WO2012052745A1 - Combinations of pi3k inhibitors with a second anti -tumor agent - Google Patents

Combinations of pi3k inhibitors with a second anti -tumor agent Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
alkyl
substituents selected
ring
groups
Prior art date
Application number
PCT/GB2011/051998
Other languages
French (fr)
Inventor
Joaquín PASTOR FERNÁNDEZ
Sonia MARTÍNEZ GONZÁLEZ
Julen Oyarzabal Santamarina
Original Assignee
Centro Nacional De Investigaciones Oncológicas (Cnio)
Snodin, Michael D.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Centro Nacional De Investigaciones Oncológicas (Cnio), Snodin, Michael D. filed Critical Centro Nacional De Investigaciones Oncológicas (Cnio)
Publication of WO2012052745A1 publication Critical patent/WO2012052745A1/en

Links

Classifications

    • 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

There is provided combinations comprising (A) a compound of formula (I), wherein R1, R2, R3, R4 and R5 have meanings given in the description, and pharmaceutically-acceptable esters, amides, solvates or salts thereof, together with (B) one or more therapeutics agents/treatments known to be useful in the treatment of diseases such as cancer or a proliferative disease, which combinations are useful in the treatment of diseases in which inhibition of a protein or lipid kinase (e.g. a PI3-K and/or mTOR) is desired and/or required, and particularly in the treatment of cancer or a proliferative disease.

Description

COMBINATIONS OF PI3K INHIBITORS WITH A SECOND ANTI -TUMOR AGENT
Field of the Invention
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 3ΌΗ 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.
Background of the Invention The malfunctioning of protein kinases (PKs) is the hallmark of numerous diseases. A large share of the oncogenes and proto-oncogenes involved in human cancers code for PKs. The enhanced activities of PKs are also implicated in many non-malignant diseases, such as benign prostate hyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis. PKs are also implicated in inflammatory conditions and in the multiplication of viruses and parasites. PKs may also play a major role in the pathogenesis and development of neurodegenerative disorders.
For a general reference to PKs malfunctioning or disregulation see, for instance, Current Opinion in Chemical Biology 1999, 3, 459 - 465.
Phosphatidylinositol 3-kinases (PI3Ks) are a family of lipid and serine/threonine kinases that catalyze the phosphorylation of the membrane lipid phosphatidylinositol (PI) on the 3'-OH of the inositol ring to produce phosphoinositol-3-phosphate (PIP), phosphoinositol-3,4-diphosphate (PIP2) and phosphoinositol-3,4,5-triphosphate (PIP3), which act as recruitment sites for various intracellular signalling proteins, which in turn form signalling complexes to relay extracellular signals to the cytoplasmic face of the plasma membrane. These 3'-phosphoinositide subtypes function as second messengers in intracellular signal transduction pathways (see e.g. Trends Biochem. Sci 22 87,267-72 (1997) by Vanhaesebroeck er a/.; Chem. Rev. 101 (8), 2365-80 (2001) by Leslie et al (2001); Annu. Rev. Cell. Dev. Boil. 17, 615-75 (2001) by Katso er a/; and Cell. Mol. Life Sci. 59 (5), 761-79 (2002) by Toker et al).
Multiple PI3K isoforms categorized by their catalytic subunits, their regulation by corresponding regulatory subunits, expression patterns and signalling specific funtions (p110ot, β, δ, γ) perform this enzymatic reaction (Exp. Cell. Res. 25 (1), 239-54 (1999) by Vanhaesebroeck and Katso et al., 2001, above).
The closely related isoforms p110a and β are ubiquitously expressed, while δ and γ are more specifically expressed in the haematopoietic cell system, smooth muscle cells, myocytes and endothelial cells (see e.g. Trends Biochem. Sci. 22 (7), 267-72 (1997) by Vanhaesebroeck et al). Their expression might also be regulated in an inducible manner depending on the cellular, tissue type and stimuli as well as disease context. Inductibility of protein expression includes synthesis of protein as well as protein stabilization that is in part regulated by association with regulatory subunits.
Eight mammalian PI3Ks have been identified so far, including four class I PI3Ks. Class la includes ΡΙ3Κα, ΡΙ3Κβ and ΡΙ3Κδ. All of the class la enzymes are heterodimeric complexes comprising a catalytic subunit (ρ110α, ρ110β or ρ110δ) associated with an SH2 domain containing p85 adapter subunit. Class la PI3Ks are activated through tyrosine kinase signalling and are involved in cell proliferation and survival. PI3Ka and ΡΙ3Κβ have also been implicated in tumorigenesis in a variety of human cancers. Thus, pharmacological inhibitors of PI3Ka and ΡΙ3Κβ are useful for treating various types of cancer. ΡΙ3Κγ, the only member of the Class lb PI3Ks, consists of a catalytic subunit ρ110γ, which is associated with a p110 regulatory subunit. ΡΙ3Κγ is regulated by G protein coupled receptors (GPCRs) via association with βγ subunits of heterotrimeric G proteins. ΡΙ3Κγ is expressed primarily in hematopoietic cells and cardiomyocytes and is involved in inflammation and mast cell function. Thus, pharmacological inhibitors of ΡΙ3Κγ are useful for treating a variety of inflammatory diseases, allergies and cardiovascular diseases.
These observations show that deregulation of phosphoinositol-3-kinase and the upstream and downstream components of this signalling pathway is one of the most common deregulations associated with human cancers and proliferative diseases (see e.g. Parsons et al., Nature 436:792 (2005); Hennessey et al., Nature Rev. Drug Discovery 4: 988-1004 (2005). The mammalian target of rapamycin (mTOR) also known as F 506 binding protein 12-rapamycin associated protein 1 (FRAP1) is a protein which in humans is encoded by the FRAP1 gene. mTOR is a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription. The inhibition of mTORs are believed to be useful for treating various diseases/conditions, such as cancer (for example, as described in Easton et al. (2006). "mTOR and cancer therapy". Oncogene 25 (48): 6436-46).
The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.
International patent applications WO 99/64401 and WO 02/10140 both disclose compounds that may be useful as agonists or antagonists of somatostatin receptors. These documents do not predominantly relate to imidazopyrazines.
International patent applications WO 2007/028051 and WO 2008/156614 disclose inter alia imidazopyrazines that may be useful as kinase inhibitors. International patent application WO 2009/007029 discloses various compounds that may be useful in the treatment of haematological diseases. However, none of these documents predominantly relate to imidazopyrazines that are substituted at the 8-position with a cyclic group.
International patent applications WO 2004/072080 and WO 2004/072081 both disclose various imidazopyrazines, which may be useful as modulators of HSP90 complex or as modulators of a certain protein kinase. International patent application WO 02/060492 also discloses various imidazopyrazines, which may be useful as inhibitors of a certain protein kinase (JAK kinases). However, all of these documents predominantly relate to imidazopyrazines that are unsubstituted at the 2-, 3- and 5-position.
International patent application WO 2004/022562 discloses various imidazopyrazines that may be useful as modulators of kinase activity. However, this document predominantly relates to imidazopyrazines that are substituted at the 8-position with an amino group containing an aromatic ring and/or imidazopyrazines that are unsubstituted at the 2-, 3-, and 4-position.
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.
Disclosure of the Invention
According to the invention, there is provided a combination of:
(A) one or more (e.g. one) compound(s) of formula I,
Figure imgf000006_0001
wherein:
R represents:
(a) -N(R a)R1b,
in which R1a 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
(b) a heterocycloalkyl (e.g. a 3- to 7-membered) group (attached to the requisite imidazopyrazine via a carbon atom), optionally substituted by one or more substituents selected from =0 and B2;
(c) a monocyclic heteroaryl group optionally substituted by one or more substituents selected from B3;
R2 and R3 independently represent:
(i) hydrogen;
(ii) Q1;
(iii) C1-12 alkyl optionally substituted by one or more substituents selected from =0, =S, =N(R10a) and Q2; or R2 or R3 may represent a fragment of formula IA,
Figure imgf000006_0002
m represents 0, 1 , 2, 3, 4, 5 or 6; each R15 represents hydrogen, halo (e.g. fluoro) or C1-6 alkyl optionally substituted by one or more substituents selected from E1; or
the two R15 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 E2;
Ra and Rb 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(RX)2)P- and/or -(C(Rx)2)r-0-(C(Rx)2)s- (wherein p is 1 or 2; r is 0 or 1 ; s is 0 or 1 ; and each Rx independently represents hydrogen or C1-6 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. forming a spiro-cycle), all of which cyclic groups, defined by the linkage of Ra and Rb, are optionally substituted by one or more substituents selected from =0 and E3; R4 represents hydrogen or a substituent selected from halo, -CN, -OR10b, -N(R 0b)R1 b, -C(O)N(R10b)R11b, -C(O)R10b, C1-6 alkyl and heterocycloalkyl (e.g. a 3- to 7-membered heterocycloalkyl), which latter two groups are optionally substituted by one or more substituents selected from E4 and =0; but wherein at least one of R2, R3 and R4 represents a substituent other than hydrogen; R5 represents aryl or heteroaryl (both of which are optionally substituted by one or more substituents selected from E5); each Q1 and Q2 independently represents, on each occasion when used herein: halo, -CN, -N02, -N(R10a)R1 a, -OR10a, -C(=Y)-R 0a, -C(=Y)-OR 0a, -C(=Y)N(R10a)R1 a, -OC(=Y)-R10a, -OC(=Y)-OR10a, -OC(=Y)N(R10a)R a, -OS(O)2OR10a, -OP(=Y)(OR 0a)(OR11a), -OP(OR10a)(OR 1a), -N(R12a)C(=Y)R11a, -N(R a)C(=Y)OR11a, -N(R12a)C(=Y)N(R 0a)R11a, -NR12aS(O)2R10a,
-NR 2aS(O)2N(R 0a)R11a, -S(O)2N(R 0a)R1 a, -SC(=Y)R10a, -S(O)2R10a, -SR10a, -S(O)R10a, C -12 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0, =S, =N(R10a) and E6), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E7); each B1, B2 and B3 independently represent halo, -N02, -CN, -N(R10a)R11a, -OR10a, -C(=Y)-R10a, -C(=Y)-OR 0a, -C(=Y)N(R10a)R11a, -N(R12a)C(=Y)R11a, -N(R12a)C(=Y)OR1 a, -N(R 2a)C(=Y)N(R 0a)R1 a, -NR12aS(O)2R10a,
-NR12aS(O)2N(R 0a)R a, -S(O)2N(R10a)R1 a, -SC(=Y)R 0a, -SC(=Y)OR10a, -S(O)2R 0a, C1- 2 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0 and E8), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E9); or, any two B1 substituents, when attached to the same carbon atom (thereby forming a spiro-cycle), may be linked together to form, a 3- to 12- membered (e.g. 3- to 6-membered) ring, optionally containing one or more (e.g. one to three) heteroatoms (preferably selected from sulfur, oxygen and nitrogen), which ring optionally contains one or more (e.g. one to three) double bonds, and which ring is itself optionally substituted by one or more substituents selected from halo, =0 and C1-3 alkyl optionally substituted by one or more fluoro atoms; each R10a, R11a, R12a, R10b, R1 b and R12b independently represent, on each occasion when used herein, hydrogen, C - 2 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0, =S, =N(R20) and E10), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E 1); or any relevant pair of R10a, R1 a and R12a (for example, when attached to the same atom, adjacent atom (i.e. 1,2-relationship) or to atoms that are two atom atoms apart, i.e. in a 1 ,3-relationship) and/or any pair of R10b and R1 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. (a) heteroatom(s) selected from oxygen, nitrogen and sulfur), optionally containing one or more unsaturations (preferably, double bonds), and which ring is optionally substituted by one or more substituents selected from =0, =S, =N(R20) and E 2; each E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11 and E12 independently represents, on each occasion when used herein:
(i) Q4;
(ii) d.i2 alkyl optionally substituted by one or more substituents selected from =0 and Q5; or any two E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11 or E12 groups, for example on C1-12 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. one to three) unsaturations (preferably, double bonds), and which ring is optionally substituted by one or more substituents selected from =0 and J1; each Q4 and Q5 independently represent, on each occasion when used herein: halo, -CN, -N02> -N(R20)R21, -OR20, -C(=Y)-R20, -C(=Y)-OR20, -C(=Y)N(R20)R21, -OC(=Y)-R20, -OC(=Y)-OR20, -OC(=Y)N(R20)R21, -OS(0)2OR20, -OP(=Y)(OR 0)(OR21), -OP(OR20)(OR21), -N(R22)C(=Y)R21, -N(R )C(=Y)OR21, -N(R22)C(=Y)N(R20)R21, -NR22S(0)2R20, -NR22S(O)2N(R20)R21, -S(O)2N(R20)R21, -SC(=Y)R20, -S(0)2R20, -SR20, -S(0)R20, C1-6 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0 and J2), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from J3); each Y independently represents, on each occasion when used herein, =0, =S, =NR23 or =N-CN; each R20, R2 , R22 and R23 independently represent, on each occasion when used herein, hydrogen, C1-6 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from J4 and =0), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from J5); or any relevant pair of R20, R21 and R22, may (for example, when attached to the same atom, adjacent atom (i.e. 1 ,2-relationship) or to atoms that are two atom atoms apart, i.e. in a 1 ,3-relationship) be linked together to form (e.g. along with the requisite nitrogen atom to which they may be attached) a 4- to 20- (e.g. 4- to 12-) membered ring, optionally containing one or more heteroatoms (for example, in addition to those that may already be present, e.g. (a) heteroatom(s) selected from oxygen, nitrogen and sulfur), optionally containing one or more unsaturations (preferably, double bonds), and which ring is optionally substituted by one or more substituents selected from J6 and =0; each J1, J2, J3, J4, J5 and J6 independently represents, on each occasion when used herein:
(i) Q7;
(ii) C1-6 alkyl or heterocycloalkyl, both of which are optionally substituted by one or more substituents selected from =0 and Q8; each Q7 and Q8 independently represents, on each occasion when used herein: -CN or, preferably, halo, -N(R50)R51, -OR50, -C(=Ya)-R50, -C(=Ya)-OR50, -C(=Ya)N(R50)R51, -N(R52)C(=Ya)R51, -NR52S(0)2R50, -S(0)2R50, -SR50, -S(0)R50 or C -6 alkyl optionally substituted by one or more fluoro atoms; each Ya independently represents, on each occasion when used herein, =0, =S, =NR53 or =N-CN; each R50, R51, R52 and R53 independently represents, on each occasion when used herein, hydrogen or C1-6 alkyl optionally substituted by one or more substituents selected from fluoro, -OR60 and -N(R6 )R62; or
any relevant pair of R50, R51 and R52 may (for example when attached to the same or adjacent atoms) be linked together to form, a 3- to 8-membered ring, optionally containing one or more heteroatoms (for example, in addition to those that may already be present, heteroatoms selected from oxygen, nitrogen and sulfur), optionally containing one or more unsaturations (preferably, double bonds), and which ring is optionally substituted by one or more substituents selected from =0 and C1-3 alkyl; R60, R6 and R62 independently represent hydrogen or C1-6 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
(B) one or more (e.g. one) other therapeutic agent(s)/treatment(s) that is/are inhibitors of protein or lipid kinases and/or useful in the treatment of a cancer and/or a proliferative disease, which combinations are referred to hereinafter as "the combinations of the invention" (and wherein the component (B) may be referred to herein as "component (B) (of combinations of the invention)"). As stated above, 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.
For instance, compounds of the invention (i.e. component (A) of the combinations 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.
More specifically, 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).
The other therapeutic treatment(s)/agent(s) (i.e. component (B)) are preferably therapeutic agents and may be selected from other PI3-K (or Akt) or mTOR inhibitors, but are preferably selected from:
(i) targeted kinase inhibitors;
(ii) receptor tyrosine kinase (RTK) inhibitors;
(iii) PIM family kinase inhibitors (e.g. a PIM-1, PIM-2 and/or PIM-3 inhibitor); (iv) Flt-3 inhibitors;
(v) EGFR or HER2 inhibitors;
(vi) therapeutic monoclonal antibodies;
(vii) MEK inhibitors;
(vii) BRaf inhibitors;
(viii) anthracyclins;
(ix) taxanes;
(x) platins;
(xi) nucleotide analogs;
(xii) alkylating agents;
(xiii) hormone therapeutic agents; (xiv) anti-tumour compounds that have potential radiosensitising and/or chemosensitising effects;
(xv) JAK inhibitors; and/or
(xvi) 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:
(a) specific (e.g. one) mTOR inhibitor(s), such as rapamycin; and/or
(b) specific (e.g. one) Akt or PI3-K inhibitor(s), such as GDC-0941.
More preferred therapeutic agents that 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):
(i) specific targeted kinase inhibitors;
(ii) specific receptor tyrosine kinase (RTK) inhibitors;
(iii) specific PIM family kinase inhibitors (e.g. PIM-1 inhibitor PIM-1, PIM-2 and/or PIM-3), such as SGI-1776;
(iv) specific Flt-3 inhibitors;
(v) specific EGFR or HER2 inhibitors, such as lapatanib;
(vi) specific therapeutic monoclonal antibodies, such as the HER2 inhibitor trastuzumab;
(vii) specific MEK inhibitors, such as PD-0325901 ;
(vii) specific BRaf inhibitors, such as GDC-0879;
(viii) specific anthracyclins, such as doxorubicin;
(ix) specific taxanes, such as paclitaxel or, particularly, docetaxel;
(x) specific platins, such as carboplatin or, particularly, cisplatin;
(xi) specific nucleotide analogs, such as 5-fluorouracil (5-FU) or gemcitabine; (xii) specific alkylating agents, such as temozolomide;
(xiii) specific hormone therapeutic agents, such as an estrogen receptor antagonist e.g. tamoxifen;
(xiv) specific anti-tumour compounds that have potential radiosensitising and/or chemosensitising effects, such as chloroquine;
(xv) specific JAK inhibitors; and/or
(xvi) specific 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- B.
Hence, component (B) may be any one of (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x), (xi), (xii), (xiii), (xiv), (xv) or (xvi). Further component (B) may be any one of the specific therapeutic agents defined by any one of (i) to (xvi). For instance, 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. PD-0325901), 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) and/or 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.
For the avoidance of doubt:
(A) the compound SGI-1776 (which is commercially available e.g. from Active Biochem) represents:
Figure imgf000015_0001
(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. 4:553-565) and is named as (2R,3S)-N-carboxy-3- phenylisoserine, N-tert-butyl ester, 13-ester with 5, 20-epoxy-1 , 2, 4, 7, 10, 13- hexahydroxytax-11-en-9-one 4-acetate 2-benzoate, trihydrate (US 4814470; EP 253738; CAS Reg. No. 114977-28-5) (or named as 1 ^,10p-trihydroxy-9-oxo- 5β,20-βροχνί3Χ-11-βηβ-2α,4,13α-ί^Ι 4-acetate 2-benzoate 13-{(2R,3S)-3-[(terf- butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoate}) is represented by the following structure:
Figure imgf000015_0002
(C) lapatinib (TYKERB®, GW572016, Glaxo SmithKline), which has been approved for use in combination with capecitabine (XELODA®, Roche) for the treatment of patients with advanced or metastatic breast cancer whose tumors over-express HER2 (ErbB2) and who have received prior therapy including an anthracycline, a taxane and trastuzumab, and is an ATP-competitive epidermal growth factor (EGFR) and HER2/neu (ErbB-2) dual tyrosine kinase inhibitor (US 6727256; US 6713485; US 7109333; US 6933299; US 7084147; US 7157466; US 7141576) which inhibits receptor autophosphorylation and activation by binding to the ATPbinding pocket of the EGFRIHER2 protein kinase domain, is named as N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-(5-((2-(methylsulfonyl)- ethylamino)-methyl)furan-2-yl)quinazolin-4-amine (or alternatively named as Λ/-[3- chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[(2-methylsulfonylethylarnino)- methyl]-2-furyl] quinazolin-4-amine), and has the structure:
Figure imgf000016_0001
(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:
Figure imgf000016_0002
Pharmaceutically-acceptable 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.
By "pharmaceutically acceptable ester, amide, solvate or salt thereof, we include salts of pharmaceutically acceptable esters or amides, and solvates of pharmaceutically acceptable esters, amides or salts. For instance, pharmaceutically acceptable esters and amides such as those defined herein may be mentioned, as well as pharmaceutically acceptable solvates or salts.
Pharmaceutically acceptable esters and amides of the compounds of the invention are also included within the scope of the invention. Pharmaceutically acceptable esters and amides of compounds of the invention may be formed from corresponding compounds that have an appropriate group, for example an acid group, converted to the appropriate ester or amide. For example, pharmaceutically acceptable esters (of carboxylic acids of compounds of the invention) that may be mentioned include optionally substituted C1-6 alkyl, C5-10 aryl and/or C5.10 aryl-d-e alkyl- esters. Pharmaceutically acceptable amides (of carboxylic acids of compounds of the invention) that may be mentioned include those of the formula -C C^R^R22, in which Rz1 and Rz2 independently represent optionally substituted C1-6 alkyl, C5-10 aryl, or C5-io aryl-C^e alkylene-. Preferably, 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.
Further compounds of the invention that may be mentioned include carbamate, carboxamido or ureido derivatives, e.g. such derivatives of existing amino functional groups.
For the purposes of this invention, therefore, prodrugs of compounds of the invention are also included within the scope of the invention.
The term "prodrug" of a relevant compound of the invention includes any compound that, following oral or parenteral administration, is metabolised in vivo to form that compound in an experimentally-detectable amount, and within a predetermined time (e.g. within a dosing interval of between 6 and 24 hours (i.e. once to four times daily)). For the avoidance of doubt, the term "parenteral" administration includes all forms of administration other than oral administration.
Prodrugs of compounds of the invention may be prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, in vivo when such prodrug is administered to a mammalian subject. The modifications typically are achieved by synthesising the parent compound with a prodrug substituent. Prodrugs include compounds of the invention wherein a hydroxyl, amino, sulfhydryl, carboxy or carbonyl group in a compound of the invention is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxy or carbonyl group, respectively.
Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, esters groups of carboxyl functional groups, N-acyl derivatives and N-Mannich bases. General information on prodrugs may be found e.g. in Bundegaard, H. "Design of Prodrugs" p. 1-92, Elesevier, New York-Oxford (1985).
Compounds of the invention may contain double bonds and may thus exist as £ (entgegen) and Z (zusammen) geometric isomers about each individual double bond. Positional isomers may also be embraced by the compounds of the invention. All such isomers (e.g. if a compound of the invention incorporates a double bond or a fused ring, the cis- and trans- forms, are embraced) and mixtures thereof are included within the scope of the invention (e.g. single positional isomers and mixtures of positional isomers may be included within the scope of the invention).
Compounds of the invention may also exhibit tautomerism. All tautomeric forms (or tautomers) and mixtures thereof are included within the scope of the invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerisations. Valence tautomers include interconversions by reorganisation of some of the bonding electrons.
Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a 'chiral pool' method), by reaction of the appropriate starting material with a 'chiral auxiliary' which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person.
All stereoisomers (including but not limited to diastereoisomers, enantiomers and atropisomers) and mixtures thereof (e.g. racemic mixtures) are included within the scope of the invention.
In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined.
The compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
The present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2H, 3H, 11C, 13C, 4C , 13N, 150, 170, 180, 32P, 33P, 35S, 8F, 36CI, 123l, and 25I. Certain isotopically-labeled compounds of the present invention (e.g., those labeled with 3H and 14C) are useful in compound and for substrate tissue distribution assays. Tritiated (3H) and carbon-14 ( 4C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron emitting isotopes such as 150, 13N, 1C and 18F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Scheme 1 and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non- isotopically labeled reagent.
Unless otherwise specified, C1-q alkyl groups (where q is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two or three, as appropriate) of carbon atoms, be branched- chain, and/or cyclic (so forming a C3.q-cycloalkyl group). Such cycloalkyl groups may be monocyclic or bicyclic and may further be bridged. Further, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic. Such alkyl groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated (forming, for example, a C2.q alkenyl or a C2.q alkynyl group).
Unless otherwise stated, the term 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 C1-q alkylene groups may not be branched.
C3.q cycloalkyl groups (where q is the upper limit of the range) that may be specifically mentioned may be monocyclic or bicyclic alkyl groups, which cycloalkyl groups may further be bridged (so forming, for example, fused ring systems such as three fused cycloalkyl groups). Such cycloalkyl groups may be saturated or unsaturated containing one or more double bonds (forming for example a cycloalkenyl group). Substituents may be attached at any point on the cycloalkyl group. Further, where there is a sufficient number (i.e. a minimum of four) such cycloalkyl groups may also be part cyclic.
The term "halo", when used herein, preferably includes fluoro, chloro, bromo and iodo.
Heterocycloalkyl groups that may be mentioned include non-aromatic monocyclic and bicyclic heterocycloalkyl groups in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom), and in which the total number of atoms in the ring system is between 3 and 20 (e.g. between three and ten, e.g between 3 and 8, such as 5- to 8-). Such heterocycloalkyl groups may also be bridged. Further, such heterocycloalkyl groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C2.q heterocycloalkenyl (where q is the upper limit of the range) group. C2-q heterocycloalkyl groups that may be mentioned include 7- azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.1.1]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), imidazolidinyl, imidazolinyl, morpholinyl, 7-oxabicyclo[2.2.1]heptanyl, 6- oxabicyclo-[3.2.1]octanyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3- sulfolenyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridyl (such as 1 ,2,3,4-tetrahydropyridyl and 1 ,2,3,6-tetrahydropyridyl), thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including 1 ,3,5-trithianyl), tropanyl and the like. Substituents on heterocycloalkyl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of heterocycloalkyl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heterocycloalkyl groups may also be in the N- or S- oxidised form. HeterocycloalkyI mentioned herein may be stated to be specifically monocyclic or bicyclic.
For the avoidance of doubt, the term "bicyclic" (e.g. when employed in the context of heterocycloalkyi groups) refers to groups in which the second ring of a two-ring system is formed between two adjacent atoms of the first ring. The term "bridged" (e.g. when employed in the context of cycloalkyl or 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 C6_2o, such as C6- 2 (e.g. C6- 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.
Unless otherwise specified, the term "heteroaryl" when used herein refers to an aromatic group containing one or more heteroatom(s) (e.g. one to four heteroatoms) preferably selected from N, O and S. Heteroaryl groups include those which have between 5 and 20 members (e.g. between 5 and 10) and may be monocyclic, bicyclic or tricyclic, provided that at least one of the rings is aromatic (so forming, for example, a mono-, bi-, or tricyclic heteroaromatic group). When the heteroaryl group is polycyclic the point of attachment may be via atom including an atom of a non-aromatic ring. However, when 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, imidazo[1 ,2-a]pyridyl, indazolyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiaziolyl, isothiochromanyl, isoxazolyl, naphthyridinyl (including 1 ,6-naphthyridinyl or, preferably, 1 ,5-naphthyridinyl and 1 ,8-naphthyridinyl), oxadiazolyl (including
1.2.3- oxadiazolyl, 1 ,2,4-oxadiazolyl and 1 ,3,4-oxadiazolyl), oxazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl (including 1 ,2,3,4-tetrahydroisoquinolinyI and 5,6,7,8-tetrahydroisoquinoIinyl), tetrahydroquinolinyl (including 1 ,2,3,4- tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl), tetrazolyl, thiadiazolyl (including 1 ,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl and 1 ,3,4-thiadiazolyl), thiazolyl, thiochromanyl, thiophenetyl, thienyl, triazolyl (including 1 ,2,3-triazolyl,
1.2.4- triazolyl and 1 ,3,4-triazolyl) and the like. Substituents on heteroaryl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of heteroaryl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heteroaryl groups may also be in the N- or S- oxidised form. Heteroaryl groups mentioned herein may be stated to be specifically monocyclic or bicyclic. When heteroaryl groups are polycyclic in which there is a non- aromatic ring present, then that non-aromatic ring may be substituted by one or more =0 group.
It may be specifically stated that the heteroaryl group is monocyclic or bicyclic. In the case where it is specified that the heteroaryl is bicyclic, then it may be consist of a five-, six- or seven-membered monocyclic ring (e.g. a monocyclic heteroaryl ring) fused with another a five-, six- or seven-membered ring (e.g. a monocyclic aryl or heteroaryl ring).
Heteroatoms that may be mentioned include phosphorus, silicon, boron and, preferably, oxygen, nitrogen and sulfur. For the avoidance of doubt, where it is stated herein that a group (e.g. a C -12 alkyl group) may be substituted by one or more substituents (e.g. selected from E6), then those substituents (e.g. defined by E6) are independent of one another. That is, such groups may be substituted with the same substituent (e.g. defined by E6) or different substituents (defined by E6).
For the avoidance of doubt, in cases in which the identity of two or more substituents in a compound of the invention may be the same, the actual identities of the respective substituents are not in any way interdependent. For example, in the situation in which there is more than one Q1 (or e.g. E6) substituent present, then those Q1 (or e.g. E6) substituents may be the same or different. Further, in the case where there are two Q1 (or two E6) substituents present, in which one represents -OR10a (or e.g. -OR20, as appropriate) and the other represents -C(O)2R 0a (or e.g. -C(0)2R20, as appropriate), then those R10a or R20 groups are not to be regarded as being interdependent. Also, when e.g. there are two -OR10a substituents present, then those -OR10a groups may be the same or different (i.e. each R 0a group may be the same or different). For the avoidance of doubt, when a term such as 'Έ1 to E12" is employed herein, this will be understood by the skilled person to mean E , E2, E3, E4, E5, E6, E7, E8, E9, E10, E 1 and E12, inclusively.
All individual features (e.g. preferred features) mentioned herein may be taken in isolation or in combination with any other feature (including preferred feature) mentioned herein (hence, preferred features may be taken in conjunction with other preferred features, or independently of them).
The skilled person will appreciate that compounds of the invention that are the subject of this invention include those that are stable. That is, compounds of the invention include those that are sufficiently robust to survive isolation from e.g. a reaction mixture to a useful degree of purity.
Compounds of the invention (i.e. component (A) of combinations of the invention) that may be mentioned include those in which: R4 represents hydrogen or a substituent selected from halo, -CN, -OR10b, -N(R10b)R11b, -C(O)N(R10b)R 1b, C1-6 alkyl and heterocycloalkyi (e.g. a 3- to 7- membered heterocycloalkyi), which latter two groups are optionally substituted by one or more substituents selected from E4 and =0.
Preferred compounds of the invention that may be mentioned include those in which:
R1 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);
R1 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; R1 preferably represents (a) or (b);
R5 does not represent phenyl or 3-pyridyl (especially phenyl) (e.g. in which the latter two groups are substituted (for example, meta to the point of attachment to the imidazopyrazine), with e.g. a urea (e.g. -N(R22)C(=Y)N(R20)R21, in which Y is preferably =0).
Further preferred compounds of the invention that may be mentioned include those in which, for example especially when R1 represents a group defined by (c) above, i.e. an optionally substituted monocyclic heteroaryl group (e.g. a 5- membered heteroaryl group such as pyrazolyl (e.g. 1 -pyrazolyl) or, especially, imidazolyl (e.g. 1-imidazolyl)) and/or R5 represents phenyl or 3-pyridyl (e.g. in which the latter two groups are substituted, for example (e.g. meta to the point of attachment to the imidazopyrazine), with e.g. a urea (e.g. -N(R 2)C(=Y)N(R20)R21, in which Y is preferably =0), then preferably:
R3 represents a substituent other than hydrogen;
when R3 represents a substituent other than hydrogen, then it is preferably Q , in which Q1 represents heterocycloalkyi (e.g. piperidinyl, which heterocycloalkyi group is attached to the imidazopyrazine via a carbon or, preferably, nitrogen atom) or Q1 more preferably represents halo, -CN, -N02, -N(R10a)R11a, -OR 0a, -C(=Y)-R10a, -C(=Y)-OR10a, -C(=Y)N(R 0a)R11a, -OC(=Y)-R10a, -OC(=Y)-OR 0a, -OC(=Y)N(R10a)R 1a, -OS(O)2OR 0a, -OP(=Y)(OR 0a)(OR 1a), -OP(OR 0a)(OR1 a), -N(R12a)C(=Y)R11a, -N(R12a)C(=Y)OR11a, -N(R 2a)C(=Y)N(R 0a)R 1a,
-NR 2aS(O)2R 0a, -NR12aS(O)2N(R10a)R11a, -S(O)2N(R10a)R 1a, -SC(=Y)R10a, -S(O)2R10a, -SR10a or -S(O)R10a (and Q preferably represents halo, -CN, -N02> -OR 0a, -C(=Y)N(R10a)R11a, -N(R12a)C(=Y)R 1a, -NR 2aS(O)2R10a, and, especially, -N(R 0a)R11a);
when R3 represents a substituent other than hydrogen, then it is preferably does not represent optionally substituted C1-12 (e.g. C^e) alkyl, heterocycloalkyl (preferably linked to the imidazopyrazine via a carbon atom), aryl (e.g. phenyl) or heteroaryl; and/or
at least one of R2 and R4 do not represent hydrogen, i.e. either one of R2 and R4 may represent hydrogen, and the other (or both) represent(s) a substituent as defined herein.
Further preferred compounds of the invention that may be mentioned include those in which, for example especially in the case when R1 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. 1-imidazolyl)) and/or R5 represents phenyl or 3-pyridyl (e.g. in which the latter two groups are substituted, for example, meta to the point of attachment to the imidazopyrazine, with e.g. a urea such as -N(R22)C(=Y)N(R20)R21, in which Y is preferably =0), then preferably:
B1, B2 and/or B3 (e.g. B3) do not represent or do not contain aromatic groups (such as pyridyl, e.g. 4-pyridyl);
B , B2 and/or B3 (e.g. B3) independently represent halo, -N02, -CN, -N(R10a)R 1a, -OR10a, -C(=Y)-R 0a, -C(=Y)-OR10a, -C(=Y)N(R10a)R1 a, -N(R12a)C(=Y)R a, -N(R 2a)C(=Y)OR1 a, -N(R12a)C(=Y)N(R10a)R11a, -NR12aS(O)2R 0a,
-NR12aS(O)2N(R 0a)R11a, -S(O)2N(R10a)R11a, -SC(=Y)R10a, -SC(=Y)OR 0a, -S(O)2R10a, Ci.i2 alkyl or heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0 and E8), or, two B1 substituents may be linked together as herein defined (i.e./e.g. to form a spiro- cycle);
each R10a, R11a, R12a, R10b, R11b and R 2b (for example when there is a B3 group present) independently represent, on each occasion when used herein, hydrogen, C - 2 alkyl or heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0, =S, =N(R20) and E 0); or any relevant pair of R 0a, R 1a and R 2a and/or any pair of R 0b and R1 b may be linked together as defined herein, but wherein when e.g. there are one or more E8, E10 and/or E12 groups present (which independently represent Q4 or C -12 alkyl optionally substituted by one or more substituents selected from =0 and Q5), then those Q4 and Q5 groups do not represent, or contain, aromatic rings, i.e. then: each Q4 and Q5 independently represent, on each occasion when used herein: halo, -CN, -N02, -N(R20)R21, -OR20, -C(=Y)-R20, -C(=Y)-OR20, -C(=Y)N(R20)R21, -OC(=Y)-R20, -OC(=Y)-OR20, -OC(=Y)N(R20)R21, -OS(0)2OR20, -OP(=Y)(OR20)(OR21), -OP(OR20)(OR21), -N(R22)C(=Y)R21, -N(R22)C(=Y)OR21, -N(R22)C(=Y)N(R20)R21, -NR22S(0)2R20, -NR22S(O)2N(R20)R21 , -S(O)2N(R20)R21, -SC(=Y)R20, -S(0)2R20, -SR20, -S(0)R20, C1-6 alkyl or heterocycloalkyi (which latter two groups are optionally substituted by one or more substituents selected from =0 and J2);
each R20, R21, R22 and R23 independently represent hydrogen, C -6 alkyl or heterocycloalkyi (which latter two groups are optionally substituted by one or more substituents selected from J4 and =0).
