WO2012052745A1 - Combinaisons d'inhibiteurs de pi3k avec un second agent antitumoral - Google Patents

Combinaisons d'inhibiteurs de pi3k avec un second agent antitumoral Download PDF

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Publication number
WO2012052745A1
WO2012052745A1 PCT/GB2011/051998 GB2011051998W WO2012052745A1 WO 2012052745 A1 WO2012052745 A1 WO 2012052745A1 GB 2011051998 W GB2011051998 W GB 2011051998W WO 2012052745 A1 WO2012052745 A1 WO 2012052745A1
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optionally substituted
alkyl
substituents selected
ring
groups
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PCT/GB2011/051998
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Joaquín PASTOR FERNÁNDEZ
Sonia MARTÍNEZ GONZÁLEZ
Julen Oyarzabal Santamarina
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Centro Nacional De Investigaciones Oncológicas (Cnio)
Snodin, Michael D.
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Publication of WO2012052745A1 publication Critical patent/WO2012052745A1/fr

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    • 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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • 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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to novel combinations of 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, or, inhibitors of the mammalian target of rapamycin (mTOR)), together with other compounds useful in the treatment of diseases such as cancer or a proliferative disease.
  • the combinations are of potential utility in the treatment of diseases such as cancer or a proliferative disease.
  • the invention also relates to the use of such combinations as medicaments, to the use of such combinations for in vitro, in situ and in vivo diagnosis or treatment of mammalian cells (or associated pathological conditions), and to pharmaceutical compositions containing them.
  • 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
  • PI3K isoforms categorized by their catalytic subunits, their regulation by corresponding regulatory subunits, expression patterns and signalling specific funtions (p110ot, ⁇ , ⁇ , ⁇ ) perform this enzymatic reaction (Exp. Cell. Res. 25 (1), 239-54 (1999) by Vanhaesebroeck and Katso et al., 2001, above).
  • the closely related isoforms p110a 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), 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.
  • Class la includes ⁇ 3 ⁇ , ⁇ 3 ⁇ and ⁇ 3 ⁇ . All of the class la enzymes are heterodimeric complexes comprising a catalytic subunit ( ⁇ 110 ⁇ , ⁇ 110 ⁇ or ⁇ 110 ⁇ ) 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 ⁇ 110 ⁇ , 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 mammalian target of rapamycin
  • FRAP1 F 506 binding protein 12-rapamycin associated protein 1
  • 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).
  • International patent application WO 02/062800 discloses various compounds for use as antagonists on a corticotropin-releasing-factor receptor.
  • International patent application WO 88/04298 also discloses ceratin compounds for use as medicaments. However, these documents do not predominantly relate to imidazopyrazines substituted at the 6-position with an aromatic group and/or relate to those imidazopyrazines unsubstituted at the 2-, 3-, and 4-position.
  • International patent application WO 2010/119264 discloses various imidazopyrazines for use as kinase inhibitors. However, this document does not specifically disclose combinations.
  • R represents:
  • R 1a and R b are linked together to form, together with the nitrogen atom to which they are necessarily attached, a 5- to 7-membered ring optionally containing a further one or two heteroatoms (e.g. selected from nitrogen, oxygen and sulfur), optionally containing one or two double bonds, and which ring is optionally substituted by one or more substituents selected from
  • a heterocycloalkyl e.g. a 3- to 7-membered
  • a heterocycloalkyl e.g. a 3- to 7-membered
  • R 2 and R 3 independently represent:
  • n 0, 1 , 2, 3, 4, 5 or 6; each R 15 represents hydrogen, halo (e.g. fluoro) or C 1-6 alkyl optionally substituted by one or more substituents selected from E 1 ; or
  • the two R 15 groups may linked together to form (along with the requisite carbon atom to which those R 5 groups are necessarily attached) a 3- to 6-membered (spiro-cyclic) ring, which ring optionally contains one or more double bonds, and optionally contains a further heteroatom selected from nitrogen, sulfur and oxygen, and which ring is optionally substituted by one or more substituents selected from E 2 ;
  • R a and R b are linked together, along with the requisite nitrogen atom to which they are necessarily attached, to form a first 3- to 7-membered cyclic group, optionally containing one further heteroatom selected from nitrogen, sulfur and oxygen, and which ring:
  • (a) is fused to a second ring that is either a 3- to 7-membered saturated heterocycloalkyl group containing one to four heteroatoms selected from oxygen, sulfur and nitrogen (preferably oxygen and nitrogen), a 3- to 12- membered saturated carbocyclic ring, or an unsaturated 5- to 12- membered carbocyclic or heterocyclic ring (in which the heteroatoms are preferably selected from sulfur and, especially, nitrogen and oxygen);
  • (b) comprises a linker group -(C(R X ) 2 ) P - and/or -(C(R x ) 2 ) r -0-(C(R x ) 2 ) s - (wherein p is 1 or 2; r is 0 or 1 ; s is 0 or 1 ; and each R x independently represents hydrogen or C 1-6 alkyl), linking together any two non-adjacent atoms of the first 3- to 7-membered ring (i.e. forming a bridged structure); or
  • (c) comprises a second ring that is either a 3- to 12-membered saturated carbocyclic ring or or a 3- to 7-membered saturated heterocycloalkyl group containing one to four heteroatoms selected from oxygen and nitrogen, and which second ring is linked together with the first ring via a single carbon atom common to both rings (i.e.
  • R 4 represents hydrogen or a substituent selected from halo, -CN, -OR 10b , -N(R 0b )R 1 b , -C(O)N(R 10b )R 11b , -C(O)R 10b , C 1-6 alkyl and heterocycloalkyl (e.g.
  • R 10b and R 1 b 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.
  • each E 1 , E 2 , E 3 , E 4 , E 5 , E 6 , E 7 , E 8 , E 9 , E 10 , E 11 and E 12 independently represents, on each occasion when used herein:
  • (ii) d.i2 alkyl optionally substituted by one or more substituents selected from 0 and Q 5 ; or any two E 1 , E 2 , E 3 , E 4 , E 5 , E 6 , E 7 , E 8 , E 9 , E 10 , E 11 or E 12 groups, for example on C 1-12 alkyl groups, e.g. when they are attached to the same or adjacent carbon atoms or on aryl groups, e.g. when attached to adjacent carbon atoms, may be linked together to form a 3- to 12-membered ring, optionally containing one or more (e.g.
  • R 60 , R 6 and R 62 independently represent hydrogen or C 1-6 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” or "component (A) of the combination of the invention”); and
  • combinations of the invention contain component (B), i.e. one or more (e.g. one) other therapeutic agents/treatments that are inhibitors of protein or lipid kinases and/or useful in the treatment of a cancer and/or a proliferative disease.
  • component (B) i.e. one or more (e.g. one) other therapeutic agents/treatments that are inhibitors of protein or lipid kinases and/or useful in the treatment of a cancer and/or a proliferative disease.
  • compounds of the invention may be combined with one or more treatments independently selected from surgery, one or more anti-cancer/anti-neoplastic/anti-tumoral agent, one or more hormone therapies, one or more antibodies, one or more immunotherapies, radioactive iodine therapy, and radiation.
  • compounds of the invention may be combined with an agent that modulates the Ras/Raf/Mek pathway (e.g. an inhibitor of MEK), the Jak/Stat pathway (e.g. an inhibitor of Jak), the PI3K/Akt pathway (e.g. an inhibitor of Akt), the DNA damage response mechanism (e.g. an inhibitor of ATM or ATR) or the stress signaling pathway (an inhibitor of p38 or NF-KB).
  • an agent that modulates the Ras/Raf/Mek pathway e.g. an inhibitor of MEK
  • the Jak/Stat pathway e.g. an inhibitor of Jak
  • the PI3K/Akt pathway e.g. an inhibitor of Akt
  • the DNA damage response mechanism e.g. an inhibitor of ATM or ATR
  • the stress signaling pathway an inhibitor of p38 or NF-KB
  • the other therapeutic treatment(s)/agent(s) are preferably therapeutic agents and may be selected from other PI3-K (or Akt) or mTOR inhibitors, but are preferably selected from:
  • RTK receptor tyrosine kinase
  • PIM family kinase inhibitors e.g. a PIM-1, PIM-2 and/or PIM-3 inhibitor
  • Flt-3 inhibitors e.g. a PIM-1, PIM-2 and/or PIM-3 inhibitor
  • agents that modulate the DNA damage response mechanism and/or the stress signaling pathway e.g. an inhibitor of ATM or ATR, an inhibitor of p38 and/or NF-KB.
  • the component (B) of the combinations of the invention may contain one or more (e.g. one) of the therapeutic agents mentioned herein (e.g. one from the list (i) to (xvi) mentioned herein).
  • a particular therapeutic agent may be categorised in one or more of the above list (i) to (xvi) of therapeutic agents (or other general therapeutic agents that may be mentioned herein).
  • Particularly preferred therapeutic agents that compound (B) may represent include:
  • component (B) of the combinations of the invention may represent include the following specific therapeutic agents (e.g. any one of those listed in a sub-group):
  • RTK receptor tyrosine kinase
  • PIM-1 inhibitor PIM-1, PIM-2 and/or PIM-3 specific PIM family kinase inhibitors
  • SGI-1776 specific PIM family kinase inhibitors
  • nucleotide analogs such as 5-fluorouracil (5-FU) or gemcitabine
  • xii specific alkylating agents, such as temozolomide
  • component (B) may be any one of (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x), (xi), (xii), (xiii), (xiv), (xv) or (xvi).
  • component (B) may be any one of the specific therapeutic agents defined by any one of (i) to (xvi).
  • compounds of the invention may be combined with component (B), in which the one or more (e.g. one) therapeutic treatment(s)/agent(s) is/are specifically selected from an MTOR inhibitor (e.g. rapamycin), preferably, an EGFR inhibitor (e.g. lapatinib), a MEK inhibitor (e.g.
  • a BRaf inhibitor e.g. GDC-0879
  • a PIM-inhibitor e.g. SGI-1776
  • an anthracyclin e.g. doxorubicin
  • a taxane e.g. docetaxel
  • a piatin e.g. cisplatin
  • a nucleotide analog e.g. 5-fluorouracil or gemcitabine
  • a specific anti-tumour compound defined by (xiv) above e.g.
