 and Q5 independently represent halo, -CN, -N02. -N(R20)R21, -OR20, -C(=Y)-R20, -C(=Y)-OR20, -C(=Y)N(R20)R21, -N(R2 )C(=Y)R21, -N(R22)C(=Y)OR21 , -N(R22)C(=Y)N(R20)R21, -NR22S(0)2R20, -NR22S(O)2N(R20)R21, -S(O)2N(R20)R21, -S(0)2R20, -SR20, -S(0)R20 or C1-6 alkyl optionally substituted by one or more fluoro atoms (and each Q5 more preferably represents halo, such as fluoro);
any two E1, E2, E3, E4, E4a, E5, E6, E7 or E8 groups may be linked together, but are preferably not linked together;
each R20, R21, R22 and R23 independently represent, on each occasion when used herein, aryl (e.g. phenyl; preferably unsubstituted, but which may be substituted by one to three J5 groups) or, more preferably, hydrogen or Ci.6 (e.g. C1.3) alkyl optionally substituted by one or more substituents selected from =0 and J4; or any pair of R20 and R21, may, when attached to the same nitrogen atom, be linked together to form a 4- to 8-membered (e.g. 5- or 6-membered) ring, optionally containing one further heteroatom selected from nitrogen and oxygen, optionally containing one double bond, and which ring is optionally substituted by one or more substituents selected from J6 and =0;
each J1, J2, J3, J4, J5 and J6 independently represent Ci-6 alkyl (e.g. acyclic d.3 alkyl or, e.g. in the case of J4, C3.5 cycloalkyl) optionally substituted by one or more substituents selected from =0 and Q8, or, more preferably, such groups independently represent a substituent selected from Q7;
each Q7 and Q8 independently represents a substituent selected from fluoro, -N(R50)R51, -OR50, -C(=Ya)-R50, -C(=Ya)-OR50, -C(=Ya)N(R50)R51, -NR52S(0)2R50, -S(0)2R50 or C1-6 alkyl optionally substituted by one or more fluoro atoms; each R , R , R52 and R substituent independently represents, on each occasion when used herein, hydrogen or Ci.6 (e.g. CV3) alkyl optionally substituted by one or more substituents selected from fluoro;
when any relevant pair of R50, R51 and R52 are linked together, then those pairs that are attached to the same nitrogen atom may be linked together (i.e. any pair of R50 and R51), and the ring so formed is preferably a 5- or 6-membered ring, optionally containing one further nitrogen or oxygen heteroatom, and which ring is optionally substituted by one or more substituents selected from =0 and d.3 alkyl (e.g. methyl);
R60, R6 and R62 independently represent hydrogen or C 3 (e.g. CL2) alkyl optionally substituted by one or more fluoro atoms.
Preferred optional substituents (in addition to any requisite substituent defined herein by R2a) on R3 (and, possibly when they represent a substituent other than hydrogen on R , R a, R1b and R2 groups) include:
=0 (e.g. in the case of alkyl, cycloalkyl or heterocycloalkyi groups);
-CN;
halo (e.g. fluoro, chloro or bromo);
C1.4 alkyl, which alkyl group may be cyclic, part-cyclic, unsaturated or, preferably, linear or branched (e.g. C1- alkyl (such as ethyl, n-propyl, isopropyl, f-butyl or, preferably, n-butyl or methyl), all of which are optionally substituted with one or more halo (e.g. fluoro) groups (so forming, for example, fluoromethyl, difluoromethyl or, preferably, trifluoromethyl) or substituted with an aryl, heteroaryl or heterocycloalkyi group (which themselves may be substituted with one or more -ORz1, -C^R22, -C(0)ORz3, -N(Rz )Rz5, -S(0)2Rz6, -S(0)2N(Rz7)Rz8;
-N(Rz9)-C(0)-Rz °, -C(0)-N(RZ 1)RZ12 and/or -N(Rz9)-C(0)-N(Rz1°) substituents; aryl (e.g. phenyl), if appropriate (e.g. when the substitutent is on an alkyl group, thereby forming e.g. a benzyl group);
-ORz1;
-C(0)Rz2;
-C(0)ORz3;
-N(Rz4)Rz5;
-S(0)2Rz6;
-S(0)2N(Rz7)Rz8;
-N(Rz9)-C(0)-Rz1°; -C(0)-N(Rz11)Rz12;
-N(RZ9)-C(0)-N(RZ °);
wherein each Rz1 to Rz12 independently represents, on each occasion when used herein, H or d.4 alkyl (e.g. ethyl, n-propyl, f-butyl or, preferably, n-butyl, methyl, isopropyl or cyclopropylmethyl (i.e. a part cyclic alkyl group)) optionally substituted by one or more halo (e.g. fluoro) groups (so forming e.g. a trifluoromethyl group). Further, any two Rz groups (e.g. Rz4 and RzS), when attached to the same nitrogen heteroatom may also be linked together to form a ring such as one hereinbefore defined in respect of corresponding linkage of R10a and R 1a or R10b and R11 groups.
Preferred compounds of the invention include those in which:
R2 represents hydrogen or a substituent selected from -N(R 0 )R1 b and, preferably, halo (e.g. chloro, bromo or iodo) and -CN (but R2 most preferably represents hydrogen);
B1, B1a, B2, B2a, B3, B3a, B4 and B a independently represent hydrogen, (e.g. C1.3) alkyl optionally substituted by one or more substituents selected from =0 and E1, any two of these together form a =0 substituent on the morpholinyl ring, or, any two B B1a, B2, B2a, B3, B3a, B4 and B a substituents when linked together, may form a linkage, for example between a B2 or B2a substituent and a B3 or B3a substituent to form a further ring, e.g. a five membered ring such as the one depicted below:
Figure imgf000031_0001
each E1, E2, E3, E4, E4a, E5, E6, E7 and E8 independently represents d.12 alkyl optionally substituted by one or more substituents selected from =0 and Q5, or, preferably (each E1 to E8 independently represents) Q4;
each R20, R2 , R22 and R23 (e.g. each R20 and R2 ) independently represents heteroaryl, preferably, aryl (e.g. phenyl) (which latter two groups are optionally substituted by one or more substituents selected from J5), or, more preferably, hydrogen or C 6 (e.g. C^) alkyl optionally substituted by one or more substituents selected from =0 and J4; or any relevant pair of R20, R21 and R22 (e.g. R20 and R21) may (e.g. when both are attached to the same nitrogen atom) may be linked together to form a 3- to 8- (e.g. 4- to 8-) membered ring, optionally containing a further heteroatom, and optionally substituted by one or more substituents selected from =0 and J6;
each J1, J2, J3, J4, J5 and J6 independently represent d-e alkyl (e.g. d 3 acyclic alkyl or C3.5 cycloalkyl) optionally substituted by one or more substituents selected from Q8, or, J1 to J6 more preferably represent a substituent selected from Q7;
each Q7 and Q8 independently represent halo, -N(R50)R51, -OR50, -C(=Ya)-OR50, -C(=Ya)-R50, -S(0)2R50 or d.3 alkyl optionally substituted by one or more fluoro atoms;
each R50, R51, R52 and R53 independently represents hydrogen or d-e (e.g. d. ) alkyl optionally substituted by one or more fluoro atoms;
each R60, R61 and R62 independently represents hydrogen or d-2 alkyl (e.g. methyl).
More preferred compounds of the invention include those in which:
R2 represents hydrogen, chloro, bromo, iodo or -CN;
each R10a, R11a, R10b, R1 b and R12a independently represents hydrogen or d-4 (e.g. d-3) alkyl, which alkyl group may by substituted by one or more substituents selected from =0 and E6 (but which alkyl group is more preferably unsubstituted); or
any relevant pair of R10a and R11a and/or R10 and R11b, may be linked together to form a 5- or, preferably, a 6-membered ring, optionally containing a further heteroatom (preferably selected from nitrogen and oxygen), which ring is preferably saturated (so forming, for example, a piperazinyl or morpholinyl group), and optionally substituted by one or more substituents selected from =0 and E8 (which E8 substituent may be situated on a nitrogen heteroatom; and/or E8 is preferably halo (e.g. fluoro) or d-3 alkyl optionally substituted by one or more fluoro atoms);
each E1, E2, E3, E4, E4a, E5, E6, E7 and E8 independently represent d-4 alkyl optionally substituted by one or more Q5 substituents, or, each of these preferably represent a substituent selected from Q4;
Q4 and Q5 independently represent halo (e.g. fluoro), -OR20, -N(R20)R21, -C(=Y)OR20, -C(=Y)N(R 0)R21, -NR22S(0)2R2°, heterocycloalkyl, aryl, heteroaryl (which latter three groups are optionally substituted with one or more substitutents selected from J2 or J3, as appropriate) and/or C1.6 alkyl (e.g. C1-3 alkyl) optionally substituted by one or more fluoro atoms;
each Y represents, on each occasion when used herein, =S, or preferably =0; each R20, R21 , R22 and R23 (e.g. each R20 and R2 ) independently represents hydrogen or (e.g. C}_3) alkyl (e.g. feri-butyl, ethyl, methyl or a part cyclic group such as cyclopropylmethyl) optionally substituted (but preferably unsubstituted) by one or more (e.g. one) J4 substituent(s); or
any relevant pair of R20, R2 and R22 (e.g. R20 and R2 ) may (e.g. when both are attached to the same nitrogen atom) be linked together to form a 5- or, preferably, a 6-membered ring, optionally containing a further heteroatom (preferably selected from nitrogen and oxygen), which ring is preferably saturated (so forming, for example, a piperazinyl or morpholinyl group), and optionally substituted by one or more substituents selected from =0 and J6 (which J6 substituent may be situated on a nitrogen heteroatom);
R22 represents alkyl or, preferably, hydrogen;
each J1 , J2, J3, J4, J5 and Js independently represent a substituent selected from Q7, or J1 to J6 (e.g. J4) represents C1-6 alkyl (e.g. C3.5 cycloalkyl);
each Q7 and Q8 independently represent -C(=Ya)-OR50, -C(=Ya)-R50, -S(0)2R50 or CL3 alkyl optionally substituted by one or more fluoro atoms;
each Ya independently represents =S or, preferably, =0;
each R50 independently represents C1-4 alkyl (e.g. fert-butyl or methyl).
Preferred R3 groups of the compounds of the compounds of the invention include substituted phenyl, optionally substituted indazolyl (e.g. 4-indazolyl), pyrimidinyl (e.g. 5-pyrimidinyl), azaindolyl (e.g. azaindol-5-yl), indolyl (e.g. 5-indolyl or 4- indolyl) and pyridyl (e.g. 3-pyridyl). Most preferred R3 groups include optionally substituted (but preferably substituted by at least one substituent, e.g. as defined by R2a) pyrimidinyl (e.g. in which X2 and X4 represent N, X3 represents C(R2a) and X1 and X5 independently represent C(R2b)).
Preferred compounds of the invention include those in which:
R2 represents hydrogen or halo (e.g. chloro);
R3 represents substituted phenyl (as defined by fragment IA), optionally substituted 5- or 6-membered monocyclic heteroaryl (as defined by fragment IA or fragment IB) or a 9- or 10-membered bicyclic heteroaryl group (which heteroaryl groups may contain one to four, e.g. 3 or, preferably, 1 or 2, heteroatoms preferably selected from nitrogen, oxygen and sulfur) both of which heteroaryl moieties are optionally substituted by one or more (e.g. two, or, preferably, one) substituent(s) selected from R2b (when it represents a substituent, i.e. it is other than hydrogen), R2a and/or E5 (e.g. -CF3, preferably, -OH, -OCH3 and/or -N(R5a)R5b or -N(R20)R21 as appropriate (e.g. -NH2));
E1 to E8 independently represent Ci_6 (e.g. C1-3, such as methyl) alkyl optionally substituted by one or more Q5 substituents, or, preferably, Q4;
Q4 represents -OR20, -N(R20)R21, -S(0)2R2°, heterocycloalkyi (e.g. a 4- to 6- membered ring, containing preferably one or two heteroatoms selected from nitrogen and oxygen; which heterocycloalkyi group may be substituted but is preferably unsubstituted), aryl (e.g. phenyl; optionally substituted with two or, preferably, one substituent selected from J3) or heteroaryl (e.g. a 5- or 6- membered monocyclic heteroaryl group preferably containing one or two heteroatoms preferably selected from nitrogen, oxygen and sulfur; which group may be substituted, but is preferably unsubstituted);
Q5 represents halo (e.g. fluoro);
Y represents =0;
R20 and R21 independently represent hydrogen, C1-3 alkyl (e.g. methyl or ethyl), which latter group is optionally substituted by one or more (e.g. one) substituent(s) selected from J4;
when there is a -N(R20)R21 moiety present, then one of R20 and R21 represents hydrogen, and the other represents hydrogen or C1-3 alkyl (e.g. methyl or ethyl), which latter group is optionally substituted by one or more (e.g. one) substituent(s) selected from J4;
J3 represents Q7;
J4 represents C-,.6 alkyl, such as C3.6 alkyl (especially C3.6 cycloalkyl, such as cyclopropyl);
Q7 represents -S(0)2R50;
R50 represents Ci.3 alkyl (e.g. methyl).
Particularly preferred compounds of the invention include those in which:
R2 represents hydrogen or chloro; R3 represents pyrimidinyl (e.g. 5-pyrimidinyl, such as 2-amino-5-pyrimidinyl (such as 2-NH2-pyrimidin-5-yl);
B\ B1a, B2, B2a, B3, B3a, B4 and B4a independently represent hydrogen. Particularly preferred compounds of the invention include those in which:
A^a represents C(R1b);
the requisite 6,5-fused bicycle represents:
(i) A, represents N, A4 represents C(R1a),
Figure imgf000035_0001
represents C(R1b) and A5 represents N;
(ii) A, represents N, A represents N, A4a represents C(R1b) and A5 represents C(R2);
(iii) A, represents C(R1), A4 represents N, 43 represents C(R1b) and A5 represents C(R2),
in which the bicycles (i) and (iii) are particularly preferred;
one of R1a and R1b (preferably R1b) is present, which represents -C(=Y)N(Rl0a)R11a or -C(=Y)-OR10a, and when the other (e.g. R1a) is present, then it preferably represents hydrogen or Q1 (especially hydrogen);
Q1 represents halo, -CN, -N02, -N(R10a)R a or -OR 0a (in which R10a and R11a preferably, and independently, represent hydrogen or C1.4 (e.g. C1.2) alkyl);
Y represents =0;
when R1a or R1b represents -C(=Y)N(R10a)R a, then preferably R10a and R11a independently represent hydrogen, C1-4 (e.g. C1-2) alkyl (optionally (and preferably) substituted by one or more (e.g. one) substituent(s) selected from E5) or heterocycloalkyi (e.g. a 5- or, particularly, 6-membered heterocycloalkyi group containing one or two heteroatoms (e.g. one oxygen heteroatom, so forming e.g. a tetrahydropyranyl group, e.g. 4-tetrahydropyranyl); and which heterocycloalkyi group is preferably unsubstituted);
R1a (when/if present) represents hydrogen;
R3 represents a fragment of formula IA (e.g. pyrimidinyl, such as 5-pyrimidinyl); X2 and X" independently represent N;
X1 and X5 independently represent C(R2 );
X3 represents C(R2a);
each R2b independently represents halo or, preferably, hydrogen;
R2a represents -N(R5a)R5 ;
R5a and R5b independently represent hydrogen; R10a and R11a independently represent hydrogen or (e.g. Ci_2) alkyl or heterocycloalkyl (e.g. a 5- or, preferably, 6-membered heterocycloalkyl group), which latter two groups are optionally (and preferably) substituted by one or more (e.g. one) substituent(s) selected from E5;
at least one of R10a and R1 a (when attached to the same nitrogen atom) represents hydrogen;
E5 represents Q";
Q4 represents -OR20;
R20 represents C1-4 (e.g. Ci.2) alkyl (e.g. methyl).
Other particularly preferred compounds of the invention include those in which: when R1a or R b represents -C(=Y)N(R10a)R1 a, then preferably R10a and R11a independently represent hydrogen, C^e (e.g. Ci_3) alkyl (optionally substituted by one or more (e.g. one) substituent(s) selected from E5; and which alkyl group may be cyclic, e.g. a C5.6 cycloalkyl group, also optionally substituted) or heterocycloalkyl (e.g. a 5- or, particularly, 6-membered heterocycloalkyl group containing one or two heteroatoms (e.g. one oxygen or nitrogen heteroatom, so forming e.g. a tetrahydropyranyl or piperidinyl group, e.g. 4-tetrahydropyranyl or 4-piperidinyl), or, R10a and R 1a may be linked together to form a 5- or 6- membered ring, preferably saturated and unsubstituted, e.g. a pyrrolidinyl;
R10a and R11a independently represent hydrogen or d. (e.g. C1.2) alkyl or heterocycloalkyl (e.g. a 5- or, preferably, 6-membered heterocycloalkyl group), which latter two groups are optionally substituted by one or more (e.g. one) substituent(s) selected from E5, or, R10a and R11a are optionally linked as hereinbefore defined;
at least one of R 0a and R 1a (when attached to the same nitrogen atom, and when R10a and R 1a are not linked together) represents hydrogen;
E5 represents Q4;
Q4 represents -OR20 or -N(R20)R21;
R20 represents hydrogen or C1- (e.g. Ci-2) alkyl (e.g. methyl).
Particularly preferred R3 groups include 2-amino-5-pyrimidinyl (e.g. 2-N-[-CH2-(4- OCH3)phenyl]2-5-pyrimidinyl and, preferably, 2-NH2-5-pyrimidinyl). Particularly preferred R1a or R1b (one of which is necessarily present, e.g. R1b) groups include -C(0)-NH2, -C(0)N(H)-CH2CH2-OCH3 and -C(0)-N(H)-[4-tetrahydropyranyl]. Particularly preferred compounds of the invention include those of the examples described hereinafter. Compounds of the invention may be made in accordance with techniques that are well known to those skilled in the art, for example as described hereinafter.