Further preferred compounds of the invention that may be mentioned include those in which (for example, when R5 represents a monocyclic aromatic group, such as phenyl or pyridyl, e.g. 3-pyridyl, e.g. in which the latter two groups are substituted, for example meta to the point of attachment to the imidazopyrazine, with e.g. a urea such as -N(R22)C(=Y)N(R20)R21, in which Y is preferably =0): R3 preferably does not represent -C(=Y)-OR 0a (particularly when, for example, R1 represents a heteroaryl group, e.g. pyridyl);
R3 preferably represents (particularly when, for example, R1 represents a heteroaryl group, e.g. pyridyl) hydrogen or, more preferably, a substituent selected from heterocycloalkyi (e.g. one that is attached to the imidazopyrazine via a nitrogen atom) or, especially, halo, -CN, -N02( -N(R10a)R1 a, -C(=Y)-R 0a, -C(=Y)N(R10a)R1 a, -OC(=Y)-R10a, -OC(=Y)-OR10a, -OC(=Y)N(R10a)R11a, -OS(O)2OR10a, -OP(=Y)(OR10a)(OR a), -OP(OR10a)(OR11a), -N(R 2a)C(=Y)R11a, -N(R12a)C(=Y)OR11a, -N(R12a)C(=Y)N(R10a)R11a, -NR12aS(O)2R 0a,
-NR12aS(O)2N(R10a)R 1a, -S(O)2N(R 0a)R1 a, -SC(=Y)R10a, -S(O)2R10a, -SR 0a and -S(O)R10a, or a fragment of formula IA as defined hereinbefore; and/or
when, for example, R1 represents a heteroaryl group (e.g. pyridyl), then R3 preferably does not represent, or contain, an aromatic group (especially when R3 represents -N(R10a)R1 a, e.g. in which R10a and R1 a are linked together to form, e.g. a piperazinyl group), i.e.:
each R10a, R 1a, R12a, R10b, R11b and R12b (for example when R1 represents a (c) group, such as pyridyl) independently represent, on each occasion when used herein, hydrogen, C1-12 alkyl or heterocycloalkyi (which latter two groups are optionally substituted by one or more substituents selected from =0, =S, =N(R20) and E10); or any relevant pair of R10a, R11a and R 2a and/or any pair of R 0b and R11b may be linked together as defined herein (and therefore be substituted by one or more E12 groups), but wherein when there are one or more E10 and/or E 2 groups present, which independently represent Q4 or C - 2 alkyl optionally substituted by one or more substituents selected from =0 and Q5, then those Q4 and Q5 groups do not represent, or contain, aromatic rings, i.e. then:
each Q4 and Q5 independently represent, on each occasion when used herein: halo, -CN, -N02, -N(R20)R21, -OR20, -C(=Y)-R20, -C(=Y)-OR20, -C(=Y)N(R20)R21, -OC(=Y)-R20, -OC(=Y)-OR20, -OC(=Y)N(R20)R21, -OS(0)2OR20, -OP(=Y)(OR20)(OR21), -OP(OR20)(OR21), -N(R 2)C(=Y)R21, -N(R22)C(=Y)OR21, -N(R22)C(=Y)N(R20)R21, -NR22S(0)2R20, -NR22S(O)2N(R20)R21, -S(O)2N(R20)R21, -SC(=Y)R20, -S(0)2R20, -SR20, -S(0)R20, C1-e alkyl or heterocycloalkyi (which latter two groups are optionally substituted by one or more substituents selected from =0 and J2);
each R20, R21, R22 and R23 independently represent hydrogen, C -6 alkyl or heterocycloalkyi (which latter two groups are optionally substituted by one or more substituents selected from J4 and =0). Further preferred compounds of the invention that may be mentioned include those in which:
an R group may not be substituted by an aromatic ring (e.g. a heteroaryl group); B1, B2 and/or B3 (e.g. B1) do not represent or do not contain aromatic (e.g. heteroaromatic) groups (especially when R represents an (a) group, i.e. -N(R1a)R1b);
B1, B2 and B3 (e.g. B1) independently represent aryl (optionally substituted by one or more substituents selected from E9) or, preferably, halo, -N02> -CN, -N(R10a)R11a, -OR10a, -C(=Y)-R 0a, -C(=Y)-OR10a, -C(=Y)N(R10a)R11a, -N(R 2a)C(=Y)R11a, -N(R12a)C(=Y)OR11a, -N(R 2a)C(=Y)N(R10a)R1 a, -NR 2aS(O)2R10a, -NR12aS(O)2N(R10a)R11a, -S(O)2N(R10a)R1 a, -SC(=Y)R10a, -SC(=Y)OR , -S(0)2R , Cm alkyl or heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0 and E8), or, two B1 substituents may be linked together (to form a spiro-cycle) as herein defined (this is especially the case when R represents an (a) group, i.e. -N(R1a)R1b);
each R10a, R11a, R 2a, R10b, R1 b and R 2b (for example when a B1 substituent is present containing such a moiety) independently represent, on each occasion when used herein, aryl (optionally substituted by one or more substituents selected from E11) or, preferably, hydrogen, C -12 alkyl or heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0, =S, =N(R20) and E10); or any relevant pair of R 0a, R1 a and R 2a and/or any pair of R10b and R11b may be linked together as defined herein (and therefore be substituted by one or more E12 groups), but wherein when there are one or more E10, E11 and/or E12 groups present, which independently represent Q4 or C-12 alkyl optionally substituted by one or more substituents selected from =0 and Q5, then those Q4 and Q5 groups do not represent, or contain, aromatic (e.g. heteroaryl) rings, i.e. then:
each Q4 and Q5 independently represent, on each occasion when used herein: aryl (optionally substituted by one or more substituents selected from J3) or, preferably, halo, -CN, -N02, -N(R20)R21, -OR20, -C(=Y)-R20, -C(=Y)-OR20, -C(=Y)N(R20)R21, -OC(=Y)-R20, -OC(=Y)-OR20, -OC(=Y)N(R20)R21, -OS(0)2OR20, -OP(=Y)(OR20)(OR21), -OP(OR20)(OR21), -N(R22)C(=Y)R21, -N(R22)C(=Y)OR21, -N(R22)C(=Y)N(R20)R21, -NR22S(0)2R20, -NR22S(O)2N(R20)R21, -S(O)2N(R20)R21, -SC(=Y)R20, -S(0)2R20, -SR20, -S(0)R20, C1-6 alkyl or heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0 and J2);
each R20, R2 , R22 and R23 independently represent hydrogen, C^e alkyl or heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from J4 and =0);
R1a and R1 are preferably linked together to form a 5- or 6-membered ring as defined herein;
when R1 represents an (a) group, then, preferably, the ring formed by the linkage of the R1a and R1b groups contains at least one (further) heteroatom (in addition to the requisite nitrogen atom to which R1a and R1b are necessarily attached) as defined herein; when R1 represents an (a) group, then the ring so formed (by the linkage of the R a and R1b 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. substituted by B1, in which B1 represents methyl substituted by E8, in which E8 represents Q4 and Q4 represents -N(R20)R21) or, in which that ring is substituted at the 3-position by an amino moiety (i.e. by B1, in which B represents -N(R10a)R11a).
Further compounds of the invention that may be mentioned include those in which for example when R1 represents an (a) group (e.g. in which R1a and R1b are linked together to form a 5- or 6-membered ring, e.g. a 1-pyrrolidinyl or 1- piperidinyl group), then preferably:
such groups are unsubstituted (i.e. do not contain any B1 groups);
when substituted (e.g. at the 3-position or, especially, at the 2-position with a B1 group), then:
B1 preferably represents -N(R10a)R11a, or, preferably, halo, -N02l -CN, -OR10a, -C(=Y)-R10a, -C(=Y)-OR10a, -C(=Y)N(R 0a)R1 a, -N(R12a)C(=Y)R11a, -N(R12a)C(=Y)OR11a, -N(R12a)C(=Y)N(R10a)R11a, -NR12aS(O)2R 0a, -NR12aS(O)2N(R10a)R11a, -S(O)2N(R10a)R 1a, -SC(=Y)R10a, -SC(=Y)OR 0a, -S(O)2R10a, heterocycloalkyl (optionally substituted by one or more substituents selected from =0 and E8), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E9);
when B represents optionally substituted C-,_ 2 alkyl (e.g. methyl), then either that alkyl group is unsubstituted or, when substituted by one or more =0 and/or E8 groups, then when E8 represents Q4, Q4 represents halo, -CN, -N02, -OR20, -C(=Y)-R20, -C(=Y)-OR20, -C(=Y)N(R20)R21, -OC(=Y)-R20, -OC(=Y)-OR20, -OC(=Y)N(R20)R21, -OS(0)2OR20, -OP(=Y)(OR20)(OR21), -OP(OR20)(OR21), -N(R22)C(=Y)R21, -N(R22)C(=Y)OR21, -N(R22)C(=Y)N(R20)R21, -NR22S(0)2R20,
-NR22S(O)2N(R20)R21, -S(O)2N(R20)R21, -SC(=Y)R20, -S(0)2R20, -SR20, -S(0)R20, C1-6 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0 and J2), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from J3); when substituted (e.g. at the 3-position with a B1 group), then:
B1 preferably represents halo, -N02, -CN, -OR10a, -C(=Y)-R10a, -C(=Y)-OR 0a, -C(=Y)N(R 0a)R 1a, -N(R12a)C(=Y)R1 a, -N(R12a)C(=Y)OR11a, -N(R12a)C(=Y)N(R10a)R a, -NR12aS(O)2R10a, -NR12aS(O)2N(R 0a)R 1a, -S(O)2N(R10a)R11a, -SC(=Y)R10a, -SC(=Y)OR 0a, -S(O)2R 0a, C1-12 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0 and E8), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E9).
Further preferred compounds of the invention that may be mentioned include those in which:
at least one of R2 and R3 does not represent an aromatic group (i.e. an optionally substituted aryl or heteroaryl group);
at least one of R2 and R3 represents hydrogen or a substituent as defined herein, but wherein each Q1 and, optionally, Q2 are independently selected from halo, -CN, -N02, -N(R 0a)R11a, -OR10a, -C(=Y)-R10a, -C(=Y)-OR10a, -C(=Y)N(R 0a)R1 a, -OC(=Y)-R10a, -OC(=Y)-OR 0a, -OC(=Y)N(R 0a)R1 a, -OS(O)2OR10a, -OP(=Y)(OR10a)(OR 1a), -OP(OR10a)(OR11a), -N(R12a)C(=Y)R 1a, -N(R 2a)C(=Y)OR11a, -N(R12a)C(=Y)N(R 0a)R a, -NR12aS(O)2R10a,
-NR aS(O)2N(R 0a)R a, -S(O)2N(R10a)R a, -SC(=Y)R10a, -S(O)2R10a, -SR10a, -S(O)R10a, C1-12 alkyl or heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0, =S, =N(R 0a) and E6), or a fragment of formula IA as defined hereinbefore;
more preferably neither R2 or R3 represent an aromatic group, i.e. these groups preferably represent hydrogen or a substituent as defined above.
Further preferred compounds of the invention that may be mentioned include those in which, for example, when R1 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:
R5 does not represent optionally substituted phenyl, naphthyl, indolyl, thiophenyl, benzo[b]furanyl, benzo[b]thiophenyl, isoxazolyl, or:
Figure imgf000032_0001
R2 does not represent d-C12 alkyl, -C(O)-O-R10a, -C(O)-N(R 0a)R11a and/or R3 does not represent H or C C6 alkyl; and/or
R2 represents hydrogen or Q1 (most preferably R2 represents hydrogen), in which Q1 is preferably selected from halo, -CN, -N02> -N(R10a)R1 a, -OR 0a, -C(=Y)-R10a -OC(=Y)-R10a, -OC(=Y)-OR10a, -OC(=Y)N(R 0a)R 1a, -OS(O)2OR10a -OP(=Y)(OR10a)(OR11a), -OP(OR10a)(OR 1a), -N(R12a)C(=Y)R11a
-N(R12a)C(=Y)OR11a, -N(R 2a)C(=Y)N(R10a)R1 a, -NR12aS(O)2R10a
-NR 2aS(O)2N(R 0a)R11a, -S(O)2N(R10a)R 1a, -SC(=Y)R10a, -S(O)2R10a, -SR10a -S(O)R10a, heterocycloalkyl (optionally substituted by one or more substituents selected from =0, =S, =N(R 0a) and E6), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E7); R3 represents C7. 2 alkyl (optionally substituted by one or more substituents selected from =0, =S, =N(R10a) and Q2), or R3 more preferably represents hydrogen or Q1, in which Q1 preferably represents C7_12 alkyl (optionally substituted by one or more substituents selected from =0, =S, =N(R10a) and E6) and in which Q1 more preferably represents halo, -CN, -N02, -N(R10a)R1 a, -OR10a -C(=Y)-R10a, -C(=Y)-OR 0a, -C(=Y)N(R 0a)R 1a, -OC(=Y)-R10a, -OC(=Y)-OR 0a -OC(=Y)N(R10a)R11a, -OS(O)2OR10a, -OP(=Y)(OR10a)(OR11a), -OP(OR10a)(OR11a) -N(R12a)C(=Y)R1 a, -N(R a)C(=Y)OR113, -N(R12a)C(=Y)N(R 0a)R11a
-NR12aS(O)2R10a, -NR12aS(O)2N(R 0a)R11a, -S(O)2N(R 0a)R a, -SC(=Y)R10a -S(O)2R10a, -SR10a, -S(O)R10a, heterocycloalkyl (optionally substituted by one or more substituents selected from =0, =S, =N(R10a) and E6), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E7); or R2 or R3 may represent a fragment of formula IA.
Preferred compounds of the invention that may be mentioned include those in which, when R1 represents -N(R1a)R1b, then:
R1a and R1b are preferably linked together to form a saturated 5-, 6- or 7- membered ring, optionally containing one further heteroatom (selected from nitrogen or, preferably oxygen and sulfur), optionally substituted by one or more =0 substituents (especially so in the case where there is a sulfur atom present, which may be substituted with one or two =0 groups) and/or B1 substituents; the ring formed when R a and R1b are linked together may, when there is a sulfur atom present, be substituted by one or two =0 groups (e.g. such that the ring contains a -S(O)- or -S(0)2- moiety), and, further, such a ring is preferably not substituted with any B1 substituents;
when two B1 groups are linked together to form a spiro-cyclic group, then such a cyclic moiety is preferably a saturated 3- to 7- (e.g. 3- to 6-) membered ring, optionally containing a heteroatom (but which ring is preferably carbocyclic; and may be substituted by one or more fluoro, =0 and methyl groups) and which group is preferably attached to the 2- or 3-position of the ring formed by the linkage of the integers R a and R1b (for example, when R1a and R1b are linked together to form a morpholinyl group);
the linkage of the R a and R1b group preferably forms a W-morpholinyl, N- thiomorpholinyl (in which the sulfur atom may be substituted with one or two =0 groups), oxazepanyl (e.g. 1 ,4-oxazepanyl) or thiazepanyl (e.g. 1 ,4-thiazepanyl) group, all of which are optionally substituted as hereinbefore defined (e.g. by one or more =0 and/or B1 substituents).
In certain embodiments, the present invention provides combinations containing compounds of the invention in which R1 is typically:
/V-morpholinyl which is unsubstituted or substituted, for instance by one or more B and/or =0 substituents;
tetrahydropyranyl, tetrahydrofuranyl or C-morpholinyl, which is unsubstituted or substituted, for instance by one or more B2 and/or =0 substituents;
2-, 3- or 4-pyridyl, which is unsubstituted or substituted, for instance by one or more B3 substituents;
when R represents substituted morpholinyl, it is preferably selected from the following structures:
Figure imgf000034_0001
In certain embodiments, the present invention provides combinations containing compounds of the invention in which:
R2 is -(CR6R7)mNR 0R11 where m is 1 , 2 or 3, and R 0 and R11 together with the nitrogen to which they are attached form the C3-C2o heterocyclic ring; and R3 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, C(0)N(R 6R17), OR16 or NR 6R17;
R2 is -(CR6R7)nNR 2S(0)2R10 where n is 1 or 2; R 2, R6, and R7 are independently selected from H and C i2 alkyl; and R10 is d-C 2 alkyl or C6-C20 aryl; and R3 is H, halo, CN, C 6 alkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, C(0)N(R16R17), OR16 or NR16R17;
R2 is -(CR6R7)nOR10 where n is 1 or 2, and R 0, R6 are independently selected from H and d-12 alkyl; and R3 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, C(0)N(R16R17), OR16 or NR 6R17;
R2 is -(CR6R7)nS(0)2R10 where n is 1 or 2; and R6, and R7 are H, R10 may be d-12 alkyl or C6-C20 aryl; and R3 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, C(0)N(R16R17), OR16 or NR16R17;
R2 is -(CR6R7)nS(O)2NR10R11 where n is 1 or 2; and R6, and R7 are H; and R3 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, C(0)N(R 6R17), OR16 or NR16R17; R2 is -C(=Y)NR10R11 where Y is O, and R10 and R11 together with the nitrogen to which they are attached form the C2-C2o heterocyclic ring. R10 and R 1 together with the nitrogen to which they are attached may form a C2-C20 heterocyclic ring selected from morphoiinyl, piperidinyl, piperazinyl, and pyrrolidinyl; and R3 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyi, C2-C6 heterocycloalkyi, C(0)N(R16R17), OR16 or NR 6R17;
R2 is -C(=Y)NR10R11 where Y is O, and R10 and R 1 are independently selected from H and d-C12 alkyl; and R3 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyi, C2-C6 heterocycloalkyi, C(0)N(R16R17), OR16 or NR16R17;
R2 is -C(=Y)NR10R11 where Y is O, and R10 and R11 are independently selected from H and C3-C12 carbocyclyl, C2-C20 heterocyclyl, C6-C20 aryl, and d-C20 heteroaryl; and R3 is H, halo, CN, d-5 alkyl, C3-C6 cycloalkyi, C2-C6 heterocycloalkyi, C(0)N(R16R17), OR16 or NR16R17;
R2 is -NHR12 where R12 is C3-C 2 carbocyclyl, C2-C20 heterocyclyl, C6-C20 aryl or d-C2o heteroaryl, or, R12 may be phenyl or 4-pyridyl; and R3 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyi, C2-C6 heterocycloalkyi, C(0)N(R 6R17), OR16 or NR16R17; R2 is -NR 2C(=Y)R11 where Y is O, R12 is H or d-C12 alkyl, and R1 is d-C12 alkyl, C3-C12 carbocyclyl, C2-C20 heterocyclyl, C6-C20 aryl, or d-C20 heteroaryl; and R3 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyi, C2-C6 heterocycloalkyi, C(0)N(R16R17), OR16 or NR 6R17;
R2 is -NR12S(0)2R10 where R 2 is H or d-C12 alkyl, and R 0 is d-C12 alkyl, C3-C12 carbocyclyl, C2-C20 heterocyclyl, C6-C20 aryl, or d-C20 heteroaryl; and R3 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyi, C2-C6 heterocycloalkyi, C(0)N(R16R17), OR16 or NR16R17;
R2 is -S(O)2NR 0R11 where R10 and R1 together with the nitrogen to which they are attached form a C2-C20 heterocyclyl ring selected from morphoiinyl, piperidinyl, piperazinyl, and pyrrolidinyl; and R3 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyi, C2-C6 heterocycloalkyi, C(0)N(R16R17), OR16 or NR 6R17;
R2 is -S(O)2NR 0R11 where R10 and R1 are independently selected from H and d-Ci2 alkyl; R10 and R11 may be independently selected from H, substituted ethyl, and substituted propyl; and R3 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyi, C2-C6 heterocycloalkyi, C(0)N(R16R17), OR16 or NR16R17;
R2 is d-C12 alkyl, and R3 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyi, C2-C6 heterocycloalkyi, C(0)N(R 6R17), OR16 or NR16R17; R2 is C2-C8 alkenyl, and R3 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, C(0)N(R 6R17), OR16 or NR16R17;
R2 is C2-C8 alkynyl (the C2-C8 alkynyl may be substituted with C2-C2o heterocyclyl, which includes, but is not limited to, morpholinyl, pipendinyl, piperazinyl, and pyrrolidinyl); and R3 is H, halo, CN, C 6 alkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, C(0)N(R16R17), OR16 or NR16R17;
R2 is C6-C20 aryl, such as phenyl; and R3 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, C(0)N(R16R17), OR16, NR16R17;
R2 is C3-C12 carbocyclyl; and R3 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, C(0)N(R16R17), OR16 or NR 6R17;
R2 is C2-C20 heterocyclyl; and R3 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, C(0)N(R 6R17), OR16 or NR16R17;
R2 is d-C20 heteroaryl; and R3 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, C(0)N(R16R17), OR16 or NR16R17;
R2 is H;
R2 is methyl (CH3), cyclopropyl, CF3, CN or CONH2.
In certain embodiments of the invention, the combination contains a compound of the invention in which:
R3 is -(CR6R7)mNR10R11 where m is 1 , 2 or 3, and R10 and R1 together with the nitrogen to which they are attached form the C3-C20 heterocyclic ring; and R2 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, C(0)N(R16R17), OR16 or NR16R17;
R3 is -(CR6R7)nNR12S(0)2R10 where n is 1 or 2; R12, R6, and R7 are independently selected from H and d-12 alkyl; and R 0 is C C12 alkyl or C6-C20 aryl; and R2 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, C(0)N(R16R17), OR16 or NR16R17;
R3 is -(CR6R7)nOR10 where n is 1 or 2, and R 0, R6 are independently selected from H and d-12 alkyl; and R2 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, C(0)N(R 6R17), OR16 or NR16R17;
R3 is -(CR6R7)nS(0)2R10 where n is 1 or 2; and R6, and R7 are H, R 0 may be C i2 alkyl or C6-C20 aryl; and R2 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, C(0)N(R16R17), OR16 or NR16R17; R3 is -(CR6R7)nS(O)2NR 0R11 where n is 1 or 2; and R6, and R7 are H; and R2 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, C(0)N(R16R17), OR16 or NR16R17;
R3 is -C(=Y)NR10R11 where Y is O, and R 0 and R11 together with the nitrogen to which they are attached form the C2-C2o heterocyclic ring; R10 and R1 together with the nitrogen to which they are attached may form a C2-C20 heterocyclic ring selected from morpholinyl, piperidinyl, piperazinyl, and pyrrolidinyl; and R2 is H, halo, CN, Ct-β alkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, C(0)N(R16R17), OR16 or NR16R17;
R3 is -C(=Y)NR10R11 where Y is O, and R10 and R11 are independently selected from H and d-C 2 alkyl; and R2 is H, halo, CN, Cr6 alkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, C(0)N(R16R17), OR16 or NR 6R17;
R3 is -C(=Y)NR10R11 where Y is O, and R 0 and R 1 are independently selected from H and C3-C12 carbocyclyl, C2-C20 heterocyclyl, C6-C20 aryi, and C1-C20 heteroaryl; and R2 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, C(0)N(R16R17), OR16 or NR1SR17;
R3 is -NHR12 where R12 is C3-C 2 carbocyclyl, C2-C20 heterocyclyl, C6-C20 aryl or d-C20 heteroaryl, or, R12 may be phenyl or 4-pyridyl; and R2 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, C(0)N(R 6R17), OR16 or NR16R17; R3 is -NR12C(=Y)R11 where Y is O, R12 is H or d-C12 alkyl, and R1 is C C12 alkyl, C3-C 2 carbocyclyl, C2-C20 heterocyclyl, C6-C20 aryl, or d-C20 heteroaryl; and R2 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, C(0)N(R 6R17), OR16 or NR16R17;
R3 is -NR12S(0)2R10 where R12 is H or d-C12 alkyl, and R10 is C,-C12 alkyl, C3-C12 carbocyclyl, C2-C20 heterocyclyl, C6-C20 aryl, or d-C20 heteroaryl; and R2 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, C(0)N(R16R17), OR16 or NR16R17;
R3 is -S(O)2NR10R11 where R 0 and R11 together with the nitrogen to which they are attached form a C2-C20 heterocyclyl ring selected from morpholinyl, piperidinyl, piperazinyl, and pyrrolidinyl; and R2 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, C(0)N(R16R17), OR16 or NR16R17;
R3 is -S(O)2NR10R11 where R10 and R11 are independently selected from H and Ci-C 2 alkyl. R10 and R11 may be independently selected from H, substituted ethyl, and substituted propyl; and R2 is H, halo, CN, C 6 alkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, C(0)N(R16R17), OR16 or NR16R17; R3 is C1-C2 alkyl, and R2 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyi, C2-C6 heterocycloalkyi, C(0)N(R16R17), OR16 or NR16R17;
R3 is C2-C8 alkenyl, and R2 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyi, C2-C6 heterocycloalkyi, C(0)N(R16R17), OR16 or NR 6R17;
R3 is C2-C8 alkynyl (the C2-C8 alkynyl may be substituted with C2-C20 heterocyclyl, which includes, but is not limited to, morpholinyl, piperidinyl, piperazinyl, and pyrrolidinyl); and R2 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyi, C2-C6 heterocycloalkyi, C(0)N(R 6R17), OR16 or NR 6R17;
R3 is C6-C20 aryl, such as phenyl; and R2 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyi, C2-C6 heterocycloalkyi, C(0)N(R16R17), OR16 or NR16R17;
R3 is C3-C12 carbocyclyl; and R2 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyi, C2-C6 heterocycloalkyi, C(0)N(R 6R17), OR16 or NR16R17;
R3 is C2-C20 heterocyclyl; and R2 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyi, C2-C6 heterocycloalkyi, C(0)N(R 6R17), OR16 or NR16R17;
R3 is C1-C20 heteroaryl; and R2 is H, halo, CN, d-6 alkyl, C3-C6 cycloalkyi, C2-C6 heterocycloalkyi, C(0)N(R 6R17), OR16 or NR16R17.
In the above two paragraphs (and in certain other paragraphs herein), 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 Q1, Q2, E6, E7, Q4, Q5, J2 or J3 (e.g. by Q1, E6 and/or E7)). Further, unless otherwise specified in the above two paragraphs:
(i) each R 6 and R17 respectively represents substituents R20 and R2 as defined herein (and more preferably, they respectively represent substituents R50 and R51 as defined herein);
(ii) each R6 and R7 may independently represent a substituent as defined by R15 herein (i.e. each may independently represent hydrogen, a substituent as defined herein, or, R6 and R7 may be linked together in the same manner as two R15 groups attached to the same carbon atom may be);
(iii) each R 0, R and R12 respectively represents a substituent as defined by the substituents R10a, R11a and R12a.
In certain embodiments, the combination contains a compound of the invention in which R2 or R3 represent a fragment of formula IA, as hereinbefore depicted, wherein: Ra and Rb form, together with the N atom to which they are attached, a group of the following formula:
Figure imgf000039_0001
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:
Figure imgf000039_0002
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. Specific examples of this group include the following structures:
Figure imgf000040_0001
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. Specific examples of this group include the following structures:
Figure imgf000040_0002
In certain embodiments, the combination contains a compound of the invention in which R2 represent a fragments of formula IA as depicted hereinbefore, in which Ra and Rb are as described above; and R3 is H, halo, CN, C-,-6 alkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, C(0)N(R16R17), OR16, NR16R17. The integers R16 and R 7 are as defined herein.
In certain embodiments, the combination contains a compound of the invention in which R3 represent a fragment of formula IA as depicted hereinbefore; and R2 is H, halo, CN, CT6 alkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, C(0)N(R1BR17), OR16, NR16R17. The integers R16 and R 7 are as defined herein.
Exemplary embodiments of R5 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. 1H-benzo[d][1,2,3]triazole, 1 H-pyrazolo [3,4-b]pyridine, 1 H- pyrazolo[3,4-d]pyrimidine, 1 H-benzo[d]imidazole, 1 H-benzo[d]imidazol-2(3H)- one, 1 H-pyrazolo[3,4-c]pyridine, 1 H-pyrazolo[4,3-d]pyrimidine, 5H-pyrrolo[3,2- djpyrimidine, 2-amino-1H-purin-6(9H)-one, quinoline, quinazoline, quinoxaline, isoquinoline, isoquinolin-1(2H)-one, 3,4-dihydroisoquinolin-1(2H)-one, 3,4- dihydroquinolin-2(1H)-one, quinazolin-2(1 H)-one, quinoxalin-2(1 H)-one, 1 ,8- napthyridine, pyrido[3,4-d]pyrimidine, and pyrido[3,2-b]pyrazine, 1,3-dihydro benzimidazolone, benzimidazole, benzothiazole and benzothiadiazole, groups. These groups may be unsubstituted or substituted.
The attachment site of the R5 group to the C-6 position of the requisite imidazopyrazine ring of formula I may be at any carbon (carbon-linked) of the R5 group (e.g. fused bicyclic C4-C2o heterocyclyl or fused bicyclic C^C2o heteroaryl group R5 group).
More exemplary embodiments of R5 include, but are not limited to, the following groups, where the wavy line indicates the site of attachment to the pyrazine ring:
Figure imgf000042_0001
Preferred compounds of the invention include those in which:
R represents:
(a) -N(R1a)R b, in which R1a and R1b 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 (e.g. by one to three) substituents selected from =0 and B1;
(b) a heterocycloalkyl (e.g. a 3- to 7-membered) heterocycloalkyl group (attached to the requisite imidazopyrazine via a carbon atom), optionally substituted by one or more (e.g. by one to three) substituents selected from =0 and B2;
(c) a monocyclic heteroaryl group optionally substituted by one or more (e.g. by one to three) substituents selected from B3;
when R represents optionally substituted heterocycloalkyl, then that heterocycloalkyl group preferably contains 1 , 2 or 3 heteroatoms preferably selected from nitrogen, oxygen and sulfur;
when R1 represents optionally substituted monocyclic heteroaryl, then 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;
R2 and R3 may represent a fragment of formula IA, although R2 and R3 more preferably, and independently, represent C -12 (e.g. C -5) alkyl optionally substituted by one or more substituents selected from =0 and Q2, or, R2 and R3 more preferably represent a substituent selected from Q1;
m represents 0, 1 or 2;
each R15 represents hydrogen or C1-6 (e.g. C -3) alkyl, which latter group is preferably unsubstituted;
when Ra and Rb are linked together, they form a first 5- or 6-membered cyclic group, optionally containing one further heteroatom selected from nitrogen, sulfur and oxygen, which cyclic group is optionally substituted by one or more substituents selected from =0 and, preferably, E3;
R4 represents hydrogen or a substituent selected from halo, -CN, -OR10 , -N(R10b)R11b, d.6 alkyl and/or heterocycloalkyl (e.g. a 5- or 6-membered heterocycloalkyi), which latter two groups are optionally substituted by one or more substituents selected from E4 and =0;
when R4 represents heterocycloalkyi, then it is preferably a 5- or 6-membered heterocycloalkyi group containing one or two heteroatoms preferably selected from nitrogen, oxygen and sulfur, which group is optionally substituted by one or more substituents selected from E4 and =0;
when R4 represents C-,.e alkyl, then that group is preferably an acyclic C1-4 alkyl group, optionally substituted by one or more substituents selected from E4 and =0;
when R5 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 E5;
when R5 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 E5;
when R5 represents bicyclic heteroaryl (e.g. a 8-, 9- or 10-membered heteroaryl group), then that group preferably consists of a 5- or 6-membered ring fused to another 5- or 6-membered ring (in which either one of those rings may contain one or more (e.g. four, or, preferably one to three) heteroatoms), in which the total number of heteroatoms is preferably one to four, and which ring is optionally substituted by one or more (e.g. two or, preferably, one) substituent(s) selected from E5 (and, if there is a non-aromatic ring present in the bicyclic heteroaryl group, then such a group may also be substituted by one or more (e.g. one) =0 groups);
optional substituents (e.g. the first optional substituent) on the R5 group (e.g. when it represents aryl, such as phenyl) are preferably selected from -OR, -SR, -CH2OR, C02R, CF2OH, CH(CF3)OH, C(CF3)20H, -(CH2)wOR, -(CH2)WNR2, -C(0)N(R)2, -NR2, -NRC(0)R, -NRC(0)NHR, -NRC(0)N(R)2, -S(0)yN(R)2, -OC(0)R, OC(0)N(R)2, -NRS(0)yR, -NRC(0)N(R)2, CN, halogen and -N02 (in which each R is independently selected from H, CVC6 alkyl, C3-C10 cycloalkyl and a 5- to 12-membered aryl or heteroaryl group, the groups being unsubstituted or substituted (for example by one or more substituents as defined herein, e.g. substituents on E5 moieties, e.g. =0, J2, J3, J4 and/or J5), w is 0, 1 or 2 and y is 1 or 2);
when R5 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, N02, ORd, SRd, NRd 2l C(0)Rd, SORd, S02Rd, S02N(R)d 2, NC(0)Rd and C02Rd (wherein each Rd is independently H or C Ce alkyl);
when R5 represents substituted aryl (e.g. phenyl), the 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 -ORd (in which Rd is independently H or (-VC6 alkyl, e.g. methyl), e.g. -OH; in this embodiment the -ORd 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 R5);
when R5 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 R5, when R5 is a phenyl group; typically, the substituents are selected from OH and NH2);
each Q and Q2 independently represent -S(O)2R10a, -SR10a, -S(O)R10a, -S(O)2N(R 0a)R11a, or, preferably, halo, -CN, -N02, -N(R10a)R 1a, -OR 0a, -C(=Y)-R 0a, -C(=Y)-OR10a, -C(=Y)N(R10a)R11a, -N(R12a)C(=Y)R11a, -NR 2aS(O)2R10a, d.12 (e.g. C1-6) alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0 and E6), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E7);
any two B substituents may be linked together as hereinbefore defined, for example to form a C3-e cycloalkyl group, or, more preferably, B1, B2 and B3 independently represent halo, -N02, -CN, -N(R10a)R11a, -OR10a, -C(=Y)-R 0a, -C(=Y)-OR 0a, -C(=Y)N(R10a)R11a or C1-12 (e.g. C1-6) alkyl optionally substituted by one or more substituents selected from =0 and E8); each R10a, R11a, R12a, R 0b, R1 b and R12 independently represent, on each occasion when used herein, hydrogen or C - 2 (e.g. C^e) alkyl (which latter group is optionally substituted by one or more substituents selected from =0 and E10); or
any relevant pair of R10a, R11a and R12a (e.g. R 0a and R11a), and/or R10b and R11b may, when attached to the same nitrogen atom, be linked together to form (along with the requisite nitrogen atom to which they are attached) a 3- to 12- (e.g. 4- to 12-) membered ring, optionally containing one or more (e.g. one to three) double bonds, and which ring is optionally substituted by one or more substituents selected from E10 and =0;
each of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11 and E 2 independently represents, on each occasion when used herein, Q4 or C1-16 alkyl (e.g. C1-6, preferably, C -3) alkyl optionally substituted by one or more substituents selected from =0 and Q5;
each Q4 and Q5 independently represent halo, -CN, -N02, -N(R20)R21, -OR20, -C(=Y)-R20, -C(=Y)-OR20, -C(=Y)N(R 0)R21, -N(R 2)C(=Y)R21, -N(R2 )C(=Y)OR21, -N(R 2)C(=Y)N(R20)R21, -NR22S(0)2R20, -NR22S(O)2N(R20)R21, -S(O)2N(R 0)R21, -S(0)2R20, -SR20, -S(0)R20 or C -e alkyl optionally substituted by one or more fluoro atoms (and each Q5 more preferably represents halo, such as fluoro);
any two E , E2, E3, E4, E5, E6, E7, Ea, E9, E10, E 1 or E12 groups may not be linked together;
each R20, R21, R22 and R23 independently represent, on each occasion when used herein, aryl (e.g. phenyl; preferably unsubstituted, but which may be substituted by one to three J5 groups) or, more preferably, hydrogen or C1-6 (e.g. C1-3) alkyl optionally substituted by one or more substituents selected from =0 and J4; or any pair of R20 and R21, may, when attached to the same nitrogen atom, be linked together to form a 4- to 8-membered (e.g. 5- or 6-membered) ring, optionally containing one further heteroatom selected from nitrogen and oxygen, optionally containing one double bond, and which ring is optionally substituted by one or more substituents selected from J6 and =0;
each J1, J2, J3, J4, J5 and J6 independently represent C -6 (e.g. Ci-3) alkyl optionally substituted by one or more substituents selected from =0 and Q8, or, more preferably, such groups independently represent a substituent selected from Q7; each Q7 and Q8 independently represents a substituent selected from fluoro, -N(R50)R51, -OR50, -C(=Ya)-R50, -C(=Ya)-OR50, -C(=Ya)N(R50)R51, -NR52S(0)2R50, -S(0)2R50 and/or C1-6 alkyl optionally substituted by one or more fluoro atoms; each Y and Ya independently represent =S or, preferably, =0;
each R50, R51, R52 and R53 substituent independently represents, on each occasion when used herein, hydrogen or C1-6 (e.g. C1-3) alkyl optionally substituted by one or more substituents selected from fluoro;
when any relevant pair of R50, R51 and R52 are linked together, then those pairs that are attached to the same nitrogen atom may be linked together (i.e. any pair of R50 and R51), and the ring so formed is preferably a 5- or 6-membered ring, optionally containing one further nitrogen or oxygen heteroatom, and which ring is optionally substituted by one or more substituents selected from =0 and C1-3 alkyl (e.g. methyl);
R60, R61 and R62 independently represent hydrogen or Ci_3 (e.g. C^) alkyl optionally substituted by one or more fluoro atoms.