  • chloroquine as may be demonstrated by the examples, for instance where a compound of the invention/examples is employed in combination and inhibits cellular proliferation in vitro; in particular such combinations may be useful in treating the following cancers: breast, colon, lung, melanoma, pancreas, ovarian, gyoblastoma, leukemia (AML), mantle cell lymphoma and/or prostate.
  • B docetaxel (TAXOTERE®, Sanofi-Aventis), which is used to treat breast, ovarian, and NSCLC cancers (US 4814470; US 5438072; US 5698582; US 5714512; US 5750561; Mangatal et al (1989) Tetrahedron 45:4177; Ringel et al (1991) J. Natl. Cancer Inst. 83:288; Bissery et al(1991) Cancer Res. 51 :4845; Herbst et al (2003) Cancer Treat. Rev. 29:407-415; Davies et al (2003) Expert. Opin. Pharmacother.
  • TXOTERE® Sanofi-Aventis
  • (D) the MEK inhibitor PD-0325901 (CAS RN 391210-10-9, Pfizer), which is a second-generation, non-ATP competitive, allosteric MEK inhibitor for the potential oral tablet treatment of cancer (US6960614; US 6972298; US 20041147478; US 2005/085550) for which phase II clinical trials have been conducted for the potential treatment of breast tumors, colon tumors, and melanoma, is named as (R)-N-(2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benz- amide, and has the structure:
  • salts of compounds of formula I 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 or amides we include salts of pharmaceutically acceptable esters or amides, and solvates of pharmaceutically acceptable esters, amides or salts.
  • pharmaceutically acceptable 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 1-6 alkyl, C 5-10 aryl and/or C 5 . 10 aryl-d-e alkyl- esters.
  • amides of carboxylic acids of compounds of the invention
  • pharmaceutically acceptable amides include those of the formula -C C ⁇ R ⁇ R 22 , in which R z1 and R z2 independently represent optionally substituted C 1-6 alkyl, C 5-10 aryl, or C 5- io aryl-C ⁇ e alkylene-.
  • C -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.
  • 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)).
  • 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 £ (entadel) 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, 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.
  • derivatisation i.e. a resolution, including a dynamic resolution
  • 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, 11 C, 13 C, 4 C , 13 N, 15 0, 17 0, 18 0, 32 P, 33 P, 35 S, 8 F, 36 CI, 123 l, and 25 I.
  • Certain isotopically-labeled compounds of the present invention e.g., those labeled with 3 H and 14 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.
  • C 1-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. 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 C 2 . q alkenyl or a C 2 . q alkynyl group).
  • C -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). However, such C 1-q alkylene groups may not be branched.
  • q cycloalkyl groups 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 .
  • 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]heptanyl, 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), imidazo
  • 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.
  • HeterocycloalkyI 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 heterocycloalkyi 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 _ 2 o, such as C 6- 2 (e.g. C 6- 0 ) 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. Ce-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 polycyclic the point of attachment may be via atom including an atom of a non-aromatic ring. However, when aryl groups are polycyclic (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 polycyclic the point of attachment may be via atom including an atom of a non-aromatic ring.
  • heteroaryl groups are polycyclic (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-1H-isoquinolinyl, 1 ,3-dihydroisoindolyl, 1,3-dihydroisoindolyl (e.g. 3,4- dihydro-1H-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-2H-1 ,4-benzoxazinyl), benzoxazolyl, benzomorpholinyl, benzoselenadiazolyl (including 2,1 ,3-benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl,
  • 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 bicyclic.
  • 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 C -12 alkyl group
  • substituents e.g. selected from E 6
  • those substituents e.g. defined by E 6
  • such groups may be substituted with the same substituent (e.g. defined by E 6 ) or different substituents (defined by E 6 ).
  • 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.
  • Preferred compounds of the invention that may be mentioned include those in which:
  • R 1 does not represent an optionally substituted heteroaryl group (especially a monocyclic heteroaryl group, e.g. a 5- or 6-membered heteroaryl group), such as a 5-membered heteroaryl group containing two heteroatoms (e.g. a pyrazolyl, such as 1 -pyrazolyl, or, especially, imidazolyl, such as 1-imidazolyl);
  • a monocyclic heteroaryl group e.g. a 5- or 6-membered heteroaryl group
  • a 5-membered heteroaryl group containing two heteroatoms e.g. a pyrazolyl, such as 1 -pyrazolyl, or, especially, imidazolyl, such as 1-imidazolyl
  • R 1 represents: (a) as defined herein, (b) as defined herein or (c) in which the heteroaryl group is a 5-membered heteroaryl group, in which the heteroatom(s) is/are selected from oxygen and sulphur, or a 6-membered heteroaryl group; R 1 preferably represents (a) or (b);
  • R 3 represents a substituent other than hydrogen
  • R 3 represents a substituent other than hydrogen, then it is preferably does not represent optionally substituted C 1-12 (e.g. C ⁇ e) alkyl, heterocycloalkyl (preferably linked to the imidazopyrazine via a carbon atom), aryl (e.g. phenyl) or heteroaryl; and/or
  • R 2 and R 4 do not represent hydrogen, i.e. either one of R 2 and R 4 may represent hydrogen, and the other (or both) represent(s) a substituent as defined herein.
  • R 1 represents a group defined by (c) above, i.e. an optionally substituted monocyclic heteroaryl group (e.g. a 5-membered heteroaryl group such as (e.g. 1-pyrazolyl) or, especially, imidazolyl (e.g
  • B 1 , B 2 and/or B 3 do not represent or do not contain aromatic groups (such as pyridyl, e.g. 4-pyridyl);
  • R 1 represents a heteroaryl group (e.g. pyridyl)
  • R 3 preferably does not represent, or contain, an aromatic group (especially when R 3 represents -N(R 10a )R 1 a , e.g. in which R 10a and R 1 a are linked together to form, e.g. a piperazinyl group), i.e.:
  • Further preferred compounds of the invention include those in which:
  • an R group may not be substituted by an aromatic ring (e.g. a heteroaryl group); B 1 , B 2 and/or B 3 (e.g. B 1 ) do not represent or do not contain aromatic (e.g. heteroaromatic) groups (especially when R represents an (a) group, i.e. -N(R 1a )R 1b );
  • R 1a and R 1 are preferably linked together to form a 5- or 6-membered ring as defined herein;
  • R 1 when R 1 represents an (a) group, then, preferably, the ring formed by the linkage of the R 1a and R 1b groups contains at least one (further) heteroatom (in addition to the requisite nitrogen atom to which R 1a and R 1b are necessarily attached) as defined herein; when R 1 represents an (a) group, then the ring so formed (by the linkage of the R a and R 1b groups), preferably does not represent a 1-pyrrolidinyl or 1-piperidinyl ring (e.g. one in which that ring is substituted at the 2-position, by for example an a methyl group substituted by an amino moiety (a methylamino group, i.e.
  • B 1 represents methyl substituted by E 8 , in which E 8 represents Q 4 and Q 4 represents -N(R 20 )R 21 ) or, in which that ring is substituted at the 3-position by an amino moiety (i.e. by B 1 , in which B represents -N(R 10a )R 11a ).
  • R 1 represents an (a) group (e.g. in which R 1a and R 1b are linked together to form a 5- or 6-membered ring, e.g. a 1-pyrrolidinyl or 1- piperidinyl group), then preferably:
  • R 2 and R 3 does not represent an aromatic group (i.e. an optionally substituted aryl or heteroaryl group);
  • R 2 or R 3 represent an aromatic group, i.e. these groups preferably represent hydrogen or a substituent as defined above.
  • R 1 represents amino (i.e. a group defined by (a) above) or, in particular, when R represents a group defined by (c) above (in particular pyridyl or imidazolyl), then:
  • R 5 does not represent optionally substituted phenyl, naphthyl, indolyl, thiophenyl, benzo[b]furanyl, benzo[b]thiophenyl, isoxazolyl, or:
  • R 2 does not represent d-C 12 alkyl, -C(O)-O-R 10a , -C(O)-N(R 0a )R 11a and/or R 3 does not represent H or C C 6 alkyl; and/or
  • R 10a may represent a fragment of formula IA.