According to a further aspect of the invention there is provided a process for the preparation of a compound of formula I which process comprises:
(i) reaction of a compound of formula II,
Figure imgf000037_0001
wherein L1 represents a suitable leaving group, such as iodo, bromo, chloro, a sulfonate group (e.g. -OS(0)2CF3, -OS(0)2CH3 or -OS(0)2PhMe), or a sulfide group (e.g. -S-C 6 alkyl, such as -SCH3) and Ai, A4, A43, A5, B\ B1a, B2, B2a, B3, B3a, B4 and B4a are as hereinbefore defined, with a compound of formula III,
R3-L2 III wherein L2 represents a suitable group such as -B(OH)2, -B(ORW)<)2 or -Sn(Rwx)3, in which each Rwx independently represents a C1.6 alkyl group, or, in the case of -BiOR^, the respective Rwx groups may be linked together to form a 4- to 6- membered cyclic group (such as a 4,4,5, 5-tetramethyl-1 ,3,2-dioxaborolan-2-yl group), thereby forming e.g. a pinacolato boronate ester group, (or L2 may represent iodo, bromo or chloro, provided that L and L2 are mutually compatible) and R3 is as hereinbefore defined. The reaction may be performed, for example in the presence of a suitable catalyst system, e.g. a metal (or a salt or complex thereof) such as Pd, Cul, Pd/C, PdCI2> Pd(OAc)2, Pd(Ph3P)2CI2> Pd(Ph3P)4 (i.e. palladium tetrakistriphenylphosphine), Pd2(dba)3 and/or NiCI2 (preferred catalysts include palladium) and a ligand such as PdCI2(dppf).DCM, f-Bu3P, (C6Hn)3P, Ph3P, AsPh3, P(o-Tol)3, 1 ,2-bis(diphenylphosphino)ethane, 2,2'-bis(di-ferf-butyl- phosphjno)-1, 1'-biphenyl, 2,2'-bis(diphenylphosphino)-1, 1'-bi-naphthyl, 1 , 1'- bis(diphenyl-phosphino-ferrocene), 1 ,3-bis(diphenylphosphino)propane, xantphos, or a mixture thereof (preferred ligands include PdCI2(dppf).DCM), together with a suitable base such as, Na2C03, K3P04, Cs2C03, NaOH, KOH, K2C03, CsF, Et3N, (/-Pr)2NEt, i-BuONa or f-BuOK (or mixtures thereof; preferred bases include Na2C03 and K2C03) in a suitable solvent such as dioxane, toluene, ethanol, dimethylformamide, dimethoxyethane, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, /V-methylpyrrolidinone, tetrahydrofuran or mixtures thereof (preferred solvents include dimethylformamide and dimethoxyethane). When L1 represents a sulfide (e.g. -SCH3), then an additive such as CuMeSal (copper(l) 3-methylsalicylate) or CuTC (copper(l)thiophene-2-carboxylate) may also be employed. The reaction may be carried out for example at room temperature or above (e.g. at a high temperature such as at about the reflux temperature of the solvent system). Alternative reaction conditions include microwave irradiation conditions, for example at elevated temperature, e.g. of about 130°C;
(ii) reaction of a compound of formula IV,
Figure imgf000038_0001
wherein L3 represents a suitable leaving group, such as one hereinbefore defined in respect of L or a sulfone (e.g. -S(0)2Ci-6 alkyl moiety, such as -S(0)2CH3) or sulfide (e.g. -S-d.6 alkyl moiety, such as -SCH3) and A1 t A4, A^, A5 and R3 as hereinbefore defined, with a compound of formula V,
Figure imgf000039_0001
wherein L4 may represent hydrogen (so forming an amine group), and B1, B1a, B2, B2a, B3, B3a, B4 and B4a are as hereinbefore defined, and the reaction may optionally be performed in the presence of an appropriate metal catalyst (or a salt or complex thereof) such as Cu, Cu(OAc)2, Cul (or Cul/diamine complex), copper tris(triphenylphosphine)bromide, Pd(OAc)2, tris(dibenzylideneacetone)- dipalladium(O) (Pd2(dba)3) or NiCI2 and an optional additive such as Ph3P, 2,2'- bis(diphenylphosphino)-1 ,1'-binaphthyl, xantphos, Nal or an appropriate crown ether such as 18-crown-6-benzene, in the presence of an appropriate base such as NaH, Et3N, pyridine, Λ/,/V-dimethylethylenediamine, Na2C03, K2C03, K3P04, Cs2C03> i-BuONa or f-BuOK (or a mixture thereof, optionally in the presence of 4A molecular sieves), in a suitable solvent (e.g. dichloromethane, dioxane, toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, /V-methylpyrrolidinone, tetrahydrofuran or a mixture thereof). This reaction may be performed at elevated temperature or under microwave irradiation reaction conditions, for example as described in process step (i). The compound of formula IV (e.g. in which L3 is chloro) may be prepared in situ, for example from a compound corresponding to a compound of formula IV, but in which L3 represents -OC1-3 alkyl (e.g. methoxy) by reaction in the presence of e.g. a chlorinating agent (such as POCI3);
(iii) for compounds of formula I in which (A5 represents C(R2) and) R2 represents halo (e.g. bromo, iodo or chloro), reaction of a corresponding compound of formula I, in which R2 represents hydrogen, with a reagent that is a source of halide ions (a halogenating reagent). For instance, an electrophile that provides a source of iodide ions includes iodine, diiodoethane, diiodotetrachloroethane or, preferably, /V-iodosuccinimide, a source of bromide ions includes N- bromosuccinimide and bromine, and a source of chloride ions includes N- chlorosuccinimide, chlorine and iodine monochloride, for instance in the presence of a suitable solvent, such as CHCI3 or an alcohol (e.g. methanol), optionally in the presence of a suitable base, such as a weak inorganic base, e.g. sodium bicarbonate. Typically, the reaction maybe performed by heating at a convenient temperature, either by conventional heating under reflux or under microwave irradiation;
(iv) for compounds of formula I in which R2 (if present; i.e. if A5 represents C(R2)) represents a substituent other that hydrogen, or halo (e.g. bromo, iodo or chloro), reaction of a corresponding compound of formula I, in which R2 represents halo (e.g. bromo, chloro or iodo), with a compound of formula VI,
R2aa-L7 VI wherein R2aa represents R2 as hereinbefore described provided that it does not represent hydrogen or halo, and L7 represents a suitable leaving group such as one hereinbefore described in respect of L1 or L2 (see e.g. process step (i); reaction conditions such as those mentioned above may also be employed).
Alternatively, the skilled person will appreciate that different reagents and reaction steps may be employed, depending on the particular R2aa substituent required;
(v) for compounds of formula I in which R1a and/or R1 represents -C(O)N(R 0a)R11a, reaction of a compound of formula VIA,
Figure imgf000040_0001
wherein i R3 represents either L1 as hereinbefore defined or R3 as hereinbefore defined, and wherein either A4 or A4a represent C(R1a) or C(R1b) respectively, in which either R1a or R1b represents the relevant -COOR 0a moiety (i.e. -COOR10a is attached to a carbon atom at either the A or A4a position), and the other one of A or A4a represents N or C(R1a) or C(R1 ) (as appropriate) in which the other R1a or R b group represents hydrogen or Q1 as hereinbefore defined, and B1, B1a, B2, B2a, B3, B3a, B4, B4a, A,, A4, A4, R3 and R10a are as hereinbefore defined (R10a is preferably hydrogen or optionally substituted alkyl), with a compound of formula VIB,
HN(R 0a)R 1a VIB wherein R 0a and R1 a are as hereinbefore defined, under standard amide coupling reaction conditions, i.e. conditions that promote the formation of an amide from a carboxylic acid (or ester thereof), for example in the presence of a suitable coupling reagent (e.g. 1 ,1 '-carbonyldiimidazole, Ν,Ν1- dicyclohexylcarbodiimide, HBTU or the like) or, in the case when R2 represents an ester (e.g. -C(0)OCH3 or -C(0)OCH2CH3), in the presence of e.g. trimethylaluminium, or, alternatively a -C(0)OH group may first be activated to the corresponding acyl halide (e.g -C(0)CI, by treatment with oxalyl chloride, thionyl chloride, phosphorous pentachloride, phosphorous oxychloride, or the like), and, in all cases, the relevant compound is reacted with a compound of formula VIB as defined above, under standard conditions known to those skilled in the art (e.g. optionally in the presence of a suitable solvent, suitable base and/or in an inert atmosphere). Alternatively, for coupling with ammonia (e.g. ammonia in alcoholic solution), the coupling reaction may take place in the presence of a suitable solvent (e.g. dichloromethane) in a sealed tube. When reaction takes place on a compound of formula VIA in which R10a represents a substituent other than hydrogen (e.g. optionally substituted alkyl), then the reaction may also take place in a sealed tube. In this case, a solution of Me3AI (e.g. 2 M in hexanes), or the like, may be added to the amine (of formula VIB), which mixture is in turn added to the compound of formula VIA (thereafter, it may be heated at reflux, then cooled before work up);
(vi) for compounds of formula I in which R1a and/or R1b is present that represents halo or -C(O)OR10a may be prepared from corresponding compounds of formula I in which R1a or R1b (as appropriate) represents hydrogen, which may be reacted in the presence of a suitable base, such as an organometallic base (e.g. an organolithium base, such as t-, s- or n-butyllithium or, preferably a lithium amide base such as diisopropylamide; which deprotonates and/or lithiates at the relevant position), followed by reaction in the presence of an electrophile that is a source of halide ions (e.g. as described in respect of process step (iii)), or C02 (to form compounds of formula I in which R1a and/or R1b represent -COOH) or a compound of formula VII,
LB-R1 1 VII wherein L8 represents a suitable leaving group, such as one hereinbefore defined in respect of L1 (or another suitable leaving group), and R1b represents -C(0)OR1t)a (and R10a is preferably not hydrogen), under standard reaction conditions, for example the deprotonation/lithiation may be performed in an inert atmosphere (e.g. under N2) in the presence of an anhydrous polar aprotic solvent (such as THF, dimethoxyethane, ethyl ether and the like), which may be performed at below room temperature (e.g. at below 0°C, at temperatures down to -78°C, depending on the strength of the base to be employed), and the subsequent 'quench', i.e. reaction with the electrophile (e.g. halide source or compound of formula VII) may also be performed at low temperatures (e.g. at the temperature of the deprotonation/lithiation), which temperature may be raised up to 0°C (or to rt) to ensure the complete reaction, before the mixture is worked up;
(vii) for compounds of formula I which contain a -C(OH)(H)-Ci.n alkyl group (which alkyl group may be substituted by one or more substituents selected from those defined herein, e.g. E3 and =0; halo; or =0, =S and =N(R20) as appropriate, but is preferably unsubstituted), for example when there is a R1 and/or R2 group present which represent such a -CiOHXHJ-d. alkyl group, reaction of a corresponding compound of formula I in which there is a -C(0)H group present (i.e. R1 and/or R2 represents -C(O)H), with a compound of formula VIII,
Rxx gX1 VIII wherein R** represents d-n alkyl optionally substituted by one or more substituents selected from e.g. E3 and =0 (but is preferably unsubstituted) and X1 represents halo (e.g. iodo, bromo or, preferably, chloro), under standard Grignard reaction conditions, e.g. in the presence of an inert atmosphere and, optionally, an anhydrous solvent;
(viii) compounds of formula I in which At and A4 both represent N, A5 represents C(R2) and represents C(R1 ) may be prepared by reaction of a compound of formula IX,
Figure imgf000043_0001
wherein L1R3 represents either L1 as hereinbefore defined or R3 as hereinbefore defined, and R2, B1, B1a, B2, B2a, B3, B3a, B4 and B4a are as hereinbefore defined, with a compound of formula X,
H-C(0)-R1b X wherein R1b represents -C(=Y)N(R10a)R1 a or -C(=Y)R10a, optionally in the presence of a suitable base (for instance a sterically hindered base, such as an amidine base, e.g. DBU) and a suitable solvent (e.g. dichloromethane) at an appropriate temperature (e.g. room temperature) for an appropriate period of time. When L1R3 in the compound of formula IX represents L , then this process step may be proceeded by process step (i) as defined above. Corresponding reactions may also take place in which A5 represents N (instead of C(R2));
(ix) compounds of formula I in which A, represents N, A4 represents C(R1a), A4a represents N and A5 represents C(R2) may be prepared by reaction of a compound of formula XI,
Figure imgf000044_0001
wherein L1R3, R2, B1, B1a, B2, B2a, B3, B3a, B4 and B a are as hereinbefore defined, with a compound of formula XII,
R a-C(Od.6 alkyl)3 XII or, a compound of formula XIII, R1a-C(0)OH XIII or, derivatives of either, wherein R1a represents -C(=Y)N(R10a)R 1a or -C(=Y)R 0a as hereinbefore defined (and is preferably hydrogen or optionally substituted CM2 alkyl; so forming e.g. triethyl orthoformate, triethyl orthoacetate, formic acid, and the like), under standard reaction conditions. When L1R3 in the compound of formula XI represents L1, then this process step may be proceeded by process step (i) as defined above. Corresponding reactions may also take place in which A5 represents N (instead of C(R2)); (x) for compounds of formula I that contain an unsubstituted amino group (e.g. a R2a or R2b substituent that represents -N(R5a)R5b in which R5a and R5b represent hydrogen), may be prepared by reaction of a corresponding amino protected compound of formula I (e.g. in which the -NH2 moiety is substituted by two 4- methoxybenzyl moieties), for instance under standard reaction conditions that may be specific to that particular protecting group (e.g. by reaction in the presence of acid, such as a mixture of trifluoroacetic acid and sulfuric acid); (xi) for compounds of formula I that contain an amino group attached to an aromatic group (e.g. a -N(R5a)R5b moiety), reaction of a compound corresponding to a compound of formula but in which there is a halo (e.g. bromo, iodo or, preferably, fluoro) group in that position by reaction of an amine (e.g. a compound of formula HN(R5a)R5b, or a protected derivative thereof) under appropriate coupling conditions known to those skilled in the art such as those conditions described hereinbefore in respect of process step (ii) above, for instance in the presence of DIPEA in an anhydrous solvent (e.g. dry dioxane).
Compounds of formula II may be prepared by reaction of a compound of formula XIV,
Figure imgf000045_0001
wherein L , L3, A^, A4a, A5 and R3 are as hereinbefore defined, with a compound of formula V, as hereinbefore defined, for example under reaction conditions such as those hereinbefore described in respect of preparation of compounds of formula I (process step (ii) above). Compounds of formula IV (for example, in which ΑΊ represents C(R1), A represents C(R1a), A4a represents C(R1b) and A5 represents C(R2)) in which L3 represents e.g. chloro, bromo or iodo, may be prepared by reaction of a compound of formula XV,
Figure imgf000045_0002
wherein Ai, A4, A4a, A5 and R3 as hereinbefore defined (or its tautomer), in the presence of a suitable reagent that provides the source of the chloro, bromo or iodo (e.g. POCI3 may be employed, or, a reagent such as p-toluenesulfonyl chloride or the like) under reaction conditions known to the skilled person, for example at reflux (e.g. in the case of reaction with POCI3) or, in the case of reaction with p-toluenesulfonyl chloride, in the presence of a base, such as an organic amine e.g. triethylamine, /V./V-dimethylaniline (or the like), and optionally a catalyst such as DMAP (and optionally in the presence of a suitable solvent, such as acetonitrile). In the case of the latter, the compound of formula I may be prepared directly form the intermediate compound IV that may be formed by reaction in the presence of a compound of formula V (which latter reaction need not follow the reaction conditions set out above in respect of process step (ii); for instance, the reaction mixture may simply be heated in the same pot, e.g. at elevated temperature such as at about 65°C.
Compounds of formula IV in which L3 represents a sulfonate, such as -S(0)2Ci.6 alkyl (e.g. -S(0)2CH3) may be prepared by oxidation of a compound of formula XVI,
Figure imgf000046_0001
wherein Rs2 represents Ci.6 alkyl (e.g. methyl), and ΑΊ, A4l A4a, A5 and R3 are as hereinbefore defined, in the presence of an oxidising agent such as m- chloroperbenzoic acid and, if necessary, a suitable solvent (e.g. dichloromethane).
Compounds of formula VIA in which A^ represents C(R1b) in which R1b represents -C(O)OR10a (and A* represents C(R1a)), may be prepared by reaction of a compound of formula XVIA,
Figure imgf000047_0001
wherein R represents C1.6 alkyl (preferably methyl), with a compound of formula
XVIB,
10a
L15-C(H)(R1a)-C(O)-C(0)0R XVIB wherein L15 represents a suitable leaving group, such as one hereinbefore defined by L1 (e.g. halo, such as bromo), and R1a and R10a are as hereinbefore defined (but R10a is preferably not hydrogen; e.g. it represents alkyl, such as ethyl), for instance the compound of formula XVIB may be ethyl bromopyruvate, under reaction conditions known to those skilled in the art, for instance in the presence of an acid (e.g. an organic acid such as para-toluenesulfonic acid) in the presence of a suitable solvent (e.g. an aromatic solvent such as toluene), which reaction mixture may be heated at elevated temperature, e.g. at reflux. This reaction may be followed by (if and as appropriate) conversion of the relevant -S-R3 moieties to other suitable leaving groups (e.g. by oxidation to -S(0)2-R3) and/or reaction with a compound of formula V or III as hereinbefore defined (and as appropriate). Alternatively, the reaction of the compound of formula XVIB defined above may take place with a compound of formula XVIA but in which the respective -S-R3 groups are replaced with a -L -R3 and an optionally substituted morpholinyl moiety, as appropriate.
Compounds of formula IX (e.g. in which L1R3 represents L1) may be prepared by reaction of a compound of formula XVII,
Figure imgf000048_0001
wherein L1R3, R2 and L3 are as hereinbefore defined, with a compound of formula V as hereinbefore defined, for example under reaction conditions such as those hereinbefore defined in respect of preparation of compounds of formula I (process step (ii) above).
Compounds of formula IX and XVII may be prepared by reaction of a compound of formula XVIII,
XVIII
Figure imgf000048_0002
wherein Lxx represents L3 (in the case of preparation of compounds of formula XVII) or represents the following moiety:
Figure imgf000048_0003
(in the case of preparation of compounds of formula IX), and R2, L1R3, B1, B1a, B2, B2a, B3, B3a, B4 and B4a are as hereinbefore defined, with o- (mesitylsulfonyl)hydroxylamine (or the like; i.e. another suitable source of -NH2), under standard reaction conditions known to those skilled in the art, e.g. in the presence of a suitable solvent (e.g. dichloromethane).
Compounds of formula XI may be prepared by reaction of a compound of formula XIX,
Figure imgf000049_0001
wherein L1, R2, L1R3, B1 , B1a, B2, B2a, B3, B3a, B4 and B4a are as hereinbefore defined, with hydrazine (or a derivative thereof, e.g. hydrazine hydrate), under standard conditions.