Preferred optional substituents on R1 and R5 (and, when they represent a substituent other than hydrogen on R2, R3 and R4 groups) include:
=0 (e.g. in the case of alkyl, cycloalkyl or heterocycloalkyl groups);
-CN;
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);
aryl (e.g. phenyl), if appropriate (e.g. when the substitutent is on an alkyl group, thereby forming e.g. a benzyl group);
-ORz ;
-C(0)Rz2;
-C(0)ORz3;
-N(Rz4)Rz5;
-S(0)2RZ6;
-S(0)2N(Rz7)Rz8;
-N(Rz9)-C(0)-Rz1°; -C(0)-N(Rz 1)Rz12;
- CR^-CCOJ- iR2 0);
wherein each Rz1 to Rz12 independently represents, on each occasion when used herein, H or C1-4 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). Further, any two Rz groups (e.g. Rz4 and Rz5), 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 R10 and R or R10a and R11a groups.
Preferred compounds of the invention (component (A) of the combinations of the invention) include those in which:
R represents: (i) -N(R1a)R1b; (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;
when R1 represents -N(R a)R b, then 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 B1 groups (such groups are preferably unsubstituted, i.e. most preferably an unsubstituted morpholinyl group);
when R1 represents an optionally substituted 5- or 6-membered heterocycloalkyl group, then such a group may contain two or preferably one heteroatom(s) (in which the heteroatom is selected from sulfur, preferably nitrogen, and, especially, oxygen). Such a ring may be substituted with one or more substituents selected from =0 and B2, but it is preferably unsubstituted. Further, it is preferably 6- membered (e.g. a tetrahydropyranyl group);
when R1 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 B3, but it is preferably unsubstituted. Further, it is preferably 6-membered (e.g. a pyridyl group);
R2 and R3 independently represent hydrogen or a substituent selected from Q ; each Q1 and Q2 (e.g. each Q ) independently represent(s) halo, -CN, -N02, -N(R 0a)R11a, -C(=Y)-R10a, -C(=Y)-OR10a, -C(=Y)N(R10a)R 1a, C1-12 alkyl or heterocycloalkyi (which latter two groups are optionally substituted by one or more substituents selected from =0, =S, =N(R 0a) and E6);
R4 represents hydrogen or a substituent selected from -N(R10b)R1 b and, preferably, halo (e.g. chloro, bromo or iodo) and -CN;
at least one (e.g. one) of R2, R3 and R4 represents hydrogen;
R5 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 E5;
B1, B2 and B3 (e.g. B ) independently represent C1-6 (e.g. C -3) alkyl optionally substituted by one or more substituents selected from =0 and E8;
each R10a, R11a, R12a, R10 , R1 b and R12b (e.g. each R10a and R 1a) independently represents hydrogen or C1-6 (e.g. C -4) alkyl optionally substituted by one or more substituents selected from =0 and E 0; or
any relevant pair of R10a, R11a and R 2a (e.g. R 0a and R11a) may (e.g. when both are attached to the same nitrogen atom) be linked together to form a 3- to 8- (e.g.
4- to 8-) membered ring, optionally containing a further heteroatom, and optionally substituted by one or more substituents selected from =0 and E12; each E1, E2, E3, E4, E5, Es, E7, E8, E9, E10, E11 and E12 independently represents d-12 alkyl optionally substituted by one or more substituents selected from =0 and Q5, or, preferably (each E to E 2 independently represent) Q4;
each Q4 and Q5 (e.g. each Q4) independently represent halo, -N(R20)R21, -OR20,
-C(=Y)-OR20, -C(=Y)N(R20)R21, -N(R22)C(=Y)R21, -N(R22)C(=Y)N(R20)R21,
-NR22S(0)2R20, -S(0)2R20 and/or C1-6 alkyl (optionally substituted by one or more substituents selected from =0 and J2);
when E8 represents Q4, then Q4 preferably represents -N(R20)R21, -OR20,
-C(=Y)-OR20, -C(=Y)N(R 0)R21 or -N(R22)C(=Y)R21;
each R20, R2 , R22 and R23 (e.g. each R20 and R21) independently represents heteroaryl, preferably, aryl (e.g. phenyl) (which latter two groups are optionally substituted by one or more substituents selected from J5), or, more preferably, hydrogen or (e.g. C1-4) alkyl optionally substituted by one or more substituents selected from =0 and J4; or
any relevant pair of R20, R2 and R22 (e.g. R20 and R21) may (e.g. when both are attached to the same nitrogen atom) may be linked together to form a 3- to 8- (e.g. 4- to 8-) membered ring, optionally containing a further heteroatom, and optionally substituted by one or more substituents selected from =0 and J6;
each J1, J2, J3, J4, J5 and J6 independently represent C1-6 (e.g. C1-3) alkyl optionally substituted by one or more substituents selected from Q8, or, J1 to J6 more preferably represent a substituent selected from Q7;
each Q7 and Q8 independently represent halo, -N(R50)R51, -OR50, -C(=Ya)-OR50, -C(=Ya)-R50, -S(0)2R50 or C1-3 alkyl optionally substituted by one or more fluoro atoms;
Y and Ya independently represent =0;
each R50, R5 , R52 and R53 independently represents hydrogen or C^6 (e.g. C^) alkyl optionally substituted by one or more fluoro atoms;
each R60, R6 and R62 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:
R1 represents -N(R1a)R b, in which R1a and R1b 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 B1 groups (such groups are preferably unsubstituted);
R2 and R3 independently represent(s) hydrogen or a substituent selected from halo (e.g. bromo, chloro, iodo) -CN, -N(R10a)R11a, -C(=Y)OR10a, -C(=Y)-R10a, -C(=Y)-N(R10a)R 1a, C1-6 alkyl (optionally substituted by one or more (e.g. one) substituent(s) selected from E6) and heterocycloalkyl (e.g. a 5- or, preferably, a 6- membered heterocycloalkyl group, which preferably contains one heteroatom (e.g. nitrogen), and which may contain one unsaturation, e.g a double bond, so forming e.g. a piperidinyl ring, e.g. 4-piperidinyl, for example in which the I mposition optionally contains a double bond), which heterocycloalkyl group is optionally substituted by one or more substituents selected from =0 and, preferably, E6 (e.g. in which the E6 substituent is located on a nitrogen heteroatom);
when R2 or R3 represents C-M2 (e.g. C -6) alkyl, then it may be straight-chained, e.g. acyclic C1-3 alkyl (e.g. methyl) or C3_6 cycloalkyl (e.g. cyclopropyl), all of which are optionally substituted by one or more fluoro atoms (so forming for example a trifluoromethyl group); R4 represents hydrogen, chloro, bromo, iodo or -CN;
one of R2 and R3 represents a substituent as defined herein, and the other represents hydrogen or a substituent as defined herein;
R5 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 R5 groups are optionally substituted by one or more (e.g. one or two) substituents selected from E5;
each R 0a, R11a, R 2a, R 0b, R 1b and R12b (e.g. each R10a and R11a) independently represents hydrogen or C1-4 (e.g. C^) alkyl (e.g. ethyl); or
any relevant pair of R 0a, R1 a and R12a (e.g. R10a and R11a) may (e.g. when both are attached to the same nitrogen atom) be linked together to form a 5- or, preferably, a 6-membered ring, optionally containing a further heteroatom (preferably selected from nitrogen and oxygen), which ring is preferably saturated (so forming, for example, a piperazinyl or morpholinyl group), and optionally substituted by one or more substituents selected from =0 and E12 (which E12 substituent may be situated on a nitrogen heteroatom; and/or E12 is preferably halo (e.g. fluoro) or C -3 alkyl optionally substituted by one or more fluoro atoms); each E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11 and E12 (e.g. each E5 and E6) independently represents a substituent selected from Q4;
each E5 independently represents halo (e.g. fluoro), -OR20, -N(R20)R21, -C(=Y)OR20, -C(=Y)N(R20)R21, -NR22S(0)2R20 and/or -N(R22)C(=Y)N(R20)R21; each E6 independently represents -OR20 (in which R20 preferably represents hydrogen), -N(R20)R21, -C(=Y)OR20, -C(=Y)N(R20)R21, -S(0)2R20 and/or C1-6 alkyl (e.g. C-i-3 alkyl) optionally substituted by one or more fluoro atoms;
each Y represents, on each occasion when used herein, =S, or preferably =0; each R20, R21, R22 and R23 (e.g. each R20 and R2 ) independently represents hydrogen or C -4 (e.g. C1-3) alkyl (e.g. fe/ -butyl, ethyl or methyl); or
any relevant pair of R20, R2 and R22 (e.g. R20 and R21) may (e.g. when both are attached to the same nitrogen atom) may be linked together to form a 5- or, preferably, a 6-membered ring, optionally containing a further heteroatom (preferably selected from nitrogen and oxygen), which ring is preferably saturated (so forming, for example, a piperazinyl or morpholinyl group), and optionally substituted by one or more substituents selected from =0 and J6 (which J6 substituent may be situated on a nitrogen heteroatom);
R22 represents C1-3 alkyl or, preferably, hydrogen;
each J1, J2, J3, J4, J5 and J6 independently represent a substituent selected from Q7;
each Q7 and Q8 independently represent -C(=Ya)-OR50, -C(=Ya)-R50, -S(0)2R50 or
Ci-3 alkyl optionally substituted by one or more fluoro atoms;
each Ya independently represents =S or, preferably, =0;
each R50 independently represents C1-4 alkyl (e.g. te/t-butyl or methyl).
Particularly preferred compounds of the invention (component (A) of the combinations of the invention) include those in which:
R1 represents: (a) -N(R a)R b, in which R1a 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 B1 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. one) substituent selected from B3; 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 , B2 and B3 (e.g. B3) preferably represents halo (e.g. fluoro), -N(R10a)R1 a (e.g -NH2) or d-2 alkyl optionally substituted by one or more E8 group;
R2 and R3 independently represent(s) hydrogen, a fragment of formula IA, C1-6 alkyl (optionally substituted by one or more (e.g. one) substituent(s) selected from Q2) or a substituent selected from Q ;
Q1 represents halo (e.g. bromo, chloro, iodo) -CN, -N(R 0a)R11a, -C(=Y)OR10a, -C(=Y)-R10a, -C(=Y)-N(R10a)R11a, C1-6 alkyl (optionally substituted by one or more (e.g. one) substituent(s) selected from E6) and heterocycloalkyl (e.g. a 5-, 7- or, preferably, a 6-membered heterocycloalkyl group, which preferably contains one or two heteroatoms (e.g. selected from nitrogen, oxygen and sulfur), and which may contain one unsaturation, e.g a double bond, so forming e.g. azepanyl or, preferably, pierazinyl (e.g. 1-piperazinyl), morpholinyl, thiomorpholinyl, piperidinyl (e.g. 4-piperidinyl, for example in which the 1 ,2-position optionally contains a double bond) or tetrahydropyranyl (e.g. 4-tetrahydropyranyl), which heterocycloalkyi group is optionally substituted by one or more substituents selected from =0 (which may be present on a sulfur atom to form e.g. a -S(0)2- moiety) and, preferably, E6 (e.g. in which the E6 substituent is located on a nitrogen heteroatom);
when R2 or R3 represents a fragment of formula IA, then it is preferably R2 that represents such a fragment;
when R2 or R3 represents a fragment of formula 1A (in an embodiment of the invention one of R2 and R3, e.g. R2, represents a fragment of formula IA), then preferably m represents 1 and each R15 independently represent hydrogen (so forming a fragment -CH2-N(Ra)(R ));
Ra and Rb 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 -CH2-CH2- 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. 2,8-diaza-spiro[4,5]- decane-8-yl, 2,8-diaza-spiro[4,5]-decane-2-yl, 3,9-diaza-spiro[5,5]undecane-3-yl, 2,7-diaza-spiro[3.5]nonane-7-yl or 2,7-diaza-spiro[3.5]nonane-2-yl), which rings are optionally substituted by one or more substituents selected from =0 and E3 (for instance the second ring may be substituted with such substituents);
when R2 or R3 represents C^2 (e.g. C1-6) alkyl, then it may be straight-chained, e.g. acyclic C1-3 alkyl (e.g. methyl) or C3-6 cycloalkyl (e.g. cyclopropyl), all of which are optionally substituted by one or more fluoro atoms (so forming for example a trifluoromethyl group);
R4 represents hydrogen, chloro, bromo, iodo, -CN, -C(O)R10b (e.g. -C(O)H) or methyl optionally substituted by one or more (e.g. one) substituent(s) selected from E4 (in which E4 preferably represents heteroaryl (e.g. imidazolyl) or, especially, -OR20, so forming e.g. a -CH2OH group or a -CH2-heteroaryl moiety); one of R2 and R3 represents a substituent as defined herein, and the other represents hydrogen or a substituent as defined herein; R5 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 R5 groups are optionally substituted by one or more (e.g. one or two) substituents selected from E5;
each Q2 independently represents halo (e.g. fluoro; and hence when substituted on alkyl, may form e.g. a -CF3 group), -OR10a (in which R 0a preferably represents hydrogen or C1-2 alkyl), -N(R10a)R10b, -C(=Y)OR10a, -C(=Y)R 0a, -C(=Y)N(R 0a)R 0b, -S(O)2R10a, alkyl (e.g. C1-3 alkyl; optionally substituted by one or more fluoro atoms), heterocycloalkyl (optionally substituted by one or more substituents selected from =0 and E6), aryl and/or heteroaryl (e.g. pyrimidinyl; which latter two aryl and heteroaryl groups are optionally substituted by one or more substituents selected from E7);
each R10a, R11a, R12a, R10b, R 1b and R12b (e.g. each R10a and R11a) independently represents hydrogen or C1-6 alkyl (e.g. ethyl or propyl or C3.6 cycloalkyl, such as cyclohexyl) optionally substituted by one or more (e.g. one) substituent(s) selected from E10; or
one of R10a 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 E10); or any relevant pair of R10a, R 1a and R 2a (e.g. R10a and R11a) may (e.g. when both are attached to the same nitrogen atom) be linked together to form a 5-, 6- or 7- membered ring, optionally containing a further heteroatom (preferably selected from nitrogen, oxygen and sulfur), which ring is preferably saturated (so forming, for example, a pyrrolidinyl, piperidinyl, azepanyl, piperazinyl, morpholinyl or thiomorpholinyl group), and optionally substituted by one or more substituents selected from =0 and E12 (which E12 substituent may be situated on a nitrogen heteroatom; and/or E 2 is preferably halo (e.g. fluoro), -N(R20)R21, -OR20, -C(0)OR20, -OC(0)R20, -C(0)R20, -S(0)2R20 or C1-3 alkyl optionally substituted by one or more fluoro atoms or substituents selected from Q5); each E , E2, E3, E4, E5, E6, E7, E8, E9, E10, E 1 and E12 (e.g. each E5 and E6) independently represents a substituent selected from Q4 or C1-2 alkyl optionally substituted by one or more substituents selected from Q5 and =0;
Q4 represents halo (e.g. fluoro or chloro), -CN, -OR20, -N(R20)R21, -C(=Y)OR20, -C(=Y)R20, -C(=Y)N(R20)R21, -N(R22)-C(=Y)-R21, -NR22S(0)2R20, -S(0)2R20, -N(R 2)C(=Y)N(R20)R21, -OC(0)R20, C1-6 alkyl (e.g. C1-3 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) or heteroaryl (e.g. imidazolyl), which latter two aryl and heteroaryl groups are optionally substituted by one or more J3 substituents;
Q5 represents halo (e.g. fluoro), -N(R20)R21, -OR20 and -0-C(0)R20;
each E3 independently represents -C(=Y)OR20 or -S(0)2R20;
each E4 independently represents halo (e.g. fluoro), -OR20 (e.g.
-OH) or heteroaryl (e.g. imidazolyl);
each E5 independently represents halo (e.g. fluoro or chloro), -CN, -OR20, -N(R20)R21, -C(=Y)OR20, -C(=Y)N(R20)R21, -N(R22)-C(=Y)-R21, -NR22S(0)2R20, -N(R22)C(=Y)N(R20)R21 and/or C1-6 alkyl (e.g. C1-3 alkyl) optionally substituted by one or more fluoro atoms;
each E6 independently represents halo (e.g. fluoro), -OR20 (in which R20 preferably represents hydrogen or C1-2 alkyl), -N(R20)R21, -C(=Y)OR20, -C(=Y)R20,
-C(=Y)N(R20)R21, -S(0)2R20 and/or C1-6 alkyl (e.g. C1-3 alkyl) optionally substituted by one or more fluoro atoms;
each E7 independently represents -N(R20)R21;
each E8 independently represents -OR20 or -C(=Y)OR20;
each E10 (which is preferably located on a nitrogen heteroatom, when a substituent on a heterocycloalkyl group) represents -S(0)2R20, -OR20,
-N(R20)R21, -N(R22)-C(0)-R21, -C(0)-OR20 or aryl (which latter group, when attached to an alkyl group may form e.g. a benzyl moiety; and which may be substituted by one or more J3 substituents);
each Y represents, on each occasion when used herein, =S, or preferably =0; each R20, R21, R22 and R23 (e.g. each R20 and R21) independently represents hydrogen, C1-4 (e.g. C^) alkyl (e.g. te/t-butyl, ethyl or methyl; which alkyl group is optionally substituted by one or more substituents selected from J4) or aryl (e.g. phenyl; especially in the case of -S(0)2R20, and which aryl group is optionally substituted by one or more J5 substituents); or any relevant pair of R , R and R (e.g. R and R ) may (e.g. when both are attached to the same nitrogen atom) may be linked together to form a 5- or 6- membered ring, optionally containing a further heteroatom (preferably selected from nitrogen and oxygen), which ring is preferably saturated (so forming, for example, a pyrrolidinyl, piperazinyl or morpholinyl group), and optionally substituted by one or more substituents selected from =0 and J6 (which J6 substituent may be situated on a nitrogen heteroatom);
R22 represents C1-3 alkyl or, preferably, hydrogen;
each J1, J2, J3, J4, J5 and J6 independently represent a substituent selected from Q7;
each Q7 and Q8 independently represent halo, -N(R50)R51, -C(=Ya)-OR50, -C(=Ya)-N(R50)R51, -C(=Ya)-R50, -S(0)2R50 or d_3 alkyl optionally substituted by one or more fluoro atoms;
each Ya independently represents =S or, preferably, =0;
each R50 and R51 independently represents hydrogen, C-M alkyl (e.g. te -butyl or methyl) or R50 and R51, 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).
Other preferred compounds of the invention (component (A) of the combinations of the invention) that may be mentioned include:
R1 represents -N(R a)R1b as hereinbefore defined (especially in which R1a and R1b 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;
R2 represents a substituent other than hydrogen, and R3 and R4 independently represent hydrogen or a substituent other than hydrogen;
R2 represents a substituent other than hydrogen;
R2 represents Q1 or C1-2 alkyl (e.g. methyl) optionally substituted by Q2 (e.g. at the terminal position of the methyl group);
R3 and R4 independently represent C -2 alkyl or, preferably, hydrogen or Q1 (e.g. in which Q1 preferably represents halo (e.g. chloro) or heterocycloalkyl optionally substituted by one or more E6 groups);
at least one of R3 and R4 represent hydrogen; R5 represents: (a) phenyl (which is preferably substituted e.g. by one E5 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 E5 substituent(s) (e.g. located at the 2- position (and optionally 6-position), when R5 represents pyrimidinyl, or, at the 6- position when R5 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;
Q1 represents -C(O)N(R10a)R 1a or -C(O)OR10a (e.g. in which R10a is C,-2 alkyl); Q2 represents fluoro, -N(R 0a)R 1a or heterocycloalkyl (e.g. piperazinyl or morpholinyl) optionally (and preferably) substituted by one or more (e.g. one) substituent(s) (preferably located on a nitrogen heteroatom) selected from =0 and, preferably, E6;
R 0a and R11a (for instance when Q1 represents -C(O)N(R10a)R 1a) independently represent hydrogen, acyclic C1-3 (e.g. C -2) alkyl (e.g. methyl or ethyl) (optionally substituted by one or more (e.g. one) E10 substituent), cycloalkyl (e.g. cyclohexyl) (optionally substituted by one or more (e.g. one) E10 substituent) or heterocycloalkyl (e.g. a 5- or 6-membered heterocycloalkyl group (e.g. containing one heteroatom, so forming e.g. piperidinyl, such as 4-piperidinyl, or tetrahydropyranyl, such as 4-tetrahydropyranyl) (optionally substituted by one or more (e.g. one) E10 substituent, which may be located on a nitrogen heteroatom); when Q2 represents -N(R10a)R11a, then R10a and R11a 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. one) substituent(s) (optionally located on a nitrogen heteroatom) selected from =0, E12 and C -2 alkyl (e.g. methyl) optionally substituted by one or more fluoro atoms (and, e.g. in the case of rings containing S, with one or more (e.g. one or two) =0, which carbonyl group(s) are located on the S to form e.g. a -S(0)2- moiety); when E5 represents a substituent on phenyl, then it is preferably Q4 (e.g. -OR20); when E5 represents a substituent on monocyclic heteroaryl, then it is preferably Q4 (e.g. -N(R20)R21) or C1-2 alkyl (e.g. methyl) optionally substituted by one or more fluoro atoms (so forming e.g. a -CF3 group);
E6 and E12 preferably represent Q4;
E10 represents Q4;
for instance when E5 represents Q4, then Q4 represents -OR20 or -N(R20)R21; for instance when E6 and E12 represent Q4, then Q4 represents -S(0)2R20 (e.g.
-S(0)2C1-4 alkyl), -C(0)R20 or -OC(0)R20;
E10 represents -N(R20)R21, -OR20 or -C(0)OR20;
for instance when E 0 represents Q4 (and E10 is a substituent on an alkyl or cycloalkyl group), then Q4 represents -N(R20)R21 or -OR20 (e.g. -OCH3 or -OH); for instance when E10 represents Q4 (and E10 is a substituent on a heterocycloalkyl group), then Q4 represents -C(0)OR20;
R20 and R2 independently represent hydrogen or alkyl (e.g. methyl, ethyl or butyl (e.g isobutyl)), which alkyl group may (e.g. in the case when E12 represents
-C(0)R20) be substituted with a J4 substituent; or
for instance, when E 0 represents -N(R20)R21, then R20 and R21 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);
J4 represents Q7;
Q7 represents -N(R50)R51;
R50 and R5 independently represent hydrogen, or, preferably, d_2 alkyl (e.g. methyl).
Most preferred compounds of the invention (component (A) of the combinations of the invention) include those in which:
R represents 1-piperidinyl or, preferably, 4-morpholinyl;
R2 represents hydrogen or, preferably, methyl, -CF3, -CH2-[4-S(0)2CH3- piperazinyl], -0(O)N(H)ethyl, -C(0)NH2, -C(0)Oethyl, -C(0)N(H)-CH2CH2- N(CH3)2, -C(0)N(H)methyl, -CH2-[4-morpholinyl], -C(0)N(H)-CH2CH2-OCH3, -C(0)N(H)-[(1-C(0)OCH2CH3)-piperidin-4-yl], -C(0)N(H)-[4-tetrahydropyranyl], -C(0)N(H)-[4-OH-cyclohexyl], -CH2-[4-C(0)i-butyl-2,6-diemthyl-piperazinyl], -CH2-[4-S(0)2CH3-2,6-dimethyl-piperazinyl], -CH2-[4-(S(0)2CH2CH3)-piperazinyl], -CH2-[4-(S(0)2CH2-C(H)(CH3)2)-piperazinyl], -CH2-[1,1-dioxo-thiomorpholinyl], -CH2-[piperazinyl], -CH2-[4-(C(0)CH2N(CH3)2)-piperazinyl] or
-CH2-[4-(C(0)C(H)(CH3)-0-C(0)CH3)-piperazinyl];
R3 represents 4-piperidinyl (e.g. containing a double bond at the 3,4-position and a -C(0)-C(H)(CH3)2 substituent at the 1 -position) or, preferably, hydrogen;
R4 represents hydrogen or halo (e.g. chloro);
at least one of R3 and R4 (preferably both) represent hydrogen;
R5 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)CH3-5-pyrimidinyl.
Particularly preferred compounds of the invention include those of the examples descibred hereinafter. For example:
ethyl 6-(3-hydroxyphenyl)-8-morpholinoimidazo[1 ,2-a]pyrazine-2-carboxylate (2- 01);
6-(3-hydroxyphenyl)-8-morpholinoimidazo[1 ,2-a]pyrazine-2-carboxylic acid (2-02);
6-(3-hydroxyphenyl)-8-morpholinoimidazo[1 ,2-a]pyrazine-2-carbaldehyde (2-03);
3-(2-(hydroxymethyl)-8-morpholinoimidazo[1 ,2-a]pyrazin-6-yl)phenol (2-04);
tert-butyl 4-((6-(3-hydroxyphenyl)-8-morpholinoimidazo[1,2-a]pyrazin-2-yl)methyl)- piperazine-1-carboxylate (2-05);
1 -(4-((6-(3-hydroxyphenyl)-8-morpholinoimidazo[1 ,2-a]pyrazin-2-yl)methyl)- piperazin-1-yl)ethanone (2-06);
3- (2-((4-methylpiperazin-1-yl)methyl)-8-morpholinoimidazo[1,2-a]pyrazin-6- yhphenol (2-07);
4- ((6-(3-hydroxyphenyl)-8-morpholinoimidazo[1 ,2-a]pyrazin-2-yl)methyl)piperazin- 2-one (2-08);
3-(8-morpholino-2-(morpholinomethyl)imidazo[1 ,2-a]pyrazin-6-yl)phenol (2-09); 1-(4-((6-(3-hydroxyphenyl)-8-morpholinoimidazo[1,2-a]pyrazin-2-yl)methyl)- piperazin-1-yl)sulfonylmethane (2-10);
(6-(3-hydroxyphenyl)-8-morpholinoimidazo[1 ,2-a]pyrazin-2-yl)(4-sulfonylmethyl- piperazin-1-yl)methanone (2-11);
3-(8-morpholinoimidazo[1 ,2-a]pyrazin-6-yl)phenol (2-12);
3-(2-(trifluoromethyl)-8-morpholinoimidazo[1 ,2-a]pyrazin-6-yl)phenol (2-13);
3-(2-cyclopropyl-8-morpholinoimidazo[1,2-a]pyrazin-6-yl)phenol (2-14); (6-(1 H-indazol-4-yl)-8-morpholinoimidazo[1 ,2-a]pyrazin-2-yl)(4-methylpiperazin-1 - yl)methanone (2-15);
(6-(1H-indazol-4-yl)-8-morpholinoimidazo[1 ,2-a]pyrazin-2-yl)(4-sulfonylmethyl- piperazin-1-yl)methanone (2-16);
6-(1H-indazol-4-yl)-2-((4-sulfonylmethylpiperazin-1-yl)methyl)-8-morpholino- imidazo[1 ,2-a]pyrazine (2-17);
(6-(1H-indazol-4-yl)-8-morpholinoimidazo[1,2-a]pyrazin-2-yl)(piperazin-1-yl)- methanone (2-18);
2- cyclopropyl-6-(1 H-indazol-4-yl)-8-morpholinoimidazo[1 ,2-a]pyrazine (2-19); 2-(trifluoromethyl)-6-(1 H-indazol-4-yl)-8-morpholinoimidazo[1 ,2-a]pyrazine (2-20); 6-(1 H-indazol-4-yl)-8-morpholinoimidazo[1 ,2-a]pyrazine-2-carboxamide (2-21 ); 6-(1 H-indazol-4-yl)-8-morpholinoimidazo[1 ,2-a]pyrazine-2-carbonitrile (2-22);
3- (2-methyl-8-morpholinoimidazo[1,2-a]pyrazin-6-yl)phenol (2-23);
6-(1 H-indazoI-4-yl)-2-methyl-8-morpholinoimidazo[1 ,2-a]pyrazine (2-24);
6-(1 H-indol-5-yl)-2-methyl-8-morpholinoimidazo[1 ,2-a]pyrazine (2-25);
2-methyl-8-morpholino-6-(pyridin-3-yl)imidazo[1,2-a]pyrazine (2-26);
6-(5-methoxypyridin-3-yl)-2-methyl-8-morpholinoimidazo[1 ,2-a]pyrazine (2-27); N-sulfonylmethyl-3-(2-methyl-8-morpholinoimidazo[1,2-a]pyrazin-6-yl)benzen- amine (2-28);
1-methyI-3-(4-(2-methyl-8-morpholinoimidazo[1 ,2-a]pyrazin-6-yl)phenyl)urea (2- 29);
5- (2-methyl-8-morpholinoimidazo[1 ,2-a]pyrazin-6-yl)pyridin-3-ol (2-30);
2- methyl-8-morpholino-6-(pyridin-4-y!)imidazo[1,2-a]pyrazine (2-31);
6- (3-methoxyphenyl)-2-methyl-8-morpholinoimidazo[1,2-a]pyrazine (2-32);
5-chloro-2-methyl-8-morpholino-6-(pyridin-4-yl)imidazo[1 ,2-a]pyrazine (2-33);
5- chIoro-2-methyl-8-morpholino-6-(pyridin-3-yl)imidazo[1 ,2-a]pyrazine (2-34); 8-morpholino-6-phenylimidazo[1,2-a]pyrazine-2-carboxamide (2-35);
6- (1H-indazol-4-yl)-2-methyl-8-morpholinoimidazo[1,2-a]pyrazine-5-carbonitrile (2-36);
3-(3-(4-methylpiperazin-1-yl)-8-morpholinoimidazo[1 ,2-a]pyrazin-6-yl)phenol (2- 37);
6-(1H-indazol-4-yl)-3-(4-methylpiperazin-1-yl)-8-morpholinoimidazo[1 ,2-a]- pyrazine (2-38);
3- (3-(4-sulfonylmethylpiperazin-1-yl)-8-morpholinoimidazo[1,2-a]pyrazin-6- yl)phenol (2-39); 3-(8-morpholino-3-(piperazin-1-yl)imidazo[1,2-a]pyrazin-6-yl)phenol (2-40);
6-(1H-indazol-4-yl)-3-(4-sulfonylmethylpiperazin-1-yl)-8-morpholinoimidazo[1 ,2- alpyrazine (2-41);
3-bromo-6-(1 H-indazol-4-yl)-2-methyl-8-morpholinoimidazo[1 ,2-a]pyrazine (2-42); tert-butyl 2-(4-(6-(1 H-indazol-4-yl)-2-methyl-8-morpholinoimidazo[1 ,2-a]pyrazin-3- yl)-5,6-dihydropyridin-1 (2H)-yl)acetate (2-43);
3-(1,2,3,6-tetrahydropyridin-4-yl)-6-(1H-indazol-4-yl)-2-methyl-8-morpholino- imidazo[1 ,2-a]pyrazine (2-44);
3-(1,2,3,6-tetrahydro-1-methylpyridin-4-yl)-6-(1H-indazol-4-yl)-2-methyl-8- morpholinoimidazo[1 ,2-a]pyrazine (2-45);
3-(1 ,2,3,6-tetrahydro-1 -sulfonyImethylpyridin-4-yl)-6-(1 H-indazol-4-yl)-2-methyl-8- morpholinoimidazo[1 ,2-a]pyrazine (2-46);
tert-butyl 2-(4-(6-(1 H-indazol-4-yl)-2-methyl-8-morpholinoimidazo[1 ,2-a]pyrazin-3- yl)piperidin-1 -yl)acetate (2-47);
5-chloro-6-(3-methoxyphenyl)-2-methyl-8-morpholinoimidazo[1 ,2-a]pyrazine (2- 48);
3-(5-chloro-2-methyl-8-morpholinoimidazo[1,2-a]pyrazin-6-yl)phenol (2-49);
5- (2-((4-sulfonylmethylpiperazin-1-yl)methyl)-8-morpholinoimidazo[1 ,2-a]pyrazin-
6- yl)pyrimidin-2-amine (2-50);
6-(1H-indazol-4-yl)-8-morpholino-3-(piperazin-1-yl)imidazo[1 ,2-a]pyrazine (2-51); ethyl 6-(1 H-indazol-4-yl)-8-morpholinoimidazo[1 ,2-a]pyrazine-2-carboxylate (2- 52);
5-iodo-6-(3-methoxyphenyl)-2-methyl-8-moφholinoimidazo[1 ,2-a]pyrazine (2-53); 5-chloro-6-(1 H-indazol-4-yl)-2-methyl-8-morpholinoimidazo[1 ,2-a]pyrazine (2-54); 5-bromo-6-(1 H-indazol-4-yl)-2-methyl-8-morpholinoimidazo[1 ,2-a]pyrazine (2-55);
5- iodo-2-methyl-8-morpholino-6-(pyridin-3-yl)imidazo[1 l2-a]pyrazine (2-56);
6- (1H-indazol-4-yl)-2-methyl-8-morpholino-3-(piperidin-4-yl)imidazo[1 ,2-a]- pyrazine (2-57);
6-(1H-indazol-4-yl)-2-methyl-3-(1-methylpiperidin-4-yl)-8-morpholinoimidazo[1 ,2- a]pyrazine (2-58);
6-(1H-indazol-4-yl)-2-methyl-3-(1-sulfonylmethylpiperidin-4-yl)-8-mo holino imidazo[1 ,2-a]pyrazine (2-59);
5-chloro-6-( 1 H-indazol-4-yl)-8-morpholino-2-((4-sulfonylmethylpiperazin- 1 -yl)- methyl)imidazo[1 ,2-a]pyrazine (2-60); 6-(6-methoxypyridin-3-yl)-2-((4-sulfonylmethylpiperazin-1-yl)methyl)-8- morpholinoimidazo[1 ,2-a]pyrazine (2-61);
6-(3-methoxyphenyl)-2-methyl-8-morpholinoimidazo[1,2-a]pyrazine-3-carbonitrile (2-62);
tert-butyl 4-(6-(1 H-indazol-4-yl)-2-methyl-8-morpholinoimidazo[1 ,2-a]pyrazine-3- carboxamido)piperidine-1 -carboxylate (2-63);
6-(1H-indazol-4-yl)-2-methyI-8-morpholino-N-(piperidin-4-yl)imidazo[1,2-a]- pyrazine-3-carboxamide (2-64);
6-(5-methoxypyridin-3-yI)-2-((4-sulfonylmethylpiperazin-1-yl)methyl)-8- morpho!inoimidazo[1 ,2-a]pyrazine (2-65);
5- (2-((4-sulfonyl methylpiperazin-1-yl)methyl)-8-morpholinoimidazo[1 ,2-a]pyrazin-
6- yl)pyridin-2-amine (2-66);
6-(2-methoxypyrimidin-5-yl)-2-((4-suIfonylmethylpiperazin-1-y!)methyl)-8- morpholinoimidazo[1 ,2-a]pyrazine (2-67);
4-(2-((4-sulfonylmethylpiperazin-1 -yl)methyl)-8-morpholinoimidazo[1 ,2-a]pyrazin- 6-yl)benzamide (2-68);
5- (2-((4-sulfonylmethylpiperazin-1-yl)methyl)-8-morpholinoimidazo[1 ,2-a]pyrazin-
6- yl)indolin-2-one (2-69);
6-(5-fluoro-1H-indol-4-yl)-2-((4-sulfonylmethylpiperazin-1-yl)methyl)-8-morpholi imidazo[1 ,2-a]pyrazine (2-70);
6-(1H-indol-4-yl)-2-((4-sulfonylmethylpiperazin-1-yl)methy!)-8-morpholino- imidazo[1 ,2-a]pyrazine (2-71);
3-(2-((4-sulfonylmethylpiperazin-1-yl)methyl)-8-morpholinoimidazo[1 ,2-a]pyrazin- 6-yl)benzamide (2-72);
6-(1 H-indazol-4-yl)-3-iodo-2-methyl-8-morpholinoimidazo[1 ,2-a]pyrazine (2-73); N-ethyl-6-(1H-indazol-4-yl)-8-morpholinoimidazo[1 ,2-a]pyrazine-2-carboxamide (2-74);
2-((4-sulfonylmethylpiperazin-1-yl)methyl)-8-morpholino-6-(1H-pyrrolo[2,3- b]pyridin-5-yl)imidazo[1 ,2-a]pyrazine (2-75).
Compounds of the invention may be made in accordance with techniques that are well known to those skilled in the art, for example as described hereinafter.