  • Preferred compounds of the invention include those in which, when R 1 represents -N(R 1a )R 1b , then:
  • the present invention provides combinations containing compounds of the invention in which R 1 is typically:
  • R represents substituted morpholinyl, it is preferably selected from the following structures:
  • the present invention provides combinations containing compounds of the invention in which:
  • R 2 is -(CR 6 R 7 ) m NR 0 R 11 where m is 1 , 2 or 3, and R 0 and R 11 together with the nitrogen to which they are attached form the C 3 -C 2 o heterocyclic ring; and R 3 is H, halo, CN, d-6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, C(0)N(R 6 R 17 ), OR 16 or NR 6 R 17 ;
  • R 2 is -(CR 6 R 7 ) n NR 2 S(0) 2 R 10 where n is 1 or 2; R 2 , R 6 , and R 7 are independently selected from H and C i2 alkyl; and R 10 is d-C 2 alkyl or C 6 -C 20 aryl; and R 3 is H, halo, CN, C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, C(0)N(R 16 R 17 ), OR 16 or NR 16 R 17 ;
  • R 2 is -(CR 6 R 7 ) n OR 10 where n is 1 or 2, and R 0 , R 6 are independently selected from H and d- 12 alkyl; and R 3 is H, halo, CN, d- 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, C(0)N(R 16 R 17 ), OR 16 or NR 6 R 17 ;
  • R 2 is -(CR 6 R 7 ) n S(0) 2 R 10 where n is 1 or 2; and R 6 , and R 7 are H, R 10 may be d-12 alkyl or C 6 -C 20 aryl; and R 3 is H, halo, CN, d- 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, C(0)N(R 16 R 17 ), OR 16 or NR 16 R 17 ;
  • R 10 and R 1 together with the nitrogen to which they are attached may form a C 2 -C 20 heterocyclic ring selected from morphoiinyl, piperidinyl, piperazinyl, and pyrrolidinyl; and R 3 is H, halo, CN, d- 6 alkyl, C 3 -C 6 cycloalkyi, C 2 -C 6 heterocycloalkyi, C(0)N(R 16 R 17 ), OR 16 or NR 6 R 17 ;
  • R 2 is -NR 12 S(0) 2 R 10 where R 2 is H or d-C 12 alkyl, and R 0 is d-C 12 alkyl, C 3 -C 12 carbocyclyl, C 2 -C 20 heterocyclyl, C 6 -C 20 aryl, or d-C 20 heteroaryl; and R 3 is H, halo, CN, d-6 alkyl, C 3 -C 6 cycloalkyi, C 2 -C 6 heterocycloalkyi, C(0)N(R 16 R 17 ), OR 16 or NR 16 R 17 ;
  • R 2 is -S(O) 2 NR 0 R 11 where R 10 and R 1 together with the nitrogen to which they are attached form a C 2 -C 20 heterocyclyl ring selected from morphoiinyl, piperidinyl, piperazinyl, and pyrrolidinyl; and R 3 is H, halo, CN, d- 6 alkyl, C 3 -C 6 cycloalkyi, C 2 -C 6 heterocycloalkyi, C(0)N(R 16 R 17 ), OR 16 or NR 6 R 17 ;
  • R 2 is -S(O) 2 NR 0 R 11 where R 10 and R 1 are independently selected from H and d-Ci 2 alkyl; R 10 and R 11 may be independently selected from H, substituted ethyl, and substituted propyl; and R 3 is H, halo, CN, d- 6 alkyl, C 3 -C 6 cycloalkyi, C 2 -C 6 heterocycloalkyi, C(0)N(R 16 R 17 ), OR 16 or NR 16 R 17 ;
  • R 2 is d-C 12 alkyl, and R 3 is H, halo, CN, d- 6 alkyl, C 3 -C 6 cycloalkyi, C 2 -C 6 heterocycloalkyi, C(0)N(R 6 R 17 ), OR 16 or NR 16 R 17 ;
  • R 2 is C 2 -C 8 alkenyl, and R 3 is H, halo, CN, d- 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, C(0)N(R 6 R 17 ), OR 16 or NR 16 R 17 ;
  • R 2 is C 2 -C 8 alkynyl (the C 2 -C 8 alkynyl may be substituted with C 2 -C 2 o heterocyclyl, which includes, but is not limited to, morpholinyl, pipendinyl, piperazinyl, and pyrrolidinyl); and R 3 is H, halo, CN, C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, C(0)N(R 16 R 17 ), OR 16 or NR 16 R 17 ;
  • R 2 is C 6 -C 20 aryl, such as phenyl; and R 3 is H, halo, CN, d- 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, C(0)N(R 16 R 17 ), OR 16 , NR 16 R 17 ;
  • R 2 is C 3 -C 12 carbocyclyl; and R 3 is H, halo, CN, d- 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, C(0)N(R 16 R 17 ), OR 16 or NR 6 R 17 ;
  • R 2 is C 2 -C 20 heterocyclyl
  • R 3 is H, halo, CN, d- 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, C(0)N(R 6 R 17 ), OR 16 or NR 16 R 17 ;
  • R 2 is d-C 20 heteroaryl
  • R 3 is H, halo, CN, d- 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, C(0)N(R 16 R 17 ), OR 16 or NR 16 R 17 ;
  • R 2 is H
  • R 2 is methyl (CH 3 ), cyclopropyl, CF 3 , CN or CONH 2 .
  • the combination contains a compound of the invention in which:
  • R 3 is -(CR 6 R 7 ) m NR 10 R 11 where m is 1 , 2 or 3, and R 10 and R 1 together with the nitrogen to which they are attached form the C 3 -C 20 heterocyclic ring; and R 2 is H, halo, CN, d-6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, C(0)N(R 16 R 17 ), OR 16 or NR 16 R 17 ;
  • R 3 is -(CR 6 R 7 ) n NR 12 S(0) 2 R 10 where n is 1 or 2; R 12 , R 6 , and R 7 are independently selected from H and d-12 alkyl; and R 0 is C C 12 alkyl or C 6 -C 20 aryl; and R 2 is H, halo, CN, d-6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, C(0)N(R 16 R 17 ), OR 16 or NR 16 R 17 ;
  • R 3 is -(CR 6 R 7 ) n OR 10 where n is 1 or 2, and R 0 , R 6 are independently selected from H and d-12 alkyl; and R 2 is H, halo, CN, d- 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, C(0)N(R 6 R 17 ), OR 16 or NR 16 R 17 ;
  • R 3 is -(CR 6 R 7 ) n S(0) 2 R 10 where n is 1 or 2; and R 6 , and R 7 are H, R 0 may be C i2 alkyl or C 6 -C 20 aryl; and R 2 is H, halo, CN, d- 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, C(0)N(R 16 R 17 ), OR 16 or NR 16 R 17 ; R 3 is -(CR 6 R 7 ) n S(O) 2 NR 0 R 11 where n is 1 or 2; and R 6 , and R 7 are H; and R 2 is H, halo, CN, d-6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, C(0)N(R 16 R 17 ), OR 16 or NR 16 R 17 ;
  • R 3 is -NR 12 S(0) 2 R 10 where R 12 is H or d-C 12 alkyl, and R 10 is C,-C 12 alkyl, C 3 -C 12 carbocyclyl, C 2 -C 20 heterocyclyl, C 6 -C 20 aryl, or d-C 20 heteroaryl; and R 2 is H, halo, CN, d-6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, C(0)N(R 16 R 17 ), OR 16 or NR 16 R 17 ;
  • R 3 is -S(O) 2 NR 10 R 11 where R 0 and R 11 together with the nitrogen to which they are attached form a C 2 -C 20 heterocyclyl ring selected from morpholinyl, piperidinyl, piperazinyl, and pyrrolidinyl; and R 2 is H, halo, CN, d- 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, C(0)N(R 16 R 17 ), OR 16 or NR 16 R 17 ;
  • R 3 is -S(O) 2 NR 10 R 11 where R 10 and R 11 are independently selected from H and Ci-C 2 alkyl. R 10 and R 11 may be independently selected from H, substituted ethyl, and substituted propyl; and R 2 is H, halo, CN, C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, C(0)N(R 16 R 17 ), OR 16 or NR 16 R 17 ; R 3 is C 1 -C2 alkyl, and R 2 is H, halo, CN, d- 6 alkyl, C 3 -C 6 cycloalkyi, C 2 -C 6 heterocycloalkyi, C(0)N(R 16 R 17 ), OR 16 or NR 16 R 17 ;
  • R 3 is C 2 -C 8 alkenyl, and R 2 is H, halo, CN, d- 6 alkyl, C 3 -C 6 cycloalkyi, C 2 -C 6 heterocycloalkyi, C(0)N(R 16 R 17 ), OR 16 or NR 6 R 17 ;
  • R 3 is C 2 -C 8 alkynyl (the C 2 -C 8 alkynyl may be substituted with C 2 -C 20 heterocyclyl, which includes, but is not limited to, morpholinyl, piperidinyl, piperazinyl, and pyrrolidinyl); and R 2 is H, halo, CN, d- 6 alkyl, C 3 -C 6 cycloalkyi, C 2 -C 6 heterocycloalkyi, C(0)N(R 6 R 17 ), OR 16 or NR 6 R 17 ;
  • R 3 is C 6 -C 20 aryl, such as phenyl; and R 2 is H, halo, CN, d- 6 alkyl, C 3 -C 6 cycloalkyi, C 2 -C 6 heterocycloalkyi, C(0)N(R 16 R 17 ), OR 16 or NR 16 R 17 ;
  • R 3 is C 3 -C 12 carbocyclyl; and R 2 is H, halo, CN, d- 6 alkyl, C 3 -C 6 cycloalkyi, C 2 -C 6 heterocycloalkyi, C(0)N(R 6 R 17 ), OR 16 or NR 16 R 17 ;
  • R 3 is C 2 -C 20 heterocyclyl; and R 2 is H, halo, CN, d- 6 alkyl, C 3 -C 6 cycloalkyi, C 2 -C 6 heterocycloalkyi, C(0)N(R 6 R 17 ), OR 16 or NR 16 R 17 ;
  • R 3 is C1-C 20 heteroaryl; and R 2 is H, halo, CN, d- 6 alkyl, C 3 -C 6 cycloalkyi, C 2 -C 6 heterocycloalkyi, C(0)N(R 6 R 17 ), OR 16 or NR 16 R 17 .
  • any relevant alkyl, cycloalkyi, heterocycloalkyi, aryl or heteroaryl groups may be optionally substituted by relevant substituents defined herein (for example, by a substituent defined by Q 1 , Q 2 , E 6 , E 7 , Q 4 , Q 5 , J 2 or J 3 (e.g. by Q 1 , E 6 and/or E 7 )).
  • relevant substituents defined herein for example, by a substituent defined by Q 1 , Q 2 , E 6 , E 7 , Q 4 , Q 5 , J 2 or J 3 (e.g. by Q 1 , E 6 and/or E 7 )).
  • each R 6 and R 17 respectively represents substituents R 20 and R 2 as defined herein (and more preferably, they respectively represent substituents R 50 and R 51 as defined herein);
  • each R 6 and R 7 may independently represent a substituent as defined by R 15 herein (i.e. each may independently represent hydrogen, a substituent as defined herein, or, R 6 and R 7 may be linked together in the same manner as two R 15 groups attached to the same carbon atom may be);
  • each R 0 , R and R 12 respectively represents a substituent as defined by the substituents R 10a , R 11a and R 12a .
  • the combination contains a compound of the invention in which R 2 or R 3 represent a fragment of formula IA, as hereinbefore depicted, wherein: R a and R b form, together with the N atom to which they are attached, a group of the following formula: ring A is a first 3- to 7-membered saturated / -containing heterocyclic ring which is fused to a second ring as hereinbefore defined to form a heteropolycyclic ring system in which the first ring is selected from, but not limited to, azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine and homopiperazine, said group being fused to a second ring as hereinbefore defined.
  • the second ring is typically a 3- to 7- membered saturated N-containing heterocyclic ring as defined above in respect of the first ring, the second ring is a 5- to 12-membered unsaturated heterocyclic group. More typically the second ring is a 5-, 6- or 7- membered saturated N-containing heterocyclic ring or a 5- to 7- membered unsaturated heterocyclic ring.
  • Typical examples of the second ring include azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, homopiperazine, pyrrole, imidazole, pyridine, pyridazine, pyrimidine, pyrazine, tetrahydrofuran and tetrahydropyran.
  • Examples of the resulting heteropolycyclic system include octahydropyrrolo[1 ,2- a]pyrazine and octahydro-pyrrolo[3,4-c]pyrrole.