Compounds of formula XIV in which L1 represents a sulfide such as -SCH3, L3 represents a sulfide such as -SCH3, and and A5 both represent N, A represents C(R1a) and Ata represents C(R1 b) may be prepared by reaction of a compound of formula XX,
Figure imgf000049_0002
wherein Rs3 represents Ci-6 alkyl (preferably methyl), with a compound of formula XXI,
L15-C(H)(R1a)-C(0)-R1 b XXI wherein L15 represents a suitable leaving group, such as one hereinbefore defiend by L1 (e.g. halo, such as bromo) and R1a and R1b are as hereinbefore defined, and R1a preferably represents hydrogen (or a protected derivative thereof; e.g. the compound of formula XXI may be bromoacetaldehyde diethyl acetal, or, when R1b represents -C(0)Oethyl, the compound of formula XXI may be ethyl bromopyruvate), for example in the presence of an acid catalyst (e.g. p- toluenesulfonic acid or the like), which reaction may be performed at room temperature or preferably at elevated temperature e.g. at about 65°C. Corresponding reactions may also take place in which A5 represents C(R2).
Compounds of formula XIV in which L3 represents halo (e.g. chloro) and L1 represents a sulfide (e.g. -SCH3) (and, preferably, A5 represents N, A represents C(R1a), A4a represents C(R1 ) and represents N), may also be prepared by reaction of a compound of formula XXII,
Figure imgf000050_0001
wherein A^ A4, A4a, A5 and R are as hereinbefore defined (and R represents a group defined by Rs2 and is preferably methyl), under halogenation reaction conditions such as those described herein, e.g. in the presence POCI3.
Compounds of formula XIV in which L3 represents halo (especially chloro) may be prepared by reaction of a compound of formula XXIII,
XXIII
Figure imgf000050_0002
wherein L1, A1 t A^, A^ and A5 are as hereinbefore defined, for example, in the presence of a base such as a metal hydroxide (e.g. KOH), in the presence of solvent (e.g. an alcohol such as methanol), followed by isolation of any intermediate product and then reaction under conditions such as those hereinbefore described in respect of preparation of compounds of formula IV (e.g. the conditions deployed in the reaction of a compound of formula XV in the presence of POCI3, which reaction mixture may be heated at reflux for an appropriate period of time).
Compounds of formula XV may be prepared by reaction of a corresponding compound of formula XXIV,
Figure imgf000051_0001
wherein A! , A4, A4A, A5 and R3 as hereinbefore defined, in the presence of a suitable reagent for the replacement of the -O- moiety with a -N(H)- moiety, for example ammonia or a source thereof (e.g. ammonium acetate), under standard reaction conditions, for instance optionally in the presence of a suitable solvent (e.g. acetic acid), at elevated temperature (e.g. at about 160°C under microwave irradiation reaction conditions).
Compounds of formula XV in which A5 represents C(R2) (and preferably, AT represents C(R1), A4 represents N, A4A represents C(R1b) and A5 represents C(H); further, R1b may represent -C(O)OR10a) may also be prepared by reaction of a compound of formula XXV,
Figure imgf000051_0002
or a derivative thereof (e.g. a carboxylic acid ester such as a -C(0)0-ethyl, for instance A^ may represent -C(R1 ), in which R1b represents -C(O)OR10a and R10a is preferably ethyl), wherein Ai, A , A4a and R3 are as hereinbefore defined (but, preferably, Ai represents C(R1), Ai represents N and A a represents C(R1 ), in which R1 may represent -C(O)OR10a), with a source of ammonia, such as ammonium acetate, for example under reaction conditions such as those described herein (e.g. above), or in the presence of an alcoholic solvent (e.g. ethanol). Compounds of formula XV, or protected derivatives thereof (which includes salts, e.g. a bromide salt), in which A5 represents C(R2) (and, preferably, A,a represents N and/or, preferably, Α represents C(R1) and A4 represents C(R1a)) may be prepared by reaction of a compound of formula XXVI,
or a protected derivative thereof, e.g. a methyl protected derivative thereof, for instance, when the A-! to A4a-containing ring represents an imidazole ring (i.e. A4a represents N, and the other ring members are C, then the N at A a may be protected, e.g. by a methyl group, so forming for example 1-methyl-1 H-imidazole- 4-carboxamide) and wherein Αι, A4 and A4a are as hereinbefore defined, with a compound of formula XXVII,
L 2-C(H)(R2)-C(0)-R3 XXVII wherein L12 represents a suitable leaving group, such as one hereinbefore defined in respect of L1 (e.g. halo, preferably, bromo), and R2 and R3 are as hereinbefore defined (and R2 is preferably hydrogen), for example at elevated temperature (e.g at reflux) in the presence of an appropriate solvent (e.g. acetonitrile, dimethylformamide, and the like, or mixtures thereof).
Compounds of formula XV, in which A5 represents N (e.g. A^ A4 and A4a respectively represent C(R1), C(R1a) and C(R1b) and A5 represents N, or, A represents N(R1 ), A4 represents C(R1a) and A4a and A5 both represent N) may also be prepared by intramolecular cyclisation of a compound of formula XXVIII,
Figure imgf000053_0001
wherein R3, Αι, A4 and A4a are as hereinbefore defined, by reaction in the presence of a base, for instance an aqueous basic solution such as ammonium hydroxide, or a metal alkyl-oxide (e.g. potassium terf-butoxide) in an alcoholic solution (e.g. butanol), for instance at elevated temperature e.g. at about 120°C under microwave irradiation reaction conditions.
Compounds of formula XV, in which R3 is replaced with a -OH group and A5 represents N (e.g. A1 t A4 and A,a respectively represent C(R1), C(R a) and C(R1b) and A5 represents N, or, Ai represents N(R1 ), A4 represents C(R1a) and A4a and A5 both represent N) may also be prepared by reaction of a compound of formula XXIX,
Figure imgf000053_0002
wherein A^ A4 and A4a are as hereinbefore defined, with phosgene, triphosgene, carbonyl diimidazole, or the like, i.e. another suitable reagent that acts as a similar source of a carbonyl group, under reaction conditions such as those described hereinafter. Such amido-compounds may be prepared by coupling of the corresponding carboxylic acid with ammonia (or a suitable source thereof, e.g. NH4CI in NH3/ eOH).
Compounds of formula XVI may be prepared by reaction of a compound of formula XXX,
Figure imgf000054_0001
wherein A4, A a, A5 and R3 are as hereinbefore defined, with a compound of formula XXXI,
S2 13 XXXI wherein L 3 represents a suitable leaving group (such as halo, e.g. iodo) and Rs2 is as hereinbefore defined (e.g. methyl iodide), for example in the presence of aqueous NaOH solution and an alocoholic solvent (e.g. methanol).
Compounds of formula XVI (or the bicyclic core of compounds of formula XVI) may also be prepared by intramolecular reaction of a compound of formula XXXII,
XXXII
Figure imgf000054_0002
wherein L17 represents a suitable leaving group (e.g. halo, such as chloro), Ai is preferably N, A4 is C(R a) and A5 is C(R1b), for example in the presence of base at elevated temperature, followed by standard modification and/or introduction of functional groups.
Compounds of formula XVIA may be prepared by reaction of a compound of formula XXXI IA,
Figure imgf000055_0001
with a compound of formula XXXIIB
L18.RS3 XXXIIB wherein L18 represents a suitable leaving group, such as one hereinbefore defined by L1 (and preferably bromo, chloro or especially iodo), for instance in the presence of a base (e.g. an organic amine, such as DIPEA or the like) and a suitable solvent (e.g. DCM).
Compounds of formula XVII may be prepared by reaction of a compound of formula XXXIII,
XXXIII
Figure imgf000055_0002
wherein R2, iJR3 and L3 are as hereinbefore defined, with a suitable aminating agent, for instance a hydroxylamine compound (e.g. a sulfonyl-hydroxylamine, such as o-(meistylsulfonyl)hydroxylamine), under standard reaction conditions.
Compounds of formula XIX in which L1 represents chloro (or halo) may be prepared by reaction of a compound of formula XXXIV, XXXIV
Figure imgf000056_0001
wherein L1R3, R2, B1, B1a, B2, B2a, B3, B3a, B4 and B4a are as hereinbefore defined, with a reagent, or mixture of reagents, that are suitable for converting the amino moiety to a chloro (or other halo) moiety, for example, TiCI4 and terf-butyl nitrite, under conditions such as those described hereinafter.
Compounds of formula XXII in which A5 represents N (and preferably in which A5 represents N, A4 represents C(R1a), A4a represents C(R1 ) and A represents N) may be prepared by reaction of a compound of formula XXXV,
Figure imgf000056_0002
wherein A,, ) and A4a are as hereinbefore defined (but, preferably, < represents C(R1a), A4a represents C(R b) and A, represents N), in the presence of a compound of formula XXXI as hereinbefore defined but in which Rs2 represents R53.
Compounds of formula XXIV in which in which A5 represents C(R2) (and, preferably, Ai represents C(R1), 4 represents C(R1a), A^ represents C(R1b) and A5 represents C(H)), may be prepared by reaction of a compound of formula XXXVI, XXXVI
Figure imgf000057_0001
wherein A, and 3 are as hereinbefore defined, with a compound of formula XXXVII,
R3-C(0)-CH2-L9 XXXVII wherein L9 represents a suitable leaving group, for example one hereinbefore defined in respect of L1 (e.g. halo, and preferably, bromo), under standard reaction conditions, for example, optionally in the presence of a suitable base (preferably an inorganic base, such as NaH, K3P04, Cs2C03, f-BuONa, f-BuOK, and, more preferably an inorganic carbonate such as Na2C03 and, preferably, K2C03) and a suitable solvent (e.g. an aprotic solvent such as dichloromethane or, preferably, acetone). The reaction may be performed at elevated temperature, for example, at above 100°C (e.g. at about 120°C) under microwave irradiation conditions.
Compounds of formula XXV may be prepared by reaction of a compound of formula XXXVIII,
XXXVIII
Figure imgf000057_0002
or a derivative thereof (e.g. ester such as ethyl ester), wherein A A4 and fi^a are as hereinbefore defined, with a compound of formula XXXIX,
L 0-CH2-C(O)-R3 XXXIX wherein L10 represents a suitable leaving group, such as one hereinbefore defined in respect of L1 (e.g. halo, such as bromo), and R3 is as hereinbefore defined, under standard reaction conditions, for example optionally in the presence of a suitable base and solvent (such as those hereinbefore described in respect of preparation of compounds of formula XXIV (by reaction of a compound of formula XXXVI and XXXVII), e.g. K2C03 in acetone).
Compounds of formula XXVI may be prepared by reaction of a compound of formula XXXVIII as hereinbefore defined, or a derivative thereof (e.g. an ester, such as an ethyl ester), with ammonia or a suitable source thereof (e.g. NH4CI in a solution of NH3 in an alcohol such as methanol).
Compounds of formula XXVIII may be prepared by reaction of a compound of formula XXIX as hereinbefore defined with a compound of formula XL,
R3-C(0)-L11 XL wherein L11 represents a suitable leaving group such as one hereinbefore defined by L1 (e.g. halo, such as chloro) or -OH (or an ester, thereof) under standard acylation or amide coupling reaction conditions, e.g. in the case of acylation, the presence of an appropriate base (e.g. an organic amine base such as triethylamine) and an appropriate solvent (e.g. pyridine, dichloromethane, dioxane, etc, or mixtures thereof), or, in the case of amide couplings, under conditions described hereinafter (or e.g. in the presence of polyphosphoric acid, which advantageously may form a compound of formula XXVIII in situ, which may undergo subsequent reaction to provide the compound of formula XV isoquinolinone directly).
Compounds of formula XXIX may be prepared by (partial) hydrolysis of a compound of formula XLI,
Figure imgf000058_0001
wherein A<, and A a are as hereinbefore defined, under standard hydrolysis reaction conditions, e.g. in the presence of an aqueous hydroxide base (e.g. potassium hydroxide) in a suitable solvent such as tetrahydrofuran. Compounds of formula XXIX (or the corresponding carboxylic acid or ester) may also be prepared by amination of a compound of formula XXVI as hereinbefore defined, or compounds of formula XLI may also be prepared by amination of a compound of formula XLII,
Figure imgf000059_0001
wherein Ai, A4 and A4a are as hereinbefore defined, under reaction conditions such as those described hereinafter, e.g. in the presence of sodium hydride, followed by o-(diphenylphosphinyl)hydroxylamine.
Compounds of formula XXXI IA may be prepared by reaction of a compound of formula XLIIA,
XLIIA
Figure imgf000059_0002
In the presence of a suitable reagent for the conversion of a carbonyl group to a thiocarbonyl group, for instance in the presence of Lawesson's reagent or phosphorous pentasulfide, in the presence of a suitable solvent (e.g. dry pyridine), which reaction mixture may be heated at elevated temperature, for instance at reflux.
Compounds of formula XXXIX in which L10 represents halo (e.g. chloro or, preferably, bromo) may be prepared by reaction of a compound corresponding to a compound of formula XXXIX but in which L 0 represents hydrogen, with a source of halide ions (e.g. such as one hereinbefore described in respect of preparation of compounds of formula I; process step (iii) above), such as N- chlorosuccinimide or /V-bromosuccinimide, under standard reaction conditions e.g. in the presence of a suitable base (such as an organic base e.g. triethylamine or the like) and trimethylsilylfluoromethanesulfonate, or the like.
Compounds corresponding to compounds of formula XXXIX but in which L10 represents hydrogen may themselves be prepared from compounds of formula XLIII,
XLIII in which L11 represents a suitable leaving group, such as one hereinbefore defined in respect of L1 (e.g. halo, such as chloro or, preferably bromo), with a compound that allows the introduction of the -C(0)CH3 moiety, such as tributyl(1- ethoxyvinyl)tin in the presence of a precious metal catalyst/ligand (e.g. dichlorobis(triphenyl-phosphine)palladium (II)) and a suitable solvent (e.g. dimethylformamide, or the like). Compounds of formula XLI may be prepared by reaction of a compound of formula XLII as hereinbefore defined, for example by reaction in the presence of base (e.g. a metal hydride, such as sodium hydride) and an appropriate reagent for the introduction of the amino group, e.g. o-(diphenylphosphinyl)- hydroxylamine, or another reagent suitable for electrophilic aminations, under reaction conditions such as those described hereinafter.
Compounds of formula XLII may be prepared by reaction of a compound of formula XLIV,
Figure imgf000060_0001
wherein Ai, A4 and A a are as hereinbefore defined, in the presence of hydroxylamine (e.g. the hydrochloride thereof), followed by dehydration (in the presence of a suitable dehydrating agent, such as phthalic anhydride). Compounds of formula XLIIA may be prepared by reaction of a corresponding compound of formula XLIVA,
XLIVA
Figure imgf000061_0001
wherein L19 represents a suitable leaving group such as one hereinbefore defined by L1 (e.g. bromo), in the presence of a source of ammonia (e.g. liquid ammonia), for instance under coupling reaction conditions e.g. in the presence of a metal catalyst e.g. copper.
Compounds of formula XLIVA may be prepared using standard methods, for instance, by the reaction of 6-azauracil in the presence of bromine and water. Other specific transformation steps (including those that may be employed in order to form compounds of formula I) that may be mentioned include:
(i) reductions, for example of a carboxylic acid (or ester) to either an aldehyde or an alcohol, using appropriate reducing conditions (e.g. -C(0)OH (or an ester thereof), may be converted to a -C(0)H or -CH2-OH group, using DIBAL and LiAIH4, respectively (or similar chemoselective reducing agents));
(ii) reductions of an aldehyde (-C(O)H) group to an alcohol group (-CH2OH), using appropriate reduction conditions such as those mentioned at point (i) above;
(iii) oxidations, for example of a moiety containing an alcohol group (e.g. -CH2OH) to an aldehyde (e.g. -C(O)H), for example in the presence of a suitable oxidising agent, e.g. Mn02 or the like;
(iv) reductive amination of an aldehyde and an amine, under appropriate reaction conditions, for example in "one-pot" procedure in the presence of an appropriate reducing agent, such as a chemoselective reducing agent such as sodium cyanoborohydride or, preferably, sodium triacetoxyborohydride, or the like. Alternatively, such reactions may be performed in two steps, for example a condensation step (in the presence of e.g. a dehydrating agent such as trimethyl orthoformate or gS04 or molecular sieves, etc) followed by a reduction step (e.g. by reaction in the presence of a reducing agent such as a chemoselective one mentioned above or NaBH4, AIH4, or the like);
(v) amide coupling reactions, i.e. the formation of an amide from a carboxylic acid (or ester thereof), for example when R2 represents -C(0)OH (or an ester thereof), it may be converted to a -C(O)N(R10 )R11b group (in which R10b and R11b are as hereinbefore defined, and may be linked together, e.g. as defined above), and which reaction may (e.g. when R2 represents -C(O)OH) be performed in the presence of a suitable coupling reagent (e.g. 1 ,1 '-carbonyldiimidazole, Λ/,Λ - dicyclohexylcarbodiimide, or the like) or, in the case when R2 represents an ester (e.g. -C(0)OCH3 or -C(0)OCH2CH3), in the presence of e.g. trimethylaluminium, or, alternatively the -C(0)OH group may first be activated to the corresponding acyl halide (e.g -C(0)CI, by treatment with oxalyl chloride, thionyl chloride, phosphorous pentachloride, phosphorous oxychloride, or the like), and, in all cases, the relevant compound is reacted with a compound of formula HN(R10a)R11a (in which R10a and R11a are as hereinbefore defined), under standard conditions known to those skilled in the art (e.g. optionally in the presence of a suitable solvent, suitable base and/or in an inert atmosphere);
(vi) conversion of a primary amide to a nitrile functional group, for example under dehydration reaction conditions, e.g. in the presence of POCI3, or the like;
(vii) nucleophilic substitution reactions, where any nucleophile replaces a leaving group, e.g. methylsulfonylpiperazine may replace a chloro leaving group, or, aromatic nucleophilic substitution reactions such as the substitution of ammonia (or a protected derivative thereof, e.g. a dibenzyl derivative) onto an aromatic group bearing a leaving group (e.g. onto a 2-chloropyrimidinyl moiety);
(viii) transformation of a methoxy group to a hydroxy group, by reaction in the presence of an appropriate reagent, such as boron fluoride-dimethyl sulfide complex or BBr3 (e.g. in the presence of a suitable solvent such as dichloromethane);
(ix) specific deprotection steps, for example a hydroxy group protected as a silyl ether (e.g. a fert-butyl-dimethylsilyl protecting group) may be deprotected by reaction with a source of fluoride ions, e.g. by employing the reagent tetrabutylammonium fluoride (TBAF).