According to a further aspect of the invention there is provided a process preparation of a compound of formula I which process comprises: (i) reaction of a compound of formula IB,
Figure imgf000063_0001
wherein L1 represents a suitable leaving group, such as iodo, bromo, chloro or a sulfonate group (e.g. -OS(0)2CF3, -OS(0)2CH3 or -OS(0)2PhMe), and R1, R2, R3, and R4 are as hereinbefore defined, with a compound of formula IC,
R5-L2 IC wherein L2 represents a suitable group such as -B(OH)2, -B(ORwx)2 or -Sn(Rw )3, in which each Rwx independently represents a C1-6 alkyl group, or, in the case of -B(ORwx)2, the respective Rw groups may be linked together to form a 4- to 6- membered cyclic group (such as a 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl group), thereby forming e.g. a pinacolato boronate ester group, (or L2 may represent iodo, bromo or chloro, provided that L and L2 are mutually compatible) and R5 is as hereinbefore defined. The reaction may be performed, for example in the presence of a suitable catalyst system, e.g. a metal (or a salt or complex thereof) such as Pd, Cul, Pd/C, PdCI2, Pd(OAc)2, Pd(Ph3P)2CI2, Pd(Ph3P)4 (i.e. palladium tetrakistriphenylphosphine), Pd2(dba)3 and/or NiCI2 (preferred catalysts include palladium) and a ligand such as PdCI2(dppf).DCM, i-Bu3P, (CsHn^P, Ph3P, 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 PdCI2(dppf).DC ), together with a suitable base such as, Na2C03, K3P04, Cs2C03, NaOH, KOH, 2C03, CsF, Et3N, (/-Pr)2NEt, f-BuONa or f-BuOK (or mixtures thereof; preferred bases include Na2C03 and K2C03) in a suitable solvent such as dioxane, toluene, ethanol, dimethylformamide, dimethoxyethane, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, W-methylpyrrolidinone, tetrahydrofuran or mixtures thereof (preferred solvents include dimethylformamide and dimethoxyethane). The reaction may be carried out for example at room temperature or above (e.g. at a high temperature such as at about the reflux temperature of the solvent system). Alternative reaction conditions include microwave irradiation conditions, for example at elevated temperature of about 130°C;
(ii) reaction of a compound of formula ID,
Figure imgf000064_0001
wherein L3 represents a suitable leaving group, such as one hereinbefore defined in respect of L1, and R2, R3, R4 and R5 are as hereinbefore defined, with a compound of formula IE,
R1-L4 IE wherein L4 represents a suitable leaving group, such as one hereinbefore described in respect of L2, under reaction conditions such as those descibred in respect of process step (i) above, or, in the case where R1 represents -N(R a)R b, L4 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) (Pd2(dba)3) or NiCI2 and an optional additive such as Ph3P, 2,2 - bis(diphenylphosphino)-1 ,1'-binaphthyl, xantphos, Nal or an appropriate crown ether such as 18-crown-6-benzene, in the presence of an appropriate base such as NaH, Et3N, pyridine, A/.W-dimethylethylenediamine, Na2C03, K2C03, K3P04, Cs2C03, f-BuONa or f-BuOK (or a mixture thereof, optionally in the presence of 4A molecular sieves), in a suitable solvent (e.g. dichloromethane, dioxane, toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran or a mixture thereof). This reaction may be performed at elevated temperature or under microwave irradiation reaction conditions, for example as described in process step (i). The compound of formula ID (e.g. in which L4 is chloro) may be prepared in situ, for example from a compound corresponding to a compound of formula ID, but in which L4 represents -OC -3 alkyl (e.g. methoxy) by reaction in the presence of e.g. a chlorinating agent (such as POCI3);
(iii) reaction of a compound of formula IF,
Figure imgf000065_0001
wherein R1, R4 and L1 are as hereinbefore defined, with a compound of formula IG,
R2-C(0)-C(R3)(H)-L5 IG wherein L5 represents a suitable leaving group, such as one hereinbefore defined in respect of l_ (and, especially, L5 represents halo, such as chloro or bromo), and R2 and R3 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. it may be a carbonyl derivative, for instance R2-C(-OCH3)2-C(R3)(H)-L5, in which R2 preferably represents H). Such an intermediate compound of formula IG in which R3 represents -N(R10a)R11a (in which R10a and R11a may be linked together to form an optionally piperazinyl group) and L5 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,
Figure imgf000066_0001
wherein R1, R4 and R5 are as hereinbefore defined, with a compound of formula IH,
R3-C(H)(L6a)-C(H)(L6b)-R3 IH wherein L6a and L independently represent a suitable leaving group, for example benzotriazole groups (or the like), and each R3 is as hereinbefore defined (e.g. each of the R3 groups are the same), which reaction may be performed following similar conditions reported in literature (J. Org.Chem. 1990, 55, 3209-3213, J.Org.Chem, 2003, 68, 4935-4937), in 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. Additionally an inorganic base can be added to ensure completion of the reaction;
(v) for compounds of formula I in which R3 or R4 represents bromo, iodo or chloro, reaction of a corresponding compound of formula I, in which R3 or R4 (as appropriate) represents hydrogen, with a reagent that is a source of halide ions (a halogenating reagent). For instance, an electrophile that provides a source of iodide ions includes iodine, diiodoethane, diiodotetrachloroethane or, preferably, /V-iodosuccinimide, a source of bromide ions includes 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 CHCI3 or an alcohol (e.g. methanol), optionally in the presence of a suitable base, such as a weak inorganic base, e.g. sodium bicarbonate. Typically, the reaction maybe performed by heating at a convenient temperature, either by conventional heating under reflux or under microwave irradiation; (vi) for compounds of formula I in which R3 or R4 represents a substituent other that hydrogen, or halo (e.g. bromo, iodo or chloro), reaction of a corresponding compound of formula I, in which R3 or R4 (as appropriate) represents bromo, chloro or iodo, with a compound of formula IJ,
R3/4-L7 IJ wherein R3M represents R3 or R4 (as appropriate), and L7 represents a suitable leaving group such as one hereinbefore described in respect of process step (i) or (ii) above. Alternatively, the skilled person will appreciate that different reagents and reaction steps may be employed, depending on the particular R3 or R4 substituent required (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:
(i) reductions of a carboxylic acid (or ester) to either an aldehyde or an alcohol, using appropriate reducing conditions (e.g. when R2 represents -C(0)OH (or an ester thereof), it may be converted to a -C(0)H or -CH2-OH group, using DIBAL and LiAIH4, respectively (or similar chemoselective reducing agents);
(ii) reductions of an aldehyde (-C(O)H) group to an alcohol group (-CH2OH), using appropriate reduction conditions such as those mentioned at point (i) above;
(iii) oxidations, for example of a moiety containing an alcohol group (e.g. -CH2OH) to an aldehyde (e.g. -C(O)H) 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. Mn02 or mcpba or the like;
(iv) reductive amination of an aldehyde and an amine, under appropriate reaction conditions, for example in "one-pot" procedure in the presence of an appropriate reducing agent, such as sodium cyanoborohydride or, preferably, sodium triacetoxyborohydride, or the like (and hence when e.g. R2 represents -C(0)H, such a group may be converted to a -CH2-N(R10a)R a group (or -CH2-N(Ra)(Rb), i.e. a specific fragment of formula la), in which R10a and R1 a are as hereinbefore defined, and may be linked together as hereinbefore defined to form e.g. a 5- or 6-membered ring optionally containing a further heteroatom such as oxygen or nitrogen); (v) formation of 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(R10a)R11a group (in which R10a and R 1a are as hereinbefore defined, and may be linked together, e.g. as defined above), and which reaction may (e.g. for -COOH) be performed in the presence of a suitable coupling reagent (e.g. 1,1 '-carbonyldiimidazole, A/./v'-dicyclohexylcarbodiimide, or the like) or, in the case of an ester (e.g. -C(0)OCH3 or -C(0)OCH2CH3), be performed in the presence of e.g. trimethylaluminium, or, alternatively the -C(0)OH group may first be activated to the corresponding acyl halide (e.g -C(0)CI, by treatment with oxalyl chloride, thionyl chloride, phosphorous pentachloride, phosphorous oxychloride, or the like), and, in all cases, the relevant compound is reacted with a compound of formula HN(R10a)R11a (in which R10a and R1 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);
(vi) conversion of a primary amide to a nitrile functional group, for example under dehydration reaction conditions, e.g. in the presence of POCI3, or the like;
(vii) nucleophilic substitution (e.g. aromatic nucleophilic substitution) reactions, where any nucleophile replaces a leaving group, e.g. an amine may replace a
-S(0)CH3 leaving group, 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);
(viii) transformation of a methoxy group to a hydroxy group, by reaction in the presence of an appropriate reagent, such as boron fluoride-dimethyl sulfide complex or BBr3 (e.g. in the presence of a suitable solvent such as dichloromethane);
(ix) alkylation, acylation or sulfonylation reactions, which may be performed in the presence of base and solvent (such as those described hereinbefore);
(x) specific deprotection steps, such as deprotection of an N-Boc protecting group by reaction in the presence of an acid, or, a hydroxy group protected as a silyl ether (e.g. a tert-butyl-dimethylsilyl protecting group) may be deprotected by reaction with a source of fluoride ions, e.g. by employing the reagent tetrabutylammonium fluoride (TBAF). Further, a -0-C(0)-CH3 may be converted to a -OH group by reaction with sodium methoxide in methanol, or similar hydrolysis reactions may be performed;
(xi) hydrogenations, e.g. of a double bond to a single bond for instance under standard hydrogenation reaction conditions, e.g. under a hydrogen atmosphere in the presence of a catalyst such as Pd/C;
(xii) Grignard reactions, e.g. the addition of a nucleophilic organometalic reagent, for instance the addition of eMgCI to a carbonyl group;
(xiii) formation of a urea functional group by reaction of a isocyanate with an amine, e.g. when R5 represent phenyl substituted by -NH2, this may be converted to a -N(H)-C(O)-N(R20)R21 moiety.
Intermediate compounds described herein are either commercially available, are known in the literature, or may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions. Further, processes to prepare compounds of formula I may be described in the literature, for example in:
Werber.G. et al.; J. Heterocycl. Chem.; EN; 14; 1977; 823-827;
Andanappa K. Gadad et al. Bioorg. Med. Chem. 2004, 12, 5651-5659;
Paul Heinz et al. Monatshefte fur Chemie, 1977, 108, 665-680;
M.A. El-Sherbeny et al. Boll. Chim. Farm. 1997, 136, 253-256;
Nicolaou, K. C; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 2-49;
Bretonnet et al. J. Med. Chem. 2007, 50, 1872 ;
Asuncion Marin et al. Farmaco 1992, 47 (1), 63-75;
Severinsen, R. et al. Tetrahedron 2005, 61, 5565-5575;
Nicolaou, K. C; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 2-49;
M. Kuwahara et al., Chem. Pharm Bull., 1996, 44, 122;
Wipf, P.; Jung, J.-K. J. Org. Chem. 2000, 65(20), 6319-6337;
Shintani, R.; Okamoto, K. Org. Lett. 2005, 7 (21), 4757-4759;
Nicolaou, K. C; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 2-49;
J. Kobe et al., Tetrahedron, 1968, 24, 239 ;
P.F. Fabio, A.F. Lanzilotti and S.A. Lang, Journal of Labelled Compounds and Pharmaceuticals, 1978, 15, 407;
F.D. Bellamy and K. Ou, Tetrahedron Lett, 1985, 25, 839;
M. Kuwahara et al., Chem. Pharm Bull., 1996, 44, 122; A.F. Abdel-Magid and C.A Maryanoff. Synthesis, 1990, 537;
M. Schlosser et al. Organometallics in Synthesis. A Manual, (M. Schlosser, Ed.),
Wiley &Sons Ltd: Chichester, UK, 2002, and references cited therein;
L. Wengwei et al., Tetrahedron Lett, 2006, 47, 1941 ;
M. Plotkin et al. Tetrahedron Lett., 2000, 41, 2269;
Seyden-Penne, J. Reductions by the Alumino and Borohydrides, VCH, NY, 1991 ;
O. C. Dermer, Chem. Rev., 1934, 14, 385;
N. Defacqz, et al., Tetrahedron Lett, 2003, 44, 9111 ;
S.J. Gregson et ai, J. Med. Chem., 2004, 47, 1161 ;
A. M. Abdel Magib, et al., J. Org. Chem., 1996, 61, 3849;
A.F. Abdel-Magid and C.A Maryanoff. Synthesis, 1990, 537;
T. Ikemoto and M. Wakimasu, Heterocycles, 2001 , 55, 99;
E. Abignente et al., II Farmaco, 1990, 45, 1075;
T. Ikemoto et al., Tetrahedron, 2000, 56, 7915;
T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Wiley,
NY, 1999;
S. Y. Han and Y.-A. Kim. Tetrahedron, 2004, 60, 2447;
J. A. H. Lainton et al., J. Comb. Chem., 2003, 5, 400; or
Wiggins, J. M. Synth. Commun., 1988, 18, 741.
For example, intermediate compounds, and compounds of the invention may be prepared in accordance with the following scheme (Scheme I)·
Figure imgf000071_0001
Figure imgf000071_0002
R2= H
Compound 1-01 was reacted with an intermediate (lll-a) of formula R2-C(=0)-CH2-X or an intermediate (lll-b) of formula R2-C(=0)-CH-R3-X, where R2 and R3 are as hereinbefore defined and X represents a suitable leaving group (e.g. a halide), without solvent or in the presence of a suitable reaction solvent such as DME or 2-propanol, at a convenient temperature, typically heating at 90°C, to obtain compounds of formula (ll-a) or formula (ll-b).
Compounds of formula (ll-a) can be reacted with a halogenating agent, such as N-bromoSuccinimide, N-iodosuccininide, N-chlorosuccinimide or others, and X represents an halogen group such as CI, Br or Iodine atom, in the presence of a suitable reaction solvent such as CHCI3, typically heating at a convenient temperature, either by conventional heating under reflux or under microwave irradiation, for a period of time to ensure the completion of the reaction, to obtain compounds of formula (X).
Compounds of formula (X) can react with an intermediate (VII) of formula R1-Nu, where R is as hereinbefore defined and Nu represents a nucleophilic group, such as an amine (and R1-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. Further, reaction may be with an intermediate (VIII) of formula R5-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 R5 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 Na2C03 or K2C03, in the presence of a metal catalyst, such as palladium, and a suitable ligand, such us PdCI2(dppf).DCM, Pd(PPh3)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).
Compounds of formula (XI) can react with an intermediate (XIV) of formula R3-B(OR)2, in which the -B(OR)2 moeity is as defined above, and R3 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).
Compounds of formula (ll-b) can react with an intermediate (VII) of formula R1-Nu (as hereinbefore defined), in a suitable solvent such as DCM, dioxane at room temperature or by heating, for a period of time to ensure the completion of the reaction to afford compounds of formula (IV-b).
Compounds of formula (IV-b) can react with an intermediate (VIII) of formula R5-B(OR)2 as hereinbefore defined, under reaction conditions hereinbefore described (e.g. the reaction of (X) with (VIII)), to obtain compounds of formula (Xll-b).
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).
Compound (V) was reacted with an intermediate (lll-a) of formula R2-C(=0)-CH2-X or an intermediate (lll-b) of formula R2-C(=0)-CH-R3-X, both of which are as hereinbefore defined, under reaction conditions hereinbefore described (e.g. the reaction of (1-01) with (lll-a) or (lll-b)), to obtain compounds of formula (IV-a).
Compounds of formula (IV-a) can react with an intermediate (VIII) of formula R5-B(OR)2l as hereinbefore defined, e.g. under reaction conditions hereinbefore described (e.g. the reaction of (X) with (VIII)), to obtain compounds of formula (VI).
Compounds of formula (VI) can be reacted with a halogenating agent, for example as described hereinbefore (e.g. reaction of (11-3) to (X)), to obtain compounds of formula (IX).
The halogen atom X of compounds of formula (IX) can be substituted via a coupling reaction with an intermediate (XVI) of formula R4-B(OR)2, in which the -B(OR)2 moiety is as hereinbefore defined, and R4 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(PPh3)4 or PdCI2(dppf)2. Additionally an inorganic aqueous base can be added such as Na2C03 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.
Compounds of formula (V) can react with an intermediate (VIII) of formula R5-B(OR)2 as hereinbefore defined, e.g. under reaction conditions hereinbefore described (e.g. the reaction of (X) with (VIII)), to obtain compounds of formula (XVI).
Compounds of formula (XVI) can react with an intermediate of formula XX, in which Bzt is Benzotriazol, following similar conditions reported in literature (J. Org.Chem. 1990, 55, 3209-3213, J.Org.Chem, 2003, 68, 4935-4937), in a suitable solvent, such as DCE, heating at a convenient temperature, in a period of time to ensure completion of the reaction, typically at reflux for 5h. Additionally an inorganic base can be added to ensure completion of the reaction.
Compounds of formula (ll-a) can react with sodium methoxide in the presence of methanol, at room temperature or by heating at a convenient temperature, such as 60°C, to obtain compounds of formula (XVII).
Compounds of formula (XVII) can react with an intermediate (VIII) of formula R5-B(OR)2 as hereinbefore defined, e.g. under reaction conditions hereinbefore described (e.g. the reaction of (X) with (VIII)), to obtain compounds of formula (XVIII).
Compound of formula (XVIII) can react with POCI3 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).
Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds of the invention. Although specific starting materials and reagents are depicted in the Scheme 1 and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions.
The substituents R1, R2, R3, R4 and R5 in final compounds of the invention or relevant intermediates may be modified one or more times, after or during the processes described above by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions, oxidations, alkylations, acylations, hydrolyses, esterifications, etherifications, halogenations or nitrations. Such reactions may result in the formation of a symmetric or asymmetric final compound of the invention or intermediate. The precursor groups can be changed to a different such group, or to the groups defined in formula I, at any time during the reaction sequence.
For example, when R2, R3 and R4 groups such as C02Et, CHO, CN and/or CH2CI, are present, these groups can be further derivatized to other fragments described in R2, R3 and R4 in compounds of the invention, following synthetic protocols very well know to the person skilled in the art and/or according to the experimental part described in the patent. Other specific transformation steps that may be mentioned include: the reduction of a nitro or azido group to an amino group; the hydrolysis of a nitrile group to a carboxylic acid group; and standard nucleophilic aromatic substitution reactions, for example in which an iodo-, preferably, fluoro- or bromo-phenyl group is converted into a cyanophenyl group by employing a source of cyanide ions (e.g. by reaction with a compound which is a source of cyano anions, e.g. sodium, copper (I), zinc or potassium cyanide, optionally in the presence of a palladium catalyst) as a reagent (alternatively, in this case, palladium catalysed cyanation reaction conditions may also be employed). Other transformations that may be mentioned include: the conversion of a halo group (preferably iodo or bromo) to a 1-alkynyl group (e.g. by reaction with a 1- alkyne), which latter reaction may be performed in the presence of a suitable coupling catalyst (e.g. a palladium and/or a copper based catalyst) and a suitable base (e.g. a tri-(C1-6 alkyl)amine such as triethylamine, tributylamine or ethyldiisopropylamine); the introduction of amino groups and hydroxy groups in accordance with standard conditions using reagents known to those skilled in the art; the conversion of an amino group to a halo, azido or a cyano group, for example via diazotisation (e.g. generated in situ by reaction with NaN02 and a strong acid, such as HCI or H2S04, at low temperature such as at 0°C or below, e.g. at about -5°C) followed by reaction with the appropriate nucleophile e.g. a source of the relevant anions, for example by reaction in the presence of a halogen gas (e.g. bromine, iodine or chlorine), or a reagent that is a source of azido or cyanide anions, such as NaN3 or NaCN; the conversion of -C(0)OH to a -NH2 group, under Schmidt reaction conditions, or variants thereof, for example in the presence of HN3 (which may be formed in by contacting NaN3 with a strong acid such as H2S04), or, for variants, by reaction with diphenyl phosphoryl azide ((PhO)2P(0)N3) in the presence of an alcohol, such as tert-butanol, which may result in the formation of a carbamate intermediate; the conversion of -C(0)NH2 to -NH2, for example under Hofmann rearrangement reaction conditions, for example in the presence of NaOBr (which may be formed by contacting NaOH and Br2) which may result in the formation of a carbamate intermediate; the conversion of -C(0)N3 (which compound itself may be prepared from the corresponding acyl hydrazide under standard diazotisation reaction conditions, e.g. in the presence of NaN02 and a strong acid such as H2S04 or HCI) to -NH2, for example under Curtius rearrangement reaction conditions, which may result in the formation of an intermediate isocyanate (or a carbamate if treated with an alcohol); the conversion of an alkyl carbamate to -NH2, by hydrolysis, for example in the presence of water and base or under acidic conditions, or, when a benzyl carbamate intermediate is formed, under hydrogenation reaction conditions (e.g. catalytic hydrogenation reaction conditions in the presence of a precious metal catalyst such as Pd); halogenation of an aromatic ring, for example by an electrophilic aromatic substitution reaction in the presence of halogen atoms (e.g. chlorine, bromine, etc, or an equivalent source thereof) and, if necessary an appropriate catalyst/Lewis acid (e.g. AICI3 or FeCIs).
Compounds of the invention bearing a carboxyester functional group may be converted into a variety of derivatives according to methods well known in the art to convert carboxyester groups into carboxamides, N-substituted carboxamides, Ν,Ν-disubstituted carboxamides, carboxylic acids, and the like. The operative conditions are those widely known in the art and may comprise, for instance in the conversion of a carboxyester group into a carboxamide group, the reaction with ammonia or ammonium hydroxide in the presence of a suitable solvent such as a lower alcohol, dimethylformamide or a mixture thereof; preferably the reaction is carried out with ammonium hydroxide in a methanol/dimethyl- formamide mixture, at a temperature ranging from about 50°C to about 100°C. Analogous operative conditions apply in the preparation of N-substituted or N,N- disubstituted carboxamides wherein a suitable primary or secondary amine is used in place of ammonia or ammonium hydroxide. Likewise, carboxyester groups may be converted into carboxylic acid derivatives through basic or acidic hydrolysis conditions, widely known in the art. Further, amino derivatives of compounds of the invention may easily be converted into the corresponding carbamate, carboxamido or ureido derivatives.
Compounds of the invention may be isolated from their reaction mixtures using conventional techniques (e.g. recrystallisations). It will be appreciated by those skilled in the art that, in the processes described above and hereinafter, the functional groups of intermediate compounds may need to be protected by protecting groups.
The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods (and the need can be readily determined by one skilled in the art). Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection is readily determined by one skilled in the art. The protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes.
Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter. For example, protected compounds/intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques.
The type of chemistry involved will dictate the need, and type, of protecting groups as well as the sequence for accomplishing the synthesis.
The use of protecting groups is fully described in "Protective Groups in Organic Synthesis", 3rd edition, T.W. Greene & P.G.M. Wutz, Wiley-lnterscience (1999). Medical and Pharmaceutical Uses
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.
For the avoidance of doubt, although 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 (which also includes compounds that may possess some pharmacological activity, but that activity is appreciably lower than that of the "active" compounds of the invention to which they are metabolised), may also be described as "prodrugs". Thus, 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. Thus, 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.
The term "inhibit" may refer to any measurable reduction and/or prevention of catalytic kinase (e.g. PI3K, particularly class I PI3K, and/or mTOR) activity. The reduction and/or prevention of kinase activity may be measured by comparing the kinase activity in a sample containing a compound of the invention, 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. measurable by some test or marker, for example in an in vitro or in vivo assay or test, such as one described hereinafter, or otherwise another suitable assay or test known to those skilled in the art) or subjective (e.g. the subject gives an indication of or feels an effect). 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 μΜ or below (for example at a concentration of below 50 μΜ, or even below 10 μΜ, such as below 1 μΜ), when tested in an assay (or other test), for example as described hereinafter, or otherwise another suitable assay or test known to the skilled person. 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). Hence, 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). 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).
The 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. Other associated diseases that may be mentioned (particularly due to the key role of kinases in the regulation of cellular proliferation) include other cell proliferative disorders and/or non- malignant diseases, such as benign prostate hyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis, psoriasis, bone disorders, atherosclerosis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis. Other disease states that may be mentioned include cardiovascular disease, stroke, diabetes, hepatomegaly, Alzheimer's disease, cystic fibrosis, hormone- related diseases, immunodeficiency disorders, destructive bone disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukaemia, liver disease, pathologic immune conditions involving T cell activation and CNS disorders.
As stated above, the 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 passages, kidney carcinoma, myeloid disorders, lymphoid disorders, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, Hodgkin's and leukaemia; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-ce!l-lymphoma, Hodgkin's lymphoma, non- Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannomas; and other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, thyroid follicular cancer and Kaposi's sarcoma. In particular, 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.
Further, the protein or lipid kinases (e.g. PI3K, such as class I PI3K, and/or mTOR) may also be implicated in the multiplication of viruses and parasites. They may also play a major role in the pathogenesis and development of neurodegenerative disorders. Hence, 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.
According to a further aspect of the present invention, there is provided a method of treatment of a disease (e.g. cancer or another disease as mentioned herein) which is associated with the inhibition of protein or lipid kinase (e.g. PI3K, such as class I PI3K, and/or mTOR) 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.
"Patients" include mammalian (including human) patients. Hence, the method of treatment discussed above may include the treatment of a human or animal body.
The term "effective amount" refers to an amount of a compound 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.
According to a further aspect of the invention there is thus provided a pharmaceutical formulation including a combination of the invention, as hereinbefore defined, in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier.
Depending on e.g. potency and physical characteristics of the active components of the combination of the invention (i.e. active ingredients), 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.
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.
For instance, compounds of the invention may be combined with a therapeutic/chemotherapeutic agent (component (B)). Most preferred combinations of the invention include those in which component (B), i.e. the therapeutic/chemotherapeutic agent, is as hereinbefore defined. 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. Examples of 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.
Examples of 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. 41575-94-4), 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. 85622-93-1, TEMODAR®, TEMODAL®, Schering Plough), 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).
More examples of 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/Bcl-xL inhibitor, Abbott Laboratories and Genentech), PTK787/ZK 222584 (Novartis), fulvestrant (FASLODEX®, AstraZeneca), leucovorin (folinic acid), lonafamib (SARASAR™, SCH 66336, Schering Plough), sorafenib (NEXAVAR®, BAY43-9006, Bayer Labs), gefitinib (IRESSA®, AstraZeneca), irinotecan (CAMPTOSAR®, CPT-11, Pfizer), tipifarnib (ZARNESTRA™, Johnson & Johnson), capecitabine (XELODA®, Roche), ABRAXANE™ (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, 11), vandetanib (rINN, ZD6474, ZACTIMA®, AstraZeneca), chloranmbucil, AG1478, AG1571 (SU 5271 ; Sugen), temsirolimus (TORISEL®, Wyeth), pazopanib (GlaxoSmithKline), canfosfamide (TELCYTA®, Telik), thioTepa and cyclosphosphamide (CYTOXAN®, NEOSAR®); alkyl sulfonates such as busuifan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analog topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, calicheamicin gamma II, calicheamicin omega II, dynemicin, dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L- norleucine, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino- doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; antiadrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; tiaziquone; 2,2',2"- trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thioTepa; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine (NAVELBINE®); novantrone; teniposide; edatrexate; daunomycin; aminopterin; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylomithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above. 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® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; as well as troxacitabine (a 1 ,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors such as MEK inhibitors (WO 2007/044515); (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, for example, PKC-alpha, Raf and H-Ras, such as oblimersen (GENASENSE®, Genta Inc.); (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®, LEUVECTIN®, and VAXID®; PROLEUKN® rlL-2; topoisomerase 1 inhibitors such as LURTOTECAN®; ABARELIX® rmRH; (ix) anti-angiogenic agents such as bevacizumab (AVASTIN®, Genentech); and pharmaceutically acceptable salts, acids and derivatives of any of the above.
Also included in the definition of "chemotherapeutic agent" are therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idee), pertuzumab (OMNITARG™, rhuMab 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).
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, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pertuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, rolizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, trastuzumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, and visilizumab.
By "bringing into association", we mean that the two components are rendered suitable for administration in conjunction with each other. Thus, in relation to the process for the preparation of a kit of parts as hereinbefore defined, by bringing the two components "into association with" each other, we include that the two components of the kit of parts may be:
(i) provided as separate formulations (i.e. independently of one another), which are subsequently brought together for use in conjunction with each other in combination therapy; or
(ii) packaged and presented together as separate components of a "combination pack" for use in conjunction with each other in combination therapy. Depending on the disorder, and the patient, to be treated, as well as the route of administration, individual components of the combinations of the invention (or a combination product itself) may be administered at varying therapeutically effective doses to a patient in need thereof. However, the dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the mammal over a reasonable timeframe. One skilled in the art will recognize that the selection of the exact dose and composition and the most appropriate delivery regimen will also be influenced by inter alia the pharmacological properties of the formulation, the nature and severity of the condition being treated, and the physical condition and mental acuity of the recipient, as well as the potency of the specific compound, the age, condition, body weight, sex and response of the patient to be treated, and the stage/severity of the disease.
Administration may be continuous or intermittent (e.g. by bolus injection). The dosage may also be determined by the timing and frequency of administration. In the case of oral or parenteral administration the dosage can vary from about 0.01 mg to about 1000 mg per day of a combination of the invention.
In any event, the medical practitioner, or other skilled person, will be able to determine routinely the actual dosage, which will be most suitable for an individual patient. The above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention. 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. Advantageously, 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). Such 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.
Examples/Biological Tests
Determination of the activity of PI3 kinase activity of compounds of the invention is possible by a number of direct and indirect detection methods. Certain exemplary compounds described herein were prepared, characterized, and tested for their PI3K binding activity and in vitro activity against tumor cells. The range of PI3K binding activities was less than 1 nM to about 10 μΜ (i.e. certain compounds of the examples/invention had PI3K binding activity IC50 values of less than 10 nM). Compounds of the examples/invention had tumor cell-based activity IC50 values less than 100 nM (see Table 4 below). PI3K activity assay
The kinase activity was measured by using the commercial ADP Hunter™ Plus assay available from DiscoveRx (#33-016), which is a homogeneous assay to measure the accumulation of ADP, a universal product of kinase activity. The enzyme, PI3K (ρ110α/ρ85α was purchased from Carna Biosciences (#07CBS- 0402A). The assay was done following the manufacturer recommendations with slight modifications: Mainly the kinase buffer was replace by 50 mM HEPES, pH 7.5, 3 mM MgCI2, 100 mM NaCI, 1 mM EGTA, 0.04% CHAPS, 2 mM TCEP and 0.01 mg/ml BGG. The PI3K was assayed in a titration experiment to determine the optimal protein concentration for the inhibition assay. To calculate the IC50 of the ETP-compounds, serial 1 :5 dilutions of the compounds were added to the enzyme at a fixed concentration (2.5 μg ml. The enzyme was preincubated with the inhibitor and 30 μΜ PIP2 substrate (P9763, Sigma) for 5 min and then ATP was added to a final 50 μΜ concentration. Reaction was carried out for 1 hour at 25°C. Reagent A and B were sequentially added to the wells and plates were incubated for 30 min at 37 °C. Fluorescence counts were read in a Victor instrument (Perkin Elmer) with the recommended settings (544 and 580 nm as excitation and emission wavelengths, respectively). Values were normalized against the control activity included for each enzyme (i.e., 100 % PI3 kinase activity, without compound). These values were plot against the inhibitor concentration and were fit to a sigmoid dose-response curve by using the Graphad software. Cellular Mode of Action
Cell culture: The cell lines were obtained from the American Type Culture Collection (ATCC). U20S (human osteosarcoma) was cultured in Dulbecco's modified Eagle's medium (DMEM). PC3 (human prostate carcinoma), MCF7 (human breast cardinoma), 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% C02 and passaged when confluent using trypsin/EDTA. U2foxRELOC and U2nesRELOC assay: The U2nesRELOC assay and the U2foxRELOC assay have been described previously (1 , 2). Briefly, cells were seeded at a density of 1.0*105 cells/ml into black-wall clear-bottom 96-well microplates (BD Biosciences) After incubation at 37°C with 5% C02 for 12 hours, 2μΙ of each test compound were transferred from the mother plates to the assay plates. Cells were incubated in the presence of the compounds for one hour. Then cells were fixed and the nucleus stained with DAPI (Invitrogen). Finally the plates were washed with 1X PBS twice and stored at 4°C before analysis. Compounds of the invention have a range of in vitro cell potency activities from about 1 nM to about 10 μΜ.
Image acquirement and processing: Assay plates were read on the BD Pathway™ 855 Bioimager equipped with a 488/10 nm EGFP excitation filter, a 380/10 nm DAPI excitation filter, a 515LP nm EGFP emission filter and a 435LP nm DAPI emission filter. Images were acquired in the DAPI and GFP channels of each well using 10x dry objective. The plates were exposed 0.066 ms (Gain 31) to acquire DAPI images and 0.55 ms (Gain 30) for GFP images.
Data analysis: The BD Pathway Bioimager outputs its data in standard text files. Data were imported into the data analysis software BD Image Data Explorer. The nuclear/cytoplasmic (Nuc/Cyt) ratios of fluorescence intensity were determined by dividing the fluorescence intensity of the nucleus by the cytoplasmic. A threshold ratio of greater than 1.8 was employed to define nuclear accumulation of fluorescent signal for each cell. Based on this procedure we calculated the percentage of cells per well displaying nuclear translocation or inhibition of nuclear export. Compounds that induced a nuclear accumulation of the fluorescent signal greater than 60% of that obtained from wells treated with 4nM LMB were considered as hits. In order to estimate the quality of the HCS assay, the Z' factor was calculated by the equation: Z" = 1 - [(3 χ std. dev. of positive controls) + (3 χ std. dev. of negative controls) / (mean of positive controls) - (mean of negative controls)].
PI3K signalling
AKT phosphorylation Inhibition. Western Blot Analysis: Subconfluent cells were incubated under different conditions and washed twice with TBS prior to lysis. Lysis buffer was added containing 50 mM Tris HCI, 150 mM NaCI, 1% NP- 40, 2mM Na3V04, 100 mM NaF, 20 mM Na4P207 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 μΜ.
Cytotoxicity assessment
The compounds were tested on 96-well trays. Cells growing in a flask were harvested just before they became confluent, counted using a haemocytometer and diluted down with media adjusting the concentration to the required number of cells per 0.2 ml (volume for each well). Cells were then seeded in 96-well trays at a density between 1000 and 4000 cells/well, depending of the cell size. Cells were left to plate down and grow for 24 hours before adding the drugs. Drugs were weighed out and diluted with DMSO to get them into solution to a concentration of 10mM. From here a "mother plate" with serial dilutions was prepared at 200X the final concentration in the culture. The final concentration of DMSO in the tissue culture media should not exceed 0.5%. The appropriate volume of the compound solution (usually 2 microlitres) was added automatically (Beckman FX 96 tip) to media to make it up to the final concentration for each drug. The medium was removed from the cells and replaced with 0.2 ml of medium dosed with drug. Each concentration was assayed in triplicate. Two sets of control wells were left on each plate, containing either medium without drug or medium with the same concentration of DMSO. A third control set was obtained with the cells untreated just before adding the drugs (seeding control, number of cells starting the culture). Cells were exposed to the drugs for 72 hours and then processed for MTT colorimetric read-out. Compounds of the invention have a range of in vitro cell potency activities from about 1 nM to about 10 μΜ. mTOR assay
Mammalian target of rapamycin (mTOR) was assayed by monitoring phosphorylation of GFP-4EBP using a homogeneous time-resolved fluorescence resonante energy transfer format and assay reagents from Invitrogen. In the presence of 10 μΜ ATP, 50 mM Hepes (pH 7.5), 0.01 % (v/v) Polysorbate 20, 10 mM MnCI2, 1mM EGTA, and 2.5 mM DTT, the mTOR-mediated phosphorylation of 200 nM GFP-4E-BP1 was measured under initial rate conditions. After incubation at room temperature for 60 min, the reaction was terminated by addition of 10 mM EDTA, and phosphorylated GFP-4E-BP1 was detected with 2 nM Tb-anti-p4E-BP1 antibody before reading on a Perkin-Elmer Wallac 1420 Fluorescence Reader (exc 340; em 490/520).
Where compound names are given herein, they are typically generated with ChemDraw.
The invention is illustrated by way of the following examples, in which the following abbreviations (or chemical symbols) may be employed:
"dba" dibenzylidene acetone; "DC " dichloromethane; "MeOH" methanol; "EtOH" ethanol; "THF" tetrahydrofuran; "DMF" dimethylformamide; "CHCI3" chloroform; "DME" dimethoxyethane; "Et20" diethyl ether; "Hex" hexane; "EtOAc" ethyl acetate; "Pd(PPh3)4" tetrakis(triphenylphosphine)palladium; "KOAc" potassium acetate; "DIPEA" diisopropylethylamine; "Pd(PPh3) " tetrakis(triphenylphosphine)- palladium; "Pd(dppf)CI2.DCM" 1,1'-bis(diphenylphosphino)ferrocenepalladium(ll) dichloride, dichloromethane; "min." minutes; and "h." hours.
Cell viability assays and combination assays
Cells were seeded at 10000-50000 cells/well in 96 plates for 16 h. On day two, nine serial 1:3 compound dilutions were made in DMSO in a 96 well plate. The compounds were added to duplicate wells in 96-well cell plates a using a FX BECKMAN robot (Beckman Coulter) and incubated at 37°C with C02 atmosphere. After 3 days, relative numbers of viable cells were measured by MTT (Sigma) according to manufacturer's instruction and read on EndVision (Perkin Elmer). EC50 values were calculated using ActivityBase from IDBS. Drugs in combination assays were dosed starting at 4 x EC50 concentrations and continuing with serial dilutions 1:2. PI3K inhibitors and chemotherapeutic agents were added simultaneously.
An additional exemplary in vitro cell proliferation assay includes the following steps:
1. An aliquot of 200 μΙ of cell culture containing optimal density (between 104 - 5x104 cells) (see Examples for cell lines and tumour type) in medium was deposited in each well of a 96-well flat bottom plates.