  • Specific examples of the hetero olycyclic system include the following structures:
  • ring A is a first 3- to 7-membered saturated A/-containing heterocyclic group as hereinbefore defined (which contains a linker group), which includes, but is not limited to, a bridgehead group (i.e. a linker group linking any two non-adjacent atoms of the first ring), thereby forming, for example 3,8-diaza-bicyclo[3.2.1]octane, 2,5-diaza-bicyclo [2.2.1]heptane, 8-aza-bicyclo[3.2.1]octane, 2-aza-bicyclo[2.2.1]heptane, 3,6-diaza- bicyclo[3.1.1]heptane, 6-aza-bicyclo[3.1.1]heptane, 3,9-diaza- bicyclo[4.2.1]nonane and/or 2-oxa-7,9-diazabicyclo[3.3.1]nonane.
  • a linker group which includes, but is not limited to, a bridge
  • ring A is a first 3- to 7-membered saturated N-containing heterocyclic group as hereinbefore defined, which is spiro-fused at any available ring carbon atom to a second 3- to 12- membered saturated carbocyclic ring, typically to a 3- to 6- membered saturated carbocyclic ring, or to a 4- to 7- membered saturated N-containg heterocyclic group.
  • Examples include a group in which the first ring is selected from azetidine, pyrrolidine, piperidine and piperazine which is spiro-fused at a ring carbon atom to a second ring selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, azetidine, pyrrolidine, piperidine, piperazine and tetrahydropyran.
  • the ring so formed may, for instance, be a group derived from 3,9-diazaspiro[5.5]undecane, 2,7-diazaspiro[3.5]nonane, 2,8- diazaspiro[4.5]decane or 2,7-diazaspiro[4.4]nonane.
  • this group include the following structures:
  • the combination contains a compound of the invention in which R 2 represent a fragments of formula IA as depicted hereinbefore, in which R a and R b are as described above; and R 3 is H, halo, CN, C-,- 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, C(0)N(R 16 R 17 ), OR 16 , NR 16 R 17 .
  • the integers R 16 and R 7 are as defined herein.
  • the combination contains a compound of the invention in which R 3 represent a fragment of formula IA as depicted hereinbefore; and R 2 is H, halo, CN, C T6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, C(0)N(R 1B R 17 ), OR 16 , NR 16 R 17 .
  • R 16 and R 7 are as defined herein.
  • R 5 include, but are not limited to: pyrrole, pyrazole, triazole, tetrazole, thiazole, isothiazole, oxazole, isoxazole, isoindole, 1,3-dihydro- indol-2-one, pyridine-2-one, pyridine, pyridine-3-ol, imidazole, 1H-indazole, 1H- indole, indolin-2-one, 1-(indolin-1-yl)ethanone, pyrimidine, pyridazine, pyrazine and isatin groups.
  • the attachment site of the R 5 group to the C-6 position of the requisite imidazopyrazine ring of formula I may be at any carbon (carbon-linked) of the R 5 group (e.g. fused bicyclic C 4 -C 2 o heterocyclyl or fused bicyclic C ⁇ C 2 o heteroaryl group R 5 group).
  • R 5 More exemplary embodiments of R 5 include, but are not limited to, the following groups, where the wavy line indicates the site of attachment to the pyrazine ring:
  • Preferred compounds of the invention include those in which:
  • R represents:
  • a heterocycloalkyl e.g. a 3- to 7-membered
  • heterocycloalkyl group preferably contains 1 , 2 or 3 heteroatoms preferably selected from nitrogen, oxygen and sulfur;
  • R 1 represents optionally substituted monocyclic heteroaryl
  • that heteroaryl group preferably contains 1 , 2, 3 or 4 nitrogen heteroatoms and, optionally, 1 or 2 additional heteroatoms preferably selected from nitrogen, oxygen and sulfur;
  • n 0, 1 or 2;
  • each R 15 represents hydrogen or C 1-6 (e.g. C -3 ) alkyl, which latter group is preferably unsubstituted;
  • R 4 represents C-,. e alkyl
  • R 5 represents aryl (e.g. phenyl), then that group may be unsubstituted but is preferably substituted by at least one (e.g. two or, preferably, one) substituent(s) selected from E 5 ;
  • R 5 represents monocyclic heteroaryl (e.g. a 5- or 6-membered heteroaryl group), then that group preferably contains 1 , 2, 3 or 4 nitrogen atoms and, optionally 1 or 2 additional heteroatoms selected from oxygen and sulfur, and which heteroaryl group is optionally substituted by one or more substituents selected from E 5 ;
  • optional substituents are preferably selected from -OR, -SR, -CH 2 OR, C0 2 R, CF 2 OH, CH(CF 3 )OH, C(CF 3 ) 2 0H, -(CH 2 ) w OR, -(CH 2 ) W NR 2 , -C(0)N(R) 2 , -NR 2 , -NRC(0)R, -NRC(0)NHR, -NRC(0)N(R) 2 , -S(0) y N(R) 2 , -OC(0)R, OC(0)N(R) 2 , -NRS(0) y R, -NRC(0)N(R) 2 , CN, halogen and -N0 2 (in which each R is independently selected from H, CVC 6 alkyl, C 3 -C 10 cycloalkyl and a 5- to 12-member
  • R 5 represents aryl (e.g. phenyl), then that group is substituted by one or two substituents (e.g. by a first substituent as defined above, and, optionally a further substituent (or a further two substituents) preferably selected from halo, C - 2 alkyl, CN, N0 2 , OR d , SR d , NR d 2l C(0)R d , SOR d , S0 2 R d , S0 2 N(R) d 2 , NC(0)R d and C0 2 R d (wherein each R d is independently H or C Ce alkyl);
  • substituents e.g. by a first substituent as defined above, and, optionally a further substituent (or a further two substituents) preferably selected from halo, C - 2 alkyl, CN, N0 2 , OR d , SR d , NR d 2l C(0)R d , S
  • R 5 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 it is situated at position 3 or 4; particularly preferred are phenyl groups substituted by -OR d (in which R d is independently H or (-VC 6 alkyl, e.g. methyl), e.g.
  • the -OR d group, or -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 definitions above for R 5 );
  • R 5 when R 5 represents heteroaryl, it is unsubstituted or substituted (when substituted, it may be substituted by one or more substitutents selected from those listed in respect of substituents on R 5 , when R 5 is a phenyl group; typically, the substituents are selected from OH and NH 2 );
  • E , E 2 , E 3 , E 4 , E 5 , E 6 , E 7 , E a , E 9 , E 10 , E 1 or E 12 groups may not be linked together;
  • aryl e.g. phenyl; preferably unsubstituted, but which may be substituted by one to three J 5 groups
  • C 1-6 e.g. C 1-3 alky
  • each R 50 , R 51 , R 52 and R 53 substituent independently represents, on each occasion when used herein, hydrogen or C 1-6 (e.g. C 1-3 ) alkyl optionally substituted by one or more substituents selected from fluoro;
  • R 60 , R 61 and R 62 independently represent hydrogen or Ci_ 3 (e.g. C ⁇ ) alkyl optionally substituted by one or more fluoro atoms.
  • R 1 and R 5 are exemplary optional substituents on R 1 and R 5 (and, when they represent a substituent other than hydrogen on R 2 , R 3 and R 4 groups) include:
  • halo e.g. fluoro, chloro or bromo
  • alkyl which alkyl group may be cyclic, part-cyclic, unsaturated or, preferably, linear or branched (e.g. C -4 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);
  • halo e.g. fluoro
  • aryl e.g. phenyl
  • substitutent is on an alkyl group, thereby forming e.g. a benzyl group
  • each R z1 to R z12 independently represents, on each occasion when used herein, H or C 1-4 alkyl (e.g. ethyl, n-propyl, f-butyl or, preferably, n-butyl, methyl or isopropyl) 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 z5 ), 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 10 and R or R 10a and R 11a groups.
  • Preferred compounds of the invention include those in which:
  • R represents: (i) -N(R 1a )R 1b ; (ii) an optionally substituted 5- or 6-membered heterocycloalkyl group (attached via a carbon atom); or (iii) an optionally substituted 5- or 6-membered heteroaryl group;
  • R 1 represents -N(R a )R b
  • R a and R b are preferably linked together to form a 6-membered ring containing a further oxygen heteroatom (so forming a morpholinyl group), which ring may be unsubstituted, or may be substituted by one or more B 1 groups (such groups are preferably unsubstituted, i.e. most preferably an unsubstituted morpholinyl group);
  • R 1 represents an optionally substituted 5- or 6-membered heterocycloalkyl group
  • such a group may contain two or preferably one heteroatom(s) (in which the heteroatom is selected from sulfur, preferably nitrogen, and, especially, oxygen).
  • R 1 when R 1 represents optionally substituted 5- or 6-membered heteroaryl, then such a group may contain two or, preferably, one heteroatom(s) (in which the heteroatom is selected from sulfur, preferably oxygen and, especially, nitrogen). Such a ring may be substituted with one or more substituents selected from B 3 , but it is preferably unsubstituted. Further, it is preferably 6-membered (e.g. a pyridyl group);
  • R 4 represents hydrogen or a substituent selected from -N(R 10b )R 1 b and, preferably, halo (e.g. chloro, bromo or iodo) and -CN;
  • At least one (e.g. one) of R 2 , R 3 and R 4 represents hydrogen
  • R 5 represents aryl (e.g. phenyl) or heteroaryl (e.g. a 5- or preferably a 6- membered monocyclic heteroaryl group, or a 8-, 9- or 10-membered bicyclic heteroaryl group), both of which are are optionally substituted by one or more substituents selected from E 5 ;
  • aryl e.g. phenyl
  • heteroaryl e.g. a 5- or preferably a 6- membered monocyclic heteroaryl group, or a 8-, 9- or 10-membered bicyclic heteroaryl group
  • any relevant pair of R 10a , R 11a and R 2a may (e.g. when both are attached to the same nitrogen atom) be linked together to form a 3- to 8- (e.g.