Intermediate compounds described herein are either commercially available, are known in the literature, or may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions. Further, processes to prepare compounds of formula I may be described in the literature, for example in:
Werber.G. et al.; J. Heterocycl. Chem.; EN; 14; 1977; 823-827;
Andanappa K. Gadad et al. Bioorg. Med. Chem. 2004, 12, 5651-5659;
Paul Heinz et al. Monatshefte fur Chemie, 1977, 108, 665-680;
M.A. El-Sherbeny et al. Boll. Chim. Farm. 1997, 136, 253-256;
Nicolaou, K. C; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 2-49; Bretonnet et al. J. Med. Chem. 2007, 50, 1872 ;
Asuncion Marin et al. Farmaco 1992, 47 (1), 63-75;
Severinsen, R. et al. Tetrahedron 2005, 61, 5565-5575;
Nicolaou, K. C; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 2-49; M. Kuwahara et al., Chem. Pharm Bull, 1996, 44, 122;
Wipf, P.; Jung, J.- . J. Org. Chem. 2000, 65(20), 6319-6337;
Shintani, R.; Okamoto, K. Org. Lett. 2005, 7 (21), 4757-4759;
Nicolaou, K. C; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 2-49; J. Kobe et al., Tetrahedron, 1968, 24, 239 ;
P.F. Fabio, A.F. Lanzilotti and S.A. Lang, Journal of Labelled Compounds and Pharmaceuticals, 1978, 15, 407;
F.D. Bellamy and K. Ou, Tetrahedron Lett , 1985, 25, 839;
M. Kuwahara et al., Chem. Pharm Bull., 1996, 44, 122;
A.F. Abdel-Magid and C.A Maryanoff. Synthesis, 1990, 537;
M. Schlosser et al. Organometallics in Synthesis. A Manual, (M. Schlosser, Ed.), Wiley &Sons Ltd: Chichester, UK, 2002, and references cited therein;
L. Wengwei et al. , Tetrahedron Lett, 2006, 47, 1941 ;
M. Plotkin et al. Tetrahedron Lett, 2000, 41, 2269;
Seyden-Penne, J. Reductions by the Alumino and Borohydrides, VCH, NY, 1991 ;
O. C. Dermer, Chem. Rev., 1934, 14, 385;
N. Defacqz, et al., Tetrahedron Lett. , 2003, 44, 91 1 1 ;
S.J. Gregson er a/., J. Med. Chem., 2004, 47, 1 161 ;
A. M. Abdel Magib, er a/., J. Org. Chem. , 1996, 61, 3849;
A.F. Abdel-Magid and C.A Maryanoff. Synthesis, 1990, 537;
T. Ikemoto and M. Wakimasu, Heterocycles, 2001 , 55, 99;
E. Abignente et al., II Farmaco, 1990, 45, 1075; T. Ikemoto ef a/. , Tetrahedron, 2000, 56, 7915;
T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Wiley, NY, 1999;
S. Y. Han and Y.-A. Kim. Tetrahedron, 2004, 60, 2447;
J. A. H. Lainton et al. , J. Comb. Chem. , 2003, 5, 400; or
Wiggins, J. M. Synth. Commun., 1988, 18, 741.
The substituents R3, B1, B a, B2, B a, B3, B3a, B4, B4a, A,, A2, A3, A4, A4a and A5 in final compounds of the invention or relevant intermediates may be modified one or more times, after or during the processes described above by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions, oxidations, alkylations, acylations, hydrolyses, esterifications, etherifications, halogenations or nitrations. Such reactions may result in the formation of a symmetric or asymmetric final compound of the invention or intermediate. The precursor groups can be changed to a different such group, or to the groups defined in formula I, at any time during the reaction sequence.
For example, when substituents in the compounds of the invention (e.g. represented by R3, B1, B1a, B2, B2a, B3, B3a, B4, B a, Ai, A2, A3, A4, A43 and A5) such as C02Et, CHO, CN and/or CH2CI, are present, these groups can be further derivatized to other fragments described (e.g. by those integers mentioned above) in compounds of the invention, following synthetic protocols very well know to the person skilled in the art and/or according to the experimental part described in the patent. Other specific transformation steps that may be mentioned include: the reduction of a nitro or azido group to an amino group; the hydrolysis of a nitrile group to a carboxylic acid group; and standard nucleophilic aromatic substitution reactions, for example in which an iodo-, preferably, fluoro- or bromo-phenyl group is converted into a cyanophenyl group by employing a source of cyanide ions (e.g. by reaction with a compound which is a source of cyano anions, e.g. sodium, copper (I), zinc or potassium cyanide, optionally in the presence of a palladium catalyst) as a reagent (alternatively, in this case, palladium catalysed cyanation reaction conditions may also be employed). Other transformations that may be mentioned include: the conversion of a halo group (preferably iodo or bromo) to a 1-alkynyl group (e.g. by reaction with a 1 - alkyne), which latter reaction may be performed in the presence of a suitable coupling catalyst (e.g. a palladium and/or a copper based catalyst) and a suitable base (e.g. a tri-(Ci.6 alkyl)amine such as triethylamine, tributylamine or ethyldiisopropylamine); the introduction of amino groups and hydroxy groups in accordance with standard conditions using reagents known to those skilled in the art; the conversion of an amino group to a halo, azido or a cyano group, for example via diazotisation (e.g. generated in situ by reaction with NaN02 and a strong acid, such as HCI or H2S0 , at low temperature such as at 0°C or below, e.g. at about -5°C) followed by reaction with the appropriate nucleophile e.g. a source of the relevant anions, for example by reaction in the presence of a halogen gas (e.g. bromine, iodine or chlorine), or a reagent that is a source of azido or cyanide anions, such as NaN3 or NaCN; the conversion of -C(0)OH to a -NH2 group, under Schmidt reaction conditions, or variants thereof, for example in the presence of HN3 (which may be formed in by contacting NaN3 with a strong acid such as H2S04), or, for variants, by reaction with diphenyl phosphoryl azide ((PhO)2P(0)N3) in the presence of an alcohol, such as ferf-butanol, which may result in the formation of a carbamate intermediate; the conversion of -C(0)NH2 to -NH2, for example under Hofmann rearrangement reaction conditions, for example in the presence of NaOBr (which may be formed by contacting NaOH and Br2) which may result in the formation of a carbamate intermediate; the conversion of -C(0)N3 (which compound itself may be prepared from the corresponding acyl hydrazide under standard diazotisation reaction conditions, e.g. in the presence of NaN02 and a strong acid such as H2S04 or HCI) to -NH2, for example under Curtius rearrangement reaction conditions, which may result in the formation of an intermediate isocyanate (or a carbamate if treated with an alcohol); the conversion of an alkyl carbamate to -NH2, by hydrolysis, for example in the presence of water and base or under acidic conditions, or, when a benzyl carbamate intermediate is formed, under hydrogenation reaction conditions (e.g. catalytic hydrogenation reaction conditions in the presence of a precious metal catalyst such as Pd); halogenation of an aromatic ring, for example by an electrophilic aromatic substitution reaction in the presence of halogen atoms (e.g. chlorine, bromine, etc, or an equivalent source thereof) and, if necessary an appropriate catalyst/Lewis acid (e.g. AICI3 or FeCI3).
Compounds of the invention bearing a carboxyester functional group may be converted into a variety of derivatives according to methods well known in the art to convert carboxyester groups into carboxamides, N-substituted carboxamides, Ν,Ν-disubstituted carboxamides, carboxylic acids, and the like. The operative conditions are those widely known in the art and may comprise, for instance in the conversion of a carboxyester group into a carboxamide group, the reaction with ammonia or ammonium hydroxide in the presence of a suitable solvent such as a lower alcohol, dimethylformamide or a mixture thereof; preferably the reaction is carried out with ammonium hydroxide in a methanol/dimethyl- formamide mixture, at a temperature ranging from about 50°C to about 100°C. Analogous operative conditions apply in the preparation of N-substituted or N,N- disubstituted carboxamides wherein a suitable primary or secondary amine is used in place of ammonia or ammonium hydroxide. Likewise, carboxyester groups may be converted into carboxylic acid derivatives through basic or acidic hydrolysis conditions, widely known in the art. Further, amino derivatives of compounds of the invention may easily be converted into the corresponding carbamate, carboxamido or ureido derivatives.
Compounds of the invention may be isolated from their reaction mixtures using conventional techniques (e.g. recrystallisations). It will be appreciated by those skilled in the art that, in the processes described above and hereinafter, the functional groups of intermediate compounds may need to be protected by protecting groups.
The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods (and the need can be readily determined by one skilled in the art). Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), 9-fluorenylmethyleneoxycarbonyl (Fmoc) and 2,4,4-trimethylpentan-2-yl (which may be deprotected by reaction in the presence of an acid, e.g. HCI in water/alcohol (e.g. MeOH)) or the like. The need for such protection is readily determined by one skilled in the art.
The protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes.
Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter. For example, protected compounds/intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques.
The type of chemistry involved will dictate the need, and type, of protecting groups as well as the sequence for accomplishing the synthesis. The use of protecting groups is fully described in "Protective Groups in Organic Synthesis", 3rd edition, T.W. Greene & P.G.M. Wutz, Wiley-lnterscience (1999).
Medical and Pharmaceutical Uses Compounds of the invention are indicated as pharmaceuticals. According to a further aspect of the invention there is provided a compound of the invention, as hereinbefore defined, for use as a pharmaceutical.
Compounds of the invention may inhibit protein or lipid kinases, such as a PI3 kinase (especially a class I PI3K), for example as may be shown in the tests described below (for example, the test for PI3Koc inhibition described below) and/or in tests known to the skilled person. The compounds of the invention may also inhibit mTOR. Thus, the compounds of the invention may be useful in the treatment of those disorders in an individual in which the inhibition of such protein or lipid kinases (e.g. PI3K, particularly class I PI3K, and/or mTOR) is desired and/or required (for instance compounds of the invention may inhibit PI3K, particularly class I PI3K and, optionally, may also inhibit mTOR).
The term "inhibit" may refer to any measurable reduction and/or prevention of catalytic kinase (e.g. PI3K, particularly class I PI3K, and/or mTOR) activity. The reduction and/or prevention of kinase activity may be measured by comparing the kinase activity in a sample containing a compound of the invention and an equivalent sample of kinase (e.g. PI3K, particularly class I PI3K, and/or mTOR) in the absence of a compound of the invention, as would be apparent to those skilled in the art. The measurable change may be objective (e.g. measurable by some test or marker, for example in an in vitro or in vivo assay or test, such as one described hereinafter, or otherwise another suitable assay or test known to those skilled in the art) or subjective (e.g. the subject gives an indication of or feels an effect).
Compounds of the invention may be found to exhibit 50% inhibition of a protein or lipid kinase (e.g. PI3K, such as class I PI3K, and/or mTOR) at a concentration of 100 μΜ or below (for example at a concentration of below 50 μΜ, or even below 10 μΜ, such as below 1 μΜ), when tested in an assay (or other test), for example as described hereinafter, or otherwise another suitable assay or test known to the skilled person.
Compounds of the invention are thus expected to be useful in the treatment of a disorder in which a protein or lipid kinase (e.g. PI3K, such as class I PI3K, and/or mTOR) is known to play a role and which are characterised by or associated with an overall elevated activity of that kinase (due to, for example, increased amount of the kinase or increased catalytic activity of the kinase). Hence, compounds of the invention are expected to be useful in the treatment of a disease/disorder arising from abnormal cell growth, function or behaviour associated with the protein or lipid kinase (e.g. PI3K, such as class I PI3K, and/or mTOR). Such conditions/disorders include cancer, immune disorders, cardiovascular diseases, viral infections, inflammation, metabolism/endocrine function disorders and neurological disorders. The disorders/conditions that the compounds of the invention may be useful in treating hence includes cancer (such as lymphomas, solid tumours or a cancer as described hereinafter), obstructive airways diseases, allergic diseases, inflammatory diseases (such as asthma, allergy and Chrohn's disease), immunosuppression (such as transplantation rejection and autoimmune diseases), disorders commonly connected with organ transplantation, AIDS- related diseases and other associated diseases. Other associated diseases that may be mentioned (particularly due to the key role of kinases in the regulation of cellular proliferation) include other cell proliferative disorders and/or non- malignant diseases, such as benign prostate hyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis, psoriasis, bone disorders, atherosclerosis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis. Other disease states that may be mentioned include cardiovascular disease, stroke, diabetes, hepatomegaly, Alzheimer's disease, cystic fibrosis, hormone- related diseases, immunodeficiency disorders, destructive bone disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukaemia, liver disease, pathologic immune conditions involving T cell activation and CNS disorders. As stated above, the compounds of the invention may be useful in the treatment of cancer. More, specifically, the compounds of the invention may therefore be useful in the treatment of a variety of cancer including, but not limited to: carcinoma such as cancer of the bladder, breast, colon, kidney, liver, lung (including non-small cell cancer and small cell lung cancer), esophagus, gall- bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, skin, squamous cell carcinoma, testis, genitourinary tract, larynx, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, small cell lung carcinoma, lung adenocarcinoma, bone, adenoma, adenocarcinoma, follicular carcinoma, undifferentiated carcinoma, papilliary carcinoma, seminona, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, Hodgkin's and leukaemia; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non- Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplasia syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannomas; and other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, thyroid follicular cancer and Kaposi's sarcoma.
Further, the protein or lipid kinases (e.g. PI3K, such as class I PI3K, and/or mTOR) may also be implicated in the multiplication of viruses and parasites. They may also play a major role in the pathogenesis and development of neurodegenerative disorders. Hence, compounds of the invention may also be useful in the treatment of viral conditions, parasitic conditions, as well as neurodegenerative disorders.
Compounds of the invention are indicated both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions.
According to a further aspect of the present invention, there is provided a method of treatment of a disease (e.g. cancer or another disease as mentioned herein) which is associated with the inhibition of protein or lipid kinase (e.g. PI3K, such as class I PI3K, and/or mTOR), i.e. where such inhibition is desired and/or required (for example, a method of treatment of a disease/disorder arising from abnormal cell growth, function or behaviour associated with protein or lipid kinases, e.g. PI3K, such as class I PI3K, and/or mTOR), which method comprises administration of a therapeutically effective amount of a compound of the invention, as hereinbefore defined, to a patient suffering from, or susceptible to, such a condition.
"Patients" include mammalian (including human) patients. Hence, the method of treatment discussed above may include the treatment of a human or animal body. The term "effective amount" refers to an amount of a compound, which confers a therapeutic effect on the treated patient. The effect may be objective (e.g. measurable by some test or marker) or subjective (e.g. the subject gives an indication of or feels an effect). Compounds of the invention may be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, sublingually, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form.
Compounds of the invention may be administered alone, but are preferably administered by way of known pharmaceutical formulations, including tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like. The type of pharmaceutical formulation may be selected with due regard to the intended route of administration and standard pharmaceutical practice. Such pharmaceutically acceptable carriers may be chemically inert to the active compounds and may have no detrimental side effects or toxicity under the conditions of use.
Such formulations may be prepared in accordance with standard and/or accepted pharmaceutical practice. Otherwise, the preparation of suitable formulations may be achieved non-inventively by the skilled person using routine techniques and/or in accordance with standard and/or accepted pharmaceutical practice.
According to a further aspect of the invention there is thus provided a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier.
Depending on e.g. potency and physical characteristics of the compound of the invention (i.e. active ingredient), pharmaceutical formulations that may be mentioned include those in which the active ingredient is present in at least 1 % (or at least 10%, at least 30% or at least 50%) by weight. That is, the ratio of active ingredient to the other components (i.e. the addition of adjuvant, diluent and carrier) of the pharmaceutical composition is at least 1 :99 (or at least 10:90, at least 30:70 or at least 50:50) by weight.
The amount of compound of the invention in the formulation will depend on the severity of the condition, and on the patient, to be treated, as well as the compound(s) which is/are employed, but may be determined non-inventively by the skilled person.
The invention further provides a process for the preparation of a pharmaceutical formulation, as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, or a pharmaceutically acceptable ester, amide, solvate or salt thereof with a pharmaceutically-acceptable adjuvant, diluent or carrier. Compounds of the invention may also be combined with other therapeutic agents that are inhibitors of protein or lipid kinases (e.g. PI3K, such as class I PI3K, a PI family kinase (e.g. PIM-1 , PIM-2- and/or PI -3) and/or mTOR) and/or useful in the treatment of a cancer and/or a proliferative disease. Compounds of the invention may also be combined with other therapies.
According to a further aspect of the invention, there is provided a combination product comprising:
(A) a compound of the invention, as hereinbefore defined; and
(B) another therapeutic agent that is useful in the treatment of cancer and/or a proliferative disease,
wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
Such combination products provide for the administration of a compound of the invention in conjunction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises a compound of the invention, and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including a compound of the invention and the other therapeutic agent).
Thus, there is further provided:
(1) a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, another therapeutic agent that is useful in the treatment of cancer and/or a proliferative disease, and a pharmaceutically-acceptable adjuvant, diluent or carrier; and
(2) a kit of parts comprising components:
(a) a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and
(b) a pharmaceutical formulation including another therapeutic agent that is useful in the treatment of cancer and/or a proliferative disease in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.
The invention further provides a process for the preparation of a combination product as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, or a pharmaceutically acceptable ester, amide, solvate or salt thereof with the other therapeutic agent that is useful in the treatment of cancer and/or a proliferative disease, and at least one pharmaceutically-acceptable adjuvant, diluent or carrier.
By "bringing into association", we mean that the two components are rendered suitable for administration in conjunction with each other. Thus, in relation to the process for the preparation of a kit of parts as hereinbefore defined, by bringing the two components "into association with" each other, we include that the two components of the kit of parts may be:
(i) provided as separate formulations (i.e. independently of one another), which are subsequently brought together for use in conjunction with each other in combination therapy; or
(ii) packaged and presented together as separate components of a "combination pack" for use in conjunction with each other in combination therapy.
Depending on the disorder, and the patient, to be treated, as well as the route of administration, compounds of the invention may be administered at varying therapeutically effective doses to a patient in need thereof. However, the dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the mammal over a reasonable timeframe. One skilled in the art will recognize that the selection of the exact dose and composition and the most appropriate delivery regimen will also be influenced by inter alia the pharmacological properties of the formulation, the nature and severity of the condition being treated, and the physical condition and mental acuity of the recipient, as well as the potency of the specific compound, the age, condition, body weight, sex and response of the patient to be treated, and the stage/severity of the disease.