2. Control wells were prepared containing medium without cells
3. The compound was added to the experimental wells and incubated for 3 days.
4. One quarter volume of MTT reagent with respect to the volume of cell culture medium present in each well was added and incubated 24h at 37°C with 5% C02.
5. One quarter volume of solubilisation buffer with respect to the volume of cell culture medium present in each well was added and incubated 24h at
37°C with 5% C02.
6. Formazan salt formed was recorded and reported in graphs as relative growth vs. cells treated only with dmso.
The individual measured EC50 values against the particular cell of the exemplary compounds and of the chemotherapeutic agent are compared to the combination EC50 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.
Examples and Experimental
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.
Table 1 - P razine Intermediates
Figure imgf000096_0001
Table 2 - Intermediates
Figure imgf000096_0002
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Table 3 -Final Products prepared in accordance with the procedures described herein
Figure imgf000102_0002
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
ο ο
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
130
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Experimental Part
Preparation of the intermediates
Method A1
Preparation of intermediate 1-01.
Figure imgf000134_0002
To a mixture of 2-amino pyrazine (50 g, 0.5 mol) in chloroform (1000 ml) cooled to 0°C was added pyridine (100 ml, 1.21 mol) and bromine (54 ml, 1.05 mmol) dropwise. The mixture was stirred at rt for 16h, then water was added. The organic phase was extracted, dried (MgS04), filtered and evaporated to obtain I-
01 , 48 g (Y: 36 %) of a yellow solid which was dried in vacuo. of intermediate 1-53
Figure imgf000135_0001
To a mixture of 2-amino-3-chloropyrazine (3.627 g, 28.00 mmol) in acetonitrile (20 mL), /V-iodosuccinimide (6.929 g, 30.800 mmol) and trifluoroacetic acid (2.2 mL) were added. The reaction mixture was stirred at rt for 18 h. EtOAc was added and the mixture was washed with Na2S203, dried, filtered and evaporated. The residue was purified in by column chromatography (EtOAc:Cyclohexane, 0: 00 to 40:60) to render 5.1 g of Intermediate I-53 (71%).
Figure imgf000135_0002
A solution of intermediate 1-01(15 g, 59.3 mmol) in morpholine (15 ml, 178 mmol) was heated at 120°C in a Parr reactor for 48h. A brown solid appears. The solid was suspended in DCM and washed with NaHC03 aq. sat (twice). The organic phase was dried (NaS04), filtered and evaporated to dryness to obtain I-02, 14.8 g of a brown solid (Y: 96 %) Method A3
Preparation of intermediate 1-03.
Figure imgf000136_0001
A mixture of intermediate 1-02 (360 mg, 1.35 mmol), indazole-4-boronic acid hydrochloride (600 mg, 2.97 mmol), K2C03 (2 mL of saturated solution), PdCI2(dppf).DCM (112 mg, 0.135 mmol) in DME (5 mL) was heated under microwave irradiation for 10 min at 130 °C. The reaction mixture was filtered through a celite pad, washing with DCM. The filtrate was dried over Na2S04 and concentrated. The crude was purified by flash column chromatography (Isolute Si 11 10 g cartridge) eluting with a gradient of DCM/MeOH (from 100% to 90:10) to yield 250 mg of the intermediate I-03 pure (Y: 62 %).
Preparation of intermediate 1-69.
Figure imgf000136_0002
A mixture of Intermediate 1-70 (45 mg, 0.15 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)aniline (40 mg, 0.18 mmol), PdCI2(dppf) (12 mg, 0.02 mmol) and Na2C03 (sat aq sol; 0.75 mL) in 1,2-DME (0.75 mL) was heated under microwave irradiation at 130 °C for 1h. The mixture was diluted with DCM.MeOH, adsorbed on celite and purified by chromatography (Isolute 5g; MeOH:DCM, 0:100 to 20:809 to give Intermediate I-69 (50 mg, 100%) as a yellow solid. Method A4
Preparation of intermediate 1-05.
Figure imgf000137_0001
Intermediate 1-01 (2 g, 7.9 mmol) was solved in 2-chloroacetone (3 ml,). The reaction was heated in a sealed tube at 90°C for 16h. A precipitate appears. Then Et20 was added. The precipitate was filtered off as a salt. The resulting solid was suspended in DCM and treated with an aqueous saturated solution of Na2C03. The organic phase was extracted, dried (MgS04), filtered and evaporated to obtain the intermediate I-05 (1.2 g of a brown solid, Y: 35 %)
Preparation of intermediate I-28.
Figure imgf000137_0002
Intermediate I-02 (1.2 g, 4.7 mmol) and ethyl 2-chloroacetoacetate (2.3 g, 14.2 mmol) were suspended in EtOH (12 ml_). The mixture was heated under microwave irradiation for 1 h at 150°C. After cooling down to room temperature, petroleum ether was added and the solid formed was filtered off. The filtrate was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel (c-Hex /EtAOAc 8:2) to obtain a solid that was washed with petroleum ether to give the desired product 1-28 (231 mg, Y: 33%).
Preparation of intermediate I-35.
Figure imgf000137_0003
Intermediate I-02 (2 g, 7.72 mmol) and methyl 4-chloroacetoacetate (3.56 ml_,
30.88 mmol) were heated in two sealed tubes (half of material in each tube) at
90°C for 2h. Volatiles were removed under reduced pressure and the residue was purified by flash chromatography on silica gel (c-Hex /EtAOAc 10:0 to 6:4) to obtain a solid that was washed with diethyl ether to render the desired product I- 35 (1.17g, Y: 49%).
Preparation of intermediate I-57.
Figure imgf000138_0001
A mixture of Intermediate I-02 (8.17 g, 31.52 mmol) and 1 ,3-dichloroacetone (6.0 g, 47.29 mmol) in 2-propanol (15 ml_) was heated in a sealed tube at 55°C for 2 days. On cooling, the mixture was filtered and rinsed with Et20 and MeOH. The solid was purified by flash chromatography on silica gel (MeOH:DCM, 5:95) and the product obtained was washed with MeOH and dried to give Intermediate I-57 (3.97 g, 38%).
Method A5
Preparation of intermediate I-06.
Figure imgf000138_0002
Intermediate I-05 (0.62 g, 2.13 mmol) was dissolved in CHCI3 (4 ml.) and N- bromosuccinimide (455 mg, 2.56 mmol) was added. The reaction mixture was heated under microwave irradiation at 120 °C for 1 h. On cooling, the mixture was adsorbed in silica and purified by Biotage column chromatography (DCM/MeOH from 100% to 95:5) to give intermediate I-06 (720 mg, Y: 91%) as a yellow solid. Method A6
Preparation of intermediate 1-09.
Figure imgf000139_0001
Intermediate 1-07 (1.00 g, 2.87 mmol) was dissolved in DCM (28 mL) and N- bromosuccinimide (0.61 g, 3.44 mmol) and trifluoroacetic acid (0.25ml_) were added. The reaction mixture was stirring at rt for 16h and then heated at 60°C for 2h more. The reaction mixture was cooled, and washed with water. The organic phase was dried (Na2S04), filtered and the solvent removed in vacuum. The residue was purified by biotage with a gradient cyclohexane/EtOAc: from 100% to 50:50 The desired fractions were collected to obtained 1.15 g of a white solid as intermediate 1-09 (Y: 94 %).
Method A7
Preparation of intermediate 1-10.
Figure imgf000139_0002
A mixture of Intermediate I-05 (1.75 g, 6.015 mmol), morpholine (0.526 mL, 6.015 mmol) and DCM (20 mL) was stirred at rt for 16h. Additional morpholine (0.526 mL, 6.015 mmol) was added and the mixture was stirred at rt for 18h more. Na2C03 sat. aq. was added. The organic phase was separated, dried (Na2S04), filtered and evaporated till dryness to obtain 1.8 g of intermediate 1-10 (Y: quantitative). The resulting product was used in the next step without further purification. termediate 1-11.
Figure imgf000140_0001
Intermediate I-06 (0.72 g, 1.95 mmol) was dissolved in DCM (6 mL) and morpholine (0.68 mL, 7.79 mmol) was added in one portion. The reaction mixture was stirred at rt for 3 h. The mixture was purified, together with a second batch of the same reaction, by column chromatography (DCM/MeOH from 100% to 50:50) to give the expected product intermediate 1-11 (980 mg, Y: 76%) as a clear yellow solid.
Preparation of intermediate I-48
Figure imgf000140_0002
To a mixture of Intermediate 1-47 (2.25 g, 5.22 mmol) in acetonitrile (20 mL) morpholine (0.59 mL, 6.79 mmol) and N,N-diisopropylethylamine (1.36 mL, 7.84 mmol) were added. The reaction mixture was heated under microwave irradiation at 160°C for 30 min. On cooling, NH4CI was added and the mixture was extracted with DCM. The organic layer was dried (Na2S04), filtered and evaporated. The residue was precipitated with Et20 and MeOH to render Intermediate 1-48 (1.875g, 75%) as a white solid. The filtrate was evaporated and purified by column chromatography (Cyclohexane:EtOAc, 100:0 to 60:40) to render 620 mg of Intermediate I-48 (24%). Pre aration of intermediate 1-36.
Figure imgf000141_0001
Intermediate 1-07 (0.50 g, 1.40 mmol) was suspended in DCE (8 mL) and piperidine (0.18 mL, 1.7 mmol) was added dropwise. The reaction mixture was heated at 60°C for 16 h. Additional piperidine (0.05 mL) was added and heating conitinued for 2h. The suspension at RT was filtered affording a solid (imurities) and the filtrate that was concentrated. The resulting residue was triturated with Et20 to render another solid (impurities) and the filtrate that was concentrated to afford the required intermediate I-36 as light orange solid (400 mg, Y: 80%). Method A8
Preparation of intermediate 1-13.
Figure imgf000141_0002
To a solution of intermediate 1-12 (2 g, 5.6 mmol) in DCM (50 mL) was added dropwise DIBAL (3.8mL, 1 M in toluene, 22.75mmol) at -78 °C stirring at that temperature for 40 min. The reaction was quenched with cold methanol and stirred for 10 min. more. The mixture was poured into a Diphasic mixture of saturated NaHC03 and DCM and allowed to warm to room temperature with occasional stirring. It was then passed though a Celite bed to remove a gelatinous mass, and the bed was throughly washed with DCM. After the organic layer was separated, the aqueous layer was extrated with DCM. The combined organic phase was dried (Na2S04), filtered and concentrated under reduced pressure to obtain a light yellow solid, 1.674 g, Y: 96 % as intermediate 1-13 which was used in next reaction step without further purification. Method A9
Preparation of intermediate 1-14.
Figure imgf000142_0001
To a stirred slurry of LiAIH4 (556 mg, 14.64 mmol) in dry THF was slowly added intermediate 1-12 (5.63 mmol) in THF (28 mL) at 0°C. After the addition, the reaction mixture was stirred at room temperature for 2h and quenched with saturated NH4CI/NH4OH. The mixture was poured into CHCIa/MeOH (3:1) and it was then passed though a Celite bed to remove a gelatinous mass, and the bed was throughly washed with CHCI3. The organic layer was washed with saturated NaCI. The organic phase was dried (Na2S04), filtered and evaporated under reduced pressure to obtain the expected product 1-14 as a light yellow solid (1.02 g, Y: 57% yield) which was used in next reaction step without further purification.
Preparation of intermediate 1-40
Figure imgf000142_0002
A solution of Intermediate 1-39 (1g, 2.952 mmol) in THF (10 mL) was slowly added to a stirred slurry of NaBH4 (123 mg, 3.247 mmol) in dry THF (11 mL) at 0°C. The mixture was stirred 2h at rt. The solvent was removed and the residue was suspended in H20 and extracted with EtOAc. The organic layer was dried (Na2S04), filtered and evaporated concentrated. The residue was used in the next experiment without further purification. reparation of intermediate 1-49
Figure imgf000143_0001
To a solution of Intermediate 1-48 (1.3 g, 2.7 mmol) in DCM (25 mL) was added diisobutylaluminum hydride (1M in toluene) (2.7 mL, 2.7 mmol) drowise at 0°C. The reaction mixture was stirred at rt for 16h and more DIBAL (2.7 mL) was added. Stirring was continued at rt for 2 days and another eq. of DIBAL was added (2.7 mL). After 2 days the reaction was quenched with cold MeOH, stirred for 10 min and poured into a biphasic mixture of H2C7DCM. The suspension was filtered off to render Intermediate I-49 (0.86 g). The organic layer was extracted with DCM, dried, filtered and evaporated to render Intermediate 1-49 (320 mg) as a white solid.
Method A10
Preparation of intermediate 1-16
Figure imgf000143_0002
A mixture of intermediate 1-13 (520 mg, 1.67 mmol), 1-boc-piperazine (405 mg, 2.17 mmol) and trimethyl orthoformate (1.83 mL, 16.71 mmol) was stirred in 1 ,2- dichloroethane (14 mL) for 6h at room temperature. Then sodium triacetoxyborohydride (425 mg, 2.0 mmol) was added and the reaction mixture was stirred for 48h at room temperature. The mixture was then quenched with brine and extrated with DCM. The organic phase was dried (Na2S04), filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography in Biotage by eluting it with cyclohexane/ ethyl acetate and then with DCM/MeOH to obtain intermediate 1-16, 475 mg, Y: 60 % as a light yellow solid. Method A11
Preparation of intermediate 1-17.
Figure imgf000144_0001
Intermediate 1-16 (0.380 mg, 0.789 mmol) was dissolved in DCM (10 mL) and 2N HCI (2ml_) was added and the reaction was stirred at rt for 16h. Because only starting material was observed, the solvent was evaporated and THF 3 mL and 3mL HCI (2N) were added and the reaction mixture was stirred for 2h. The solvent was removed in vacuo to obtain intermediate 1-17 as a chiorohydrate salt (307 mg, Y: 93%) which was used in the next reaction without further purification.
Method A12
Preparation of intermediate I-23.
Figure imgf000144_0002
Methylpiperazine (0.282mmol, 32μΙ) and AIMe3 2M in hexanes (0.282mmol, 0.14mL) in dry DCM (4mL) was stirred at rt for 15min. Then intermediate 1-12 (100mg, 0.282 mmol) was added and the mixture was stirred at rt for 3h and then at 40°C overnight. The reaction was quenched with sat sol of ammonium chloride and diluted with DCM. The organic phase was dried (Na2S04), filtered and evaporated to afford a residue which was triturated with Et20-DCM precipitating an off white solid as an impurity. The filtrate was purified by flash chromatography (Biotage Hex-EtOAc from 100 % to 70:30 and then DCM-MeOH/NH3 7N 80:20 to obtain 67 mg (Y: 48 %) of required product as intermediate 1-23. Method A13
Preparation of intermediate I-29
Figure imgf000145_0001
2N NaOH (0.85 mL) was added to a stirred mixture of intermediate I-28 in MeOH. The reaction was stirred at 50°C for 1.5h and at reflux for 20 min. The solvent was evaporated and water was added and the pH was adjusted to 4 by addition of AcOH. The mixture was diluted with EtOAc (until a clear solution was obtained (ca 250 mL). The layers were separated and the aqueous layer was extracted twice with EtOAc. The organic layer was dried and evaporated. The residue was azeotropically dried with toluene to give 261 mg (Y: 100%) of desired product I-29 which was used in next reaction step without further purification.
Method A14
Preparation of intermediate I-27
Figure imgf000145_0002
4-Amine-1-BOC piperidine was added to a stirred mixture of intermediate I-29, DIPEA and HATU in DMF. The reaction was stirred at rt for 4h .The reaction mixture was directly chromatographed on silica gel (biotage c-Hex/ EtOAc 10 to 100% EtOAc) to obtain the desired product (233 mg, Y: for two steps: 69 %). Method A15
Preparation of Intermediate I-30
Figure imgf000146_0001
Intermediate 1-12 (240 mg) in a seal tube, was suspended in a solution of MeOH/NH3 7N. The reaction mixture was heated at 100°C for 16h. The solvent was evaporated to dryness and the residue was washed with MeOH and Et20. the resulting yellow solid was dried in vacuo to obtain 200 mg of desired product I-30. Alternatively, a precipitate may appear, which may be filtered off to obtain the desired product I-30.
Method A16
Preparation of Intermediate I-44
Figure imgf000146_0002
A mixture of Intermediate I-43 (0.15 g, 0.51 mmol), 2-aminopyrimidine-5-boronic acid, pinacol ester (136 mg, 0.613 mmol) and PdCI2(dppf) (42 mg, 0.051 mmol) and sat. sol. Na2C03 (1.96 mL) in 1 ,2-DME (1.96 ml.) was stirred at r.t. for 1h 30 min. DCM was added and the mixture was washed with H20 and sat. NaCI. The organics were dried (Na2S04), filtered and evaporated. The residue was purified by column chromatography (DCM:MeOH, 99:1 to 90:10) to render Intermediate I- 44 (10 mg, 8%) as a beige solid. Method A18
Preparation of intermediate I-39
Figure imgf000147_0001
To a solution of Intermediate I-35 (3.76 g, 12.11 mmol) in DMF (120 mL) was added POCI3 (3.38 mL, 36.34 mmol) at -20 °C. The mixture was stirred at rt overnight under N2 and diluted with H20/ice. The white solid was filtered off and dried to render 2.95 g (63%) of Intermediate I-39. It was used in the next experiment without further purification.
Method A20
Preparation of intermediate I-50
Figure imgf000147_0002
To a solution of Intermediate I-49 (1.18 g, 2.7 mmol) in CHCI3 (54 mL) activated Mn02 (4.0 g, 45.93 mmol) was added. The reaction mixture was refluxed for 8 h. On cooling, the mixture was filtered through celite. The filtrate was evaporated to render Intermediate I-50 (0.67 g). It was used in the next reaction without further purification. Method A21
Preparation of intermediate I-58
Figure imgf000148_0001
To a suspension of Intermediate I-57 (0.232 g, 0.7 mmol) and K2C03 (0.193 g, 1.4 mmol) in Acetonitrile (20 ml.) was added 8-methanesulfonyl-3,8-diaza-bicyclo [3.2.1]octane ((0.133 g, 0.7 mmol). The reaction mixture was refluxed for 24 h and concentrated. The residue was suspended in DCM and washed with brine. The organic layer was dried, filtered and evaporated. The residue was triturated from MeOH to give Intermediate I-58 (0.189 g, 56%) as a white solid.
Method A22
Preparation of intermediate I-60
Figure imgf000148_0002
To a solution of Intermediate 1-17 (100 mg, 0.297 mmol), BOP (158 mg, 0.356 mmol) and (s)-(-)-2-acetoxypropionic acid (41 mg, 0.356 mmol) in CH2CI2 (3 ml_), Et3N (0.083 mL, 0.594 mmol) was added. The mixture was stirred at RT for 2 days. CH2CI2 was added and the mixture was washed with water. The organic layer was dried over Na2S04> filtered and evaporated. The residue was purified by column chromatography (Biotage, CH2CI2:MeOH, 100:0 to 60:40) to give Intermediate I-60 (130 mg, 88%) as a colourless oil. Method A23
Preparation of intermediate 1-61
Figure imgf000149_0001
A 2M solution of trimethylaluminum in hexanes (5.5 mL, 11.02 mmol) was added to a mixture of Ν,Ο-dimethylhydroxylamine hydrochloride (1.075 g, 11.02 mmol) in DCM (10 mL) and the reaction was stirred at rt for 40 min. A solution of Intermediate 1-12 (0.783 g, 2.20 mmol) in DCM (16 mL) was added and the reaction mixture was stirred at 40°C for 2 h. On cooling, the mixture was carefully quenched with 1N HCI and diluted with DCM. After 30 min stirring layers were separated and the aqueous layer was extracted with DCM (x2). The combined organic layers were washed with brine, dried, filtered and evaporated. The residue was purified by column chromatography (Biotage, cHex/EtOAc 50:50 to 0:100) to give Intermediate 1-61(545 mg, 67%).
Method A24
Preparation of intermediate I-62
Figure imgf000149_0002
To a mixture of Intermediate 1-61 (545 mg, 1.47 mmol) in THF (15 mL) was added MeMgBr (2.2 mL, 2.2 mmol) at 0 °C. The reaction was stirred at 0°C for 1h. Additional MeMgBr (1.1 mL, 1.1 mmol) was added and the reaction was stirred at 0° C for 1 h. The mixture was quenched with sat NH4CI, and extracted with EtOAc (x3). The combined organic layers were dried, filtered and evaporated to give Intermediate I-62 (458 mg, 96%). Method A25
Preparation of intermediate 1-63
Figure imgf000150_0001
To a mixture of Intermediate 1-62 (0.1 g, 0.308 mmol) and 1-Boc-piperazine (0.115 g, 0.615 mmol) in DCM (4 mL) was added Ti(iPrO)4 (0.182 mi_, 0.615 mmol). The reaction was stirred at reflux for 2h. Et2AICN (0.62 mL, 0.615 mmol) was added and the reaction mixture was stirred at reflux for 5h. On cooling, the mixture was quenched with sat NaHC03 and extracted with EtOAc (x3). The combined organic layers were washed with brine, dried, filtered and evaporated. The residue was purified by column chromatography (biotage, cHex/EtOAc 10:90 to 0:100) to give Intermediate I-63 (100 mg, 63%).
Method A26
Preparation of intermediate 1-64
Figure imgf000150_0002
To a stirred solution of MeMgBr (1 mL, 0.96 mmol) was added a solution of Intermediate I-63 (50 mg, 0.096 mmol) in THF (1.5 mL) at 0°C. The reaction was stirred at 0°C for 4 h and the mixture was poured onto ice cold sat NH4CI. The mixture was extracted with EtOAc and the combined organic layers were dried, filtered and evaporated. The residue was purified by column chromatography (biotage, cHex/EtOAc 10:90 to 0:100) to give Intermediate I-64 (22 mg, 45%). Method A27
Preparation of intermediate 1-68
Figure imgf000151_0001
MsCI (0.046 mL, 0.589 mmol) was added to solution of Intermediate 1-67 (0.175 g, 0.393 mmol) and TEA (0.274 mL, 1.96 mmol) in DCM (4 mL) at 0°C. The reaction mixture was stirred at rt for 3 h and poured onto sat NaHC03. The mixture was extracted with DCM and the combined organic layers were dried, filtered and evaporated. The residue was purified on silica gel (DCM:MeOH, 90:10) to afford Intermediate I-68 (133 mg, 70%).
Method A28
Preparation of intermediate I-70
Figure imgf000151_0002
To a solution of Intermediate 1-02 (150 mg, 0.58 mmol) in Toluene (6.8 mL), 2- chloro-1,1-dimethoxypropane (0.758 mL, 5.8 mmol) and p-toluensulfonic acid (18 mg, 0.09 mmol) were added. The reaction mixture was refluxed for 24 h and additional amounts of 2-chloro-1 ,1-dimethoxypropane (10 eq) and p- toluensulfonic acid (0.16 eq) were added. The reaction mixture was refluxed for 15 h and the solvent was removed. The residue was purified by column chromatography (Isolute 10g; AcOEt-cyclohexane 0:100 to 50:50) to give the Intermediate I-70 (55 mg, 32%) as a beige solid. Example B1
Preparation of Final product 2-01
Figure imgf000152_0001
A mixture of intermediate 1-12 (100 mg, 0.282 mmol), 3-hydroxyphenylboronic acid (85 mg, 0.685 mmol), and PdCI2(dppf) DCM (23 mg. 0.028 mmol) in D E (1.2 mL) was added a saturated aqueous solution of sodium carbonate (1ml_). The mixture was heated to 130 °C under microwave irradiation for 3 min. The reaction mixture was cooled, diluted with chloroform, washed with brine. The organic phase was dried (Na2S04), filtered and the solvent removed in vacuo. The residue was purifired by biotage chromatography with a gradient cyclohexane/EtOAc: from 100 % to 50:50. The desired fractions were collected and the solvent evaporated. The resulting solid was crystallised with MeOH to obtain a white solid as final product 2-01 (44 mg, Y: 68% yield).
Preparation of Final product 2-10
Figure imgf000152_0002
A mixture of intermediate 1-18 (200 mg, 0.435 mmol), 3-hydroxyphenylboronic acid (132mg, 0.985 mmol), and PdCI2(dppf).DCM (36 mg. 0.044 mmol) in DME (1.8 mL) was added an aqueous saturated solution of potasium carbonate (1mL). The mixture was heated to 130 °C under microwave irradiation for 3 min. The reaction mixture was cooled, diluted with chloroform, washed with brine. The organic phase was dried (Na2S04), filtered and evaporated. The residue was purified by biotage chromatography and eluted with a gradient DCM/MeOH: from 100 % to 50:50. The desired fractions were collected and the resulting residue was purified again with EtOAc and then EtOAc/MeOH 20:1. The desired fractions were collected to obtain a white solid, 27 mg, Y: 13 %, as final product 2-10.
Preparation of Final product 2-11
Figure imgf000153_0001
Intermediate I-24 (165mg, 0.349mmol), 3-hydroxyphenylboronic acid (0.523mmol, 72mg) and PdCI2(dppf).DCM (0.035mmol, 29mg) were suspended in a saturated solution of sodium carbonate (1.8ml_) and 1,2-DME (1.8mL). The mixture was heated under microwave irradiation at 130°C for 10min. The mixture was diluted with DCM and washed with water. The organic layer was dried (Na2S04), filtered and evaporated. The resulting residue was purified by Biotage chromatography (DCM-EtOAc from 50:50 to 100 % of EtOAc) to afford a product still impure which was repurified using DCM-MeOH 95:5. The resulting oil was precipitated with DCM-MeOH-Et20 (approx. 10:1:5) to give the desired product 2- 11 (63mg, Y: 36%).
Preparation of Final product 2-13
Figure imgf000153_0002
A mixture of intermediate I-26 (225 mg, 0.641 mmol), 3-hydroxyphenylboronic acid (194 mg, 1.410 mmol), and PdCI2(dppf).DCM (53 mg, 0.064 mmol) in DME (2.8 mL) was added a saturated aqueous solution of potassium carbonate (0.5mL). The mixture was heated to 130 °C under microwave irradiation for 3 min. The reaction mixture was cooled, diluted with DCM, washed with brine. The organic phase was dried (Na2S04), filtered and the solvent removed in vacuum. The resulting residue was purified by biotage chromatography and eluted with a gradient EtOAc/MeOH: from 100% to 50:50. The desired fractions were collected to yield a yellow solid which was crystallised in MeOH to obtain the desired product 2-13 (150 mg, Y: 64 %).
Preparation of Final product 2-14
Figure imgf000154_0001
Intermediate 1-15 (210 mg, 0.650 mmol), 3-hydroxyphenylboronic acid (0.975 mmol, 134 mg) and PdCI2(dppf).DCM (0.065 mmol, 54 mg) were suspended in saturated solution of sodium carbonate (2.6mL) and 1,2-DME (2.6ml_). The mixture was heated under microwave irradiation at 130°C for 10 min. The mixture was diluted with DCM and washed with water. The organic layer was dried (Na2S04), filtered and the solvent was evaporated in vacuo. The resulting residue was purified by flash chromatography (DCM-EtOAc from 100 % to 40:60) to afford the desired product 2-14 (69 mg, Y: 31%) as a white solid.
Preparation of Final product 2- 5
Figure imgf000154_0002
Intermediate I-23 (50mg, 0.122mmol), indazole-4-boronic acid hydrochloride (0.183mol, 36mg) and PdCI2(dppf).DCM (0.012mmol, 10mg) were suspended in a saturated solution of sodium carbonate (0.6 mL) and 1 ,2-DME (0.6ml_). The mixture was heated under microwave irradiation at 130°C for 10min. The mixture was diluted with DCM and washed with brine. The organic layer was dried (Na2S04), filtered and the solvent was evaporated. The resulting residue was purified by flash chromatography (DCM-MeOH/NH3 7N from 100% to 90:10). The desired fractions were collected to obtain final product 2-15 (48mg, Y: 88%) as a white solid.
Preparation of Final product 2-16
Figure imgf000155_0001
Intermediate I-24 (55mg, 0.116mmol), indazole-4-boronic acid hydrochloride (0.174mmol, 35mg) and PdCI2(dppf).DC (0.012mmol, 10mg) were suspended in a saturated solution of sodium carbonate (0.6 mL) and 1 ,2-DME (0.6mL). The mixture was heated under microwave irradiation at 130°C for 10 min. The mixture was diluted with DC and washed with water. The organic layer was dried (Na2S04), filtered and the solvent evaporated in vacuo. The resulting residue was purified by flash chromatography (EtOAc-MeOH from 100% to 98:2) to obtain the desired final product 2-16 as a white solid (32mg, Y: 54%).
Preparation of Final product 2-17
Figure imgf000155_0002
A mixture of intermediate 1-18 (160 mg, 0.348 mmol), PdCI2(dppf).DCM (cat. amount), a saturated solution of K2C03 (0.5 mL), indazole-4-boronic acid hydrochloride (150 mg, 0.766 mmol), in DME (3.5 mL) was heated under microwave irradiation at 130 °C for 10 min. The mixture was diluted with DCM (30 mL), washed with brine (40 mL). The organic phase was dried (Na2S04), filtered and concentrated. The crude was purified by Biotage flash column chromatography eluting with a gradient of EtOAc/MeOH (from 100% to 60:40), the resulting solid was triturated with MeOH and filtered to obtain the desired product 2-17 (43 mg) as a white solid.
Preparation of Final product 2-18
Figure imgf000156_0001
Intermediate I-25 (150mg, 0.303mmol), indazole-4-boronic acid hydrochloride (1.5 equiv, 0.454mmol, 90mg) and PdCI2(dppf)2. DCM (O.lequiv, 0.03mmol, 25mg) were suspended in sat sol of sodium carbonate (1.5mL) and 1,2-DME (1.5mL). The mixture was heated under microwave irradiation at 130°C for 10min. The mixture was diluted with DCM and washed with water. The organic layer was dried over sodium sulfate to yield the crude product which was purified by flash chromatography (EtOAc-MeOH 0-5%) to afford the required (120mg as yellow solid, 75%). This product (120mg, 0.225mmol) was suspended in dry methanol (2.25mL) and AmberlystR(5) (400mg) was added. The mixture was slowly stirred at rt for 48 h. The resin was washed with MeOH, and then with MeOH-NH3 7N. This phase was collected and evaporated to obtain final product 2-18 as a syrup
(83 mg, Y: 85 %).
reparation of Final product 2-19
Figure imgf000157_0001
Intermediate 1-15 (140mg, 0.433mmol), 4-indazoleboronic acid (1.5 equiv, 0.650mmol, 129 mg) and PdCI2(dppf).DCM (0.043mmol, 36mg) were suspended in a saturated solution of sodium carbonate (2ml_) and 1,2-DME (2ml_). The mixture was heated under microwave irradiation at 130°C for 10min. The mixture was diluted with DCM and washed with water. The organic layer was dried (Na2S04), filtered and evaporated. The residue was purified by flash chromatography (DCM-EtOAc from 80:20 to 100 % on EtOAc) and then by HPLC to afford final product 2-19 (40mg, Y: 26 %).
Preparation of Final product 2-20
Figure imgf000157_0002
A reaction mixture of intermediate 1-26 (140 mg, 0.4 mmol), indazole-4-boronic acid hydrochloride (175 mg, 0.87 mmol), K2C03 (300 mg), PdCI2(dppf).DCM (cat amount) in DME (3 mL) and water (1 ml_), was heated under microwave irradiation at 130 °C for 10 min. The dark reaction mixture was diluted with DCM (25 mL), washed with saturated solution of NaHCOs (2 x 30 mL) and brine (30 mL). The organic phase was dried (Na2S04), filtered and concentrated. The resulting residue was purified by flash column chromatography eluting with a gradient system of DCM/MeOH (from 100 % to 97:3). The desired fractions were collected and precipitated with DCM/cyclohexane, to obtain the final product 2-20 (40 mg, Y: 26 %). reparation of Final product 2-23
Figure imgf000158_0001
A mixture of intermediate 1-10 (100 mg, 0.337 mmol), 3-hydroxyphenylboronic acid (0.102 g, 0.740 mmol), and PdCI2(dppf).DCM (28 mg, 0.034 mmol) in DME (1.463 mL) was added an aquous saturated solution of potassium carbonate (0.5mL). The mixture was heated to 130 °C under microwave irradiation for 10 min. The reaction mixture was cooled, diluted with DCM, washed with brine. The organic phase was dried (Na2S04), filtered and the solvent removed in vacuum. The residue was purified by biotage chromatography and eiuted with a gradient EtOAc/MeOH from 100% to 50:50. The desired fractions were collected and the residue was crystallised in DCM to obtain the desired product 2-23 (44 mg, Y: 42 %).
Preparation of Final product 2-24
Figure imgf000158_0002
A mixture of intermediate 1-10 (700 mg, 2.356 mmol), indazole-4-boronic acid hydrochloride (701 mg, 3.534 mmol) and PdCI2(dppf).DCM (190 mg. 0.235 mmol) in DME (11 mL) was added a saturated aqueous solution of potassium carbonate (11 mL). The mixture was heated to 130 °C in the microwave for 0.5 h. The reaction mixture was diluted with EtOAc and washed with water. The organic phase was separated, dried (Na2S04), filtered and evaporated to give a brown oil. This residue was purified column chromatography (hexane/EtOAc mixtures) to give the desired product 2-24 as green foam (456 mg, 58% yield). reparation of Final product 2-27
Figure imgf000159_0001
A mixture of intermediate 1-10 (200 mg, 0.673 mmol), 3-methoxypyridine-5- boronic acid pinacol ester (348 mg, 1.481 mmol), and PdCI2(dppf).DCM (56 mg. 0.067 mmol) in DME (2.9 ml_) was added a saturated solution of sodium carbonate (1 ml_). The mixture was heated to 130 °C under microwave irradiation for 10 min. The reaction mixture was cooled, diluted with DCM, washed with brine. The organic phase was dried (Na2S04), filtered and the solvent removed in vacuum. The residue was purified by biotage chromatography twice and eiuted with a gradient EtOAc/MeOH from 100% to 50:50. The desired fractions were collected to obtain 120 mg of the desired product 2-27 as a yellow solid (Y: 55%).
Preparation of Final product 2-42
Figure imgf000159_0002
Intermediate 1-11 (1.36 g, 3.62 mmol) was suspended in DME (5 mL) and indazole-4-boronic acid.HCI (0.86 g, 4.34 mmol), PdCI2(dppf).DCM (300 mg, 0.36 mmol), K2C03 (1.5 g, 10.85 mmol) and H20 (2.5 mL) were added. The reaction mixture was heated under microwave irradiation at 130 °C for 30 min. On cooling, the mixture was evaporated and the residue was purified by column chromatography (DCM/MeOH from 100 % to 98:2) to give the expected product 2-42 (230 mg, Y: 15%) as a yellow solid. reparation of Final product 2-71
Figure imgf000160_0001
A mixture of intermediate 1-18 (100 mg, 0.218 mmol), PdCI2(dppf).DC (cat. amount), a saturated solution of K2C03 (1 mL), indol-4-boronic acid hydrochloride (53 mg, 0.327 mmol), in DME (1 mL) was heated under microwave irradiation at 130 °C for 10 min. The mixture was diluted with DCM (30 mL), washed with brine (40 mL). The organic phase was dried (Na2S0 ), filtered and concentrated. The crude was purified by Biotage flash column chromatography eluting with a gradient of DCM/MeOH (from 100% to 50:50) to obtain the desired product 2-71 (39 mg) as a white solid.
Preparation of Final product 2-70
Figure imgf000160_0002
A mixture of intermediate 1-18 (100 mg, 0.218 mmol), PdCI2(dppf).DCM (cat. amount), a saturated solution of K2C03 (0.5 mL), 5-fluoro-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1-tert-butyldimethylsilyl-indole (98 mg, 0.26 mmol, CAS: 1072009-08-5), in DME (1 mL) was heated under microwave irradiation at 130 °C for 1 h. The organic phase was concentrated. The crude was purified by Biotage flash column chromatography eluting with a gradient of DCM/MeOH (from 100% to 90: 0) to obtain the desired product 2-70 (39 mg) as a white solid.
Preparation of Final product 2-35
Figure imgf000161_0001
Intermediate I-30 (50 mg, 0.15 mmol) was dissolved in DME (1 mL) and phenylboronic acid (22 mg, 0.18 mmol), K2C03 (64 mg, 0.46 mmol), PdCI2(dppf)- DCM (13 mg, 15 umol) and H20 (0.5 mL) were added. The mixture was heated under microwave irradiation at 130 °C for 1 h. On cooling, the mixture was purified by column chromatography (Biotage, 25-S, 5% to 10% MeOH in DCM), and the product obtained was precipitated with Et20 and filtered to give the expected product 2-35 (45 mg, Y: 91%) as a white solid.
Preparation of final product 2-63.