  • each Q 4 and Q 5 (e.g. each Q 4 ) independently represent halo, -N(R 20 )R 21 , -OR 20 ,
  • Q 4 preferably represents -N(R 20 )R 21 , -OR 20 ,
  • each J 1 , J 2 , J 3 , J 4 , J 5 and J 6 independently represent C 1-6 (e.g. C 1-3 ) alkyl 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 5 , R 52 and R 53 independently represents hydrogen or C ⁇ 6 (e.g. C ⁇ ) alkyl optionally substituted by one or more fluoro atoms;
  • each R 60 , R 6 and R 62 independently represents hydrogen or C ⁇ 2 alkyl (e.g. methyl). More preferred compounds of the invention (component (A) of the combinations of the invention) include those in which:
  • R 1 represents -N(R 1a )R b , in which R 1a and R 1b are linked together to form a 6- membered ring containing a further oxygen heteroatom (so forming a morpholinyl group), which ring may be unsubstituted, or may be substituted by one or more B 1 groups (such groups are preferably unsubstituted);
  • R 2 or R 3 represents C-M2 (e.g. C -6 ) alkyl, then it may be straight-chained, e.g. acyclic C 1-3 alkyl (e.g. methyl) or C 3 _ 6 cycloalkyl (e.g. cyclopropyl), all of which are optionally substituted by one or more fluoro atoms (so forming for example a trifluoromethyl group);
  • R 4 represents hydrogen, chloro, bromo, iodo or -CN;
  • R 2 and R 3 represents a substituent as defined herein, and the other represents hydrogen or a substituent as defined herein;
  • R 5 represents aryl (e.g. phenyl) or heteroaryl (e.g. a 5- or preferably a 6- membered monocyclic heteroaryl group, or a 10- or, preferably, 9-membered bicyclic heteroaryl group, in which, in both cases, there is one or two heteroatom(s) present, preferably selected from nitrogen, so forming e.g. pyridyl, indazolyl, indolyl, pyrimidinyl, indolonyl or pyrrolopyridine, such as pyrrolo[2,3]pyridine), both of which R 5 groups are optionally substituted by one or more (e.g. one or two) substituents selected from E 5 ;
  • heteroaryl e.g. a 5- or preferably a 6- membered monocyclic heteroaryl group, or a 10- or, preferably, 9-membered bicyclic heteroaryl group, in which, in both cases, there is one or two heteroatom(
  • each R 0a , R 11a , R 2a , R 0b , R 1b and R 12b independently represents hydrogen or C 1-4 (e.g. C ⁇ ) alkyl (e.g. ethyl); or
  • each E 1 , E 2 , E 3 , E 4 , E 5 , E 6 , E 7 , E 8 , E 9 , E 10 , E 11 and E 12 (e.g. each E 5 and E 6 ) independently represents a substituent selected from Q 4 ;
  • halo e.g. fluoro
  • R 22 represents C 1-3 alkyl or, preferably, hydrogen
  • each J 1 , J 2 , J 3 , J 4 , J 5 and J 6 independently represent a substituent selected from Q 7 ;
  • Ci -3 alkyl optionally substituted by one or more fluoro atoms
  • each R 50 independently represents C 1-4 alkyl (e.g. te/t-butyl or methyl).
  • composition (A) of the combinations of the invention include those in which:
  • R 1 represents: (a) -N(R a )R b , in which R 1a and R b are linked together to form a 6-membered ring optionally containing a further heteroatom (e.g. an oxygen heteroatom) (so forming e.g. a morpholinyl or piperidinyl group), which ring may be unsubstituted, or may be substituted by one or more B 1 groups; (b) a monocyclic heteroaryl group (preferably containing one or two heteroatoms (preferably selected from nitrogen; so forming e.g. a pyrimidinyl or pyridyl group) optionally (and preferably) substituted by one or more (e.g.
  • a further heteroatom e.g. an oxygen heteroatom
  • a monocyclic heteroaryl group preferably containing one or two heteroatoms (preferably selected from nitrogen; so forming e.g. a pyrimidinyl or pyridyl group) optionally (
  • substituent selected from B 3 one) substituent selected from B 3 ; or (c) a 6-membered heterocycloalkyl group (containing two or, preferably, one heteroatom preferably selected from nitrogen and, especially, oxygen, so forming for example a tetrahydropyranyl group);
  • B , B 2 and B 3 preferably represents halo (e.g. fluoro), -N(R 10a )R 1 a (e.g -NH 2 ) or d-2 alkyl optionally substituted by one or more E 8 group;
  • R 2 and R 3 independently represent(s) hydrogen, a fragment of formula IA, C 1-6 alkyl (optionally substituted by one or more (e.g. one) substituent(s) selected from Q 2 ) or a substituent selected from Q ;
  • R 2 or R 3 represents a fragment of formula IA, then it is preferably R 2 that represents such a fragment;
  • R 2 or R 3 represents a fragment of formula 1A (in an embodiment of the invention one of R 2 and R 3 , e.g. R 2 , represents a fragment of formula IA), then preferably m represents 1 and each R 15 independently represent hydrogen (so forming a fragment -CH 2 -N(R a )(R ));
  • R a and R b are linked together to form a 4-, 5- or 6-membered cyclic group (preferably containing no further heteroatoms, and so forming a azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl group), which further comprises: (a) a fused 6- or preferably 5-membered heterocycloalkyi (e.g. pyrrolidinyl) group (preferably containing one heteroatom, e.g. nitrogen, so forming e.g.
  • a 5,5-fused bicycle (b) a -CH 2 -CH 2 - linker group (thereby forming a bridged cyclic structure) or (c) a 4-, 5- or 6-membered heterocycloalkyi group (in which there is preferably one nitrogen heteroatom, so forming e.g. pyrrolidinyl or piperidinyl) linked together via a single common carbon atom to form a spiro-cycle (e.g.
  • R 2 or R 3 represents C ⁇ 2 (e.g. C 1-6 ) alkyl, then it may be straight-chained, e.g. acyclic C 1-3 alkyl (e.g. methyl) or C 3-6 cycloalkyl (e.g. cyclopropyl), all of which are optionally substituted by one or more fluoro atoms (so forming for example a trifluoromethyl group);
  • R 4 represents hydrogen, chloro, bromo, iodo, -CN, -C(O)R 10b (e.g. -C(O)H) or methyl optionally substituted by one or more (e.g. one) substituent(s) selected from E 4 (in which E 4 preferably represents heteroaryl (e.g. imidazolyl) or, especially, -OR 20 , so forming e.g. a -CH 2 OH group or a -CH 2 -heteroaryl moiety); one of R 2 and R 3 represents a substituent as defined herein, and the other represents hydrogen or a substituent as defined herein; R 5 represents aryl (e.g.
  • phenyl or heteroaryl (e.g. a 5- or 6-membered monocyclic heteroaryl group, or a 10- or, preferably, 9-membered bicyclic heteroaryl group, in which, in both cases, there is one or two heteroatom(s) present, preferably selected from nitrogen, so forming e.g. pyrazolyl, pyridyl, indazolyl, indolyl, pyrimidinyl, indolonyl or pyrrolopyridine, such as pyrrolo[2,3]pyridine), both of which R 5 groups are optionally substituted by one or more (e.g. one or two) substituents selected from E 5 ;
  • heteroaryl e.g. a 5- or 6-membered monocyclic heteroaryl group, or a 10- or, preferably, 9-membered bicyclic heteroaryl group, in which, in both cases, there is one or two heteroatom(s) present, preferably selected from nitrogen, so forming
  • each R 10a , R 11a , R 12a , R 10b , R 1b and R 12b independently represents hydrogen or C 1-6 alkyl (e.g. ethyl or propyl or C 3 . 6 cycloalkyl, such as cyclohexyl) optionally substituted by one or more (e.g. one) substituent(s) selected from E 10 ; or
  • R 10a and R a may represent heterocyloalkyl (e.g. a 5- or preferably 6- membered heterocycloalkyl group e.g. containing one heteroatom, so forming e.g. a piperidinyl or a tetrahydropyranyl group; which heterocycloalkyl group is optionally substituted by one or more (e.g. one) substituent selected from E 10 ); or any relevant pair of R 10a , R 1a and R 2a (e.g. R 10a and R 11a ) may (e.g.
  • C 1-3 alkyl optionally substituted by one or more fluoro atoms
  • aryl which latter group, when attached to an alkyl group may form e.g. a benzyl moiety
  • heteroaryl e.g. imidazolyl
  • Q 5 represents halo (e.g. fluoro), -N(R 20 )R 21 , -OR 20 and -0-C(0)R 20 ;
  • each E 4 independently represents halo (e.g. fluoro), -OR 20 (e.g.
  • heteroaryl e.g. imidazolyl
  • C 1-6 alkyl e.g. C 1-3 alkyl
  • each E 7 independently represents -N(R 20 )R 21 ;
  • each E 10 (which is preferably located on a nitrogen heteroatom, when a substituent on a heterocycloalkyl group) represents -S(0) 2 R 20 , -OR 20 ,
  • R 22 represents C 1-3 alkyl or, preferably, hydrogen
  • each J 1 , J 2 , J 3 , J 4 , J 5 and J 6 independently represent a substituent selected from Q 7 ;
  • each R 50 and R 51 independently represents hydrogen, C- M alkyl (e.g. te -butyl or methyl) or R 50 and R 51 , when attached to the same carbon atom, may be linked together to form a 5- or preferably, 6-membered ring (e.g. containing a further heteroatom, so forming e.g. piperazinyl) optionally substituted by methyl (e.g. which substituent is located in the additional nitrogen heteroatom).
  • C- M alkyl e.g. te -butyl or methyl
  • R 50 and R 51 when attached to the same carbon atom, may be linked together to form a 5- or preferably, 6-membered ring (e.g. containing a further heteroatom, so forming e.g. piperazinyl) optionally substituted by methyl (e.g. which substituent is located in the additional nitrogen heteroatom).
  • R 1 represents -N(R a )R 1b as hereinbefore defined (especially in which R 1a and R 1b are linked together to form a 6-membered ring optionally (and preferably) containing a further heteroatom (e.g. oxygen), so forming e.g. a piperidinyl or, preferably, a morpholinyl group;
  • a further heteroatom e.g. oxygen
  • R 2 represents a substituent other than hydrogen, and R 3 and R 4 independently represent hydrogen or a substituent other than hydrogen;
  • R 2 represents a substituent other than hydrogen
  • R 2 represents Q 1 or C 1-2 alkyl (e.g. methyl) optionally substituted by Q 2 (e.g. at the terminal position of the methyl group);
  • R 3 and R 4 independently represent C -2 alkyl or, preferably, hydrogen or Q 1 (e.g. in which Q 1 preferably represents halo (e.g. chloro) or heterocycloalkyl optionally substituted by one or more E 6 groups);
  • R 3 and R 4 represent hydrogen;
  • R 5 represents: (a) phenyl (which is preferably substituted e.g. by one E 5 substituent located preferably at the meta position); (b) a 5- or 6-membered (e.g. 6-membered) monocyclic heteroaryl group (e.g. containing one or two heteroatoms preferably selected from nitrogen, so forming e.g. pyrimidinyl, such as 5-pyrimidinyl, or pyridyl, such as 3-pyridyl), which monocyclic heteroaryl group is optionally substituted e.g. by one or two E 5 substituent(s) (e.g.