Administration may be continuous or intermittent (e.g. by bolus injection). The dosage may also be determined by the timing and frequency of administration. In the case of oral or parenteral administration the dosage can vary from about 0.01 mg to about 1000 mg per day of a compound of the invention.
In any event, the medical practitioner, or other skilled person, will be able to determine routinely the actual dosage, which will be most suitable for an individual patient. The above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
Compounds of the invention may have the advantage that they are effective inhibitors of protein or lipid kinases (e.g. PI3K, such as class I PI3K, and/or mTOR). Advantegously, compounds of the invention may inhibit (e.g. selectively) certain protein or lipid kinases (e.g. PI3K, such as class I PI3K), without exhibiting inhibition (or significant inhibition) of other protein or lipid kinases. For instance, the compounds of the invention may selectively inhibit only one protein or lipid kinase (e.g. PI3K, such as class I PI3K).
Compounds of the invention may also have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the above- stated indications or otherwise.
Compounds of the invention may be beneficial as they are medicaments with targeted therapy, i.e. which target a particular molecular entity by inferring or inhibiting it (e.g. in this case by inhibiting one or more protein or lipid kinases as hereinbefore described). Compounds of the invention may therefore also have the benefit that they have a new effect (for instance as compared to known compounds in the prior art), for instance, the new effect may be a particular mode of action or another effect resultant of the targeted therapy. Targeted therapies may be beneficial as they may have the desired effect (e.g. reduce cancer, by reducing tumor growth or carcinogenisis) but may also have the advantage of reducing side effects (e.g. by preventing the killing of normal cells, as may occur using e.g. chemotherapy).
Furthermore, compounds of the invention may selectively target particular protein or lipid kinases (e.g. the ones described herein) compared to other known protein or lipid kinases (as may be shown experimentally hereinafter; see Table 4 for example). Accordingly, compounds of the invention may have the advantage that certain, specific, cancers may be treated selectively, which selective treatment may also have the effect of reducing side effects.
Examples/Biological Tests Determination of the activity of PI3 kinase activity of compounds of the invention is possible by a number of direct and indirect detection methods. Certain exemplary compounds described herein were prepared, characterized, and tested for their PI3K binding activity and in vitro activity against tumor cells. The range of PI3K binding activities was less than 1 nM to about 10 μ (i.e. certain compounds of the examples/invention had PI3K binding activity ICS0 values of less than 10 nM). Compounds of the examples/invention had tumor cell-based activity IC50 values less than 100 nM (see Table(s) below). PI3K activity assay
The kinase activity was measured by using the commercial ADP Hunter™ Plus assay available from DiscoveRx (#33-016), which is a homogeneous assay to measure the accumulation of ADP, a universal product of kinase activity. The enzyme, PI3K (ρ1 10α/ρ85α was purchased from Carna Biosciences (#07CBS- 0402A). The assay was done following the manufacturer recommendations with slight modifications: Mainly the kinase buffer was replace by 50 mM HEPES, pH 7.5, 3 mM MgCI2, 100 mM NaCI, 1 mM EGTA, 0.04% CHAPS, 2 mM TCEP and 0.01 mg/ml BGG. The PI3K was assayed in a titration experiment to determine the optimal protein concentration for the inhibition assay. To calculate the IC50 of the ETP-compounds, serial 1 :5 dilutions of the compounds were added to the enzyme at a fixed concentration (2.5 μg/ml. The enzyme was preincubated with the inhibitor and 30 μΜ PIP2 substrate (P9763, Sigma) for 5 min and then ATP was added to a final 50 μΜ concentration. Reaction was carried out for 1 hour at 25°C. Reagent A and B were sequentially added to the wells and plates were incubated for 30 min at 37 °C. Fluorescence counts were read in a Victor instrument (Perkin Elmer) with the recommended settings (544 and 580 nm as excitation and emission wavelengths, respectively). Values were normalized against the control activity included for each enzyme (i.e., 100 % PI3 kinase activity, without compound). These values were plot against the inhibitor concentration and were fit to a sigmoid dose-response curve by using the Graphad software. Cellular Mode of Action
Cell culture: The cell lines were obtained from the American Type Culture Collection (ATCC). U20S (human osteosarcoma) was cultured in Dulbecco's modified Eagle's medium (DMEM). PC3 (human prostate carcinoma), MCF7 (human breast cardinoma), HCT1 16 (human colon carcinoma), 768-0 (human neuroblastoma), U251 (human glyoblastoma) were grown in RPMI. All media were supplemented with 10% fetal bovine serum (FBS) (Sigma) and antibiotics- antimycotics. Cell were maintained in a humidified incubator at 37°C with 5% C02 and passaged when confluent using trypsin/EDTA. U2foxRELOC and U2nesRELOC assay: The U2nesRELOC assay and the U2foxRELOC assay have been described previously (1 , 2). Briefly, cells were seeded at a density of 1.0*105 cells/ml into black-wall clear-bottom 96-well microplates (BD Biosciences) After incubation at 37°C with 5% C02 for 12 hours, 2μΙ of each test compound were transferred from the mother plates to the assay plates. Cells were incubated in the presence of the compounds for one hour. Then cells were fixed and the nucleus stained with DAPI (Invitrogen). Finally the plates were washed with 1X PBS twice and stored at 4°C before analysis. Compounds of the invention have a range of in vitro cell potency activities from about 1 nM to about 10 μΜ.
Image acquirement and processing: Assay plates were read on the BD Pathway™ 855 Bioimager equipped with a 488/10 nm EGFP excitation filter, a 380/10 nm DAPI excitation filter, a 515LP nm EGFP emission filter and a 435LP nm DAPI emission filter. Images were acquired in the DAPI and GFP channels of each well using 10x dry objective. The plates were exposed 0.066 ms (Gain 31) to acquire DAPI images and 0.55 ms (Gain 30) for GFP images.
Data analysis: The BD Pathway Bioimager outputs its data in standard text files. Data were imported into the data analysis software BD Image Data Explorer. The nuclear/cytoplasmic (Nuc/Cyt) ratios of fluorescence intensity were determined by dividing the fluorescence intensity of the nucleus by the cytoplasmic. A threshold ratio of greater than 1.8 was employed to define nuclear accumulation of fluorescent signal for each cell. Based on this procedure we calculated the percentage of cells per well displaying nuclear translocation or inhibition of nuclear export. Compounds that induced a nuclear accumulation of the fluorescent signal greater than 60% of that obtained from wells treated with 4n LMB were considered as hits. In order to estimate the quality of the HCS assay, the Z' factor was calculated by the equation: Z = 1 - [(3 χ std. dev. of positive controls) + (3 χ std. dev. of negative controls) / (mean of positive controls) - (mean of negative controls)].
PI3K signalling
AKT phosphorylation Inhibition.Western Blot Analysis: Subconfluent cells were incubated under different conditions and washed twice with TBS prior to lysis. Lysis buffer was added containing 50 mM Tris HCI, 150 mM NaCI, 1 % NP- 40, 2mM Na3V04, 100 mM NaF, 20 mM Na P207 and protease inhibitor cocktail (Roche Molecular Biochemicals). The proteins were resolved on 10% SDS-PAGE and transferred to nitrocellulose membrane (Schleicher & Schuell, Dassel, Germany). The membranes were incubated overnight at 4°C with antibodies specific for Akt, phospho-Ser-473-Akt (Cell Signaling Technology) and a-tubulin (Sigma), they were washed and then incubated with IRDye800 conjugated anti- mouse and Alexa Fluor 680 goat anti-rabbit IgG secondary antibodies. The bands were visualized using an Odyssey infrared imaging system (Li-Cor Biosciences). Compounds of the invention have a range of in vitro cell potency activities from about 1 nM to about 10 μΜ.
Cytotoxicity assessment
The compounds were tested on 96-well trays. Cells growing in a flask were harvested just before they became confluent, counted using a haemocytometer and diluted down with media adjusting the concentration to the required number of cells per 0.2 ml (volume for each well). Cells were then seeded in 96-well trays at a density between 1000 and 4000 cells/well, depending of the cell size. Cells were left to plate down and grow for 24 hours before adding the drugs. Drugs were weighed out and diluted with DMSO to get them into solution to a concentration of 10mM. From here a "mother plate" with serial dilutions was prepared at 200X the final concentration in the culture. The final concentration of DMSO in the tissue culture media should not exceed 0.5%. The appropriate volume of the compound solution (usually 2 microlitres) was added automatically (Beckman FX 96 tip) to media to make it up to the final concentration for each drug. The medium was removed from the cells and replaced with 0.2 ml of medium dosed with drug. Each concentration was assayed in triplicate. Two sets of control wells were left on each plate, containing either medium without drug or medium with the same concentration of DMSO. A third control set was obtained with the cells untreated just before adding the drugs (seeding control, number of cells starting the culture). Cells were exposed to the drugs for 72 hours and then processed for MTT colorimetric read-out. Compounds of the invention have a range of in vitro cell potency activities from about 1 nM to about 10 μΜ. mTOR assay
Mammalian target of rapamycin (mTOR) was assayed by monitoring phosphorylation of GFP-4EBP using a homogeneous time-resolved fluorescence resonante energy transfer format and assay reagents from Invitrogen. In the presence of 10 μΜ ATP, 50 mM Hepes (pH 7.5), 0.01 % (v/v) Polysorbate 20, 10 mM MnCI2, 1 rnM EGTA, and 2.5 mM DTT, the mTOR-mediated phosphorylation of 200 nM GFP-4E-BP1 was measured under initial rate conditions. After incubation at room temperature for 60 min, the reaction was terminated by addition of 10 mM EDTA, and phosphorylated GFP-4E-BP1 was detected with 2 nM Tb-anti-p4E-BP1 antibody before reading on a Perkin-Elmer Wallac 1420 Fluorescence Reader (exc 340; em 490/520).
Where compound names are given herein, they are typically generated with ChemDraw.
The invention is illustrated by way of the following examples, in which the following abbreviations (or chemical symbols) may be employed:
"dba" dibenzylidene acetone; "DCM" dichloromethane; "MeOH" methanol; "EtOH" ethanol; "THF" tetrahydrofuran; "DMF" dimethylformamide; "CHCI3" chloroform; "DME" dimethoxyethane; "Et20" diethyl ether; "Hex" hexane; "EtOAc" ethyl acetate; "Pd(PPh3)4" tetrakis(triphenylphosphine)palladium; "KOAc" potassium acetate; "DIPEA" diisopropylethylamine; "Pd(PPh3)4" tetrakis(triphenylphosphine)- palladium; "Pd(dppf)CI2.DCM" 1 ,1 '-bis(diphenylphosphino)ferrocenepalladium(ll) dichloride, dichloromethane; "min." minutes; and "h." hours.
Examples and Experimental
Preparation of Final Product 1-01.
Figure imgf000079_0001
To a solution of Intermediate 1-01 (80 mg, 0.272 mmol, 1.0 eq) in DME (2.0 mL) were added 2-aminopyrimidine-5-boronic acid, pinacol ester (120 mg, 0.544 mmol, 2.0 eq), Pd(dppf)CI2 (1 12 mg, 0.136 mmol, 0.5 eq) and Cs2C03 (177 mg, 0.544 mmol, 2.0 eq). The reaction mixture was heated at 130 °C for 18 h. More reagents 2-aminopyrimidine-5-boronic acid, pinacol ester (2.0 eq), Pd(dppf)CI2 (0.5 eq) and Cs2C03 (2.0 eq) were added and the reaction mixture was heated at 130 °C for 8 h. On cooling, the mixture was filtered off and the filtrate was evaporated. The residue was dissolved in DCM (100 mL), washed with water (2 x 50 mL), dried with MgS0 , filtered and evaporated. The residue was purified by column chromatography (60% EtOAc in cyclohexane and eOH) and by HPLC- preparative to afford the desired product (2.5 mg, 2.5%).
Preparation of Intermediate 1-01.
Figure imgf000080_0001
A mixture of Intermediate I-02 (80 mg, 0.247 mmol, 1.0 eq) in 7N NH3 in MeOH (8 mL) was heated in a sealed tube at 95 °C for 4 days. On cooling, the mixture was evaporated and the residue was triturated from MeOH, filtered and washed with DCM. The filtrate was evaporated to afford the desired product (26 mg, 36%). 1H-NMR (300 MHz, CDCI3) δ 8.19 (s, 1 H), 6.92 (s, 1 H), 5.59 (s, 1 H), 4.81 (m, 2H), 4.05 (m, 2H), 3.85 (m, 4H), 2.48 (s, 3H).
Preparation of Intermediate I-02.
Figure imgf000080_0002
To a solution of Intermediate I-03 (0.1 g, 0.531 mmol, 1 .0 eq) in dry Toluene (10 mL) ethyl bromopyruvate (0.333 mL, 2.65 mmol, 5.0 eq) and p-toluensulfonic acid (16 mg, 0.085 mmol, 0.16 eq) were added. The reaction mixture was heated at 110 °C for 8 h and stirred at rt for 18 h. The mixture was evaporated, the residue was dissolved in DCM (50 mL) and washed with water (2 x 50 mL). The organic layer was dried (MgS04), filtered and evaporated.
The residue was dissolved in MeCN (10 mL) and morpholine (0.464 mL, 0.462 mmol, 10 eq) was added. The reaction mixture was heated at 85 °C for 3 h. On cooling, the mixture was evaporated and the residue was purified by automated column chromatography (Biotage, 20% EtOAc in cyclohexane). The product obtained was triturated from EtOH and filtered to afford the desired product (82 mg, 48%).
1H NMR (300 MHz, CDCI3) 6 8.15 (s, 1 H), 4.89 (m, 2H), 4.41 (q, J = 7.1 Hz, 2H), 4.04 (m, 2H), 3.84 (s, 4H), 2.49 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H).
Pre aration of Intermediate I-03.
Figure imgf000081_0001
To a solution of Intermediate I-04 (1.496 g, 9.3 mmol, 1 eq) in DCM (70 mL) DIPEA (9.76 mL, 56.0 mmol, 6 eq) and Mel (1.28 mL, 20.5 mmol, 2.2 eq) were added. The reaction mixture was heated at 25 °C for 24 h. The mixture was evaporated and the residue was purified by automated column chromatography (Biotage, EtOAc:cyclohexane, 40:60 to 70:30) to afford the desired product (0.960 g, 55%) as a yellow solid.
Ή NMR (300 MHz, CDCI3) δ 4.73 (s, 2H), 2.64 (m, 3H), 2.63 (s, 3H).
Preparation of Intermediate 1-04.
Figure imgf000081_0002
To a solution of Intermediate 1-05 (1.328 g, 10.37 mmol, 1.0 eq) and elemental sulfur (91 mg, 2.6 mmol, 0.25 eq) in dry pyridine (90 mL) was added phosphorus pentasulfide (4.61 g, 20.7 mmol, 2.0 eq). The reaction mixture was refluxed for 5 h and allowed to cool upon standing at 25 °C for 18 h. The reddish-brown supernatant liquid was decanted, additional pyridine was added to wash the solid and it was decanted again. Pyridine was removed in vacuo and the resulting residue was covered with water (90 mL), boiled for 30 min and allowed to stand at 4 °C for 6 h. The suspension was filtered and the solid was washed with water and dried in vacuo for 18 h to give a pale brown solid (1.496 g, 90%).
Preparation of Intermediate I-05.
Figure imgf000082_0001
A mixture of Intermediate I-06 (2.5 g, 13.02 mmol, 1 eq), copper (50 mg, 0.781 mmol, 0.06 eq) and liquid ammonia (~150 mL) were heated in a Parr reactor at 120 °C for 3 days. On cooling, excess of ammonia was vented off and the residual solid was dissolved in MeOH/water (200 mL, 1 :1 ). eOH was removed in vacuo and the water solution was acidified to pH 4 with HCI. The resulting suspension was filtered off to afford the desired product (1.328 g, 80%) as a white solid.
1H NMR (300 MHz, DMSO) δ 1 1.68 (s, 1 H), 10.87 (s, 1 H), 5.94 (s, 2H).
Preparation of Intermediate I-06.
Figure imgf000082_0002
A mixture of 6-Azauracil (5.0 g, 44.2 mmol, 1.0 eq), bromine (5.0 mL, 97 mmol, 2.2 eq) and water (70 mL) was stirred at 25 °C for 27 h. The colourless crystalline precipitate was collected by filtration to give the desired product (4.6 g, 55%).
Preparation of Final Product 1-02.
Figure imgf000083_0001
To a solution of Intermediate I-07 (50 mg, 0.142 mmol, 1 eq) in DME (5 mL) were added 2-aminopyrimidine-5-boronic acid, pinacol ester (63 mg, 0.284 mmol, 2 eq), Pd(dppf)CI2 (123 mg, 0.149 mmol, 1 .05 eq) and Cs2C03 (92 mg, 0.284 mmol, 2 eq). The reaction mixture was heated at 130 °C for 20 h. On cooling, the mixture was filtered off and the filtrate was evaporated. The residue was purified by automated column chromatography (Biotage, 7N NH3 in MeOH:DCM, 0: 100 to 5:95) to afford the desired product (15 mg, 9%) as a white solid.
Preparation of Intermediate I-07.
Figure imgf000083_0002
To a solution of 2-methoxyethylamine (0.4 mL, 4.64 mmol, 3 eq) in dry DCM (20 mL) was slowly added a 2 M solution of trimethylaluminium in hexane (2.32 mL) at rt under Argon. The mixture was stirred for 30 min and added to a solution of Intermediate 1-02 (0.5 g, 1.54 mmol, 1.0 eq) in DCM (20 mL). The reaction mixture was heated at 50 °C overnight. Additional amounts of trimethylaluminium (2.0 eq) and 2-methoxyethylamine (2.0 eq) in DCM (20 mL) were added and the reaction mixture was heated for 8 h. The mixture was quenched with 0.2 M HCI (20 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were dried (MgS0 ), filtered and concentrated. The residue was triturated from MeOH to afford the desired product (0.385 g, 71 %) as a white solid.
Preparation of Final Product 1-03.
Figure imgf000084_0001
To a solution of Intermediate I-08 (80 mg, 0.13 mmol) in 1 ,2-DCE (4 mL) at 0 °C trifluoroacetic acid (2 mL) and 98% H2S04 (4 drops) were added. The reaction mixture was stirred at rt for 6 h and stored at -24 °C for 18 h. The mixture was evaporated and the residue was dissolved in water (2 mL) and cooled to 0 °C. Aqueous NH OH was added up to pH~8 and the resulting yellow solid was filtered, washed and dried. The solid was purified by column chromatography (EtOAc:MeOH, 99: 1 ) and the product obtained was recrystallized from EtOAc/hexane to give the desired product (32 mg, 64%) as a white solid.