Figure imgf000161_0002
PdCI2(dppf) was added to a degassed mixture of intermediate I-27 (100 mg, 0.21 mmol), indazol 4-boronic acid hydrochloride (0.091 g, 0.43 mmol) and an aqueous saturated solution of Na2C03 (0.25 mL) in DME (1 mL). The vial was sealed and heated at 130°C under microwaves for 10 min. The mixture was diluted with EtOAc, washed with water, brine, dried and evaporated. The residue was purified by Biotage chromatography in DCM/MeOH 2 to 10% MeOH) to obtain 52 mg of desired compound 2-63. Example B2
Preparation of Final product 2-21
Figure imgf000162_0001
A suspension of final compound 2-52 (160 mg, 0.5 mmol) in MeOH/NH3 7N was heated in a sealed tube at 90°C for 6h. A precipitate appears which was filtered off to obtain 75 mg of the desired product 2-21 as a brown solid (Y: 41 %)
Preparation of Final product 2-77
Figure imgf000162_0002
To a mixture of intermediate I-32 (70 mg, 0.185 mmol) with dry D F (3 drops) in benzene (2 mL) was added oxalyl chloride (2 equiv, 0.370mmol, 31 uL). The mixture was stirred at rt for 3h, then same amount of reagents was added and stirring continued for 1h. No reaction observed so volatiles were removed under reduced pressure and the residue was dissolved in dioxane (2 mL) and NH3 in dioxane 0.5N (2 mL) was added. The mixture was stirred at rt overnight and solvent was evaporated under vacuum. The residue was purified by preparative HPLC affording 3 mg of final product 2-77 (Y: 4%). Example B3
Preparation of Final product 2-22
Figure imgf000163_0001
Final product 2-21 (50 mg, 0.138 mmol) in POCI3 (2 ml) was heated to reflux for 2h. The solvent was evaporated in vacuo and the residue was suspended in DCM and Na2S04 aq. solution. The organic phase was extracted, dried (MgS04), filtered and evaporated to obtain a light brown solid which was washed with Et20. The precipitate was filtered and dried to obtain the desired product 2-22 (25 mg, Y: 53 %) as a pure solid.
Example B4
Preparation of Final product 2-33
Figure imgf000163_0002
A mixture of final product 2-31 (50 mg, 0.169 mmol) and NCS (18 mg, 0.135 mmol, 0.8 eq) in THF (2 ml_) was heated at 60°C for 18h. A saturated solution of NaHC03 was added and the mixture was extracted with EtOAc. The organic phase was separated, dried (Na2S04), filtered and evaporated till dryness. The residue was purified by using a sep-pack in a manifold, eluent: cyclohexane/EtOAc, 2/1. The desired fractions were collected and the solvent was evaporated till dryness to obtain 15mg, Y: 27% of desired product 2-33. Preparation of Final product 2-54
Figure imgf000164_0001
A mixture of final product 2-24 (60 mg, 0.179 mmol) and NCS (31 mg, 0.233 mmol) in dioxane (2 mL) was heated at 50°C for 18h. The organic phase was evaporated till dryness. The residue was purified by using column chromatograpy (hexane/EtOAc mixtures) and then by HPLC. The desired fractions were collected and the solvent was evaporated till dryness to obtain 9 mg, Y: 14 % of desired product 2-54.
Preparation of Final product 2-56
Figure imgf000164_0002
A mixture of final product 2-31 (0.2 g, 0.677 mmol) and NIS (233 mg, 1.016 mmol) in THF (4 mL) was heated at 65°C for 18h. A saturated solution of NaHC03 was added and the mixture was extracted with EtOAc. The organic phase was separated, dried (Na2S04), filtered and evaporated till dryness. The residue was purified by using a sep-pack in a manifold and then by HPLC. The desired fractions were collected and the solvent was evaporated till dryness to obtain 2 mg of desired product 2-56. reparation of Final product 2-60
Figure imgf000165_0001
A mixture of final product 2-17 (45 mg, 0.1 mmol) and NCS (20 mg, 0.15 mmol) in acetonitrile (2 mL) was stirred at room temperature for 4h. A saturated solution of NaHC03 was added and the mixture was extracted with EtOAc. The organic phase was separated, dried (Na2S04), filtered and evaporated till dryness. The residue was purified by column chromatograpy (DCM/MeOH 100% to 95:5) and then by HPLC. The desired fractions were collected and the solvent was evaporated till dryness to obtain 10 mg, of desired product 2-60.
Preparation of Final product 2-12
Figure imgf000165_0002
To a solution of final product 2-32 (1.249 mmol) in THF (4.5 mL) was added NIS (1.249 mmol) and the reaction mixture was stirred at rt for 24h. Excess of NIS (0.31 mmol, 70 mg) was added stirring the reaction for 16h more. A saturatated aqueous solution of NaHC03 and DCM was added. The organic phase was extracted, dried (Na2S04), filtered and evaporated. The residue was purified by flash chromatography in Biotage, eluent: CH2Cl2-AcOEt CH2Cl2 to obtain 38.6 mg of final product 2-12 and 41 mg of the corresponding regioisomer, final product 2.53. reparation of Final product 2-96
Figure imgf000166_0001
Final product 2-93 (30mg, 88umol) was suspended in acetonitrile (2 mL) and NCS (12mg, 88umol) was added. The mixture was stirred at rt for 15h and filtered to render a solid that was reprecipitated (DMSO/MeOH/formic acid) affording the final product 2-96 (15mg, 42%) as a yellow solid with purity of 90% (contaminated with 10% starting material).
Preparation of Final product 2-108
Figure imgf000166_0002
Final product 2-50 (50mg, 0.11mmol) was suspended in DCM (1 mL) and NCS (14mg, 0.11mmol) was added. The mixture was stirred at rt for 20h. The suspension was filtered and rinsed with DCM to render the final product 2-108 (41 mg, 76%) as white solid. reparation of Final product 2-112
Figure imgf000167_0001
Final product 2-67 (35mg, 72μηηοΙ) was suspended in DCM (1 mL) and NCS (10mg, 72umol) was added. The mixture was stirred at rt for 20h. NaHC03 sat sol was added to the mixture and it was extracted with DCM (x2). The combined organic layer was dried, filtered and concentrated. The residue was precipitated with diethyl ether to afford the final product 2-112 (35mg, 93%) as white solid
Example B5
Preparation of Final product 2-38
Figure imgf000167_0002
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. 210 mg (0.44 mmol) of this solid and intermediate I-03 (130 mg, 0.44 mmol) were dissolved in DCE and refluxed for 5 h. The reaction mixture was cooled to rt and then KOH (powder, 250 mg) was added. The mixture was stirred for 20 min at rt, filtered off and washed (DCM). The solvent was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography eluting with a gradient of DCM/ eOH (from 100% to 96:4), yielding final product 2-38, 30 mg, Y: 16 %.
Preparation of Final product 2-41
Figure imgf000168_0001
A mixture of benzotriazole (300 mg, 2.43 mmol) 4-methylsulfonylpiperazine (400 mg, 2.43 mmol) in EtOH (20 mL) was stirred for 20 min. Glyoxal (0.160 mL of a 40% w solution in water, 1.2 mmol) was added, and the resultant mixture was stirred for 16 h. The white solid formed was filtered off, washing with EtOH and diethylether to yield 280 mg that was used in next reaction step without further purification. Another batch of this reaction was progressed. 497 mg (0.844 mmol) of this solid and intermediate 1-03 were heated in DCE under reflux for 6h. The 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/NH3 7N (from 100% to 95:5), to yield desired final product 2-41 (50 mg, Y: 12.3 %).
Example B6
Preparation of Final product 2-43
Figure imgf000169_0001
Final product 2-42 (230 mg, 0.56 mmol) was dissolved in 1 ,4-dioxane (3 mL) and Pd(PPh3)4 (64 mg, 56 umol), Cs2C03 (363 mg, 1.11 mmol), 1-N-boc-4-(4,4,5,5- tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (198 mg, 0.64 mmol) and H20 (2 mL) were added. The mixture was heated under microwave irradiation at 140 °C for 1 h. On cooling, the solvents were removed and the residue was purified by column chromatography (DCM/MeOH from 98:2 to 94:6) to give the final product 2-43 (260 mg, Y: 91 %) as a yellow solid. Example B7
Preparation of Final product 2-44
Figure imgf000169_0002
Final product 2-43 (200 mg, 0.39 mmol) was dissolved in MeOH (7 mL) and Amberlyst(r) 15 (1 g, 4.7 mmol) was added. The reaction mixture was stirred at rt for 24 h and filtered. The resin was suspended in MeOH/NH37N (10 mL), stirred for 10 min and filtered. This treatment was repeated 3 times. The filtrates were together evaporated and the residue was precipitated from DCM (5 mL) and filtered to give the expected product 2-44 (43 mg, Y: 27%), as a white solid. Example B8
Preparation of Final product 2-45
Figure imgf000170_0001
Final product 2-44 (35 mg, 84 umol) was suspended in DCM (1.5 mL) and formaldehyde (0.1 mL, 1.26 mmol) and sodium cyanoborohydride (32 mg, 0.5 mmol) were added. The reaction mixture was stirred at rt for 20 h. The reaction was adsorbed in silica and purified by column chromatography (DCM/MeOH from 96:4 to 70:30) and then by HPLC to give the expected product 2-45 (3.2 mg) as a white solid.
Preparation of Final product 2-58
Figure imgf000170_0002
Final product 2-57 (20 mg, 48 umol) was suspended in DCM (1.5 mL) and formaldehyde (52 μΙ, 0.72 mmol) and sodium cyanoborohydride (18 mg, 0.29 mmol) were added. The reaction mixture was stirred at rt for 1 h. The reaction was adsorbed in silica and purified by column chromatography (DCM/MeOH from 96:4 to 70:30) and then by HPLC to give the expected product 2-58 (9 mg) as a white solid. Example B9
Preparation of Final product 2-46
Figure imgf000171_0001
Final product 2-44 (30 mg, 72 umol) was suspended in acetonitrile (1 mL) and DIPEA (19 μΙ_, 0.11 mmol) and MeS02CI (6 μΙ_, 79 umol) were added. The solution was stirred at rt for 2.5 h. Excess of eS02CI (3 μΙ_, 0.5 eq) was added. The reaction mixture was stirred for 3 days and evaporated. The residue was dissolved in HCI 1M (10 mL) and extracted with DCM (3 x 7 mL). The organic phase was dried (Na2S04), filtered and the solvent evaporated in vacuo. The resulting residue was purified by HPLC to give the expected product 2-46 (10 mg, Y: 28%) as a white solid.
Example B10
Preparation of Final product 2-47
Figure imgf000171_0002
Final product 2-43 (50 mg, 97 umol) was dissolved in MeOH (100 mL) and hydrogenated in the H-Cube (Pd/C 10%, 60 °C, Full H2, 1 mL/min). The resulting solution was evaporated and the residue was purified by HPLC to give the expected product 2-47 (14 mg, Y: 28%) as a white solid. Example B11
Preparation of Final product 2-30
Figure imgf000172_0001
Boron fluoride-dimethyl sulfide complex (0.226 mL, 2.151 mmol) was added to a stirred solution of final product 2-27 (70 mg, 0.2165mmol) in DCM (1.3 mL) at rt. The mixture was stirred at rt for 24 h. Additional amount of boron fluoride- dimethyl sulfide complex (2.1 mL) was added, and the mixture was stirred at rt for 48 h more. A saturated solution of NaHC03 was added and the mixture was extracted with DCM/MeOH 90:1. The organic phase was separated, dried (Na2S04), filtered and evaporated to dryness. The residue was purified by biotage chromatography and eluted with a gradient DCM/MeOH from 100 % to 50:50. The desired fractions were collected to obtain 20 mg of desired product 2-30 as a solid (Y: 30 %).
Preparation of Final product 2-88
Figure imgf000172_0002
Boron trifluoride-dimethyl sulfide complex (0.084 mL, 0.8 mmol) was added to a stirred solution of final product 2-62 (28 mg, 0.08 mmol) in DCM (1.5 mL) at rt. The mixture was stirred at rt for 24 h. Additional amount of boron fluoride- dimethyl sulfide complex (total of 0.3 mL) was added, and the mixture was stirred at rt for 48 h more. Then, THF (1 mL) was added and the mixture was heated at 50°c for 53h. A saturated solution of NaHC03 was added and the mixture was extracted with DCM/MeOH 90:1. The organic phase was separated, dried (Na2S04), filtered and evaporated to dryness. The residue was purified by biotage chromatography and eluted with a gradient DCM/MeOH from 100% to 95:5. The desired fractions were collected to obtain 7 mg of desired product 2-88 as a solid (Y: 26%).
Example B12
Preparation of Final product 2-57
Figure imgf000173_0001
Final Product 2-47 (174 mg, 0.34 mmol) was dissolvend in MeOH (7 ml) and Amberlyst 15 (1g) was added. The reaction mixture was stirred at room temperature for 24h and filtered. The resin was suspended in MeOH/NH3 7N stirred for 10 min. and the organic phase was collected. The solvent was evaporated and the residue was precipitated with MeOH, and then purified by HPLC to obtain 9 mg as a formiate salt of Final product 2-57.
Preparation of Final product 2-236
Figure imgf000173_0002
A 4M solution of HCI in dioxane (1 mL) was added at 0°C to Final product 2-232 (12 mg, 0.023 mmol). The reaction mixture was stirred at rt for 3 h. Solvents were removed and the residue was purified by column chromatography (Isolute SCX-2 cartridge, MeOH to NH3 7N in MeOH) to give Final product 2-236 (9 mg, 92%). Example B13
Preparation of Final product 2-52
Figure imgf000174_0001
To a reaction mixture of intermediate 1-12 (150 mg, 0.42 mmol), indazole-4- boronic acid hydrochloride (0.93 mmol, 0.150 mg), and PdCI2(dppf).DCM (35 mg, 0.042 mmol) in DME (2 ml), was added a saturated solution of potassium carbonate (0.5 ml). The mixture was heated at 130°C under microwave irradiation for 10 min. A precipitate appears which was filtered, washed with DCM and dried. The resulting solid (0.160 mg, Y: 96 %) is the expected final compound 2-52 and was used in next reaction step without further purification.
Preparation of Final product 2-92
Figure imgf000174_0002
Intermediate 1-30 (100mg, 0.31 mmol) was dissolved in DME (2 mL) and pyridine- 3-boronic acid (45mg, 0.37mmol), K2C03 (127mg, 0.92mmoi), PdCI2(dppf) DCM and water (1 mL) were added. The reaction mixture was heated under microwave irradiation at 130°C for 1h. The volatiles were removed under vacuum and the residue was purified by flash chromatography (DCM-MeOH 95:5 to 90:10). The product obtained was precipitated in MeOH affording the final product 2-92 as off- white solid (96mg, 97%). reparation of Final product 2-93
Figure imgf000175_0001
Intermediate 1-30 (100mg, 0.31 mmol) was dissolved in DME (2 mL) and 2- aminopyrimidine-5-boronic acid pinacol ester (81 mg, 0.37mmol), K2C03 (127mg, 0.92mmol), PdCI2(dppf) DCM and water (1 mL) were added. The reaction mixture was heated under microwave irradiation at 130°C for 1h. The volatiles were removed under vacuum and the residue was purified by flash chromatography (DCM-MeOH 95:5 to 90:10). The product obtained was precipitated in MeOH affording the final product 2-93 as off-white solid (96mg, 97%).
Preparation of Final product 2-165
Figure imgf000175_0002
Final product 2-178 (50 mg, 0.087 mmol) was dissolved in 1,4-dioxane (0.3 mL) and Pd(PPh3)4 (10 mg, 0.009 mmol), Cs2C03 (57 mg, 0.174 mmol), methylboronic acid (6 mg, 0.1 mmol) and water (0.2 mL) were added. The mixture was heated under microwave irradiation at 140°C for 1 h. Water was added and the mixture was extracted with DCM. The organics were dried (Na2S04), filtered and evaporated. The residue was purified by column chromatography-TLC in the Chromatotron (DCM:MeOH, 15:1) twice. The desired fractions were collected and evaporated to obtain Final compound 2-165 (22 mg, 52%). Example B14
Preparation of Final product 2-62
Figure imgf000176_0001
To a solution of final Product 2-12 (0.087 mmol) in DMF dry (1ml) was added zinc cyanide (0.091 mmol), tris(dibenzy!idenaceton)dipalladium (Pd2dba3) (0.004 mmol), , '-bis(diphenylphosphino)ferrocene (DPPF) (0.011 mmol). The mixture was heated at 140°C for 1h under microwave irradiation. The solution was diluted with ethyl acetate, washed with water and a saturated solution of NaCI. The organic phase was dried (Na2S04), filtered and the solvent evaporated. The residue was purified by flash column chromatography, eluent: CH2CI2- AcOEt/CH2CI2 1 :100-1 :50 to obtain 22.9 mg as a white solid of compound 2-62.
Preparation of Final product 2-36
Figure imgf000176_0002
A mixture of final product 2-73 (38 mg, 0.163 mmol), Zn(CN)2 (10 mg, 0.087 mmol), diphenylphosphineferrocene (6 mg, 0.01 mmol) and Pd2(dba)3 (4 mg, 0.004 mmo) in DMF (0.5 ml_) was heated for 1 h at 120 °C under microwave irradiation. Then, more Zn(CN)2 (10 mg, 0.087 mmol), dppf (6 mg, 0.01 mmol, 0.125 eq) and Pd2(dba)3 (4 mg, 0.004 mmol, 0.05 eq) were added and the mixture was heated 1.5 h at 120°C under microwave irradiation. This excess was added twice. The solvent was removed in vacuo and the residue was purified by column chromatography (EtOAc and EtOAc/MeOH mixtures) and then by HPLC to obtain 1.2 mg of desired product 2-36. Example B15
Preparation of Final product 2-79
Figure imgf000177_0001
Final product 2-52 (25mg, 0.064mmol) was suspended in EtOH (1.5ml_) and methyl amine (2M in THF, 1.27 mmol, 0.7mL) was added. The reaction mixture was heated in a sealed tube at 100°C for 18h. The reaction mixture was then directly adsorbed in silica to be purified by column chromatography (5% to 10% of MeOH in DCM) rendering 5mg of the final product 2-79 as a white solid (Y. 21%).
Preparation of Final product 2-217
Figure imgf000177_0002
Final product 2-214 (300 mg, 0.78 mmol) was suspended in eOH/NH3 7N (10 mL) and heated under microwave irradiation at 130 °C for 24 h. The mixture was evaporated and purified by column chromatography (MeOH in DCM, 100:0 to 40:60) rendering 80 mg of final product 2-217 as a white solid (Y. 29%).
Example B16
Preparation of Final product 2-87
Figure imgf000178_0001
Pyrrolidine (0.54 mmol, 45 uL) was dissolved in EtOH (5 mL) in a sealed tube and AIMe3 (0.54 mmol, 0.26 mL) was added. The mixture was stirred at rt for 15min and then, the final product 2-52 (0.27 mmol, 105 mg) was added. The reaction mixture was stirred at rt for 1h and 4h at 40°C. On cooling, the reaction was carefully quenched with NH4CI sat sol and extracted with CHCI3-iPrOH 1:1 (x3). The combined organic layer was dried, filtered and concentrated. The crude product was purified by flash chromatography (DCM-MeOH 96:4 to 90:10) rendering the final product 2-87 (15mg, 13%) as white solid.
Preparation of Final product 2-139
Figure imgf000178_0002
Final product 2-52 (0.127 mmol, 50 mg) was dissolved in EtOH (3 mL) and N,N- dimethyl-1 ,3-propanediamine (1.27 mmol, 0.16 mL) and AIMe3 (1.27 mmol, 0.64 mL) were added. The mixture was heated at 150°C for 3 days and under microwave irradiation at 180 °C for 1 h. On cooling, the reaction was carefully quenched with NH4CI sat. sol. and extracted with DCM (x2). The combined organic layers were dried, filtered and concentrated. The crude product was purified by flash chromatography (DCM-MeOH:NH3(7N); 100:0 to 80:20) rendering the final product 2-139 (18 mg, 31 %) as white solid. Example B17
Preparation of Final product 2-97
Figure imgf000179_0001
A mixture of intermediate I-34 (100mg, 0.28mmol), AcOH (40uL, 0.52mmol), 2,8- diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester hydrochloride (90mg, 0.29mmol) in DCE (5mL) was stirred at rt for 40 min. Then, NaBH(OAc)3 (90mg, 0.40mmol) was added and stirring continued for 5h. The reaction mixture was quenched by adding 4N aq sol of KOH and it was extracted with EtOAc (x2). The combined organic layer was washed with brine, dried (Na2S04), filtered and concentrated the crude product (150 mg, 93%) that was used in next reaction step without further purification. Part of this crude product (50mg) was further purified by preparative HPLC rendering the final product 2-97 (13 mg).
Method B18
Preparation of Final product 2-155
Figure imgf000179_0002
A mixture of iodine (34 mg, 0.133 mmol), triphenylphosphine (29 mg, 0.111 mmol) and imidazole (9 mg, 0.133 mmol) in DMF (2 mL) was stirred at RT for 1h. Then, Final product 2-144 (55 mg, 0.111 mmol) was added and the mixture was stirred at 70°C overnight. The mixture was evaporated and the residue was purified by using a sep-pack in a manifold (DCM:MeOH, 92:8) to render 10 mg of Final product 2- 55 (16%). Method B19
Preparation of Final product 2-177
Figure imgf000180_0001
Final product 2-138 (0.3 g, 0.81 mmol) was suspended in THF (6 mL) and MeMgCI (3M, 2.7 mL, 8.1 mmol) was slowly added at 0 °C. The reaction mixture was stirred for 4 h and then carefully quenched with H20. The resulting mixture was purified by column chromatography (DCM:MeOH, 95:5 to 85:15). The product obtained was precipitated with DCM and drops of MeOH and filtered to render Final product 2-177 (20 mg, 7%) as a yellow solid. The filtrate was evaporated and purified by column chromatography (DCM.MeOH, 95:5 to 85:15) and by prep-HPLC to give Final product 2-177 (38 mg, 13%) as a yellow solid.
Method B20
Preparation of Final product 2-191
Figure imgf000180_0002
To a solution of Intermediate I-52 (50 mg, 0.146 mmol), BOP (78 mg, 0.176 mmol) and 4-aminotetrahydropyran.HCI (0.024 mL, 0.176 mmol) in DCM (1.5 mL) was added Et3N (0.041 mL, 0.293 mmol). The mixture was stirred at rt for 2h.
DCM was added and the mixture was washed with water. The organic phase was dried, filtered and evaporated. The residue was purified by column chromatography (DCM:MeOH, 100:0 to 60-40) and by prep-HPLC to render 4 mg (6 %) of Final product 2-191 as a white solid.
Method B21
Preparation of Final product 2-234
Figure imgf000181_0001
Final product 2-231 (40 mg, 0.078 mmol) was suspended in sodium methoxide 0.5 M in MeOH, 3 mL) and the reaction mixture was stirred at RT for 45 min. H20 (3 mL) was added, the solution was slightly acidified with HCI and extracted with n-BuOH. The organics were dried over Na2S0 , filtered and evaporated. The residue was purified by chromatotron (DCM:MeOH, 10:1). The residue was dissolved in MeOH (4 mL), amberlyst (0.3 g) was added and the mixture was stirred at rt for 2 h, filtered and washed with MeOH. The resine was suspended in NH3/MeOH (7 N, 35 mL) and stirred for 1 h. The mixture was filtered and the filtrate was evaporated. The residue was purified by chromatotron (DCM/MeOH, 10:1) to give Final product 2-234 (12 mg, 33%) as a white solid.
Method B22
Preparation of Final product 2-237
Figure imgf000181_0002
Intermediate I-28 (500 mg, 1.540 mmol), indazole-4-boronic acid hydrochloride (3.387mmol, 672 mg) and PdCI2(dppf).DCM (0.154 mmol, 127 mg) were suspended in a saturated solution of sodium carbonate (1.5 mL) and 1 ,2-DME (7mL). The mixture was heated under microwave irradiation at 130°C for 10 min. The mixture was diluted with EtOAc and washed with water. The organic layer was dried (Na2S04), filtered and the solvent evaporated in vacuo. The resulting residue was purified by flash chromatography (DCM-MeOH from 100:0 to 96:4) to obtain the Final Product 2-237 as a white solid (88 mg, Y: 14%).
Method B23
Preparation of Final product 2-238
Figure imgf000182_0001
Final Product 2-237 (88 mg, 0.217 mmol) was suspended in MeOH (2 mL) and treated with 2N NaOH (0.24 mL, 0.48 mmol). The reaction mixture was refluxed for 4 h. Solvents were evaporated and the residue was dissolved in EtOAc, treated with AcOH and washed with water. The organic layer was dried, filtered and evaporated to give the Final Product 2-238 (82 mg, 00%).
Method B24
Pre aration of Final product 2-241
Figure imgf000182_0002
To a solution of Final product 2-44 (50 mg, 0.12 mmol) and N,N- diisopropylethylamine (0.031 mL, 0.181 mmol) in acetonitrile (2 mL) was added isobutyryl chloride (0.014 mL, 0.132 mmol). The mixture was stirred at rt for 4 h and evaporated. H20 was added and the mixture was extracted with DCM. The organic layer was dried (Na2S04), filtered and evaporated to render Final Product 2-241 (51 mg, 87%).
Method B25
Preparation of Final product 2-243
Figure imgf000183_0001
A mixture of Final Compound 2-245/lntermediate I-69 (62 mg, 0.13 mmol), 1- methylpiperazine (0.019 mL, 0.17 mmol), TEA (0.024 mL, 0.17 mmol), HOBT (26 mg, 0.17 mmol) and EDCI (33 mg, 0.17 mmol) in THF (1 mL) was stirred at rt overnight and evaporated. The residue was purified by column chromatography (Isolute 5 g; MeOH:DCM, 1:99 to 20:80 and Flash-NH2 5g; MeOH:DCM, 0:100 to 2:98) to give the Final Product 2-243 (49 mg, 67%) as a white solid.
Method B26
Preparation of Final product 2-245
Figure imgf000183_0002
To a solution of Intermediate 1-69 (50 mg, 0.16 mmol) in DCM (1.3 mL) was added methyl 4-isocyanatobenzoate (31 mg, 0.18 mmol). The reaction mixture was stirred at rt for 5 h. Cyclohexane was added and the mixture was filtered to give Final Product 2-245 (46 mg) as a beige solid. The filtrate was evaporated and the residue was purified by column chromatography (Isolute 5g; MeOH:DCM, 0:100 to 5:95) to give Final product 2-245 (25 mg) as a light yellow solid. Total yield: 91%.
General Procedure
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.
Method 1
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.
Method 2
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.
Method 3
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 40% of B within 8 min at 50 °C, DAD. Method 4
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: 0% of B to 30% of B within 8 min at 50 °C, DAD.
Method 5
Reversed phase HPLC was carried out on a Gemini C18 (50 x 2.0 mm; 3um), Solvent A: water with 0.1% formic acid; Solvent B: acetonitrile with 0.1% formic acid. Gradient: 10% of B to 95% of B within 4 min at 50 °C, DAD.
Table 4; Analytical data and PI3Kcc activity - Rt means retention time (in minutes), [M+H]+ means the protonated mass of the compound, method refers to the method used for (LC)MS.
Biological activity in PI3Ka for certain examples is represented in Table 4 by semi-quantative results: IC50 >1μΜ (+), IC50 <100 nM (+++), 100 nM<IC50< 1 μΜ (++). Biological activity in PI3Ka for certain examples is also represented in Table 4 by quantative results.
PI3Ka
Cpd. 1H NMR (300 MHz; δ in ppm, J in
Rt [M+1]+ Meth. IC50
Nr. Hz)
(μΝΙ)
DMSO δ 9.48 (s, 1H), 8.45 (s, 1H), 7.82 (s, 1H), 7.36 (m, 2H), 7.24 (d, J = 7.7, 1H),
2-05 7.277 495.3 1 0.476 6.74 (d, J = 7.5, 1H), 4.23 (m, 4H), 3.78 (m,
4H), 3.62 (s, 2H), 3.35 (m, 4H), 2.40 (m,
4H), 1.38 (s, 9H).
DMSO δ 9.48 (s, 1H), 8.45 (s, 1H), 7.83 (s, 1H), 7.36 (dd, J = 11.7, 5.0, 2H), 7.22 (t, J
0.451
2-06 4.707 437.2 1 = 7.9, 1H), 6.74 (dd, J = 7.9, 1.6, 1 H), 4.23
(++) (m, 4H), 3.77 (m, 4H), 3.62 (s, 2H), 3.40
(m, 4H), 2.41-2.39 (m, 4H), 1.96 (s, 3H).
DMSO δ 9.48 (s, 1H), 8.45 (s, 1 H), 7.80 (s, 1H), 7.37 (dd, J = 12.2, 5.0, 2H), 7.22 (t, J
2-07 4.577 409.2 1 27 = 7.9, 1H), 6.74 (d, J = 9.5, 1 H), 4.24 (m,
4H), 3.78 (m, 4H), 3.58 (s, 2H), 2.42-2.31 (m, 4H), 2.14 (s, 4H), 1.39 (s, 3H).
DMSO δ 9.48 (s, 1 H), 8.46 (s, 1 H), 7.86 (s, 1 H), 7.74 (s, 1 H), 7.38 (dd, J = 11.8, 5.0,
0.54
2-08 4.714 409.2 1 2H), 7.23 (t, J = 7.9, 1 H), 6.75 (dd, J = 8.0,
(++) 1.7, 1H), 4.24 (m, 4H), 3.78 (m, 4H), 3.69
(s, 2H), 3.16 (m, 2H), 2.64 (t, J = 5.3, 2H).
DMSO δ 9.48 (s, 1H), 8.45 (s, 1H), 7.83 (s,
0.444 1H>, 7.38 (m, 2H), 7.22 (t, J = 7.9, 1H),
2-09 4.601 396.2 1
(++) 6.74 (dd, J = 7.5, 2.0, 1H), 4.24 (m, 4H),
3.78 (m, 4H), 3.58 (m, 6H), 2.45 (m, 4H).
DMSO δ 9.48 (s, 1H), 8.46 (s, 1H), 7.83 (s, 1H), 7.37 (dd, J = 11.9, 4.9, 2H), 7.23 (t, J
0.037
2-10 4.409 473.2 1 = 7.8, 1 H), 6.75 (dd, J = 7.9, 1.7, 1 H), 4.24
(+++)
(m, 4H), 3.78 (m, 4H), 3.67 (s, 2H), 3.12 (m, 4H), 2.87 (s, 3H), 2.56 (m, 4H).
DMSO δ 9.51 (s, 1H), 8.49 (s, 1H), 8.34 (s,
1H), 7.37 (m, 2H), 7.25 (t, J = 7.8, 1H),
2-11 6.401 487 1 0.044
6.77 (d, J = 8.1 , 1H), 4.25 (s, 6H), 3.80 (s, 6H), 3.22 (s, 4H), 2.92 (s, 3H).
CDCI3 δ 7.67 (d, J =0.7, 1H), 7.35 (t, J =7.9 Hz, 1H), 7.22 (m, 1H), 7.18 (m, 1 H), 6.95
2-12 5.599 397.1 1 ++
(ddd, J =8.2, 2.6, 0.9 Hz, 1H), 4.28 (m, 4H), 3.85 (s, 3H), 3.84 (m, 4H), 2.46 (s, 3H).
DMSO δ 9.53 (s, 1H), 8.50 (d, J = 13.9,
2-13 7.691 365.1 1 0.108
2H), 7.38 (dd, J = 9.6, 4.9, 2H), 7.26 (t, J = P13Ka
Cpd. 1H NMR (300 MHz; δ in ppm, J in
t [M+1]+ Meth. IC50
Nr. Hz)
(μΜ)
(++) 7.8, 1H), 6.79 (dd, J = 7.9, 1.6, 1H), 4.25
(m, 4H), 3.80 (m, 4H).
DMSO δ 9.46 (s, 1H), 8.38 (s, 1H), 7.69 (s, 1H), 7.37 (dd, J = 12.3, 5.0, 2H), 7.21 (t, J
0.34
2-14 7.025 337 1 = 7.9, 1H), 6.73 (dd, J = 7.9, 1.6, 1H), 4.21
(++) (m, 4H), 3.77 (m, 4H), 2.03 (ddd, J = 13.2,
8.3, 4.9, 1H), 0.92 (m, 2H), 0.79 (m, 2H).
DMSO δ 13.25 (s, 1H), 8.65 (s, 1H), 8.55 (s, 1H), 8.40 (s, 1H), 7.67 (d, J = 6.8, 1H),
0.741
2-15 3.131 447.2 1 7.58 (m, 1H), 7.45 (m, 1H), 4.29 (s, 4H),
(++) 4.08 (s, 2H), 3.82 (s, 4H), 3.70 (s, 2H),
2.48 (s, 4H), 2.28 (s, 3H).
DMSO δ 13.24 (s, 1H), 8.65 (s, 1H), 8.55 (s, 1H), 8.44 (s, 1H), 7.67 (d, J = 7.0, 1H),
0.254
2-16 4.152 511.2 1 7.58 (d, J = 8.3, 1H), 7.45 (t, J = 7.7, 1H),
(++) 4.29 (s, 6H), 3.82 (s, 6H), 3.23 (s, 4H),
2.92 (s, 3H).
DMSO δ 13.20 (s, 1 H), 8.58 (d, J = 15.8, 2H), 7.99 (d, J = 37.6, 1H), 7.52 (m, 3H),
2-17 3.171 497.20 1 0.095 4.27 (d, J = 4.4, 4H), 3.81 (m, 4H), 3.70 (s,
2H), 3.14 (t, J = 9.4, 4H), 2.87 (s, 3H), 2.58
(s, 4H).
DMSO δ 8.64 (s, 1H), 8.55 (s, 1H), 8.40 (s,
1H), 8.30 (s, 1H), 7.66 (d, J = 7.1, 1H),
0.182 7.58 (d, J = 8.3, 1H), 7.44 (m, 1 H), 4.89 (br
2-18 3.745 432.5 1
(++) s, 1H), 4.28 (br s, 4H), 4.07 (br s, 1 H), 3.81
(br s, 4H), 3.70 (br s, 1 H), 2.92 (brs, 4H) (rotamers observed)
DMSO) δ 13.26 (s, 1H), 8.53 (s, 3H), 7.79 (s, 1H), 7.62 (d, J = 7.1 , 1 H), 7.55 (d, J =
2-19 4.151 361.2 1 0.438 8.2, 1H), 7.42 (d, J = 7.5, 1H), 4.24 (s, 4H),
3.79 (s, 4H), 2.06 (m, 1H), 0.94 (m, 2H),
0.81 (m, 2H).
DMSO δ 13.26 (s, 1H), 8.59 (m, 3H), 7.67
2-20 4.63 389.10 1 1.8 (d, J = 7.1, 1H), 7.60 (d, J = 8.3, 1H), 7.45
(m, 1 H), 4.28 (s, 4H), 3.82 (m, 4H).
DMSO δ 13.20 (s, 1H), 8.58 (s, 1H), 8.50
2-21 5.25 364.1 1 - (s, 1 H), 8.34 (s, 1 H), 7.83 (s, 1H), 7.61 (d,
J = 7.1 , 1 H), 7.52 (d, J = 8.2, 1 H), 7.39 (m, PI3Ka
Cpd. 1H NMR (300 MHz; δ in ppm, J in
Rt [M+1]+ eth. IC50
Nr. Hz)
(μΜ)
2H), 4.27 (s, 4H), 3.75 (s, 4H).
DMSO δ 13.19 (s, 1H), 8.73 (s, 1H), 8.58
0.618 (s, 1H), 8.47 (s, 1H), 7.61 (d, J = 7.1 , 1H),
2-22 6.72 346 1
(++) 7.53 (d, J = 8.2, 1 H), 7.38 (t, J = 7.7, 1 H),
4.21 (s, 4H), 3.75 (m, 4H).
DMSO δ 9.45 (s, 1 H), 8.43 (s, 1H), 7.69 (d,
0.096 J = 0.7, 1 H), 7.38 (m, 2H), 7.22 (t, J = 7.9,
2-23 5.438 311.1 1
(+++) 1 H), 6.74 (dd, J = 8.0, 1.6, H), 4.23 (m,
4H), 3.78 (m, 4H).
DMSO δ 13.19 (s, 1H), 8.58 (s, 1H), 8.55
2.6 (s, 1H), 7.79 (s, 1H), 7.64 (d, J = 7.1 , 1H),
2-24 5.576 335.1 1
(+) 7.54 (d, J = 8.2, 1H), 7.42 (m, 1H), 4.26 (m,
4H), 3.80 (m, 4H), 2.37 (s, 3H).
DMSO δ 11.18 (s, 1H), 8.48 (s, 1H), 8.05 (d, J = 0.7, 1H), 7.70 (d, J = 0.7, 1H), 7.58
2-25 6.033 334.1 1 10
(d, J = 1.4, 2H), 7.37 (m, 1H), 6.43 (m, 1 H), 4.26 (m, 4H), 3.80 (m, 4H), 2.35 (m, 3H).