  • R 5 represents pyrimidinyl, or, at the 6- position when R 5 represents 3-pyridyl; in each case a substituent is preferably at the postion para relative to the point of attachment to the requisite imidazopyrazine of formula I); or (c) a 9- or 10-membered (e.g. 9-membered) bicyclic heteroaryl group (e.g. indazolyl, such as 4-indazolyl, or azaindolyl, such as 7-azaindolyl i.e. pyrrolo[2,3-b]pyridyl, such as 7-azaindol-5yl), which bicyclic heteroaryl group is preferably unsubstituted;
  • indazolyl such as 4-indazolyl, or azaindolyl, such as 7-azaindolyl i.e. pyrrolo[2,3-b]pyridyl, such as 7-azaindol-5yl
  • Q 1 represents -C(O)N(R 10a )R 1a or -C(O)OR 10a (e.g. in which R 10a is C, -2 alkyl);
  • R 0a and R 11a (for instance when Q 1 represents -C(O)N(R 10a )R 1a ) independently represent hydrogen, acyclic C 1-3 (e.g. C -2 ) alkyl (e.g. methyl or ethyl) (optionally substituted by one or more (e.g. one) E 10 substituent), cycloalkyl (e.g. cyclohexyl) (optionally substituted by one or more (e.g. one) E 10 substituent) or heterocycloalkyl (e.g. a 5- or 6-membered heterocycloalkyl group (e.g. containing one heteroatom, so forming e.g.
  • acyclic C 1-3 e.g. C -2 alkyl (e.g. methyl or ethyl) (optionally substituted by one or more (e.g. one) E 10 substituent)
  • cycloalkyl e.g. cyclohexyl
  • piperidinyl such as 4-piperidinyl, or tetrahydropyranyl, such as 4-tetrahydropyranyl) (optionally substituted by one or more (e.g. one) E 10 substituent, which may be located on a nitrogen heteroatom);
  • Q 2 represents -N(R 10a )R 11a
  • R 10a and R 11a are preferably linked together to form a 5- or preferably 6-membered ring preferably containing a further (e.g. nitrogen, oxygen or sulfur) heteroatom (so forming, e.g., piperazinyl, morpholinyl or thiomorpholinyl) optionally (and preferably) substituted by one or more (e.g.
  • E 5 represents a substituent on phenyl, then it is preferably Q 4 (e.g. -OR 20 );
  • E 5 represents a substituent on monocyclic heteroaryl, then it is preferably Q 4 (e.g. -N(R 20 )R 21 ) or C 1-2 alkyl (e.g. methyl) optionally substituted by one or more fluoro atoms (so forming e.g. a -CF 3 group);
  • E 6 and E 12 preferably represent Q 4 ;
  • E 10 represents Q 4 ;
  • E 10 represents -N(R 20 )R 21 , -OR 20 or -C(0)OR 20 ;
  • Q 4 represents -N(R 20 )R 21 or -OR 20 (e.g. -OCH 3 or -OH); for instance when E 10 represents Q 4 (and E 10 is a substituent on a heterocycloalkyl group), then Q 4 represents -C(0)OR 20 ;
  • R 20 and R 2 independently represent hydrogen or alkyl (e.g. methyl, ethyl or butyl (e.g isobutyl)), which alkyl group may (e.g. in the case when E 12 represents
  • R 20 and R 21 may be linked together to form a 5- or preferably 6-membered ring, optionally containing a further heteroatom (e.g. oxygen, so forming e.g. morpholinyl);
  • a further heteroatom e.g. oxygen, so forming e.g. morpholinyl
  • J 4 represents Q 7 ;
  • Q 7 represents -N(R 50 )R 51 ;
  • R 50 and R 5 independently represent hydrogen, or, preferably, d_ 2 alkyl (e.g. methyl).
  • composition (A) of the combinations of the invention include those in which:
  • R represents 1-piperidinyl or, preferably, 4-morpholinyl
  • R 2 represents hydrogen or, preferably, methyl, -CF 3 , -CH 2 -[4-S(0) 2 CH 3 - piperazinyl], -0(O)N(H)ethyl, -C(0)NH 2 , -C(0)Oethyl, -C(0)N(H)-CH 2 CH 2 - N(CH 3 ) 2 , -C(0)N(H)methyl, -CH 2 -[4-morpholinyl], -C(0)N(H)-CH 2 CH 2 -OCH 3 , -C(0)N(H)-[(1-C(0)OCH 2 CH 3 )-piperidin-4-yl], -C(0)N(H)-[4-tetrahydropyranyl], -C(0)N(H)-[4-OH-cyclohexyl], -CH 2 -[4-C(0)i-butyl-2,6-diemthyl-piperazinyl], -CH 2 -[4
  • R 3 represents 4-piperidinyl (e.g. containing a double bond at the 3,4-position and a -C(0)-C(H)(CH 3 ) 2 substituent at the 1 -position) or, preferably, hydrogen;
  • R 4 represents hydrogen or halo (e.g. chloro);
  • R 3 and R 4 represent hydrogen
  • R 5 represents 3-hydroxy phenyl, 2-amino-5-pyrimidinyl, 4-indazolyl, 3-pyridyl, 6- amino-pyridyl, 7-azaindol-5-yl (i.e. pyrrolo[2,3-b]pyrid-5-yl), 2-methyl-5- pyrimidinyl, 2-amino-6-methyl-5-pyrimidinyl or 2-N(H)CH 3 -5-pyrimidinyl.
  • Particularly preferred compounds of the invention include those of the examples descibred hereinafter.
  • examples descibred hereinafter For example:
  • a process preparation of a compound of formula I which process comprises: (i) reaction of a compound of formula IB,
  • L 1 represents a suitable leaving group, such as iodo, bromo, chloro or a sulfonate group (e.g. -OS(0) 2 CF 3 , -OS(0) 2 CH 3 or -OS(0) 2 PhMe), and R 1 , R 2 , R 3 , and R 4 are as hereinbefore defined, with a compound of formula IC,
  • R 5 -L 2 IC wherein L 2 represents a suitable group such as -B(OH) 2 , -B(OR wx ) 2 or -Sn(R w ) 3 , in which each R wx independently represents a C 1-6 alkyl group, or, in the case of -B(OR wx ) 2 , the respective R w 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.
  • L 2 represents a suitable group such as -B(OH) 2 , -B(OR wx ) 2 or -Sn(R w ) 3 , in which each R wx independently represents a C 1-6 alkyl group, or, in the case of -B(OR wx ) 2 , the respective R w groups may be linked together to form a 4- to
  • 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 5 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.
  • catalysts include palladium and a ligand such as PdCI 2 (dppf).DCM, i-Bu 3 P, (CsHn ⁇ P, Ph 3 P, AsPhs, P(o-Tol) 3 , 1 ,2-bis(diphenylphosphino)ethane, 2,2'-bis(di-te/f-butyl- phosphino)-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 PdCI 2 (dppf).DC ), together
  • L 3 represents a suitable leaving group, such as one hereinbefore defined in respect of L 1 , and R 2 , R 3 , R 4 and R 5 are as hereinbefore defined, with a compound of formula IE,
  • R 1 -L 4 IE wherein L 4 represents a suitable leaving group, such as one hereinbefore described in respect of L 2 , under reaction conditions such as those descibred in respect of process step (i) above, or, in the case where R 1 represents -N(R a )R b , L 4 may represents hydrogen (so forming an amine group), and the reaction may 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) (Pd 2 (dba) 3 ) or NiCI 2 and an optional additive such as Ph 3 P, 2,2 - bis(diphenylphosphino)-1 ,1'-binaphthyl, xantphos, Nal or an appropriate crown
  • the compound of formula ID (e.g. in which L 4 is chloro) may be prepared in situ, for example from a compound corresponding to a compound of formula ID, but in which L 4 represents -OC -3 alkyl (e.g. methoxy) by reaction in the presence of e.g. a chlorinating agent (such as POCI 3 );
  • R 2 -C(0)-C(R 3 )(H)-L 5 IG wherein L 5 represents a suitable leaving group, such as one hereinbefore defined in respect of l_ (and, especially, L 5 represents halo, such as chloro or bromo), and R 2 and R 3 are as hereinbefore defined, under standard reaction conditions, for example in the presence of a suitable reaction solvent such as DME or 2- propanol, at a convenient temperature, typically heating at 90°C, followed by reaction with a compound of formula IC as hereinbefore defined.
  • the compounds of formula IG may be a protected derivative thereof (e.g.
  • Such an intermediate compound of formula IG in which R 3 represents -N(R 10a )R 11a (in which R 10a and R 11a may be linked together to form an optionally piperazinyl group) and L 5 may represent a suitable leaving group, may also be prepared by reaction of glyoxal with benzotraizole and an amine (e.g. a cyclic amine such as piperazine or a substituted derivative thereof), which may be an intermediate compound that is not isolated (e.g. which may be used in situ); (iv) reaction of a compound of formula IFA,
  • L 6a and L independently represent a suitable leaving group, for example benzotriazole groups (or the like), and each R 3 is as hereinbefore defined (e.g. each of the R 3 groups are the same)
  • a suitable solvent such as DCE
  • heating at a convenient temperature for a period of time to ensure completion of the reaction, typically at reflux for 5h.
  • an inorganic base can be added to ensure completion of the reaction;
  • an electrophile that provides a source of iodide ions includes iodine, diiodoethane, diiodotetrachloroethane or, preferably, /V-iodosuccinimide, a source of bromide ions includes W-bromosuccinimide and bromine, and a source of chloride ions includes A/-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.
  • a suitable solvent such as CHCI 3 or an alcohol (e.g. methanol)
  • a suitable base such as a weak inorganic base, e.g. sodium bicarbonate.