Preparation of Intermediate I-08.
Figure imgf000084_0002
A 2M solution of trimethylaluminium in hexanes (0.33 mL, 0.66 mmol) was added dropwise to a solution of 2-methoxyethylamine (0.055 mL, 0.65 mmol) in dry DCM (5 mL) at rt. The mixture was stirred for 4 h at rt and then added dropwise to a solution of Intermediate 1-09 (100 mg, 0.16 mmol) in dry DCM (5 mL). The reaction mixture was refluxed for 18 h. On cooling, the mixture was quenched with 0.5 N HCI (5 mL) and extracted with DCM (4 x 50 mL). The combined organic fractions were dried (MgS04), filtered and evaporated. The residue was purified by column chromatography (EtOAc) to give the desired product (82 mg, 79%) as a white solid.
1H NMR (300 MHz, CDCI3) d 8.92 (s, 2H), 8.14 (s, 1 H), 7.41 (t, J = 5.5 Hz, 1 H), 7.26 (s, 1H), 7.21 (d, J = 8.6 Hz, 4H), 6.86 (d, J = 8.6 Hz, 4H), 4.85 (s, 4H), 3.89 (m, 8H), 3.80 (s, 6H), 3.70 (dd, J = 10.4, 5.2 Hz, 2H), 3.60 (t, J = 4.9 Hz, 2H), 3.42 (s, 3H).
Preparation of Intermediate I-09.
Figure imgf000085_0001
A mixture of Intermediate 1-10 (1.89 g, 1.19 mmol), morpholine (2.01 mL, 23.8 mmol) and triethylamine (3.36 mL, 23.8 mmol) in dioxane (50 mL) was stirred at rt for 3 days. The mixture was evaporated and the residue was purified by column chromatography (EtOAc yclohexane, 10:90) to give the desired product (444 mg, 22%) as a white solid.
1H NMR (300 MHz, CDCI3) δ 8.98 (s, 2H), 8.31 (s, 1 H), 7.30 (s, 1 H), 7.23 (d, J = 8.7 Hz, 4H), 6.88 (d, J = 8.7 Hz, 4H), 4.92 (s, 4H), 4.51 (q, J = 7.0 Hz, 4H), 3.91 (m, 8H), 3.82 (s, 6H), 1.47 (d, J = 7.1 Hz, 3H).
Pre aration of Intermediate 1-10.
Figure imgf000085_0002
A mixture of Intermediate 1-1 1 (650 mg, 1.19 mmol) and N,N-dimethylaniline (0.5 mL) in POCI3 (6 mL) was stirred at 80 °C for 21 h. On cooling, more N,N- dimethylaniline (0.5 mL) and POCI3 (6 mL) were added and the reaction mixture was heated at 90 °C for 24 h. POCI3 was removed in vacuo, the residue was taken up in DCM (200 mL) and the mixture was poured onto ice. After stirring for 15 minutes, NaHC03 was added portionwise up to pH~8 and the organic layer was separated, washed with water (25 mL), dried (Na2S04), filtered and evaporated to give the desired product (1.89 g) as a blue oil. It was used in the next reaction step without further purification.
Pre aration of Intermediate 1-1 1.
Figure imgf000086_0001
A mixture of Intermediate 1-12 (220 mg, 0.37 mmol) and NH4OAc (383 mg, 4.96 mmol) in EtOH (5 mL) was heated under microwave irradiation for 1 h at 150 °C. The mixture was cooled to 0 °C and the resulting solid was filtered off, washed with water/EtOH (1 :1 ) and dried to give the desired product (190 mg, 94%) as a white solid.
1H NMR (300 MHz, DMSO) δ 8.74 (s, 2H), 8.19 (s, 1 H), 7.41 (s, 1 H), 7.19 (d, J = 8.7 Hz, 4H), 6.89 (d, J = 8.7 Hz, 4H), 4.78 (s, 4H), 4.34 (q, J = 7.1 Hz, 2H), 3.73 (s, 6H), 1.33 (t, J = 7.1 Hz, 3H).
Preparation of Intermediate 1-12.
Figure imgf000086_0002
A mixture of Intermediate 1-13 (1.21 g, 2.65 mmol), diethyl 3,5- pyrazoledicarboxylate (539 mg, 2.54 mmol) and K2C03 (440 mg, 3.18 mmol) in acetone (20 mL) was stirred overnight at rt. Water (50 mL) was added and the mixture was extracted with DCM (4 x 150 mL). The combined organic layers were washed with brine (50 mL), dried (MgS04), filtered and evaporated. The residue was purified by column chromatography (EtOAc:cyclohexane, 30:70) and the product obtained was triturated from Et20 to give the desired product (898 mg, 66%) as a white solid.
1H N R (300 MHz, DMSO) δ 9.02 (s, 2H), 7.34 (s, 1 H), 7.22 (d, J = 8.6 Hz, 4H), 6.89 (d, J = 8.7 Hz, 4H), 6.14 (s, 2H), 4.83 (s, 4H), 4.31 (q, J = 7.1 Hz, 2H), 4.23 (q, J = 7.1 Hz, 2H), 3.73 (s, 6H), 1.31 (t, J = 7.1 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H).
Pre aration of Intermediate 1-13.
Figure imgf000087_0001
To a mixture of Intermediate 1-14 (879 mg, 2.33 mmol) and TEA (0.96 mL, 7 mmol) in THF (50 mL) at 0 °C was added dropwise trimethylsilyl trifluoromethanesulfonate (1.27 mL, 7 mmol). The reaction mixture was stirred for 2 h at 0 °C and NBS (626 mg, 3.45 mmol) was added portionwise. The mixture was stirred for 1 h at 0 °C, diluted with water (30 mL) and extracted with EtOAc (4 x 150 mL). The combined organic layers were washed with saturated aqueous NaHC03, dried (MgS04), filtered and evaporated to give the desired product (1.06 g, 100%) as a brown oil.
H NMR (300 MHz, DMSO) δ 8.95 (s, 2H), 7.15 (d, J = 8.7 Hz, 4H), 6.87 (d, J = 8.7 Hz, 4H), 4.79 (s, 4H), 4.00 (q, J = 7.1 Hz, 2H), 3.71 (s, 6H), 2.53 (s, 2H), 1.16 (t, J = 7.1 Hz, 3H). Pre aration of Intermediate 1-14.
Figure imgf000088_0001
A mixture of Intermediate 1-15 (1.81 g, 4.37 mmol), tributyl(1 -ethoxyvinyl)tin (1.42 mL, 4.24 mmol) and dichlorobis(triphenylphosphine)palladium(ll) (0.15 g, 0.21 mmol) in dry DMF (15 mL) was heated at 100 °C for 22 h. On cooling, the reaction mixture was diluted with Et20 (300 mL) and treated with aqueous 15% KF solution (100 mL). The mixture was vigorously stirred for 1 h, the organic layer was separated and washed with saturated NaHC03 (50 mL), brine (50 mL), dried (MgS04), filtered and evaporated. The residue was purified by column chromatography (EtOAc:cyclohexane, 10:90) to give the desired product (997 mg, 61 %).
1H NMR (300 MHz, CDCI3) δ 8.92 (s, 2H), 7.19 (d, J = 8.6 Hz, 4H), 6.87 (d, J = 8.7 Hz, 4H), 4.85 (s, 4H), 3.78 (s, 6H).
Pre aration of Intermediate 1-15.
Figure imgf000088_0002
A mixture of 2-chloro-5-bromopyrimidine (1.0 g, 5.16 mmol), Intermediate 1-16 (1.59 g, 5.418 mmol) and DIPEA (2.68 mL, 15.48 mmol) in dry dioxane (10 mL) was heated under microwave irradiation for 1 h at 160 °C. On cooling, the mixture was diluted with EtOAc (200 mL), washed with saturated aqueous NaHC03 (50 mL), brine (50 mL), dried (MgS04), filtered and evaporated. The residue was purified by column chromatography (EtOAc:cyclohexane, 5:95 to 10:90) to give the desired product (1.81 g, 85%) as a white solid.
1H NMR (300 MHz, DMSO) δ 8.49 (s, 2H), 7.15 (d, J = 8.5 Hz, 4H), 6.86 (d, J = 8.6 Hz, 4H), 4.68 (s, 4H), 3.72 (s, 6H).
Pre aration of Intermediate 1-16.
Figure imgf000089_0001
A mixture of p-anisaldehyde (1.8 mL, 14.8 mmol) and 4-methoxybenzylamine (1.9 mL, 14.8 mmol) in EtOH (50 mL) was refluxed for 4 h. On cooling to 0 °C, NaBH4 (562 mg, 14.8 mmol) was added and the reaction mixture was stirred for 18 h at rt. On cooling to 0 °C, water (50 mL) and DCM (250 mL) were added. The organic phase was separated and the aqueous layer was extracted with DCM (2 x 250 mL). The combined organic layers were dried (MgS04), filtered and evaporated. The residue was dissolved in Et20 (100 mL) and the mixture was cooled to 0 °C. 4N HCI in dioxane (-10 mL) was added dropwise and the mixture was stirred for 2 h at 0 °C. The resulting white solid was filtered off, washed with Et20/EtOAc to give the desired product (3.99 g, 91 %) as a white solid.
1H NMR (300 MHz, DMSO) δ 9.40 (s, 2H), 7.45 (d, J = 8.7 Hz, 4H), 6.98 (d, J = 8.7 Hz, 4H), 4.03 (s, 4H), 3.77 (s, 6H).
Figure imgf000089_0002
A mixture of Intermediate 1-17 (98 mg, 0.29 mmol), HOBt hydrate (116 mg, 0.858 mmol), HBTU (278 mg, 0.74 mmol) and TEA (0.18 mL) in DMF (4 mL) was stirred for 2 h at rt. Then, a mixture, previously stirred for 1 h at rt, of 4- aminotetrahydropyrane (136 mg, 1 mmol) and TEA (0.13 mL) in DMF (1 mL) was added and the reaction mixture was stirred for 72 h at rt. The mixture was evaporated and the residue was purified by column chromatography (reverse phase, water/MeCM mixtures) to give the desired product (16 mg, 13%) as a white solid.
Preparation of Intermediate 1-17.
Figure imgf000090_0001
A mixture of Intermediate 1-18 (100 mg, 0.27 mmol), 4N KOH (3 mL) and EtOH (3 mL) was stirred for 4 h at rt. The mixture was evaporated, the residue was cooled to 0° C and AcOH was added dropwise up to pH~5. The resulting brown solid was filtered off, washed with cyclohexane and water and dried to give the desired product (95 mg, 100% yield). It was used in the next reaction step without further purification.
1H NMR (300 MHz, DMSO) d 8.88 (s, 2H), 8.68 (s, 1 H), 7.28 (s, 1 H), 7.03 (s, 1 H), 6.86 (s, 2H), 3.75 (m, 8H).
Preparation of Intermediate 1-18.
Figure imgf000090_0002
To a solution of Intermediate I-09 (136 mg, 0.22 mmol) in 1 ,2-DCE (5 mL) at 0 °C were added trifluoroacetic acid (4 mL) and 98% H2S04 (4 drops). The reaction mixture was stirred for 4 h at rt. The mixture was evaporated and the residue was cooled to 0 °C and dissolved in water (4 mL). Aqueous NH4OH was added up to pH~8 and the resulting white solid was filtered, washed and dried to give the desired product (81 mg, 100%) as a brown solid.
Figure imgf000091_0001
Intermediate I-09 (140 mg, 0.229 mmol) was suspended in a 7N NH3 solution in MeOH (5 mL) and the resulting solution was heated in a sealed tube at 100 °C for 48 h. On cooling to room temperature, the solvents were removed in vacuo to give the corresponding amide (119 mg, 89%) that, without further purification, was deprotected following a similar procedure described for the synthesis of final product 1-03, to afford 6-(2-amino-pyrimidin-5-yl)-4-morpholin-4-yl-pyrazolo[1 ,5- a]pyrazine-2-carboxylic acid amide as a yellowish solid (14.0 mg) after purification by column chromatography (DCM/7 N MeOH 3-30% as eluent).
Preparation of Final Product 1-06.
Figure imgf000091_0002
Intermediate I-09 (70 mg, 0.115 mmol) was suspended in a 2M MeNH2 solution in MeOH (5 mL) and the resulting solution was heated in a sealed tube at 100 °C for 48 h. On cooling to room temperature, the solvents were removed in vacuo to give, after purification by column chromatography using EtOAc as eluent the corresponding methylamide (55.8 mg, 81%) that was deprotected following a similar procedure described for the synthesis of final product 1-03, to afford 6-(2- amino-pyrimidin-5-yl)-4-morpholin-4-yl-pyrazolo[1 ,5-a]pyrazine-2-carboxylic acid methylamide, final product 1 -06, as a yellowish solid (14.0 mg) after purification by column chromatography (DCM/MeOH 5-10% as eluent).
Preparation of Final Product 1-07.
Figure imgf000092_0001
A 2.0 M solution of MesAI in hexanes (0.24 mL, 0.46 mmol) was added dropwise to a solution of pyrrolidine (33 mg, 0.46 mmol) in dry DCM (4 mL) at 25°C. After stirring for 4 h at this temperature, the resulting solution was added dropwise to a solution of intermediate I-09 (70 mg, 0.1 15 mmol) in dry DCM (5 mL) at 25°C and the reaction mixture was refluxed for 18 h. On cooling to 0 °C, the mixture was quenched with 0.5 N HCI and extracted with DCM (4 x). The combined organic fractions were dried and the solvents removed in vacuo to give a residue that was purified by column chromatography (EtOAc as eluent) to give the corresponding pyrrolidin amide (52 mg, 71 %) that was deprotected, following a similar procedure described for the synthesis of final product 1-03, to afford final product 1-07, [6- (2-amino-pyrimidin-5-yl)-4-morpholin-4-yl-pyrazolo[1 ,5-a]pyrazin-2-yl]-pyrrolidin-1 - yl-methanone as a yellowish solid (24.0 mg) after purification by column chromatography (DCM/MeOH 5-10% as eluent).
reparation of Final Product 1-08.
Figure imgf000093_0001
A 2.0 M solution of e3AI in hexanes (0.50 mL, 0.92 mmol) was added dropwise to a solution of Piperidin-4-ylamine (92 mg, 0.92 mmol) in dry DCM (8 mL) at 25°C. After stirring for 4 h at this temperature, the resulting solution was added dropwise to a solution of intermediate I-09 (140 mg, 0.230 mmol) in dry DCM (10 mL) at 25°C and the reaction mixture was refluxed for 18 h. On cooling to 0 °C, the mixture was quenched with 0.5 N HCI and extracted with DCM (4 x). The combined organic fractions were dried and the solvents removed in vacuo to give a residue that was purified by column chromatography (DCM/MeOH 1-10% as eluent) to give the corresponding amide (68.3 mg, 45%) that was deprotected, following a similar procedure described for the synthesis of final product 1-03, to afford final product 1-08, 6-(2-amino-pyrimidin-5-yl)-4-morpholin-4-yl- pyrazolo[1 ,5-a]pyrazine-2-carboxylic acid piperidin-4-ylamide as a yellowish solid (17.0 mg) after purification by column chromatography (DCM/7N NH3 in MeOH 5- 10% as eluent).
Preparation of Final Product 1-09.
Figure imgf000093_0002
A 2.0 M solution of Me^l in hexanes (0.50 ml_, 0.92 mmol) was added dropwise to a solution of N,N-dimethyl-1 ,3-propanediamine (94.0 mg, 0.92 mmol) in dry DCM (8 mL) at 25°C. After stirring for 4 h at this temperature, the resulting solution was added dropwise to a solution of intermediate I-09 (140 mg, 0.230 mmol) in dry DCM (10 mL) at 25°C and the reaction mixture was refluxed for 18 h. On cooling to 0 °C, the mixture was quenched with 0.5 N HCI and extracted with DCM (4 x). The combined organic fractions were dried and the solvents removed in vacuo to give a residue that was purified by column chromatography (DCM/MeOH 1 -10% as eluent) to give the corresponding amide (61 mg, 48%) that was deprotected, following a similar procedure described for the synthesis of final product 1-03, to afford final product 1-09 6-(2-amino-pyrimidin-5-yl)-4- morpholin-4-yl-pyrazolo[1 ,5-a]pyrazine-2-carboxylic acid (3-dimethylamino- propyl)-amide as a yellowish solid (18.0 mg) after purification by column chromatography (DCM/7N NH3 in MeOH 5-10% as eluent).
Preparation of Final Product 1- 0.
Figure imgf000094_0001
A 2.0 M solution of Me3AI in hexanes (0.50 mL, 0.92 mmol) was added dropwise to a solution of trans-4-[(tert-Butyldimethylsilanyl)oxy]cyclohexyl]amine, CAS: 690992-74-6, (21 1 mg, 0.92 mmol) in dry DCM (8 mL) at 25°C. After stirring for 4 h at this temperature, the resulting solution was added dropwise to a solution of intermediate I-09 (140 mg, 0.230 mmol) in dry DCM (10 mL) at 25°C and the reaction mixture was refluxed for 18 h. On cooling to 0 °C, the mixture was quenched with 0.5 N HCI and extracted with DCM (4 x). The combined organic fractions were dried and the solvents removed in vacuo to give a residue that, without purification, was deprotected, following a similar procedure described for the synthesis of final product 1-03, to afford final compound 1-11 , 6-(2-amino- pyrimidin-5-yl)-4-morpholin-4-yl-pyrazolo[1 ,5-a]pyrazine-2-carboxylic acid (4- hydroxy-cyclohexyl)-amide as a yellowish solid (10.0 mg) after purification by column chromatography (DCM/7N NH3 in MeOH 5-10% as eluent). General Procedure
The HPLC measurement was performed using a HP 1 100 from Agilent Technologies comprising a pump (binary) with degasser, an autosampler, a column oven, a diode-array detector (DAD) and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector was configured with an electrospray ionization source or API/APCI. Nitrogen was used as the nebulizer gas. The source temperature was maintained at 150 °C. Data acquisition was performed with ChemStation LC/MSD quad, software.