DMSO δ 9.09 (m, 1H), 8.56 (s, 1H), 8.48 (dd, J = 4.8, 1.6, 1 H), 8.24 (m, 1 H), 7.64 (d,
2-26 3.350 296.1 1 10 J = 0.8, 1 H), 7.40 (ddd, J = 8.0, 4.7, 0.7,
1H), 4.19 (m, 4H), 3.71 (m, 4H), 2.29 (s,
3H).
DMSO δ 8.78 (s, 1 H), 8.65 (s, 1 H), 8.26 (s,
3.9 1H), 7.85 (s, 1 H), 7.69 (s, 1H), 4.24 (d, J =
2-27 4.651 326.1 1
(+) 4.4, 4H), 3.90 (s, 3H), 3.77 (m, 4H), 2.36
(s, 3H).
DMSO δ 9.89 (s, 1H), 8.53 (s, 1H), 7.96 (s,
1 H), 7.79 (s, 1 H), 7.72 (d, J = 7.7, 1 H),
2-28 5.758 388.1 1 50 7.45 (t, J = 7.9, 1H), 7.26 (d, J = 7.9, 1H),
4.32 (s, 4H), 3.85 (d, J = 4.4, 4H), 3.08 (s,
3H), 2.41 (s, 3H).
DMSO δ 8.62 (s, 1H), 8.39 (s, 1H), 7.82 (d, J = 8.3, 2H), 7.66 (s, 1H), 7.46 (d, J = 8.2,
2-29 4.843 367.2 1 3
3H), 6.03 (s, 1 H), 4.22 (s, 4H), 3.77 (s, 4H), 2.65 (d, J = 3.5, 3H), 2.34 (s, 3H).
DMSO δ 9.97 (s, 1H), 8.61 (s, 1H), 8.57 (s,
0.235 1H), 8.09 (d, J = 2.4, 1H), 7.70 (d, J = 3.5,
2-30 3.726 312.1 1
(++) 2H), 4.24 (d, J = 4.5, 4H), 3.78 (m, 4H),
2.35 (s, 3H). PI3Ka
Cpd. 1H NMR (300 MHz; δ in ppm, J in
t [M+1]+ Meth. IC50
Nr. Hz)
(μΜ)
DMSO δ 8.69 (s, 1H), 8.56 (d, J = 5.9, 2H),
2-31 3.512 296.1 1 10 7.87 (d, J = 6.0, 2H), 7.66 (s, 1H), 4.20 (m,
4H), 3.71 (m, 4H), 2.30 (s, 3H).
CDCIs δ 7.84 (s, 1H), 7.48 (m, 1 H), 7.42 (d, J = 7.9, 1 H), 7.31 (t, J = 7.9, 1 H), 7.26 (s,
2-32 NMR - 1H), 6.87 (dd, J = 8.1 , 1.8, 1 H), 4.32 (m,
4H), 3.88 (m, 4H), 3.85 (s, 3H), 2.41 (s,
3H).
CDCb δ 8.62 (dd, J = 4.6, 1.6, 2H), 7.68 (dd, J = 4.5, 1.6, 2H), 7.55 (m, H), 4.20
2-33 4.509 330.1 1 - (m, 4H), 3.79 (dd, J = 10.4, 5.7, 4H), 2.38
(t, J = 0.5, 3H).
CDCb δ 8.99 (d, J = 1.8, 1 H), 8.55 (dd, J = 4.8, 1.6, 1H), 8.04 (m, 1H), 7.50 (d, J = 0.6,
2-34 5.260 330.1 1 - 1H), 7.31 (m, 1H), 4.22 (m, 4H), 3.80 (m, 4H), 2.40 (d, J = 0.5, 3H).
DMSO δ 8.57 (s, 1 H), 8.29 (s, 1H), 7.97 (d, J = 7.4, 2H), 7.87 (s, 1 H), 7.47 (t, J = 7.3,
2-35 4.78 324.1 2 - 3H), 7.37 (t, J = 7.2, 1H), 4.31 (s, 4H), 3.80
(d, J = 4.4, 4H).
MeOD δ 8.26 (s, 1H), 7.77 (s, 1 H), 7.70 (d, J = 8.9, 1H), 7.62 (d, J = 7.1 , 2H), 7.52 (d,
2-36 4.31 360.1 2 - J = 8.2, 1 H), 4.54 (m, 4H), 3.86 (m, 4H),
2.47 (s, 3H).
DMSO δ 9.45 (s, 1H), 7.79 (s, 1H), 7.42 (d, J = 6.9, 2H), 7.23 (m, 2H), 6.75 (d, J = 7.4,
2-37 3.37 395.20 1 ++
1H), 4.26 (m, 4H), 3.77 (m, 4H), 3.02 (m, 4H), 2.56 (m, 4H), 2.27 (s, 3H).
CDCb δ 10.16 (s, 1H), 8.51 (s, 1 H), 7.80 (s, 1H), 7.55 (d, J = 6.6, 1H), 7.42 (m, 2H),
2-38 3.06 419.2 1 ++
7.17 (s, 1 H), 4.32 (m ,4H), 3.84 (m, 4H), 3.07 (m, 4H), 2.59 (s, 4H), 2.34 (s, 3H).
DMSO δ 9.46 (s, 1H), 7.88 (s, 1H), 7.40 (m, 3H), 7.23 (t, J = 7.8, 1H), 6.76 (d, J =
2-39 4.12 459.20 1 ++
7.3, 1H), 4.27 (s, 4H), 3.77 (s, 4H), 3.38 (s, 4H), 3.13 (s, 4H), 2.98 (s, 3H).
DMSO δ 9.45 (s, 1H), 7.81 (s, 1 H), 7.42
2-40 2.90 381.20 1 ++ (m, 2H), 7.23 (m, 2H), 6.75 (d, J = 8.8, 1H),
4.26 (s, 4H), 3.77 (m, 4H), 2.93 (s, 8H). PI3Ka
Cpd. 1H NMR (300 MHz; 6 in ppm, J in
Rt [M+1]+ Meth. IC50
Nr. Hz)
(μΜ)
DMSO δ 13.20 (s, 1H), 8.45 (s, 1 H), 7.97 (s, 1H), 7.61 (dd, J = 7.1, 0.6, 1H), 7.57 (d,
2-41 6.065 483.2 1 ++ J = 8.3, 1 H), 7.44 (m, 1 H), 7.40 (d, J = 3.8,
1H), 4.30 (s, 4H), 3.80 (m, 4H), 3.37 (m, 4H), 3.17 (m, 4H), 2.98 (s, 3H).
DMSO δ 13.22 (s, 1H), 8.46 (s, 1 H), 8.05 (s, 1 H), 7.61 (dd, J = 16.1 , 7.7, 2H), 7.43 (t,
2-42 7.644 413.1 1 - J = 7.7, 1 H), 4.27 (s, 4H), 3.80 (s, 4H), 2.38
(s, 3H).
DMSO δ 13.12 (s, 1H), 8.35 (s, 1 H), 7.96 (s, 1 H), 7.51 (dd, J = 11.0, 7.7, 2H), 7.34
2-43 8.144 516.3 1 - (m, 1H), 6.02 (s, 1H), 4.21 (s, 4H), 4.03 (s,
2H), 3.74 (s, 4H), 3.57 (s, 2H), 2.38 (s, 2H), 2.28 (s, 3H), 1.38 (s, 9H).
DMSO δ 13.13 (s, 1H), 8.34 (s, 1H), 7.95 (s, 1 H), 7.50 (m, 2H), 7.35 (t, J = 7.8, 1H),
0.731
2-44 3.836 416.2 1 6.01 (s, 1H), 4.21 (s, 4H), 3.74 (m, 4H),
(++) 3.39 (s, 2H), 2.93 (s, 2H), 2.28 (s, 3H),
2.23 (s, 2H).
DMSO δ 8.33 (s, 1H), 8.12 (s, 1 H), 7.91 (s, 1H), 7.51 (d, J = 5.0, 1H),7.49 (d, J = 6.2, 1 H), 7.35 (dd, J = 8.3, 7.1 , 1H), 5.98 (s,
2-45 7.145 430.2 1 - 1H), 4.21 (m, 4H), 3.73 (m, 4H), 3.11 (s, 2H), 2.64 (m, 2H), 2.38 (m, 2H), 2.31 (s,
3H), 2.27 (s, 3H).
DMSO δ 13.25 (bs, 1H), 8.43 (s, 1H), 8.22 (s, 1H), 7.56 (t, J = 7.0, 2H), 7.41 (dd, J =
8.3, 7.2, 1H), 6.12 (s, 1 H), 4.25 (m, 4H),
2-46 6.306 494.2 1 - 3.98 (d, J = 2.6, 2H), 3.81 (m, 4H), 3.49 (m,
2H), 3.00 (s, 3H), 2.55 (m, 2H), 2.36 (s,
3H).
DMSO δ 13.17 (s, 1H), 8.49 (s, 1H), 8.26 (s, 1 H), 7.62 (d, J = 7.1 , 1 H), 7.56 (d, J = 8.2, 1H), 7.42 (m, 1H), 4.26 (s, 4H), 4.09
2-47 7.661 518.3 1 - (d, J = 12.2, 2H), 3.79 (s, 4H), 3.47 (s, 1H), 2.95 (s, 2H), 2.41 (s, 3H), 1.80 (s, 4H),
1.42 (s, 9H).
CDCI3 δ 7.57 (d, J = 0.7, 1H), 7.36 (m, 3H),
2-48 3.697 359.1 1 - 6.95 (dt, J = 6.5, 2.6, 1H), 4.28 (m, 4H), PI3Ka
Cpd. 1H NMR (300 MHz; δ in ppm, J in
Rt [M+1]+ Meth. IC50
Nr. Hz)
(μΜ)
3.87 (m, 7H), 2.47 (d, J = 0.5, 3H).
DMSO δ 9.54 (s, 1H), 7.87 (s, 1H), 7.25 (t, J = 8.1 , 1H), 7.15 (dd, J = 5.1, 3.0, 2H),
2-49 1.596 345.1 1 ++
6.80 (m, 1H), 4.17 (m, 4H), 3.74 (m, 4H),
2.39 (s, 3H).
DMSO δ 8.77 (s, 2H), 8.41 (s, 1H), 7.76 (s,
1H), 6.83 (s, 2H), 4.22 (d, J = 4.5, 4H),
2-50 2.33 474.2 2 0.001
3.77 (m, 4H), 3.66 (s, 2H), 3.11 (d, J = 4.8, 4H), 2.87 (s, 3H), 2.55 (s, 4H).
DMSO δ 13.21 (s, 1 H), 8.42 (s, 1H), 7.92 (s, 1H), 7.59 (dd, J = 16.1, 7.7, 2H), 7.43
2-51 4.95 405.2 1 - (m, 1H), 7.29 (s, 1H), 4.30 (s, 4H), 3.79 (m,
4H), 2.94 (m, 8H).
DMSO δ 8.66 - 8.32 (m, 2H), 7.74 - 7.15
2-52 NMR 0.676 (m, 3H), 4.29 (d, J = 7.3, 5H), 3.76 (s, 4H),
1.25 (t, J = 15.7, 3H).
CDCIs δ 7.67 (d, J =0.7 Hz, 1H), 7.35 (t, J =7.9 Hz, 1H), 7.22 (m, 1H), 7.18 (m, 1H),
2-53 NMR - 6.95 (ddd, J =8.2, 2.6, 0.9 Hz, 1H), 4.28
(m, 4H), 3.87 (s, 3H), 3.85 (m, 4H), 2.46 (s,
3H).
CDCI3 6 10.06 (s, 1 H), 8.19 (d, J = 0.6,
0.266
2-54 1.42 369.1 2 1 H), 7.61 (s, 1H), 7.50 (m, 3H), 4.30 (m,
(++) 4H), 3.83 (m, 4H), 2.49 (m, 3H).
CDCI3 δ 8.13 (s, 1H), 7.66 (s, 1 H), 7.54 (dt,
2-55 1.43 413.0 2 12 J = 7.2, 3.6, 1H), 7.47 (m, 2H), 4.29 (m,
4H), 3.86 (m, 4H), 2.49 (s, 3H).
CDCb δ 9.10 (d, J = 1.8, 1H), 8.54 (dd, J = 4.8, 1.6, 1H), 8.16 (m, 1H), 7.87 (m, 1H),
2-56 4.192 422.0 2 0.253
7.31 (dd, J = 7.9, 4.4, 1H), 4.25 (m, 4H), 3.80 (m, 4H), 2.40 (s, 3H).
DMSO δ 8.50 (d, J = 0.7, 1H), 8.44 (s, 1H), 8.32 (s, 1H), 7.63 (d, J = 7.0, 1H), 7.56 (d, J = 8.3, 1 H), 7.42 (dd, J = 8.2, 7.2, 1 H),
0.144
2-57 3.89 418.2 1 4.27 (m, 4H), 3.79 (m, 4H), 3.51 (t, J =
(++) 12.2, 1H), 3.25 (dd, J = 15.8, 8.2, 2H), 2.95
(t, J = 11.7, 2H), 2.43 (s, 3H), 2.15 (t, J = 11.6, 2H), 1.82 (m, 2H). PI3Ka
Cpd. 1H NMR (300 MHz; δ in ppm, J in
Rt [M+1]+ Meth. IC50
Nr. Hz)
(μΜ)
DMSO δ 8.50 (s, 1H), 8.26 (s, 1H), 8.20 (d, J = 7.4, 2H), 7.63 (d, J = 7.1, 1H), 7.55 (t, J = 9.4, 1H), 7.43 (dd, J = 8.2, 7.3, 1H), 4.26
2-58 2.80 432.2 2 ++ (m, 4H), 3.79 (m, 4H), 3.33 (t, J = 12.3,
1 H), 3.17 (d, J = 11.2, 2H), 2.57 (t, J = 11.1, 2H), 2.49 (s, 4H), 2.44 (s, 3H), 2.12 (m, 2H), 1.86 (d, J = 12.1, 2H).
DMSO δ 13.17 (s, 1H), 8.50 (s, 1H), 8.27 (s, 1H), 7.63 (d, J = 7.1 , 1H), 7.56 (d, J = 8.3, 1H), 7.43 (dd, J = 8.2, 7.2, 1H), 4.27
2-59 6.37 496.2 1 - (s, 4H), 3.80 (m, 4H), 3.72 (d, J = 11.5, 2H), 2.98 (d, J = 13.4, 2H), 2.94 (s, 3H), 2.45 (s, 3H), 1.96 (s, 4H).
DMSO δ 13.19 (s, 1H), 8.08 (s, 1 H), 8.00 (s, 1H), 7.61 (d, J = 8.1, 1H), 7.45 (m, 1H),
2-60 4.70 4.97 2 ++ 7.38 (dd, J = 7.1 , 1.0, 1H), 4.19 (m, 4H),
3.76 (m, 4H), 3.14 (m, 4H), 2.88 (s, 3H),
2.59 (m, 4H).
CDCfe δ 8.71 (d, J = 2.4, 1 H), 8.08 (dd, J = 8.6, 2.5, 1H), 7.82 (s, 1H), 7.49 (s, 1H),
2-61 3.14 488.2 2 4.5 6.83 (d, J = 8.7, 1 H), 4.37 (m, 4H), 4.00 (s,
3H), 3.90 (m, 4H), 3.77 (s, 2H), 3.30 (m, 4H), 2.80 (s, 3H), 2.71 (m, 4H).
CDCb δ 7.99 (s, 1H), 7.48 (m, 2H), 7.37 (t,
2-62 2.28 350.1 2 - J = 8.1, 1H), 6.95 (m, 1H), 4.35 (m, 4H),
3.89 (m, 7H), 2.57 (s, 3H).
DMSO δ 13.25 (s, 1H), 8.83 (s, 1H), 8.43 (s, 1H), 8.09 (d, J = 7.7, 1 H), 7.62 (d, J = 7.1 , 1H), 7.58 (d, J = 8.3, 1H), 7.44 (dd, J = 8.1 , 7.4, 1H), 4.33 - 4.21 (m, 4H), 4.13 -
2-63 7.53 561.3 1 - 4.00 (m, 1H), 3.93 (d, J = 13.1, 2H), 3.86 - 3.76 (m, 4H), 2.98 - 2.85 (m, 2H), 2.55 (s, 3H), 1.89 (d, J = 10.2, 2H), 1.55 - 1.42 (m,
2H), 1.41 (s, 9H).
DMSO δ 13.27 (s, 1H), 8.81 (s, 1H), 8.58 - 8.48 (m, 1H), 8.43 (s, 1H), 8.32 (d, J = 7.5,
2-64 2.94 461.2 2 + 1H), 8.28 - 8.20 (m, 1H), 7.63 (d, J = 7.1,
1 H), 7.59 (d, J = 8.3, 1 H), 7.45 (dd, J = 8.2, 7.2, 1H), 4.32-4.24 (m, 4H), 4.20 - 4.10 (m, PI3Ka
Cpd. 1H NMR (300 MHz; δ in ppm, J in
t [M+1]+ Meth. IC50
Nr. Hz)
(μΜ)
1 H), 3.86 - 3.78 (m, 4H), 3.15 - 3.00 (m, 2H), 2.58 (s, 3H), 2.16 - 2.03 (m, 2H), 1.85 - 1.68 (m, 2H). Two protons are missing, most likely under the water signal
CDCfe δ 8.71 (d, J = 1.7, 1 H), 8.31 (d, J = 2.8, 1H), 7.95 (s, 1H), 7.77 (dd, J = 2.7,
2-65 0.37 488.2 2 + 1.8, 1H), 7.51 (s, 1H), 4.38 (m, 4H), 3.96
(s, 3H), 3.91 (m, 4H), 3.77 (s, 2H), 3.30 (m, 4H), 2.80 (s, 3H), 2.72 (m, 4H).
DMSO δ 8.51 (d, J = 2.1, 1H), 8.33 (s, 1H), 7.90 (dd, J = 8.7, 2.4, 1H), 7.76 (s, 1H),
6.50 (d, J = 8.6, 1H), 6.10 (s, 2H), 4.22 (s,
2-66 0.367 473.2 2 0.169
4H), 3.78 (d, J = 4.6, 4H), 3.65 (s, 2H),
3.11 (s, 4H), 2.87 (s, 3H), 2.54 (d, J = 8.2,
4H).
DMSO δ 9.12 (s, 2H), 8.57 (s, 1 H), 7.81 (s,
3.44& 1H), 4.25 (d, J = 4.4, 4H), 3.97 (s, 3H),
2-67 489.2 2 ++
3.99 3.77 (m, 4H), 3.68 (s, 2H), 3.11 (d, J = 4.8,
4H), 2.87 (s, 3H), 2.56 (s, 4H).
DMSO) δ 8.65 (s, 1H), 8.04 (d, J = 8.5, 2H), 8.00 (s, 1H), 7.94 (d, J = 8.5, 2H),
2.54&
2-68 500.2 2 11 7.83 (s, 1H), 7.38 (s, 1 H), 4.27 (s, 4H),
2.64 3.79 (m, 4H), 3.68 (s, 2H), 3.12 (s, 4H),
2.87 (s, 3H), 2.56 (s, 4H).
DMSO δ 10.47 (s, 1H), 8.43 (s, 1H), 7.81 (s, 1H), 7.80 (d, J = 5.5, 1H), 7.78 (m, 1H), 6.88 (d, J = 8.0, 1 H), 4.23 (d, J = 4.5, 4H),
2-69 2.75 512.2 2 -
3.78 (m, 4H), 3.66 (s, 2H), 3.55 (s, 2H), 3.11 (d, J = 4.7, 4H), 2.87 (s, 3H), 2.56 (s,
4H).
DMSO δ 11.25 (s, 1 H), 8.24 (d, J = 2.1 , 1H), 7.93 (s, 1 H), 7.41 (m, 2H), 7.02 (dd, J
2-70 3.18 514 2 - = 11.2, 8.8, 1H), 6.70 (s, 1H), 4.21 (s, 4H),
3.78 (m, 4H), 3.69 (s, 2H), 3.12 (s, 4H), 2.87 (s, 3H), 2.57 (s, 4H).
CDCI3 δ 8.51 (s, 1H), 7.97 (s, 1 H), 7.53
4.15& (dd, J = 7.3, 0.6, 1H), 7.50 (s, 1 H), 7.43 (d,
2-71 496.2 2 - 4.73 J = 8.1, 1H), 7.28 (m, 2H), 6.98 (s, 1H),
4.37 (m, 4H), 3.89 (m, 4H), 3.77 (s, 2H), PI3Kct
Cpd. H NMR (300 MHz; δ in ppm, J in
t [M+1]+ Meth. IC50
Nr. Hz)
(μΜ)
3.27 (m, 4H), 2.77 (s, 3H), 2.71 (m, 4H).
CDCIs δ 8.37 (s, 1H), 8.12 (d, J = 7.8, 1H), 8.00 (s, 1H), 7.75 (d, J = 7.6, 1H), 7.51 (dd,
3.53&
2-72 500.2 2 - J = 13.2, 5.3, 2H), 4.37 (m, 4H), 3.90 (m,
3.89 4H), 3.76 (m, 2H), 3.29 (m, 4H), 2.79 (s,
3H), 2.71 (m, 4H).
CDCI3 δ 10.14 (m, 1 H), 8.06 (d, J = 0.9, 1 H), 7.70 (d, J = 0.7, 1 H), 7.54 (dt, J = 8.1,
2-73 5.37 461.0 2 - 1.0, 1 H), 7.46 (t, J = 7.6, 1 H), 7.40 (dd, J =
7.0, 1.2, 1H), 4.29 (m, 4H), 3.84 (m, 4H), 2.48 (d, J = 0.4, 3H).
DMSO δ 13.23 (s, 1H), 8.65 (s, 1 H), 8.56 (s, 1H), 8.44 (t, J = 6.1 , 1H), 8.40 (s, 1H),
2-74 4.55 392.1 2 0.092 7.67 (d, J = 7.1 , 1 H), 7.58 (d, J = 8.3, 1H),
7.44 (m, 1H), 4.34 (s, 4H), 3.83 (m, 4H), 3.40 (s, 2H), 1.15 (t, J = 7.1 , 3H).
DMSO δ 11.65 (s, 1H), 8.75 (d, J = 1.9, 1 H), 8.49 (s, 1 H), 8.41 (d, J = 1.7, 1 H), 7.75 (s, 1 H), 7.43 (m, 1 H), 6.45 (dd, J =
2-75 2.81 497.2 2 0.113
3.3, 1.8, 1H), 4.21 (s, 4H), 3.73 (s, 4H), 3.61 (s, 2H), 3.06 (s, 4H), 2.80 (s, 3H),
2.50 (s, 4H).
DMSO δ 13.27 (s, 1H), 8.82 (s, 1H), 8.44 (s, 1H), 8.18 (d, J = 7.7, 1H), 7.60 (dd, J = 11.7, 7.9, 2H), 7.45 (m, 1 H), 4.29 (d, J =
2-76 4.67 539.1 2 - 7.8, 4H), 4.03 (s, 1H), 3.82 (s, 4H), 3.58 (d,
J = 12.1 , 2H), 2.95 (m, 2H), 2.92 (s, 3H), 2.58 (s, 3H), 2.02 (d, J = 10.9, 2H), 1.66 (dd, J = 20.4, 11.1, 2H).
DMSO δ 13.25 (s, 1H), 9.06 (s, 1 H), 8.44 (s, 1H), 7.60 (dd, J = 11.9, 7.7, 3H), 7.45
2-77 4.12 378.1 2 - (dd, J = 8.3, 7.2, 1H), 4.27 (m, 4H), 3.81 (m, 4H), 2.61 (s, 3H).
DMSO δ 13.23 (s, 1H), 8.42 (d, J = 0.8, 1 H), 7.87 (s, 1 H), 7.63 (d, J = 7.0, 1 H), 7.57 (d, J = 8.3, 1 H), 7.43 (dd, J = 8.3, 7.2,
2-78 2.78 419.2 2 - 1H), 7.28 (s, 1H), 4.30 (m, 4H), 3.79 (m, 4H), 3.32 (s, 2H), 3.25 (dd, J = 28.1, 16.1 , 2H), 2.80 (dd, J = 20.2, 9.4, 2H), 1.86 (d, J PI3Ka
Cpd. 1H NMR (300 MHz; 6 in ppm, J in
Rt [ +1]+ Meth. IC50
Nr. Hz)
(μ )
= 10.1, 2H), 1.53 (m, 2H).
DMSO δ 13.23 (s, 1H), 8.64 (s, 1H), 8.56 (s, 1H), 8.40 (s, 1H), 8.38 (d, J = 5.0, 1H),
2-79 4.23 378.1 2 0.11 7.67 (d, J = 7.1 , 1H), 7.58 (d, J = 8.3, 1H),
7.44 (dd, J = 8.2, 7.3, 1 H), 4.34 (d, J = 4.4, 4H), 3.83 (m, 4H), 2.84 (d, J = 4.8, 3H).
DMSO δ 10.58 (s, 1H), 8.87 (s, 1H), 8.56
3.54 (s, 1H), 8.28 (d, J = 9.1 , 1H), 8.14 (d, J =
2-81 and 515.2 3 0.21 8.9, 1H), 7.81 (s, 1 H), 4.25 (s, 4H), 3.78 (s,
3.88 4H), 3.67 (s, 2H), 3.12 (s, 4H), 2.87 (s, 3H),
2.55 (s, 4H), 2.11 (s, 3H).
DMSO δ 8.61 (s, 1H), 8.41 (s, 1 H), 7.80
3.99 (m, 3H), 7.46 (d, J = 8.7, 2H), 6.02 (d, J =
2-82 and 529.2 3 0.158 4.7, 1H), 4.23 (s, 4H), 3.77 (m, 4H), 3.65
4.26 (s, 2H), 3.11 (s, 4H), 2.86 (s, 3H), 2.64 (d,
J = 4.6, 3H), 2.54 (d, J = 4.6, 4H).
CDCI3 δ 8.74 (d, J = 1.7, H), 8.22 (d, J =
4.79 1.9, 1H), 7.81 (s, 1H), 7.47 (s, 1H), 5.08 (s,
2-83 and 541.2 3 0.21 2H), 4.36 (m, 4H), 3.90 (m, 4H), 3.76 (s,
4.96 2H), 3.29 (m, 4H), 2.79 (s, 3H), 2.70 (m,
4H).
DMSO δ 13.33 (s, 1H), 8.23 (s, 1 H), 7.95
4.43 (s, 1 H), 7.72 (d, J = 8.0, 1 H), 7.52 (dd, J =
2-84 and 522.2 3 - 13.2, 7.0, 2H), 4.46 (s, 4H), 3.80 (m, 4H),
4.75 3.74 (s, 2H), 3.13 (s, 4H), 2.88 (s, 3H),
2.59 (s, 4H).
CDCb δ 8.49 (s, 1H), 8.04 (s, 1H), 7.93 (s, 1H), 7.47 (m, 2H), 7.39 (m, 2H), 4.36 (m,
2-86 4.40 392.1 1 0.891
4H), 3.84 (m, 4H), 3.47 (s, 3H), 3.10 (s,
3H).
DMSO δ 13.24 (s, 1H), 8.63 (s, H), 8.56 (s, 1H), 8.43 (s, 1H), 7.66 (d, J = 7.1 , 1 H), 7.58 (d, J = 8.3, 1 H), 7.44 (dd, J = 8.2, 7.3,
2-87 4.87 418.2 1 0.355
1H), 4.30 (d, J = 4.3, 4H), 3.95 (t, J = 6.6, 2H), 3.81 (m, 4H), 3.53 (t, J = 6.7, 2H),
1.87 (m, 4H).
DMSO δ 9.60 (s, 1H), 8.26 (s, 1H), 7.48 (d,
2-88 0.98 336.1 1 - J = 6.8, 2H), 7.25 (t, J = 8.1 , 1 H), 6.80 (d, J
= 8.6, 1 H), 4.23 (s, 4H), 3.79 (d, J = 4.3, PI3Ka
Cpd. 1H NMR (300 MHz; δ in ppm, J in
Rt [ +1]+ Meth. IC50
Nr. Hz)
(μΜ)
4H).
CDC δ 7.78 (s, 1H), 7.71 (d, J = 8.5, 2H), 7.43 (s, 1H), 6.74 (d, J = 8.5, 2H), 4.33 (m,
2-89 0.39 472.2 3 33
4H), 3.89 (m, 4H), 3.74 (s, 2H), 3.28 (m, 4H), 2.78 (s, 3H), 2.70 (m, 4H).
2.21 DMSO δ 12.93 (s, 1H), 8.22 (s, 1H), 8.11
(s, 1H), 7.89 (s, 1H), 7.74 (s, 1H), 4.22 (m,
2-90 and 447.2 3 6
4H), 3.76 (m, 4H), 3.65 (s, 2H), 3.11 (m, 3.02 4H), 2.87 (s, 3H), 2.55 (m, 4H).
DMSO δ 8.79 (s, 1H), 8.65 (dd, J = 4.6, 1.6, 2H), 8.31 (s, 1 H), 7.93 (dd, J = 4.6,
2-91 2.69 325.1 3 3.9
1.6, 3H), 7.51 (s, 1H), 4.33 (s, 4H), 3.79
(m, 4H).
DMSO δ 9.16 (d, J = 1.7, 1H), 8.67 (s, 1H), 8.57 (dd, J = 4.7, 1.6, 1H), 8.31 (m, 2H),
2-92 3.29 325.1 3 - 7.90 (s, 1H), 7.49 (dd, J = 7.4, 4.8, 2H), 4.33 (s, 4H), 3.79 (m, 4H).
DMSO δ 8.78 (s, 2H), 8.44 (s, 1H), 8.21 (s,
2-93 3.01 341.1 1 - 1 H), 7.86 (s, 1H), 7.46 (s, 1 H), 6.88 (s, 2H),
4.29 (s, 4H), 3.77 (m, 4H).
DMSO δ 11.27 (s, 1H), 8.49 (s, 1H), 8.42 (s, 1H), 7.86 (s, 1H), 7.56 (d, J = 6.8, 1 H),
2-94 4.37 363.1 1 0.944
7.45 (t, J = 6.0, 3H), 7.18 (t, J = 7.7, 1 H), 6.94 (s, 1H), 4.32 (s, 4H), 3.80 (m, 4H).
DMSO δ 11.27 (s, 1H), 8.41 (s, 1H), 8.29 (t, J = 3.7, 1H), 7.87 (s, 1H), 7.43 (m, 3H),
2-95 4.28 381.1 1 0.891
7.03 (dd, J = 11.3, 8.8, 1 H), 6.72 (s, 1 H), 4.27 (s, 4H), 3.78 (m, 4H).
DMSO δ 8.66 (s, 2H), 8.35 (s, 1H), 7.98 (s,
2-96 3.32 375.1 1 - 1H), 7.56 (s, 1H), 6.99 (s, 2H), 4.25 (s, 4H),
3.76 (m, 4H).
DMSO δ 13.21 (s, 1H), 8.60 (s, 1H), 8.55 (s, 1H), 7.90 (s, 1H), 7.64 (d, J = 7.0, 1H), 7.55 (d, J = 8.3, 1H), 7.42 (dd, J = 8.2, 7.3,
2-97 0.29 573.3 4 4.5 1H), 4.27 (m, 4H), 3.80 (m, 4H), 3.62 (s,
2H), 3.26 (t, J = 6.8, 4H), 3.05 (s, 2H), 2.40
(s, 2H), 1.66 (dd, J = 12.0, 6.1, 2H), 1.49 (s, 4H), 1.38 (s, 9H). PI3Ka
Cpd. 1H NMR (300 MHz; δ in ppm, J in
t [M+1]+ Meth. IC50
Nr. Hz)
(μΜ)
DMSO δ 13.19 (s, 1H), 8.61 (s, 1H), 8.55 (s, 1H), 7.93 (s, 1H), 7.64 (d, J = 7.0, 1H), 7.56 (d, J = 8.3, 1H), 7.43 (m, 1 H), 4.27 (m,
2-98 3.73 587.4 1 7.2
4H), 3.80 (m, 4H), 3.73 (s, 2H), 3.28 (s, 4H), 2.54 (s, 4H), 1.48 (s, 4H), 1.38 (s, 10H), 1.35 (s, 4H).
DMSO δ 13.21 (s, 1H), 8.60 (s, 1H), 8.55 (s, 1 H), 7.91 (s, 1H), 7.64 (d, J = 7.0, 1H), 7.55 (d, J = 8.3, 1H), 7.42 (m, 1H), 4.27 (s,
2-99 3.45 545.3 1 7.9
4H), 3.81 (m, 4H), 3.71 (s, 2H), 3.48 (m, 4H), 3.10 (d, J = 10.9, 2H), 2.76 (s, 2H), 2.58 (dd, J = 14.6, 8.4, 2H), 1.38 (s, 9H).
DMSO δ 13.21 (s, 1H), 8.60 (s, 1H), 8.55
(s, 1H), 7.90 (s, 1 H), 7.65 (d, J = 7.1 , 1H), 7.55 (d, J = 8.3, 1H), 7.42 (m, 1H), 4.26 (m,
2-100 3.68 573.3 1 5.3
4H), 3.80 (m, 4H), 3.71 (s, 2H), 3.28 (m, 4H), 2.64 (t, J = 6.8, 2H), 2.47 (s, 2H), 1.59
(t, J = 6.8, 2H), 1.44 (s, 4H), 1.38 (s, 9H).
DMSO δ 8.70 (dd, J = 4.5, 1.6, 2H), 8.42
2-101 2.60 359.1 1 - (s, 1H), 8.02 (s, 1H), 7.81 (m, 2H), 7.59 (s,
1H), 4.27 (s, 4H), 3.77 (m, 4H).
DMSO δ 8.96 (d, J = 1.7, 1H), 8.63 (dd, J =
4.8, 1.5, 1 H), 8.40 (s, 1H), 8.17 (m, 1H),
2-102 3.01 359.1 1 - 8.01 (s, 1H), 7.58 (s, 1H), 7.53 (dd, J = 7.9, 4.8, 1 H), 4.26 (s, 4H), 3.76 (m, 4H).
DMSO δ 11.57 (s, 1H), 8.36 (s, 1H), 8.06 (s, 1H), 7.86 (s, 1H), 7.54 (d, J = 2.6, 1H),
2-103 4.27 397.1 1 34 7.48 (m, 1H), 7.44 (m, 1H), 7.22 (m, 1H),
7.16 (d, J = 6.1, 1 H), 4.23 (s, 4H), 3.76 (m,
4H).
DMSO δ 11.58 (s, 1H), 8.36 (m, 1H), 8.01 (s, 1H), 7.58 (s, 1H), 7.53 (s, 1H), 7.52 (s,
2-104 4.74 431.1 1 93
1H), 7.25 (m, 1H), 7.11 (dd, J = 7.2, 0.8, 1H), 4.17 (m, 4H), 3.73 (t, J = 4.7, 4H).
DMSO δ 11.62 (s, 1H), 8.35 (s, 1H), 8.09 (s, 1H), 7.88 (s, 1H), 7.58 (d, J = 2.7, 1H),
2-105 4.34 415.1 1 123
7.49 (dd, J = 8.9, 4.3, 2H), 7.11 (m, 1H), 4.20 (s, 4H), 3.73 (t, J = 4.6, 4H). PI3Ka
Cpd. 1H NMR (300 MHz; δ in ppm, J in
t [M+1]+ Meth. IC50
Nr. Hz)
(μΜ)
DMSO δ 11.68 (s, 1H), 8.38 (s, 1H), 8.03 (s, 1H), 7.59 (s, 2H), 7.54 (dd, J = 8.9, 4.3, -106 4.76 449.1 1 28
1H), 7.14 (m, 1H), 4.17 (m, 4H), 3.73 (t, J =
4.7, 4H).
DMSO δ 13.13 (s, 1H), 8.57 (s, 1H), 8.49 (s, 1H), 7.90 (s, 1H), 7.59 (d, J = 7.1, 1 H), -107 4.61 393.1 1 2.6 7.49 (d, J = 8.3, 1H), 7.36 (m, 1H), 4.18 (m,
4H), 3.81 (s, 2H), 3.74 (m, 4H), 3.59 (s,
3H).
2.43 DMSO δ 8.57 (s, 2H), 7.87 (s, 1H), 6.89 (s,
2H), 4.11 (m, 4H), 3.69 (m, 4H), 3.62 (d, J
2-108 and 508.2 1 - = 14.9, 2H), 3.05 (m, 4H), 2.80 (s, 3H),
2.58 2.48 (m, 4H).
DMSO δ 8.57 (s, 1H), 8.06 (m, 2H), 6.93 (d, J = 7.2, 1H), 4.19 (s, 4H), 3.91 (s, 3H),
2-109 3.49 522.2 1 1
3.75 (s, 6H), 3.16 (s, 2H), 2.89 (s, 3H),
2.54 (s, 2H).