  • reaction maybe performed by heating at a convenient temperature, either by conventional heating under reflux or under microwave irradiation; (vi) for compounds of formula I in which R 3 or R 4 represents a substituent other that hydrogen, or halo (e.g. bromo, iodo or chloro), reaction of a corresponding compound of formula I, in which R 3 or R 4 (as appropriate) represents bromo, chloro or iodo, with a compound of formula IJ,
  • R 3M represents R 3 or R 4 (as appropriate)
  • L 7 represents a suitable leaving group such as one hereinbefore described in respect of process step (i) or (ii) above.
  • R 3M represents R 3 or R 4 (as appropriate)
  • L 7 represents a suitable leaving group such as one hereinbefore described in respect of process step (i) or (ii) above.
  • R 3M represents R 3 or R 4 (as appropriate)
  • L 7 represents a suitable leaving group such as one hereinbefore described in respect of process step (i) or (ii) above.
  • R 3 or R 4 substituent for instance in order to introduce a -CN substituent, zinc cyanide (or the like) may be employed).
  • Other specific transformation steps that may be mentioned include:
  • oxidations for example of a moiety containing an alcohol group (e.g. -CH 2 OH) to an aldehyde (e.g. -C(O)H) or of a -S- moiety to a -S(O)- or -S(0) 2 - moiety (or the reverse reduction reaction), for example in the presence of a suitable oxidising agent, e.g. Mn0 2 or mcpba or the like;
  • a suitable oxidising agent e.g. Mn0 2 or mcpba or the like
  • an amide or sulfonamide for example by reaction of a sulfonyl choride with an amine or by an amide coupling reaction, i.e. the formation of an amide from a carboxylic acid (or ester thereof), for example -C(0)OH (or an ester thereof), may be converted to -C(O)N(R 10a )R 11a group (in which R 10a and R 1a are as hereinbefore defined, and may be linked together, e.g. as defined above), and which reaction may (e.g.
  • a suitable coupling reagent e.g. 1,1 '-carbonyldiimidazole, A/./v'-dicyclohexylcarbodiimide, or the like
  • an ester e.g. -C(0)OCH 3 or -C(0)OCH 2 CH 3
  • 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 1 a 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 e.g. aromatic nucleophilic substitution
  • any nucleophile replaces a leaving group e.g. an amine may replace a
  • Such reactions include "Mitsunobu”-type reactions (or variants thereof), i.e. in which a -OH is the leaving group, which is activated by treatment with e.g. iodine and triphenylphosphine);
  • Grignard reactions e.g. the addition of a nucleophilic organometalic reagent, for instance the addition of eMgCI to a carbonyl group;
  • Wiley &Sons Ltd Chichester, UK, 2002, and references cited therein;
  • halogenating agent such as N-bromoSuccinimide, N-iodosuccininide, N-chlorosuccinimide or others
  • X represents an halogen group such as CI, Br or Iodine atom
  • a suitable reaction solvent such as CHCI 3
  • Compounds of formula (X) can react with an intermediate (VII) of formula R 1 -Nu, where R is as hereinbefore defined and Nu represents a nucleophilic group, such as an amine (and R 1 -Nu together form the group that is to be linked to the imidazopyrazine) in a suitable solvent such as DCM, dioxane at room temperature or by heating at a convenient temperature, for a period of time to ensure the completion of the reaction.
  • a suitable solvent such as DCM, dioxane at room temperature or by heating at a convenient temperature, for a period of time to ensure the completion of the reaction.
  • reaction may be with an intermediate (VIII) of formula R 5 -B(OR) 2 , which R is H or C ⁇ Ce alkyl or the two groups OR form, together with the boron atom to which they are attached a pinacolato boronate ester group, and where R 5 is as defined before, in a suitable solvent such as DME or DMF, in the presence of a suitable base, such as an inorganic aqueous base Na 2 C0 3 or K 2 C0 3 , in the presence of a metal catalyst, such as palladium, and a suitable ligand, such us PdCI 2 (dppf).DCM, Pd(PPh 3 ) 4 by heating at a convenient temperature, such as 130°C under microwave irradiation or reflux temperature under traditional heating, for a period of time that allows the completion of reaction, to obtain compounds of formula (XI).
  • a suitable solvent such as DME or DMF
  • a suitable base such as an inorganic aqueous base Na 2 C0 3
  • Compounds of formula (XI) can react with an intermediate (XIV) of formula R 3 -B(OR) 2 , in which the -B(OR) 2 moeity is as defined above, and R 3 is as hereinbefore defined, under conditions such as those described hereinbefore (e.g. reaction of (X) with (VIII); e.g. microwave irradiation conditions at about 140°C may be deployed), to obtain compounds of formula (Xll-a).
  • intermediate (XIV) of formula R 3 -B(OR) 2 in which the -B(OR) 2 moeity is as defined above, and R 3 is as hereinbefore defined, under conditions such as those described hereinbefore (e.g. reaction of (X) with (VIII); e.g. microwave irradiation conditions at about 140°C may be deployed), to obtain compounds of formula (Xll-a).
  • Compound 1-01 can react with an intermediate (VII) of formula R -Nu (as hereinbefore defined), at a convenient temperature, such us 120°C, for a period of time that allows the completion of reaction, to afford compound (V).
  • a convenient temperature such us 120°C
  • the halogen atom X of compounds of formula (IX) can be substituted via a coupling reaction with an intermediate (XVI) of formula R 4 -B(OR) 2 , in which the -B(OR) 2 moiety is as hereinbefore defined, and R 4 is as hereinbefore defined, e.g. under reaction conditions hereinbefore described (e.g. the reaction of (X) with (VIII)), for a period of time that allows the completion of reaction, to obtain compounds of formula XV.
  • the halogen atom X of compounds of formula (IX) can be substituted via coupling reaction of a CN group, by treatment with Zn(CN) 2 , in a suitable solvent such as DMF, AcCN and in the presence of a Pd catalyst, such us Pd(PPh 3 ) 4 or PdCI 2 (dppf) 2 . Additionally an inorganic aqueous base can be added such as Na 2 C0 3 aq. Heating at a convenient temperature, such as 130°C under microwave irradiation or reflux temperature under traditional heating, for a period of time that allows the completion of reaction, to obtain compounds of formula XV.
  • Compound of formula (XVIII) can react with POCI 3 by heating, typycally to reflux, for a period of time to ensure the completion of the reaction, to afford the replacement of the methoxy group by chlorine atom. Coupling of the chlorine atom with an intermediate (XX) of formula R -B(OR) 2 in which the -B(OR) 2 moiety and R are as hereinbefore defined, e.g. under reaction conditions hereinbefore described (e.g. the reaction of (X) with (VIII)), to obtain compounds of formula (XIX).
  • the substituents R 1 , R 2 , R 3 , R 4 and R 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.
  • R 2 , R 3 and R 4 groups such as C0 2 Et, CHO, CN and/or CH 2 CI, are present, these groups can be further derivatized to other fragments described in R 2 , R 3 and R 4 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 e.g. sodium, copper (I), zinc or potassium cyanide
  • a palladium catalyst e.g. sodium, copper (I), zinc or potassium cyanide
  • 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 suitable coupling catalyst e.g. a palladium and/or a copper based catalyst
  • a suitable base e.g.
  • a tri-(C 1-6 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 4 , 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 4 , at low temperature such as at 0°C or below, e.g. at about -5°C
  • 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 tert-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) and 9-fluorenylmethyleneoxycarbonyl (Fmoc).
  • BOC t-butoxycarbonyl
  • CBz benzyloxycarbonyl
  • Fmoc 9-fluorenylmethyleneoxycarbonyl
  • 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.
  • Combinations of the invention are indicated as pharmaceuticals. According to a further aspect of the invention there is provided a combination of the invention, as hereinbefore defined, for use as a pharmaceutical.
  • compounds of the invention may possess pharmacological activity as such, certain pharmaceutically-acceptable (e.g. "protected") derivatives of compounds of the invention may exist or be prepared which may not possess such activity, but may be administered parenterally or orally and thereafter be metabolised in the body to form compounds of the invention.
  • Such compounds (which may possess some pharmacological activity, provided that such activity is appreciably lower than that of the "active" compounds to which they are metabolised) may therefore be described as "prodrugs" of compounds of the invention.
  • a "prodrug of a compound of the invention” is as hereinbefore defined, including compounds that form a compound of the invention, in an experimentally- detectable amount, within a predetermined time (e.g. about 1 hour), following oral or parenteral administration. Combinations containing any prodrug of the compounds of the invention are included within the scope of the invention. Furthermore, certain compounds of the invention may possess no or minimal pharmacological activity as such, but may be administered parenterally or orally, and thereafter be metabolised in the body to form compounds of the invention that possess pharmacological activity as such.
  • Such compounds may also be described as "prodrugs".
  • the compounds of the invention that are components of the combinations of the invention are useful because they possess pharmacological activity, and/or are metabolised in the body following oral or parenteral administration to form compounds which possess pharmacological activity.
  • Compounds/combinations of the invention may inhibit protein or lipid kinases, such as a PI3 kinase (especially a class I PI3K) or mTOR, for example as may be shown in the tests described below (for example, the test for PI3Ka inhibition described below) and/or in tests known to the skilled person.
  • the compounds/combinations 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.
  • 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, or a combination containing said compound, 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 or a combination containing said compound, as would be apparent to those skilled in the art.
  • the measurable change may be objective (e.g.
  • Combinations 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
  • Combinations of the invention may be found to inhibit the above-mentioned kinases to a greater degree than compounds of the invention. Combinations 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).
  • a protein or lipid kinase e.g. PI3K, such as class I PI3K, and/or mTOR
  • combinations 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).
  • PI3K protein or lipid kinase
  • Such conditions/disorders include cancer, immune disorders, cardiovascular diseases, viral infections, inflammation, metabolism/endocrine function disorders and neurological disorders.
  • Combinations of the invention may be shown to be active e.g. in the biochemical assays described herein, may be shown to have predictive activity based on e.g. the phosphorylation assay described herein, and/or may reduce the rate of cell proliferation e.g. as may be shown in the cell proliferation assays described herein (for instance using cancer cell lines (e.g. known commercially available ones), such as those described herein).
  • cancer cell lines e.g. known commercially available ones
  • disorders/conditions that the combinations of the invention may be useful in treating hence include cancers (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.