Method 1
Reversed phase HPLC was carried out on a Gemini-NX C18 (100 x 2.0 mm; 5 urn), Solvent A: water with 0.1 % formic acid; Solvent B: acetonitrile with 0.1 % formic acid. Gradient: 5% of B to 100% of B within 8 min at 50 °C, DAD.
Method 2
Reversed phase HPLC was carried out on a Gemini-NX C18 (100 x 2.0 mm; 5 urn), Solvent A: water with 0.1 % formic acid; Solvent B: acetonitrile with 0.1 % formic acid. Gradient: 5% of B to 40% of B within 8 min at 50 °C, DAD. Table 1 : Analytical data and PI3Ka activity - Rt means retention time (in minutes), [M+H]+ means the protonated mass of the compound, method refers to the method used for (LC)MS.
Biological activity in PI3Ka for certain representative examples is represented in
Table 1 :
PI3Ka
Cpd. H NMR (300 MHz; δ in ppm, J in
Rt [ +1]+ Meth. IC50
Nr. Hz)
19 nM DMSO δ 8.98 (s, 2H), 8.38 (s, 1H), 7.91 (s, 9 1H), 7.48 (s, 1 H), 7.19 (s, 2H), 4.87 (m,
1 -01 2.9 342.1 1 (<100
2H), 4.11 (m, 2H), 3.79 (m, 4H).
nM)
Figure imgf000096_0001
Cellular activity of some representative compounds (AKT phosphorylation; see biological example above) display an inhibition < 1 μΜ.

Claims

Claims
1. A compound of formula I,
Figure imgf000097_0001
wherein:
Ai represents N or C(R1); A4 represents N or C(R a); represents N or C(R1b); wherein at least one of A4 and A a does not represent N;
A5 represents N or C(R2); each B1, B a, B2, B2a, B3, B3a, B4 and B a independently represent hydrogen or a substituent selected from halo, -C(=Y)-R 0a, -C(=Y)-OR10a, -C(=Y)N(R10a)R1 a, -S(O)2N(R10a)R11a, C,.i2 alkyl, heterocycloalkyi (which latter two groups are optionally substituted by one or more substituents selected from =0 and E ), aryl and/or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E2); or any two B1, B1 a, B2, B2a, B3, B3s, B4 and B4a substituents that are attached to the same carbon atom (i.e. B1 and B a; B2 and B2a; B3 and B3a; and/or B4 and B a) may together form a =0 group; or, any two B1, B1a, B2, B2a, B3, B3a, B4 and B a substituents may be linked together to form a further 3- to 12- membered ring, optionally containing (in addition to the atom(s) of the morpholine ring) one or more heteroatom(s), which ring optionally contains one or more double bonds, and which ring is itself optionally substituted by one or more substituents selected from halo, =0 and d-3 alkyl optionally substituted by one or more fluoro atoms;
R and R2 (when present) independently represent hydrogen or a substituent selected from halo, -CN, -OR10b, -N(R10b)R11b, -C(O)N(R10b)R1 , d.12 alkyl and heterocycloalkyl, which latter two groups are optionally substituted by one or more substituents selected from E3 and =0; one of R1a and R1b is present and represents -C(=Y)N(R10a)R11a or -C(=Y)-R10a and the other independently represents hydrogen or Q1;
Q represents:
halo, -CN, -N02l -N(R10a)R1 a, -OR10a, -C(=Y)-R 0a, -C(=Y)-OR 0a, -C(=Y)N(R10a)R11a, -OC(=Y)-R10a, -OC(=Y)-OR10a, -OC(=Y)N(R10a)R1 la, -OS(O)2OR 0a, -OP(=Y)(OR10a)(OR1 a), -OP(OR10a)(OR11a), -N(R12a)C(=Y)R11a, -N(Rl2a)C(=Y)OR11a, -N(R12a)C(=Y)N(R10a)R11a, -NR12aS(O)2R10a,
-NR 2aS(O)2N(R10a)R11a, -S(O)2N(R10a)R11a, -SC(=Y)R10a, -S(O)2R10a, -SR 0a, -S(O)R10a, alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0 and E4), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E4a);
R3 represents:
(i) a bicyclic aryl or heteroaryl group (both of which are optionally substituted by one or more substituents selected from E5); or
(ii) a fragment of formula IA or IB,
Figure imgf000099_0001
wherein any one of X2, X3, X4 and X5 represents C(R ), a second one of X1 f X2) X3, X4 and X5 represents C(R2b), and the remaining three independently represent C(R2 ) or N; or any one, two or three of Xi, X2, X3, X and X5 may represent N and those remaining represent C(H);
X6, X7, X8 and X9 independently represent C(R2b), N, O or S; each R2b represents hydrogen, halo, -CN or R2a; each R2a independently represents, on each occasion when used herein, -N(R5a)R5 , -N(R5C)-C(=Y)-R5d, -N(R5e)-C(=Y)-N(R5'), -N(R59)-C(0)-OR5h, -N(R5i)-OR5', -OR5k, -N(R5m)-S(0)2-R5n or d.12 alkyl optionally substituted by one or more halo atoms; each R5a, R5 , R5c, R5d, R5e, R5f' R5g, R5h, R5i, R5', R5k, R5m and R5n independently represent hydrogen, alkyl (optionally substituted by one or more halo atoms), heterocycloalkyl, aryl or heteroaryl (which latter three groups are optionally substituted by one or more substituents selected from halo and Ci-4 alkyl); each R10a, R11a, R10b, R11b and R12a independently represent, on each occasion when used herein, hydrogen, d.12 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0, =S, =N(R20) and E6), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E7); or any relevant pair of R103 and R11a or R10b and R11b may be linked together to form a 4- to 20- membered ring, optionally containing one or more heteroatoms, optionally containing one or more unsaturations, and which ring is optionally substituted by one or more substituents selected from =0, =S, =N(R20) and E8; each E1, E2, E3, E4, E4a, E5, E6, E7 and E8 independently represents, on each occasion when used herein:
(i) Q4;
(ii) Ci-iz alkyl optionally substituted by one or more substituents selected from =0 and Q5; or any two E , E2, E3, E4, E4a, E5, E6, E7 and E8 groups may be linked together to form a 3- to 12-membered ring, optionally containing one or more unsaturations, and which ring is optionally substituted by one or more substituents selected from =0 and J1; each Q4 and Q5 independently represent, on each occasion when used herein: halo, -CN, -N02l -N(R 0)R21, -OR20, -C(=Y)-R20, -C(=Y)-OR20, -C(=Y)N(R20)R21, -OC(=Y)-R20, -OC(=Y)-OR20, -OC(=Y)N(R20)R21, -OS(0)2OR20, -OP(=Y)(OR20)(OR21), -OP(OR20)(OR21), -N(R2 )C(=Y)R21, -N(R2 )C(=Y)OR21, -N(R22)C(=Y)N(R20)R21, -NR22S(0)2R20, -NR22S(O)2N(R20)R21, -S(O)2N(R20)R21, -SC(=Y)R20, -S(0)2R20, -SR20, -S(0)R20, C1-6 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0 and J2), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from J3); each Y independently represents, on each occasion when used herein, =0, =S, =NR23 or =N-CN; each R20, R21, R22 and R23 independently represent, on each occasion when used herein, hydrogen, alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from J4 and =0), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from J5); or any relevant pair of R , R and R , may be linked together to form a 4- to 20- membered ring, optionally containing one or more heteroatoms, optionally containing one or more unsaturations, and which ring is optionally substituted by one or more substituents selected from J6 and =0; each J1, J2, J3, J4, J5 and J6 independently represents, on each occasion when used herein:
(i) Qr;
(ii) Ci-6 alkyl or heterocycloalkyl, both of which are optionally substituted by one or more substituents selected from =0 and Q8; each Q7 and Q8 independently represents, on each occasion when used herein: halo, -CN, -N(R50)R51, -OR50, -C(=Ya)-R50, -C(=Ya)-OR50, -C(=Ya)N(R50)R51, -N(R52)C(=Ya)R51, -NR52S(0)2R50, -S(O)2RS0, -SR50, -S(0)R50 or d.6 alkyl optionally substituted by one or more fluoro atoms; each Ya independently represents, on each occasion when used herein, =0, =S, =NR53 or =N-CN; each R50, R51, R52 and R53 independently represents, on each occasion when used herein, hydrogen or d.6 alkyl optionally substituted by one or more substituents selected from fluoro, -OR60 and -N(R61)R62; or
any relevant pair of R50, R5 and R52 may be linked together to form, a 3- to 8- membered ring, optionally containing one or more heteroatoms, optionally containing one or more unsaturations, and which ring is optionally substituted by one or more substituents selected from =0 and C1.3 alkyl;
R60, R6 and R62 independently represent hydrogen or Ci.6 alkyl optionally substituted by one or more fluoro atoms, or a pharmaceutically acceptable ester, amide, solvate or salt thereof.
2. A compound as claimed in Claim 1 , wherein the requisite A1 t A4l A4a and As-containing bicyclic core represents any one of the following:
Figure imgf000102_0001
3. A compound as claimed in Claim 1 or Claim 2, wherein:
either (i) R1b is present (i.e. A43 reprsents C(R1b)) and represents -C(=Y)N(R10a)R11a or -C(=Y)-R10a and R1a (if present) represents hydrogen or Q as hereinbefore defined (this is the preferred option); or (ii) R1a is present (i.e. A4 reprsents C(R1a)) represents -C(=Y)N(R10a)R1 ia or -C(=Y)-R 0a and either R b is not present (i.e. A4a represents N) or, preferably, R1b is present (i.e. A4 represents C(R1 )) and represents hydrogen or Q1, in which Q1 represents halo, -CN, -N02> -N(R10a)R1 a, -OR103, -C(=Y)-R10a, -C(=Y)-OR10a, -C(=Y)N(R10a)R1 a, -OC(=Y)-R10a, -OC(=Y)-OR10a, -OC(=Y)N(R10a)R 1a, -OS(O)2OR 0a, -OP(=Y)(OR10a)(OR 1a), -OP(OR10a)(OR 1a), -N(R12a)C(=Y)R11a, -N(R12a)C(=Y)OR1 a,
-N(R12a)C(=Y)N(R10a)R11a, -NR12aS(O)2R10a, -NR12aS(O)2N(R10a)R11a, -S(O)2N(R 0a)R 1a, -SC(=Y)R10a, -S(O)2R10a, -SR10a, -S(O)R10a, aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E4a); and/or
R3 represents substituted phenyl, optionally substituted indazolyl (e.g. 4- indazolyl), pyrimidinyl (e.g. 5-pyrimidinyl), azaindolyl (e.g. azaindol-5-yl), indolyl (e.g. 5-indolyl or 4-indolyl) or pyridyl (e.g. 3-pyridyl).
4. A compound as claimed in any one of the preceding claims, wherein: R2 represents hydrogen, chloro, bromo, iodo or -CN; each R10a, R11a, R10b, R11 and R12a independently represents hydrogen or C^ (e.g. C^) alkyl, which alkyl group may by substituted by one or more substituents selected from =0 and E6 (but which alkyl group is more preferably unsubstituted); or any relevant pair of R10a and R1 a and/or R10b and R11 , may be linked together to form a 5- or, preferably, a 6-membered ring, optionally containing a further heteroatom (preferably selected from nitrogen and oxygen), which ring is preferably saturated (so forming, for example, a piperazinyl or morpholinyl group), and optionally substituted by one or more substituents selected from =0 and E8 (which E8 substituent may be situated on a nitrogen heteroatom; and/or E8 is preferably halo (e.g. fluoro) or alkyl optionally substituted by one or more fluoro atoms); and/or each E1, E2, E3, E4, E a, E5, E6, E7 and E8 independently represent C1-4 alkyl optionally substituted by one or more Q5 substituents, or, each of these preferably represent a substituent selected from Q4.
5. A compound as claimed in any one of the preceding claims, wherein: Q4 and Q5 independently represent halo (e.g. fluoro), -OR20, -N(R20)R21, -C(=Y)OR20, -C(=Y)N(R20)R21, -NR22S(0)2R20, heterocycloalkyl, aryl, heteroaryl (which latter three groups are optionally substituted with one or more substitutents selected from J2 or J3, as appropriate) and/or Ci_6 alkyl (e.g. Ci-3 alkyl) optionally substituted by one or more fluoro atoms; each Y represents, on each occasion when used herein, =S, or preferably =0; each R20, R21, R22 and R23 (e.g. each R20 and R21) independently represents hydrogen or C1-4 (e.g. C1.3) alkyl (e.g. fe f-butyl, ethyl, methyl or a part cyclic group such as cyclopropylmethyl) optionally substituted (but preferably unsubstituted) by one or more (e.g. one) J4 substituent(s); or any relevant pair of R20, R21 and R22 (e.g. R20 and R21) may (e.g. when both are attached to the same nitrogen atom) may be linked together to form a 5- or, preferably, a 6-membered ring, optionally containing a further heteroatom (preferably selected from nitrogen and oxygen), which ring is preferably saturated (so forming, for example, a piperazinyl or morpholinyl group), and optionally substituted by one or more substituents selected from =0 and J6 (which J6 substituent may be situated on a nitrogen heteroatom); R22 represents C^ alkyl or, preferably, hydrogen; each J1, J2, J3, J4, J5 and J6 independently represent a substituent selected from Q7, or J1 to J6 (e.g. J4) represents C e alkyl (e.g. C3.5 cycloalkyl); each Q7 and Q8 independently represent -C(=Ya)-OR50, -C(=Ya)-R50, -S(0)2R50 or C1-3 alkyl optionally substituted by one or more fluoro atoms; each Ya independently represents =S or, preferably, =0; and/or each R50 independently represents C1-4 alkyl (e.g. ierf-butyl or methyl).
6. A compound of formula I as defined in any one of Claims 1 to 5, or a pharmaceutically acceptable ester, amide, solvate or salt thereof, for use as a pharmaceutical.
7. A pharmaceutical formulation including a compound of formula I, as defined in any one of Claims 1 to 5, or a pharmaceutically acceptable ester, amide, solvate or salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
8. A compound, as defined in any one of Claims 1 to 5, or a pharmaceutically acceptable ester, amide, solvate or salt thereof, for use in the treatment of a disease in which inhibition of a PI3-K and/or mTOR is desired and/or required.
9. Use of a compound of formula I, as defined in any one of Claims 1 to 5, or a pharmaceutically acceptable ester, amide, solvate or salt thereof, for the manufacture of a medicament for the treatment of a disease in which inhibition of a PI3-K and/or mTOR is desired and/or required.
10. A compound as claimed in Claim 8 or a use as claimed in Claim 9, wherein the disease is cancer, an immune disorder, a cardiovascular disease, a viral infection, inflammation, a metabolism/endocrine function disorder, a neurological disorder, an obstructive airways disease, an allergic disease, an inflammatory disease, immunosuppression, a disorder commonly connected with organ transplantation, an AIDS-related disease, benign prostate hyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis, psoriasis, a bone disorder, atherosclerosis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis, restenosis, stroke, diabetes, hepatomegaly, Alzheimer's disease, cystic fibrosis, a hormone-related disease, an immunodeficiency disorder, a destructive bone disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukaemia, liver disease, a pathologic immune condition involving T cell activation, CNS disorders, and other associated diseases.
11. A method of treatment of a disease in which inhibition of a PI3-K and/or mTOR is desired and/or required, which method comprises administration of a therapeutically effective amount of a compound of formula I as defined in any one of Claims 1 to 5, or a pharmaceutically-acceptable ester, amide, solvate or salt thereof, to a patient suffering from, or susceptible to, such a condition.
12. A combination product comprising:
(A) a compound of formula I as defined in any one of Claims 1 to 5, or a pharmaceutically-acceptable ester, amide, solvate or salt thereof; and
(B) another therapeutic agent that is useful in the treatment of in the treatment of cancer and/or a proliferative disease,
wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
13. A process for the preparation of a compound of formula I as defined Claim 1 , which process comprises:
(i) reaction of a compound of formula II,
Figure imgf000105_0001
wherein L1 represents a suitable leaving group, and A A2, A3l A4, A4a, A5, B1, B1a, B2, B2a, B3, B3a, B4 and B4a are as defined in Claim 1 , with a compound of formula
R3-L2 III
wherein L2 represents a suitable group;
(ii) reaction of a compound of formula IV,
Figure imgf000105_0002
wherein L3 represents a suitable leaving group, and A1 t A2, A3, A^, A4a, A5 and R3 as defined in Claim 1 , with a compound of formula V,
Figure imgf000105_0003
wherein L4 may represent hydrogen (so forming an amine group), and B1, B a, B2, B2a, B3, B3a, B4 and B4a are as defined in Claim 1 , and L1 is as defined above;
(iii) for compounds of formula I in which R2 represents halo, reaction of a corresponding compound of formula I, in which R2 represents hydrogen, with a reagent that is a source of halide ions (a halogenating reagent);
(iv) for compounds of formula I in which R2 (if present; i.e. if A5 represents C(R2)) represents a substituent other that hydrogen, or halo, reaction of a corresponding compound of formula I, in which R2 represents halo, with a compound of formula VI,
R aa-L7 VI
wherein R2aa represents R2 as described in Claim 1 provided that it does not represent hydrogen or halo, and L7 represents a suitable leaving group;
(v) for compounds of formula I in which R1a and/or R1 represents -C(O)N(R 0a) 11a, reaction of a compound of formula VIA,
Figure imgf000106_0001
wherein L1R3 represents either L1 as defined above or R3 as defined in Claim 1 , and wherein either A4 or A4a represents C(R1a) or C(R1b) respectively, in which either R1a or R1 represents the relevant -COOR 0a moiety (i.e. -COOR10a is attached to a carbon atom at either the A4 or A4a position), and the other one of A, or A4a represents N or C(R1a) or C(R b) (as appropriate) in which the other R1a or R1b group represents hydrogen or Q1 as hereinbefore defined, and B1, B1a, B2, B2a Β3_ B3a B B a A4, A4, R3 and R10a are as defined in Claim 1 , with a compound of formula VIB,
HN(R 0a)R 1a VIB
wherein R10a and R11a are as defined in Claim 1 ;
(vi) for compounds of formula I in which R1a and/or R1b is present that represents halo or -C(0)OR1Ca reaction of corresponding compounds of formula I in which R a or R1 (as appropriate) represents hydrogen, with a suitable base, followed by reaction in the presence of an electrophile that is a source of halide ions, or C02 (to form compounds of formula I in which R a and/or R1 b represent -COOH) or a compound of formula VII,
L8-R1b1 VII
wherein L8 represents a suitable leaving group, such as one hereinbefore defined in respect of L1 above, and R1 b1 represents -C(O)OR10a;
(vii) for compounds of formula I which contain a -C(OH)(H)-Cvii alkyl group (which alkyl group may be substituted by one or more substituents selected from those defined herein, e.g. E3 and =0; halo; or =0, =S and =N(R20) as appropriate, but is preferably unsubstituted), for example when there is a R1 and/or R2 group present which represent such a -C(OH)(H)-C1.11 alkyl group, reaction of a corresponding compound of formula I in which there is a -C(0)H group present (i.e. R1 and/or R2 represents -C(O)H), with a compound of formula VIII,
R^MgX1 VIII
wherein R** represents Ci.n alkyl optionally substituted by one or more substituents selected from e.g. E3 and =0 (but is preferably unsubstituted) and X1 represents halo (e.g. iodo, bromo or, preferably, chloro);
(viii) compounds of formula I in which A, and A4 both represent N, A5 represents C(R2) and A43 represents C(R b) may be prepared by reaction of a compound of formula IX,
Figure imgf000107_0001
wherein i R3 represents either L1 as defined above or R3 as defined in Claim 1 , and R2, B1, B1a, B2, B2a, B3, B3a, B4 and B a are as defined in Claim 1 , with a compound of formula X,
H-C(0)-R1b X
wherein R1b represents -C(=Y)N(R 0a)R a or -C(=Y)R10a;
(ix) compounds of formula I in which AT represents N, A4 represents C(R1a), represents N and A5 represents C(R2) may be prepared by reaction of a compound of formula XI,
Figure imgf000108_0001
wherein L1R3, R2, B1, B1a, B2, B2a, B3, B3a, B4 and B a are as defined above/in Claim 1 , with a compound of formula XII,
R1e-C(OCw alkyl)3 XII or, a compound of formula XIII,
R1a-C(0)OH XIII
or, derivatives of either, wherein R1a represents -C(=Y)N(R10a)R11a or -C(=Y)R10a as defined above/in Claim 1 ;
(x) for compounds of formula I that contain an unsubstituted amino group (e.g. a R2a or R2 substituent that represents -N(R5a)R5b in which R5a and R5 represent hydrogen), may be prepared by reaction/deprotection of a corresponding amino protected compound of formula I (e.g. in which the -NH2 moiety is substituted by two 4-methoxybenzyl moieties);
(xi) for compounds of formula I that contain an amino group attached to an aromatic group (e.g. a -N(R5a)R moiety), reaction of a compound corresponding to a compound of formula but in which there is a halo (e.g. bromo, iodo or, preferably, fluoro) group in that position by reaction of an amine (e.g. a compound of formula HN(R5a)R5b, or a protected derivative thereof).
14. A process for the preparation of a pharmaceutical formulation as defined in Claim 7, which process comprises bringing into association a compound of formula I, as defined in any one of one of Claims 1 to 5, or a pharmaceutically acceptable ester, amide, solvate or salt thereof with a pharmaceutically- acceptable adjuvant, diluent or carrier.
15. A process for the preparation of a combination product as defined in Claim 12, which process comprises bringing into association a compound of formula I, as defined in any one of Claims 1 to 5, or a pharmaceutically acceptable ester, amide, solvate or salt thereof with the other therapeutic agent that is useful in the treatment of cancer and/or a proliferative disease, and at least one pharmaceutically-acceptable adjuvant, diluent or carrier.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8551980B2 (en) 2009-11-30 2013-10-08 Bayer Intellectual Property Gmbh Substituted triazolopyridines
RU2516936C2 (en) * 2012-04-27 2014-05-20 Олег Иванович Киселев CONJUGATES OF 2-METHYLTHIO-6-NITRO-1,2,4-TRIAZOLO[5,1-c]-1,2,4-TRIAZIN-7(4I')-ONE WITH GLUTADIONE AND OTHER PEPTIDES, POSSESSING ANTIVIRAL ACTIVITY
US8871767B2 (en) 2010-12-22 2014-10-28 Hengrui (Usa) Ltd. 2-arylimidazo[1,2-B]pyridazine, 2-phenylimidazo[1,2-A]pyridine, and 2-phenylimidazo[1,2-A]pyrazine derivatives
US8940736B2 (en) 2012-07-13 2015-01-27 Bristol-Myers Squibb Company Imidazotriazinecarbonitriles useful as kinase inhibitors
JP2015518010A (en) * 2012-05-31 2015-06-25 上海 インスティテュート オブ マテリア メディカ、チャイニーズ アカデミー オブ サイエンシーズＳｈａｎｇｈａｉ Ｉｎｓｔｉｔｕｔｅ Ｏｆ Ｍａｔｅｒｉａ Ｍｅｄｉｃａ， Ｃｈｉｎｅｓｅ Ａｃａｄｅｍｙ Ｏｆ Ｓｃｉｅｎｃｅｓ Pyrrolo [2,1-f] [1,2,4] triazine-based compound, production method and use
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WO2022028492A1 (en) * 2020-08-05 2022-02-10 Beigene, Ltd. Imidazotriazine and pyrrolopyrimidine derivatives as kras g12c inhibitors
US11484597B2 (en) 2019-09-19 2022-11-01 Totus Medicines Inc. Therapeutic conjugates

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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TWI828027B (en) 2016-03-28 2024-01-01 美商英塞特公司 Pyrrolotriazine compounds as tam inhibitors

Citations (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2424334A1 (en) 1973-05-22 1974-12-19 Sandoz Ag PROCESS FOR PRODUCING NEW HETEROCYCLIC COMPOUNDS
US3995039A (en) 1975-05-27 1976-11-30 Merck & Co., Inc. Pyrazolo [1,5-a] [1,3,5] triazines
WO2002060492A1 (en) * 2001-01-30 2002-08-08 Cytopia Pty Ltd Methods of inhibiting kinases
WO2003000693A1 (en) 2001-06-22 2003-01-03 Bayer Healthcare Ag Imidazotriazines for use as phosphodiesterase inhibitors
WO2003044021A2 (en) 2001-11-16 2003-05-30 Amgen Inc. Substituted indolizine-like compounds and methods of use
WO2004005290A1 (en) 2002-07-08 2004-01-15 Bayer Healthcare Ag Substituted imidazotriazines
WO2004005291A1 (en) 2002-07-08 2004-01-15 Bayer Healthcare Ag Hetero-cyclicaly substituted imidazotriazines
WO2004092177A1 (en) 2003-04-09 2004-10-28 Biogen Idec Ma Inc. Triazolopyrazines and methods of making and using the same
WO2005035532A1 (en) 2003-10-10 2005-04-21 Pfizer Products Inc. Substituted 2h-[1,2,4]triazolo[4,3-a]pyrazines as gsk-3 inhibitors
WO2005042537A1 (en) 2003-10-22 2005-05-12 Bristol-Myers Squibb Company Phenyl-aniline substituted bicyclic compounds useful as kinase inhibitors
WO2006027346A2 (en) 2004-09-06 2006-03-16 Altana Pharma Ag Novel pyrazolopyrimidines
US20060084650A1 (en) 2004-10-15 2006-04-20 Qing Dong Kinase inhibitors
WO2006046040A1 (en) 2004-10-25 2006-05-04 Piramed Limited Pharmaceutical compounds
WO2007032936A2 (en) 2005-09-09 2007-03-22 Schering Corporation Azafused cyclin dependent kinase inhibitors
WO2007038314A2 (en) 2005-09-22 2007-04-05 Bristol-Myers Squibb Company Fused heterocyclic compounds useful as kinase modulators
WO2007061737A2 (en) * 2005-11-17 2007-05-31 Osi Pharmaceuticals, Inc. FUSED BICYCLIC mTOR INHIBITORS
WO2007088168A1 (en) 2006-02-01 2007-08-09 Glaxo Group Limited Compounds
WO2007127175A2 (en) 2006-04-26 2007-11-08 F. Hoffmann-La Roche Ag Pharmaceutical compounds
WO2008113469A2 (en) 2007-03-16 2008-09-25 Bayer Schering Pharma Aktiengesellschaft Substituted imidazopyrimidines and triazolopyrimidines
WO2008116064A2 (en) 2007-03-21 2008-09-25 Bristol-Myers Squibb Company Fused heterocyclic compounds useful for the treatment of proliferative, allergic, autoimmune or inflammatory diseases
WO2008131050A1 (en) 2007-04-18 2008-10-30 Bristol-Myers Squibb Company Pyrrolotriazine kinase inhibitors
WO2009007029A1 (en) 2007-07-11 2009-01-15 Bayer Schering Pharma Aktiengesellschaft Imidazo-, pyrazolopyrazines and imidazotriazines and their use
US20090085230A1 (en) 2007-09-27 2009-04-02 Michino Fuse Semiconductor device and layout method thereof
US20090163489A1 (en) 2007-12-19 2009-06-25 Shon Booker Inhibitors of PI3 kinase
WO2010002954A1 (en) * 2008-07-02 2010-01-07 Wyeth (2-aryl-7h-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine compounds, their use as mtor kinase and pi3 kinase inhibitors, and their syntheses
WO2010119264A1 (en) 2009-04-16 2010-10-21 Centro Nacional De Investigaciones Oncólogicas (Cnio) Imidazopyrazines for use as kinase inhibitors

Patent Citations (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2424334A1 (en) 1973-05-22 1974-12-19 Sandoz Ag PROCESS FOR PRODUCING NEW HETEROCYCLIC COMPOUNDS
US3995039A (en) 1975-05-27 1976-11-30 Merck & Co., Inc. Pyrazolo [1,5-a] [1,3,5] triazines
WO2002060492A1 (en) * 2001-01-30 2002-08-08 Cytopia Pty Ltd Methods of inhibiting kinases
WO2003000693A1 (en) 2001-06-22 2003-01-03 Bayer Healthcare Ag Imidazotriazines for use as phosphodiesterase inhibitors
WO2003044021A2 (en) 2001-11-16 2003-05-30 Amgen Inc. Substituted indolizine-like compounds and methods of use
WO2004005290A1 (en) 2002-07-08 2004-01-15 Bayer Healthcare Ag Substituted imidazotriazines
WO2004005291A1 (en) 2002-07-08 2004-01-15 Bayer Healthcare Ag Hetero-cyclicaly substituted imidazotriazines
WO2004092177A1 (en) 2003-04-09 2004-10-28 Biogen Idec Ma Inc. Triazolopyrazines and methods of making and using the same
WO2005035532A1 (en) 2003-10-10 2005-04-21 Pfizer Products Inc. Substituted 2h-[1,2,4]triazolo[4,3-a]pyrazines as gsk-3 inhibitors
WO2005042537A1 (en) 2003-10-22 2005-05-12 Bristol-Myers Squibb Company Phenyl-aniline substituted bicyclic compounds useful as kinase inhibitors
WO2006027346A2 (en) 2004-09-06 2006-03-16 Altana Pharma Ag Novel pyrazolopyrimidines
US20060084650A1 (en) 2004-10-15 2006-04-20 Qing Dong Kinase inhibitors
WO2006044687A2 (en) 2004-10-15 2006-04-27 Takeda San Diego, Inc. Kinase inhibitors
WO2006046040A1 (en) 2004-10-25 2006-05-04 Piramed Limited Pharmaceutical compounds
WO2007032936A2 (en) 2005-09-09 2007-03-22 Schering Corporation Azafused cyclin dependent kinase inhibitors
WO2007038314A2 (en) 2005-09-22 2007-04-05 Bristol-Myers Squibb Company Fused heterocyclic compounds useful as kinase modulators
WO2007061737A2 (en) * 2005-11-17 2007-05-31 Osi Pharmaceuticals, Inc. FUSED BICYCLIC mTOR INHIBITORS
WO2007088168A1 (en) 2006-02-01 2007-08-09 Glaxo Group Limited Compounds
WO2007127175A2 (en) 2006-04-26 2007-11-08 F. Hoffmann-La Roche Ag Pharmaceutical compounds
WO2008113469A2 (en) 2007-03-16 2008-09-25 Bayer Schering Pharma Aktiengesellschaft Substituted imidazopyrimidines and triazolopyrimidines
WO2008116064A2 (en) 2007-03-21 2008-09-25 Bristol-Myers Squibb Company Fused heterocyclic compounds useful for the treatment of proliferative, allergic, autoimmune or inflammatory diseases
WO2008131050A1 (en) 2007-04-18 2008-10-30 Bristol-Myers Squibb Company Pyrrolotriazine kinase inhibitors
WO2009007029A1 (en) 2007-07-11 2009-01-15 Bayer Schering Pharma Aktiengesellschaft Imidazo-, pyrazolopyrazines and imidazotriazines and their use
US20090085230A1 (en) 2007-09-27 2009-04-02 Michino Fuse Semiconductor device and layout method thereof
US20090163489A1 (en) 2007-12-19 2009-06-25 Shon Booker Inhibitors of PI3 kinase
WO2009085230A1 (en) 2007-12-19 2009-07-09 Amgen Inc. Inhibitors of pi3 kinase
WO2010002954A1 (en) * 2008-07-02 2010-01-07 Wyeth (2-aryl-7h-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine compounds, their use as mtor kinase and pi3 kinase inhibitors, and their syntheses
WO2010119264A1 (en) 2009-04-16 2010-10-21 Centro Nacional De Investigaciones Oncólogicas (Cnio) Imidazopyrazines for use as kinase inhibitors

Non-Patent Citations (44)

* Cited by examiner, † Cited by third party
Title
"Cycloalkanes", IUPAC COMPENDIUM OF CHEMICAL TERMINOLOGY, pages 1, XP002581397, Retrieved from the Internet <URL:www.iupac.org/goldbook/C01497.pdf> [retrieved on 20100505] *
A. M. ABDEL MAGIB ET AL., J. ORG. CHEM., vol. 61, 1996, pages 3849
A.F. ABDEL-MAGID, C.A MARYANOFF., SYNTHESIS, 1990, pages 537
ANDANAPPA K. GADAD ET AL., BIOORG. MED. CHEM., vol. 12, 2004, pages 5651 - 5659
ASUNCION MARIN ET AL., FARMACO, vol. 47, no. 1, 1992, pages 63 - 75
BRETONNET ET AL., J. MED. CHEM., vol. 50, 2007, pages 1872
BUNDEGAARD, H.: "Design of Prodrugs", 1985, ELESEVIER, pages: I-92
CHORVAT ET AL., J. MED. CHEM., vol. 42, 1999, pages 833
CURRENT OPINION IN CHEMICAL BIOLOGY, vol. 3, 1999, pages 459 - 465
E. ABIGNENTE ET AL., II FARMACO, vol. 45, 1990, pages 1075
EASTON ET AL.: "mTOR and cancer therapy", ONCOGENE, vol. 25, no. 48, 2006, pages 6436 - 46
F.D. BELLAMY, K. OU, TETRAHEDRON LETT., vol. 25, 1985, pages 839
HENNESSEY ET AL., NATURE REV. DRUG DISCOVERY, vol. 4, 2005, pages 988 - 1004
J. A. H. LAINTON ET AL., J. COMB. CHEM., vol. 5, 2003, pages 400
J. KOBE ET AL., TETRAHEDRON, vol. 24, 1968, pages 239
KATSO, ANNU. REV. CELL. DEV. BOIL., vol. 17, 2001, pages 615 - 75
L. WENGWEI ET AL., TETRAHEDRON LETT., vol. 47, 2006, pages 1941
LESLIE ET AL., CHEM. REV., vol. 101, no. 8, 2001, pages 2365 - 80
M. KUWAHARA ET AL., CHEM. PHARM BULL., vol. 44, 1996, pages 122
M. PLOTKIN ET AL., TETRAHEDRON LETT., vol. 41, 2000, pages 2269
M. SCHLOSSER ET AL.: "Organometallics in Synthesis. A Manual", 2002, WILEY &SONS LTD
M.A. EI-SHERBENY ET AL., BOLL. CHIM. FARM., vol. 136, 1997, pages 253 - 256
N. DEFACQZ, TETRAHEDRON LETT., vol. 44, 2003, pages 9111
NICOLAOU, K. C., BULGER, P. G., SARLAH, D., ANGEW. CHEM. INT. ED., vol. 44, 2005, pages 2 - 49
O. C. DERMER, CHEM. REV., vol. 14, 1934, pages 385
P.F. FABIO, A.F. LANZILOTTI, S.A. LANG, JOURNAL OF LABELLED COMPOUNDS AND PHARMACEUTICALS, vol. 15, 1978, pages 407
PARSONS ET AL., NATURE, vol. 436, 2005, pages 792
PAUL HEINZ ET AL., MONATSHEFTE FUR CHEMIE, vol. 108, 1977, pages 665 - 680
S. Y. HAN, Y.-A. KIM., TETRAHEDRON, vol. 60, 2004, pages 2447
S.J. GREGSON ET AL., J. MED. CHEM., vol. 47, 2004, pages 1161
SEVERINSEN, R. ET AL., TETRAHEDRON, vol. 61, 2005, pages 5565 - 5575
SEYDEN-PENNE, J.: "Reductions by the Alumino and Borohydrides", 1991, VCH
SHINTANI, R., OKAMOTO, K., ORG. LETT., vol. 7, no. 21, 2005, pages 4757 - 4759
T. IKEMOTO ET AL., TETRAHEDRON, vol. 56, 2000, pages 7915
T. IKEMOTO, M. WAKIMASU, HETEROCYCLES, vol. 55, 2001, pages 99
T. W. GREENE, P. G. M. WUTS: "Protective Groups in Organic Synthesis", 1999, WILEY
T.W. GREENE, P.G.M. WUTZ: "Protective Groups in Organic Synthesis", 1999, WILEY-INTERSCIENCE
TOKER, CELL. MOL. LIFE SCI., vol. 59, no. 5, 2002, pages 761 - 79
VANHAESEBROECK, KATSO ET AL., EXP. CELL. RES., vol. 25, no. 1, 1999, pages 239 - 54
VANHAESEBROECK, TRENDS BIOCHEM. SCI, vol. 22, no. 87, 1997, pages 267 - 72
VANHAESEBROECK, TRENDS BIOCHEM. SCI., vol. 22, no. 7, 1997, pages 267 - 72
WERBER,G. ET AL., J. HETEROCYCL. CHEM.; EN, vol. 14, 1977, pages 823 - 827
WIGGINS, J. M., SYNTH. COMMUN., vol. 18, 1988, pages 741
WIPF, P., JUNG, J.-K., J. ORG. CHEM., vol. 65, no. 20, 2000, pages 6319 - 6337

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