  • cancers such as lymphomas, solid tumours or a cancer as described hereinafter
  • obstructive airways diseases such as lymphomas, solid tumours or a cancer as described hereinafter
  • allergic diseases such as asthma, allergy and Chrohn's disease
  • immunosuppression such as transplantation rejection and autoimmune diseases
  • disorders commonly connected with organ transplantation such as asthma, allergy and Chrohn's disease
  • 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
  • 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 combinations of the invention may be useful in the treatment of cancer. More, specifically, the combinations of the invention may therefore be useful in the treatment of a variety of cancers 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, gallbladder, 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
  • combinations of the invention may treat the following cancers/tumours: breast, colon, lung, melanoma, pancreas, ovarian, gyoblastoma, leukemia (AML), mantle cell lymphoma and/or prostate.
  • 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, combinations of the invention may also be useful in the treatment of viral conditions, parasitic conditions, as well as neurodegenerative disorders. Combinations of the invention are indicated both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions.
  • 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) 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 combination of the invention, as hereinbefore defined, to a patient suffering from, or susceptible to, such a condition.
  • a disease e.g. cancer or another disease as mentioned herein
  • PI3K protein or lipid kinase
  • PI3K protein or lipid kinase
  • PI3K protein or lipid kinase
  • PI3K protein or lipid kinase
  • PI3K protein or lipid kinas
  • Patients include mammalian (including human) patients.
  • 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 or combination (of the invention), 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).
  • Combinations 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.
  • Combinations 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 combination 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 ingredients are present in at least 1% (or at least 10%, at least 30% or at least 50%) by weight. That is, the ratio of active ingredients (either individually or combined) 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 each component of the combination 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 compounds which 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 (i.e. component (A) defined herein), as hereinbefore defined, or a pharmaceutically acceptable ester, amide, solvate or salt thereof, and component (B) as defined herein (i.e. when it represents one or more other therapeutic/chemotherapeutic agent), with a pharmaceutically- acceptable adjuvant, diluent or carrier.
  • a compound of the invention i.e. component (A) defined herein
  • component (B) as defined herein (i.e. when it represents one or more other therapeutic/chemotherapeutic agent
  • the invention further provides a process for the preparation of a combination product as hereinbefore defined, which process comprises bringing into association one or more (e.g. one) compound of the invention, as hereinbefore defined (by component (A) of the combinations of the invention), or a pharmaceutically acceptable ester, amide, solvate or salt thereof with the other therapeutic/chemotherapeutic agent(s) defined by component (B) of the combinations of the invention, and at least one pharmaceutically-acceptable adjuvant, diluent or carrier.
  • one or more (e.g. one) compound of the invention as hereinbefore defined (by component (A) of the combinations of the invention), or a pharmaceutically acceptable ester, amide, solvate or salt thereof with the other therapeutic/chemotherapeutic agent(s) defined by component (B) of the combinations of the invention, and at least one pharmaceutically-acceptable adjuvant, diluent or carrier.
  • compounds of the invention may be combined with a therapeutic/chemotherapeutic agent (component (B)).
  • component (B) i.e. the therapeutic/chemotherapeutic agent
  • a "chemotherapeutic agent” may be defined as a biological (large molecule) or chemical (small molecule) compound useful in the treatment of cancer, regardless of mechanism of action.
  • Classes of chemotherapeutic agents include, but are not limited to: alkylating agents, antimetabolites, spindle poison plant alkaloids, cytotoxic/antitumor antibiotics, topoisomerase inhibitors, proteins, antibodies, photosensitizers, and kinase inhibitors.
  • Chemotherapeutic agents include compounds used in "targeted therapy” and non-targeted, conventional chemotherapy.
  • chemotherapeutic agents include those mentioned herein and in e.g. WO 2010/105008, for instance: dexamethasone, thioTEPA, doxorubicin, vincristine, rituximab, cyclophosphamide, prednisone, melphalan, Ienalidomide, bortezomib, rapamycin, and cytarabine.
  • chemotherapeutic agents also include: erlotinib (TARCEVA®, Genentech/OSI Pharm.), docetaxel (TAXOTERE®, Sanofi-Aventis), 5-FU (fluorouracil, 5-fluorouracil, CAS No. 51-21-8), gemcitabine (GEMZAR®, Lilly), PD-0325901 (CAS No. 391210-10-9, Pfizer), cisplatin (cis-diamine, dichloroplatinum(ll), CAS No. 15663-27-1), carboplatin (CAS No.
  • paclitaxel TAXOL®, Bristol-Myers Squibb Oncology
  • temozolomide 4-methyl-5- oxo-2,3,4,6,8-pentazabicyclo [4.3.0]nona-2,7,9-triene-9-carboxamide, CAS No.
  • tamoxifen (Z)-2-[4- (1,2-diphenylbut-1-enyl)phenoxy]-N,N-dimethyl-ethanamine, NOLVADEX®, ISTUBAL®, VALODEX®), doxorubicin (ADRIAMYCIN®), Akti-1/2, HPPD, rapamycin, and lapatinib (TYKERB®, Glaxo SmithKline).
  • chemotherapeutic agents include: oxaliplatin (ELOXATIN®, Sanofi), bortezomib (VELCADE®, Millennium Pharm.), sutent (SUNITINIB®, SU11248, Pfizer), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), XL-518 (MEK inhibitor, Exelixis, WO 2007/044515), A R R Y - 8 86 (MEK inhibitor, AZD6244, Array BioPharma, Astra Zeneca), SF- 1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235 (PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis), ABT-869 (multi-targeted inhibitor of VEGF and PDGF family receptor tyrosine kinases, Abbott Laboratories and Genentech), ABT-263 (Bc1-2/
  • chemotherapeutic agent also included in the definition of "chemotherapeutic agent” are: (i) antihormonal agents that act to regulate or inhibit hormone action on tumors such as anti- estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA® (
  • chemotherapeutic agent therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen personal), pertuzumab (OMNITARGTM, rhuMab 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).
  • therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), r
  • Humanised monoclonal antibodies with therapeutic potential as chemotherapeutic agents in combination with the PI3K inhibitors of the invention include: alemtuzumab, apolizumab, aselizumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motoviz
  • 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:
  • 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 combination 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.
  • Combinations 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). For instance they may be more efficacious than the individual components of the combination (e.g. the components of the combination may act in synergy).
  • Combinations 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 e.g. compounds defined by component (A) hereinbefore
  • may act in synergy with the other therapies/therapeutic agent(s) e.g. compounds/therapies defined by component (B) hereinbefore).
  • synergistic effects may be measured using known techniques/methods such as those described herein, e.g. using the Chou and Talalay method. Such effects may also be measured in vivo, using xenograft studies, effects in delaying tumour growth, cell kill studies, etc. Synergistic effects in vitro are a reasonable prediction of synergy in vivo.
  • PI3K activity assay 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 ⁇ (i.e. certain compounds of the examples/invention had PI3K binding activity IC 50 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 4 below). PI3K activity assay
  • 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 ( ⁇ 110 ⁇ / ⁇ 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.
  • 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), HCT116 (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 4nM LMB were considered as hits.
  • 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 Na 3 V0 4 , 100 mM NaF, 20 mM Na 4 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 0 ⁇ .
  • 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 , 1mM EGTA, and 2.5 mM DTT, the mTOR-mediated phosphorylation of 200 nM GFP-4E-BP1 was measured under initial rate conditions.
  • An additional exemplary in vitro cell proliferation assay includes the following steps:
  • Control wells were prepared containing medium without cells
  • the compound was added to the experimental wells and incubated for 3 days.
  • the individual measured EC 50 values against the particular cell of the exemplary compounds and of the chemotherapeutic agent are compared to the combination EC 50 value.
  • the combination Index (CI) score is calculated by the Chou and Talalay method (CalcuSyn software, Biosoft). A CI less 0.8 indicates synergy. A CI between 0.8 and 1.2 indicates additivity. A CI greater than 1.2 indicates antagonism.
  • the intermediate compounds of Table 1 were prepared according to the procedures A-1 , A-2 and A-3 described hereinafter.
  • the intermediate compounds of Table 2 were prepared according to the procedures A-4 to A-28 described hereinafter.
  • the final examples of compounds of the invention were prepared according to the procedures B-1 to B-26 (and A-13) described hereinafter.
  • Procedures of methods A and B are described in more detail in the the experimental hereinafter. If an experimental procedure is not specifically described, the synthesis is performed in accordance with the methods described herein, optionally with reference to procedures known to the skilled person.
  • a procedure to prepare a final compound may or may not be accompanied by characterising data for that final compound.
  • Benzotriazole (0.7 g, 5.9 mmol) and 1-methylpiperazine (0.660 mL, 5.9 mmol) were stirred in ethanol (20 mL) at rt for 10 min.
  • Glyoxal (0.360 mL of 40% aqueous solution, 2.9 mmol) was added to the reaction mixture, and the stirring was continued for 16 h.
  • the light yellow solution was concentrated under vacuum and precipitated. A light yellow-crystal solid appeared when the resulted oil was washed with diethyl ether to yield a 1.6 g of a solid which was used in next reaction step without further purification.
  • reaction mixture was cooled to rt, KOH (156 mg podwer) was added and the resulted mixture was stirred at rt for 1 h.
  • the reaction mixture was filtered off and the filtrate was concentred under vacumn to yield a residue which was purified by flash column chromatography (eluting with a gradient of DCM/MeOH/NH 3 7N (from 100% to 95:5), to yield desired final product 2-41 (50 mg, Y: 12.3 %).
  • the HPLC measurement was performed using a HP 1100 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 RP-C18 Gemini column (150 x 4.6 mm, 5 urn); 10 min. linear gradient of 50- 100% acetonitrile in water + 100 % acetonitrile in water 2 min ): 210 nm and 254 or DAD.
  • Reversed phase HPLC was carried out on a Gemini-NX C18 (100 x 2.0 mm; 5um), 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.

Abstract

L'invention concerne des combinaisons comprenant (A) un composé de formule I, dans laquelle R1, R2, R3, R4 et R5 ont la signification donnée dans le descriptif, et des esters, des amides, des solvates ou des sels de ceux-ci pharmaceutiquement acceptables, et un ou plusieurs agents/traitements thérapeutiques dont on connaît l'utilité dans le traitement de maladies telles que le cancer ou une maladie proliférative, ces combinaisons étant utilisées dans le traitement de maladies dans lesquelles l'inhibition d'une protéine ou d'une lipide kinase (par exemple PI3-K et/ou mTOR) est recherchée et/ou requise, en particulier dans le traitement de cancer ou de maladie proliférative.
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