CDCI3 δ 8.68 (d, J = 1.6, 1 H), 8.35 (d, J = 2.8, 1 H), 7.79 (s, 1H), 7.63 (dd, J = 2.6,
2-110 2.96 522.2 1 - 1.8, 1 H), 4.31 (m, 4H), 3.94 (s, 3H), 3.88
(m, 4H), 3.83 (s, 2H), 3.33 (s, 4H), 2.80 (s,
3H), 2.75 (s, 4H).
DMSO δ 8.60 (s, H), 8.55 (d, J = 0.5, 1H), 8.38 (s, 1 H), 7.89 (s, 1H), 7.64 (d, J = 7.0, 1H), 7.56 (d, J = 8.3, 1H), 7.42 (dd, J = 8.2,
2-111 2.39 487.3 3 0.813
7.3, 1H), 4.26 (m, 4H), 3.80 (m, 4H), 3.63 (s, 2H), 2.96 (s, 4H), 2.45 (s, 4H), 1.54 (s,
4H), 1.48 (s, 4H).
DMSO δ 8.94 (s, 2H), 7.95 (s, 1H), 4.15 (s,
2-112 3.10 523.2 1 - 4H), 3.93 (s, 3H), 3.69 (m, 6H), 3.06 (s,
3H), 2.82 (s, 4H), 2.51 (m, 4H).
DMSO δ 10.52 (s, 1H), 7.97 (s, 1H), 7.58 (m, 2H), 6.91 (d, J = 8.6, 1H), 4.20 (s, 4H),
2-113 2.95 546.2 1 - 3.76 (m, 6H), 3.55 (s, 2H), 3.16 (s, 4H), 2.87 (s, 3H), 2.65 (s, 4H).
DMSO δ 11.81 (s, 1H), 8.57 (d, J = 2.1 , 1 H), 8.29 (d, J = 2.0, 1 H), 7.97 (s, 1 H),
2-114 3.15 531.2 2 - 7.54 (m, 1 H), 6.54 (dd, J = 3.4, 1.8, 1 H), 4.20 (m, 4H), 3.76 (m, 4H), 3.73 (s, 2H), PI3Ka
Cpd. 1H NMR (300 MHz; δ in ppm, J in
t [M+1]+ Meth. IC50
Nr. Hz)
(μΜ)
3.14 (t, J = 7.7, 4H), 2.87 (s, 3H), 2.56 (m,
4H).
DMSO δ 12.18 (s, 1H), 8.66 (d, J = 2.0, 1H), 8.22 (d, J = 2.1, 1H), 7.99 (s, 1H), -115 3.66 565.2 2 - 7.77 (s, 1H), 4.21 (s, 4H), 3.77 (m, 4H),
3.74 (s, 2H), 3.12 (m, 4H), 2.87 (s, 3H),
2.58 (s, 4H).
DMSO δ 8.34 (d, J = 2.2, 1 H), 7.92 (s, 1 H), 7.77 (dd, J = 8.6, 2.4, 1 H), 6.52 (d, J = 8.7,
2-116 1.67 507.0 2 - 1H), 6.22 (s, 2H), 4.17 (m, 4H), 3.75 (m,
4H), 3.71 (s, 2H), 3.11 (m, 4H), 2.87 (s, 3H), 2.54 (m, 4H).
DMSO δ 8.60 (s, 1H), 8.55 (d, J = 0.6, 1H), 7.90 (s, 1H), 7.64 (d, J = 7.0, 1H), 7.56 (d, J = 8.3, 1H), 7.42 (dd, J = 8.2, 7.3, 1 H),
2-117 0.32 445.2 3 0.851
4.27 (m, 4H), 3.80 (m, 4H), 3.72 (s, 2H), 2.96 (m, 4H), 2.65 (t, J = 6.7, 2H), 1.62 (m, 4H).
DMSO δ 8.60 (s, 1H), 8.56 (d, J = 0.6, 1H),
0.32 8.35 (s, 1H), 7.91 (s, 1H), 7.64 (d, J = 7.1 ,
1 H), 7.56 (d, J = 8.3, 1H), 7.42 (dd, J = 8.1,
2-118 and 473.2 3 1.5
7.3, 1H), 4.27 (m, 4H), 3.80 (m, 4H), 3.72 2.30 (s, 2H), 2.96 (m, 4H), 2.65 (t, J = 6.8, 2H),
1.62 (m, 6H).
DMSO δ 9.15 (m, 1H), 8.60 (m, 1H), 8.57 (m, 1H), 8.30 (m, 1H), 8.27 (m, H), 7.77
2-119 3.40 323.2 2 0.093
(m, 1H), 7.50 (m, 2H), 4.32 (m, 4H), 1.69
(m, 6H).
DMSO δ 8.76 (s, 2H), 8.37 (s, 1H), 8.19 (s,
2-120 3.82 339.2 2 1.3 1H), 7.73 (s, 1H), 7.45 (s, 1H), 6.86 (s, 2H),
4.28 (s, 4H), 1.67 (s, 6H).
DMSO δ 8.04 (s, 1H), 7.98 (s, 1H), 7.96 (d, J = 8.4, 2H), 7.83 (d, J = 8.3, 2H), 7.44 (s,
2-121 2.91 534.2 2 - 1H), 4.20 (s, 4H), 3.76 (s, 4H), 3.72 (s, 2H), 3.13 (s, 4H), 2.87 (s, 3H), 2.57 (s, 4H).
DMSO δ 11.60 (s, 1H), 8.07 (s, 1 H), 7.86 (s, 1H), 7.57 (d, J = 2.6, 1H), 7.48 (dd, J =
2-122 3.18 548.2 2 50
8.9, 4.3, 1H), 7.10 (m, 1H), 4.13 (s, 4H), 3.72 (t, J = 4.6, 4H), 3.69 (s, 2H), 3.13 (s, PI3Ka
Cpd. 1H NMR (300 MHz; δ in ppm, J in
Rt [ +1]+ Meth. IC50
Nr. Hz)
(μΜ)
4H), 2.87 (s, 3H), 2.58 (s, 4H).
DMSO δ 11.31 (s, 1H), 7.96 (s, 1H), 7.48 (dd, J = 9.0, 4.0, 1H), 7.42 (t, J = 2.7, 1H), -123 3.46 548.2 2 - 7.03 (dd, J = 10.3, 8.9, 1H), 6.29 (s, 1H),
4.11 (m, 4H), 3.73 (m, 4H), 3.72 (s, 2H), 3.13 (m, 4H), 2.87 (s, 3H), 2.59 (s, 4H).
DMSO δ 11.66 (s, 1H), 7.96 (s, 1H), 7.59 (d, J = 2.6, 1 H), 7.53 (dd, J = 8.9, 4.3, 1H),
2-124 3.58 582.2 2 - 7.13 (m, 1H), 4.12 (ddd, J = 18.3, 13.5, 8.9,
4H), 3.72 (m, 4H), 3.70 (s, 2H), 3.13 (d, J = 4.7, 4H), 2.87 (s, 3H), 2.60 (s, 4H).
CDCI3 δ 9.23 (s, 2H), 9.20 (s, 1H), 7.95 (s, 1H), 7.52 (s, 1H), 4.40 (m, 4H), 3.90 (m,
2-125 3.31 459.2 3 - 4H), 3.77 (s, 2H), 3.29 (m, 4H), 2.79 (s, 3H), 2.71 (m, 4H).
CDCb δ 8.97 (s, 1H), 8.09 (d, J = 5.6, 1H), 7.90 (s, 1H), 7.49 (s, 1H), 7.24 (m, 1 H),
2-126 2.21 472.2 3 0.776 4.36 (s, 4H), 3.89 (s, 4H), 3.76 (s, 2H),
3.28 (s, 4H), 2.78 (s, 3H), 2.70 (s, 4H), 2.60 (s, 3H).
CDCb δ 10.38 (s, 1H), 8.31 (s, 1 H), 8.13 (s, 1H), 7.90 (m, 2H), 7.52 (d, J = 8.8, 1H),
2-127 4.27 497.2 3 37 7.46 (s, 1H), 4.35 (m, 4H), 3.88 (m, 4H),
3.74 (s, 2H), 3.26 (m, 4H), 2.76 (s, 3H), 2.69 (m, 4H).
CDCIs δ 8.54 (d, J = 0.7, 1H), 7.94 (s, 1 H),
2.71 7.48 (m, 3H), 7.39 (dd, J = 8.2, 6.9, 1 H),
4.34 (m, 4H), 3.84 (m, 4H), 3.79 (s, 2H),
2-128 and 523.3 2 - 3.38 (dd, J = 9.6, 6.6, 2H), 3.16 (dd, J = 2.86 9.5, 2.4, 2H), 2.87 (m, 4H), 2.82 (s, 3H),
2.53 (d, J = 6.0, 2H).
CDCb δ 8.54 (d, J = 0.7, 1H), 7.96 (s, 1H),
2.73 7.49 (m, 3H), 7.41 (dd, J = 8.3, 6.9, 1 H),
2-129 and 551.3 2 2.5 4.35 (m, 4H), 3.86 (m, 4H), 3.81 (s, 2H),
3.03 3.16 (dd, J = 12.8, 6.3, 4H), 2.78 (m, 2H),
2.74 (s, 3H), 2.55 (s, 2H), 1.69 (m, 6H).
CDCI3 δ 8.53 (m, 1H), 7.90 (t, J = 10.1 ,
2.57
2-130 487.3 2 1.4 1H), 7.49 (m, 3H), 7.38 (m, 1H), 6.23 (m, and 1 H), 4.33 (m, 4H), 3.85 (m, 4H), 3.73 (s, PI3Ka
Cpd. 1H NMR (300 MHz; 6 in ppm, J in
Rt [M+1]+ Meth. IC50
Nr. Hz)
(μΜ)
2.80 2H), 3.31 (m, 2H), 3.00 (m, 2H), 2.27 (m,
2H), 2.03 (m, 4H), 1.48 (m, 2H).
CDC δ 10.84 (s, 1H), 8.53 (d, J = 0.8,
2.57 1H), 7.96 (s, 1H), 7.49 (m, 3H), 7.41 (dd, J
= 8.3, 6.9, 1 H), 5.89 (s, 1H), 4.35 (m, 4H), -131 and 487.3 2 14
3.86 (m, 4H), 3.71 (s, 2H), 3.18 (s, 2H), 2.71 2.55 (d, J = 20.1, 4H), 2.21 (s, 2H), 1.71 (t,
J = 5.4, 4H).
DMSO δ 9.66 (s, 2H), 8.93 (s, 1H), 8.92 (s,
2-132 2.74 320.2 2 - 2H), 7.87 (s, 1H), 7.23 (s, 2H), 6.90 (s, 2H),
2.46 (s, 3H).
DMSO δ 13.24 (s, 1H), 8.47 (s, 1H), 8.05 (s, 1H), 7.66 (d, J = 7.0, 1H), 7.57 (d, J = 8.2, 1H), 7.44 (d, J = 7.4, 1H), 7.31 (s, 1 H),
2-133 4.47 419.3 3 - 4.29 (s, 4H), 3.80 (m, 4H), 3.27 (d, J = 9.8,
2H), 2.96 (dt, J = 17.2, 9.6, 2H), 2.82 (t, J = 8.7, 1H), 1.92 (m, 2H), 1.63 (dd, J = 56.7, 6.4, 2H).
DMSO δ 13.20 (s, 1 H), 8.59 (s, 1H), 8.56 (s, 1H), 7.89 (s, 1H), 7.64 (d, J = 7.1 , 1 H), 7.55 (d, J = 8.3, 1H), 7.42 (dd, J = 8.2, 7.3,
2-134 3.04 551.3 2 5.2
1H), 4.27 (m, 4H), 3.80 (m, 4H), 3.58 (s, 6H), 2.99 (s, 3H), 2.40 (s, 4H), 1.71 (s, 4H), 1.39 (s, 2H).
CDC δ 8.91 (d, J = 2.0 Hz, 1H), 7.97 (dd, J = 8.1 , 2.3 Hz, 1H), 7.71 (s, 1H), 7.22 (d, J
2-135 0.56 506.2 3 - = 8.1 Hz, 1H), 4.27 (m, 4H), 3.83 (m, 4H),
3.76 (s, 2H), 3.26 (m, 4H), 2.76 (s, 3H), 2.68 (m, 4H), 2.60 (s, 3H).
3.43 CDCI3 δ 9.23 (s, 1H), 9.20 (s, 2H), 7.76 (s,
1H), 4.32 (m, 4H), 3.87 (m, 4H), 3.80 (s,
2-136 and 493.2 3 - 2H), 3.30 (m, 4H), 2.79 (s, 3H), 2.71 (m, 3.85 4H).
DMSO δ 13.15 (s, 1H), 8.60 (s, 2H), 8.53 (s, 1H), 7.62 (dd, J = 26.6, 4.9 Hz, 2H),
2-137 5.00 393.2 2 0.676
7.44 (m, 1H), 4.34 (s, 6H), 3.83 (s, 4H), 1.35 (t, J = 6.1 Hz, 3H).
CDCI3 δ 8.78 (s, 2H), 8.06 (s, 1H), 7.75 (s,
2-138 3.99 370.2 2 0.012
1H), 5.14 (s, 2H), 4.40 (s, 6H), 3.87 (s, 4H), PI3Ka
Cpd. H NMR (300 MHz; δ in ppm, J in
Rt [M+1]+ Meth. IC50
Nr. Hz)
(μ )
1.40 (t, J - 7.0 Hz, 3H).
DMSO δ 8.65 (s, 1H), 8.56 (s, 1H), 8.41
2.75 (m, 1H), 7.67 (d, J = 7.1 Hz, 1H), 7.59 (d, J
= 8.7 Hz, 1H), 7.44 (dd, J = 8.2, 7.3 Hz, -139 and 449.3 2 - 1H), 4.34 (m, 4H), 3.84 (m, 4H), 3.33 (m, 2.89 2H), 2.30 (m, 2H), 2.16 (s, 6H), 1.70 (d, J =
7.0 Hz, 2H).
DMSO δ 13.24 (s, 1H), 8.65 (s, 1H), 8.56 (s, 1H), 8.41 (s, 1H), 7.68 (d, J = 6.5 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.44 (dd, J =
2-140 4.60 436.2 2 - 8.3, 7.3 Hz, 1H), 4.34 (m, 4H), 3.83 (m, 4H), 3.38 (m, 4H), 3.26 (s, 3H), 1.80 (m, 2H).
DMSO δ 13.24 (s, 1H), 8.65 (s, 1H), 8.56
3.94 (s, 1H), 8.42 (s, 1H), 7.68 (d, J = 7.1 Hz,
1H), 7.58 (d, J = 8.2 Hz, 1H), 7.44 (dd, J =
2-141 and 435.3 3 0.065
8.2, 7.2 Hz, 1H), 4.34 (m, 4H), 3.84 (m, 4.24 4H), 3.41 (dd, J = 12.7, 6.1 Hz, 2H), 2.27
(m, 2H), 2.24 (s, 6H).
DMSO δ 13.24 (s, 1H), 8.65 (s, 1 H), 8.56 (s, 1H), 8.42 (s, 1H), 7.68 (d, J = 6.8 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1 H), 7.44 (m, 1H),
2-142 2.90 477.3 2 0.038
4.34 (s, 4H), 3.84 (m, 4H), 3.59 (m, 4H), 3.43 (dd, J = 12.1, 6.7 Hz, 2H), 2.45 (m, 6H).
DMSO δ 8.83 (s, 2H), 7.99 (s, 1H), 6.81 (s, 2H), 6.00 (m, 1H), 4.22 (m, 4H), 3.75 (m,
2-143 3.05 393.2 3 - 4H), 3.35 (m, 2H), 3.15 (m, 2H), 2.34 (m, 2H), 2.30 (s, 3H).
DMSO δ 13.15 (s, 1H), 8.54 (t, J = 5.9 Hz, 1H), 8.08 (s, 1H), 7.96 (s, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.42 (dd, J = 8.2, 7.2 Hz, 1H),
2-144 4.33 498.3 2 - 7.29 (m, 5H), 5.45 (s, 1H), 4.67 (s, 2H), 4.32 (d, J = 5.9 Hz, 2H), 4.19 (m, 4H), 3.74 (m, 6H).
DMSO δ 13.20 (s, 1H), 8.60 (s, 1H), 8.55 (d, J = 0.7 Hz, 1H), 7.90 (s, 1H), 7.64 (d, J
2-145 2.91 537.3 2 3
= 7.1 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.42 (dd, J = 8.2, 7.2 Hz, 1H), 4.27 (m, 4H), PI3Ka
Cpd. 1H NMR (300 MHz; δ in ppm, J in
Rt [M+1]+ Meth. IC50
Nr. Hz)
(μΜ)
3.81 (m, 4H), 3.59 (m, 6H), 2.98 (s, 3H), 2.40 (s, 4H), 1.72 (t, J = 4.8 Hz, 4H).
DMSO δ 9.16 (s, 1H), 8.67 (s, 1H), 8.58 (d, J = 4.1 Hz, 1H), 8.43 (t, J = 5.3 Hz, 1H), -146 3.24 397.2 2 0.295 8.33 (s, 1H), 8.31 (s, 1H), 7.50 (dd, J = 7.6,
5.0 Hz, 1H), 4.33 (s, 4H), 3.81 (s, 4H), 3.39 (m, 4H), 3.25 (s, 3H), 1.78 (m, 2H).
DMSO δ 9.16 (dd, J = 2.2, 0.6 Hz, 1 H), 8.68 (s, 1H), 8.58 (dd, J = 4.8, 1.6 Hz, 1H),
0.38 8.33 (q, J = 1.9 Hz, 1H), 8.30 (s, 2H), 7.50 -147 and 396.2 3 0.832 (ddd, J = 8.0, 4.8, 0.6 Hz, 1H), 4.33 (m,
1.62 4H), 3.81 (m, 4H), 3.39 (dd, J = 13.2, 6.7
Hz, 2H), 2.42 (t, J = 6.9 Hz, 2H), 2.19 (s, 6H).
DMSO δ 9.16 (d, J = 1.7 Hz, 1H), 8.67 (s, 1H), 8.58 (dd, J = 4.7, 1.6 Hz, 1H), 8.41 (t,
2-148 3.04 383.2 2 0.617 J = 5.0 Hz, 1H), 8.31 (m, 2H), 7.50 (dd, J =
8.0, 4.8 Hz, 1H), 4.33 (m, 4H), 3.81 (m, 4H), 3.48 (m, 4H), 3.28 (s, 3H).
DMSO δ 13.20 (s, 1 H), 8.61 (s, 1H), 8.55 (d, J = 0.8 Hz, 1H), 7.91 (s, 1H), 7.64 (dd, J = 7.1 , 0.6 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1 H),
2-149 3.08 565.3 2 1.3
7.43 (dd, J = 8.3, 7.2 Hz, 1H), 4.28 (m, 4H), 3.81 (m, 4H), 3.66 (s, 2H), 3.08 (m, 4H), 2.84 (s, 3H), 2.50 (s, 4H), 1.49 (s, 8H).
DMSO δ 13.21 (s, 1H), 8.61 (s, 1H), 8.55 (d, J = 0.8 Hz, 1H), 7.90 (s, 1H), 7.65 (dd, J = 7.1, 0.5 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1 H),
2-150 2.97 537.3 2 2.8
7.43 (dd, J = 8.3, 7.2 Hz, 1H), 4.27 (m, 4H), 3.80 (m, 6H), 3.13 (s, 4H), 3.05 (m, 4H), 2.82 (s, 3H), 1.77 (m, 4H).
DMSO δ 11.22 (s, 1 H), 8.19 (s, 1H), 7.93 (s, 1H), 7.47 (s, 2H), 7.41 (m, 1H), 6.51 (m,
2-151 5.73 530.2 3 - 1H), 4.20 (m, 4H), 3.77 (m, 4H), 3.72 (s,
2H), 3.13 (m, 4H), 2.87 (s, 3H), 2.57 (m, 4H).
CDCIs δ 8.55 (s, 1H), 8.43 (d, J = 5.0 Hz,
2-152 0.32 472.2 3 0.468 1H), 7.55 (s, 1H), 7.46 (s, 1H), 7.16 (d, J =
5.0 Hz, 1H), 4.26 (m, 4H), 3.82 (m, 4H), PI3Ka
Cpd. 1H NMR (300 MHz; δ in ppm, J in t [M+1]+ Meth. IC50
Nr. Hz)
(μΜ)
3.73 (s, 2H), 3.24 (m, 4H), 2.75 (s, 3H), 2.67 (m, 4H), 2.42 (s, 3H).
CDC δ 8.12 (s, 1H), 7.50 (s, 1H), 7.44 (s, 1H), 6.63 (s, 1H), 4.26 (m, 4H), 3.93 (s, -153 3.07 502.2 2 2.4 3H), 3.83 (m, 4H), 3.74 (s, 2H), 3.26 (m,
4H), 2.76 (s, 3H), 2.68 (m, 4H), 2.37 (s, 3H).
DMSO 6 9.16 (d, J = 1.7, 1H), 8.67 (s, 1H), 8.58 (dd, J = 4.7, 1.6, 1H), 8.41 (t, J = 5.0,
2-154 3.04 383.2 2 0.166 1H), 8.31 (m, 2H), 7.50 (dd, J = 8.0, 4.8,
1H), 4.33 (m, 4H), 3.81 (m, 4H), 3.48 (s, 4H), 3.28 (s, 3H).
DMSO δ 13.23 (s, 1H), 8.49 (t, J = 5.9, 1H), 8.07 (s, 1H), 7.84 (s, 1H), 7.78 (s, 1H), 7.62 (d, J = 8.4, 1 H), 7.46 - 7.37 (m, 1H),
2-155 3.08 548.2 2 - 7.37 - 7.20 (m, 5H), 7.16 (d, J = 6.8, 1H),
6.96 (d, J = 3.9, 2H), 5.48 (s, 2H), 4.29 (d, J = 5.9, 2H), 4.22 (s, 4H), 3.81 - 3.69 (m, 4H), 3.65 (s, 2H).
CDCI3 δ 8.53 (s, 1H), 7.80 (s, 1H), 7.62 - 7.34 (m, 3H), 4.89 (s, 1 H), 4.36 (m, 4H),
2-156 4.98 488.3 2 - 4.12 (m, 1 H), 3.89 (m, 4H), 3.25 (m, 2H),
2.86 (m, 1H), 2.62 (m, 1H), 2.46 (s, 3H), 1.90 (m, 4H), 1.16 (m, 6H).
DMSO δ 13.23 (s, 1H), 8.64 (s, 1H), 8.80 (m, 2H), 8.42 (s, 1H), 8.05 (m, 1H), 7.67 (d,
2-157 3.93 449.2 2 0.776 J = 6.8, 1H), 7.57 (d, J = 8.3, 1H), 7.45 (m,
1H), 4.34 (m, 4H), 3.85 (m, 4H), 3.35 (m, 2H), 3.26 (m, 2H), 1.82 (s, 3H).
DMSO δ 9.17 (d, J = 1.6, 1H), 8.67 (s, 1H), 8.57 (m, 2H), 8.32 (m, 2H), 8.05 (m, 1H),
2-158 2.75 410.2 2 2.3 7.50 (dd, J = 7.7, 5.1 , 1H), 4.34 (m, 4H),
3.81 (m, 4H), 3.33 (m, 2H), 3.24 (m, 2H), 1.80 (s, 3H).
DMSO δ 9.16 (d, J = 1.6, 1H), 8.68 (s, 1H), 8.58 (dd, J = 4.7, 1.6, 1H), 8.28 (m, 3H),
2-159 0.37 438.2 3 0.398 7.50 (dd, J = 8.0, 4.2, 1H), 4.33 (s, 4H),
3.78 (m, 4H), 3.55 (m, 4H), 3.42 (m, 2H), 2.49 (m, 2H), 2.45 (m, 4H). PI3Ka
Cpd. 1H N R (300 MHz; δ in ppm, J in
t [ +1]+ Meth. IC50
Nr. Hz)
(μΜ)
DMSO δ 8.79 (s, 2H), 8.57 (s, 1H), 8.46 (s, 1H), 8.23 (s, 1H), 6.89 (s, 2H), 4.31 (s, 4H), -160 0.37 426.2 3 - 3.81 (s, 4H), 2.35 (s, 2H), 2.25 (s, 6H), 1.69 (m, 2H), 1.23 (s, 2H).
DMSO δ 8.77 (s, 2H), 8.44 (s, 1H), 8.39 (m, 1H), 8.21 (s, 1H), 6.88 (s, 2H), 4.29 (s, -161 3.73 413.1 2 - 4H), 3.79 (s, 4H), 3.38 (m, 4H), 3.25 (s, 3H), 1.75 (m, 2H).
0.39 DMSO δ 8.79 (s, 2H), 8.46 (s, 1H), 8.30 (s,
1H), 8.23 (s, 1 H), 6.89 (s, 2H), 4.30 (s, 4H),
2-162 and 412.3 3 - 3.80 (s, 4H), 3.39 (s, 2H), 2.42 (s, 2H), 2.74 2.20 (s, 6H).
DMSO δ 8.78 (s, 2H), 8.45 (s, 1H), 8.36 (s, 1H), 8.23 (s, 1H), 6.88 (s, 2H), 4.29 (m,
2-163 5.57 399.2 3 - 4H), 4.80 (m, 4H), 3.46 (m, 4H), 3.27 (s, 3H).
0.37 DMSO δ 8.77 (s, 2H), 8.45 (s, 1H), 8.28
(m, 1H), 8.20 (s, 1 H), 6.88 (s, 2H), 4.29 (s,
2-164 and 454.3 3 0.011
4H), 3.79 (s, 4H), 3.59 (s, 4H), 3.49 (m, 2.85 2H), 2.43 (m, 6H).
DMSO δ 8.81 (s, 2H), 8.09 (s, 1H), 6.75 (s, 2H), 4.16 (s, 4H), 3.69 (m, 4H), 3.58 (s,
2-165 0.38 488.3 3 - 2H), 3.02 (s, 4H), 2.78 (s, 3H), 2.44 (m, 7H).
DMSO δ 9.14 (s, 1H), 8.96 (s, 2H), 8.80 (s,
2-166 2.48 304.1 2 1.8 4H), 7.98 (s, 1H), 6.96 (s, 2H), 2.50 (s, 3H).
CDCI3 δ 8.10 (s, 1H), 7.70 (s, 1H), 6.68 (s, 1 H), 4.24 (m, 4H), 3.96 (s, 3H), 3.82 (m,
2-167 3.49 536.2 2 - 4H), 3.75 (s, 2H), 3.28 (m, 4H), 2.80 (s, 3H), 2.71 (m, 4H), 2.23 (s, 2H).
DMSO δ 13.31 (s, 1H), 9.33 (s, 1H), 8.81 (m, 4H), 8.67 (s, 1H), 8.11 (s, 1H), 7.81 (d,
2-168 3.21 327.2 2 26
J = 7.1, 1H), 7.64 (d, J = 8.3, 1H), 7.52 (m, 1H), 2.53 (s, 3H).
0.33 DMSO δ 8.76 (s, 2H), 8.40 (s, 1H), 7.70 (s,
1H), 6.82 (s, 2H), 4.22 (m, 4H), 3.76 (m,
2-169 and 514.3 3 0.11
4H), 3.69 (s, 2H), 3.32 (s, 4H), 3.04 (s, 4H), 3.07 2.81 (s, 3H), 1.74 (m, 4H). PI3Ka
Cpd. 1H NMR (300 MHz; 6 in ppm, J in
t [M+1f Meth. IC50
Nr. Hz)
(μΜ)
DMSO δ 8.76 (s, 2H), 8.40 (s, 1H), 7.75 (s, 1H), 6.82 (s, 2H), 4.22 (m, 4H), 3.76 (m, -170 2.14 500.3 2 - 4H), 3.68 (s, 2H), 3.38 (m, 2H), 2.96 (dd, J
= 9.9, 3.8, 2H), 2.90 (s, 3H), 2.81 (m, 2H), 2.59 (m, 2H).
DMSO δ 8.76 (s, 2H), 8.34 (s, 1H), 7.63 (s, 1H), 6.81 (s, 2H), 4.19 (m, 4H), 3.75 (m,
2-171 4.13 338.2 2 0.05
4H), 2.03 (m, 1H), 0.91 (m, 2H), 0.79 (m, 2H).
DMSO δ 8.79 (s, 2H), 8.47 (d, J = 0.8, 1H),
2-172 4.72 366.2 2 0.032 8.44 (s, 1H), 6.92 (s, 2H), 4.23 (m, 4H),
3.78 (m, 4H).
CDCIs δ 8.54 (s, 2H), 7.74 (s, 1H), 7.30 (d,
0.33
J = 4.2, 1H), 4.25 (m, 4H), 3.86 (s, 2H),
2-173 and 506.2 3 - 3.83 (m, 4H), 3.32 (m, 4H), 2.79 (s, 7H), 2.59 2.32 (s, 3H).
DMSO δ 8.78 (s, 2H), 8.46 (s, 1H), 7.89 (d,
2-174 3.11 298.2 2 0.191 J = 1.0, 1H), 7.56 (d, J = 1.0, 1H), 6.84 (s,
2H), 4.26 (m, 4H), 3.76 (m, 4H).
0.32 DMSO δ 8.76 (s, 2H), 8.40 (s, 1H), 7.75 (s, nd 1H), 6.83 (s, 2H), 4.22 (m, 4H), 3.76 (m,
2-175 a 397.2 3 0.083
4H), 3.57 (m, 6H), 2.44 (m, 4H).
2.40
DMSO δ 8.75 (s, 2H), 8.37 (s, 1 H), 8.19 (d, J = 6.4, 2H), 7.58 (s, H), 6.82 (s, 2H), 6.46
2-176 4.29 405.2 3 - (s, 2H), 4.21 (d, J = 4.4, 4H), 3.85 (s, 2H), 3.76 (m, 4H).
DMSO δ 8.77 (s, 2H), 8.42 (s, 1H), 7.67 (s,
2-177 3.45 356.2 2 - 1H), 6.82 (s, 2H), 5.09 (s, 1 H), 4.23 (s, 4H),
3.76 (s, 4H), 1.48 (s, 6H).
DMSO δ 8.81 (s, 2H), 8.04 (s, 1H), 6.82 (s, 2H), 4.18 (s, 4H), 3.71 (m, 4H), 3.60 (s,
2-178 2.72 553.2 2 - 2H), 3.03 (s, 4H), 2.79 (s, 3H), 2.48 (d, J = 4.7, 4H).
DMSO δ 8.88 (s, 2H), 7.91 (s, 1H), 7.30 (s, 1H), 6.89 (s, 2H), 4.25 (s, 4H), 3.75 (m,
2-179 3.76 460.2 2 - 4H), 3.39 (m, 4H), 3.12 (m, 4H), 2.99 (s, 3H).
2-180 0.32 499.2 3 - DMSO δ 8.74 (s, 2H), 7.88 (s, 1H), 7.23 (s, PI3Ka
Cpd. 1H NMR (300 MHz; δ in ppm, J in
t [M+1]+ Meth. IC50
Nr. Hz)
(μΜ)
and 2H), 4.44 (s, 4H), 3.77 (s, 4H), 3.70 (s, 2H),
3.12 (s, 4H), 2.87 (s, 3H), 2.56 (s, 4H). 3.18
DMSO δ 8.76 (s, 2H), 8.37 (s, 1H), 7.61 (s, -181 3.17 312.2 2 0.11 1H), 6.80 (s, 2H), 4.21 (s, 4H), 3.75 (s, 4H),
2.33 (s, 3H).
DMSO δ 13.24 (s, 1H), 8.64 (s, 1H), 8.55 (s, 1H), 8.43 (s, 1H), 8.12 (d, J = 8.6, 1H), 7.67 (d, J = 7.1, 1H), 7.58 (d, J = 8.1, 1H),
2-182 5.08 519.2 2 0.245
7.43 (d, J = 8.2, 1H), 4.33 (s, 4H), 4.05 (m, 6H), 3.83 (m, 4H), 2.91 (m, 1 H), 1.77 (m, 2H), 1.56 (m, 2H), 1.20 (t, J = 7.1 , 3H).
DMSO δ 13.22 (s, H), 8.46 (s, 1H), 8.11 (s, 1H), 7.65 (d, J = 7.1 , 1 H), 7.60 (d, J =
2-183 3.45 576.2 2 0.17 8.3, 1 H), 7.46 (d, J = 7.3, 1H), 4.30 (m,
4H), 3.82 (m, 4H), 3.71 (s, 2H), 3.11 (m, 4H), 2.86 (s, 3H), 2.58 (m, 4H).
DMSO δ 8.64 (s, 2H), 8.30 (s, 1H), 8.22 (s,
2-184 3.05 355.2 2 - 1H), 8.07 (s, 1H), 6.74 (s, 2H), 4.16 (m,
4H), 3.65 (m, 4H), 2.68 (d, J = 3.9, 3H).
DMSO δ 8.62 (s, 2H), 7.85 (d, J = 0.8, 1H),
2-185 4.10 346.2 2 - 6.94 (s, 2H), 4.17 (m, 4H), 3.74 (m, 4H),
2.38 (d, J = 0.5, 3H).
DMSO δ 13.17 (s, 1H), 8.58 (s, 1H), 8.49 (s, 1H), 8.35 (s, 1H), 8.31 (m, 1 H), 7.61 (d,
2-186 4.15 422.2 2 0.066 J = 7.2, 1H), 7.51 (d, J = 8.2, 1H), 7.39 (d,
J = 7.2, 1H), 4.27 (m, 4H), 3.77 (m, 4H), 3.42 (m, 4H), 3.21 (s, 4H).
DMSO δ 8.74 (s, 2H), 7.83 (s, 1 H), 7.20 (s,
2-187 4.02 337.2 2 - 2H), 4.43 (s, 4H), 3.76 (m, 4H), 2.37 (s,
3H).
DMSO δ 8.77 (s, 2H), 8.44 (s, 1H), 8.25 (s, 1H), 8.09 (d, J = 8.5, 1H), 6.88 (s, 2H),
2-188 4.03 496.2 2 0.003 4.28 (s, 4H), 4.04 (m, 5H), 3.79 (m, 4H),
2.87 (s, 2H), 1.78 (d, J = 9.9, 2H), 1.57 (dt, J = 12.2, 8.4, 2H), 1.19 (t, J = 7.1 , 3H).
DMSO δ 8.65 (s, 2H), 8.46 (s, 1H), 8.33 (s,
2-189 3.39 389.2 2 - 1H), 6.99 (s, 2H), 4.26 (s, 4H), 3.78 (m,
4H), 2.83 (d, J = 4.8, 3H). PI3Ka
Cpd. 1H NMR (300 MHz; δ in ppm, J in
t [M+1]+ Meth. IC50
Nr. Hz)
(μΜ)
CDCIs δ 8.83 (d, J = 1.8, 2H), 8.14 (s, 1H), 7.44 (s, 1H), 5.43 (s, 2H), 4.10 (dd, J = -190 3.11 311.2 2 - 11.4, 3.4, 2H), 3.84 (m, 1H), 3.67 (t, J =
11.5, 2H), 2.49 (s, 3H), 2.15 (m, 2H), 1.90 (m, 2H).
DMSO δ 8.71 (s, 2H), 8.38 (s, 1H), 8.18 (s, 1H), 8.03 (d, J = 8.4, 1H), 6.81 (s, 2H), -191 3.53 425.2 2 0.013 4.22 (m, 4H), 3.96 (s, 1H), 3.83 (d, J =
11.1 , 2H), 3.73 (m, 4H), 3.33 (m, 2H), 1.66 (m, 4H).
DMSO δ 8.70 (s, 2H), 8.37 (s, 1H), 8.15 (s, 1H), 7.83 (d, J = 8.5, 1H), 6.80 (s, 2H),
2-192 3.40 439.2 2 0.01 4.50 (d, J = 4.4, 1H), 4.20 (s, 4H), 3.72 (m,
4H), 3.33 (m, 1H), 1.75 (m, 4H), 1.42 (m, 2H), 1.18 (m, 2H).
DMSO δ 8.77 (s, 2H), 8.44 (s, 1H), 8.22 (s, 1H), 6.89 (s, 2H), 4.24 (m, 4H), 4.02 (m,
2-193 4.64 510.3 2 - 2H), 3.78 (m, 4H), 3.63 (m, 2H), 3.41 (m, 4H), 1.42 (s, 9H).
DMSO δ 8.66 (s, 2H), 8.50 (s, 1 H), 8.36 (s,
2-194 3.77 433.3 2 - 1H), 7.00 (s, 2H), 4.25 (m, 4H), 3.78 (m,
4H), 3.48 (m, 4H), 3.28 (s, 3H).
DMSO δ 8.76 (s, 2H), 8.37 (s, 1H), 7.65 (s, 1H), 6.81 (s, 2H), 4.23 (m, 4H), 3.92 (d, J =
2-195 4.52 382.2 2 - 9.5, 2H), 3.77 (m, 4H), 3.46 (t, J = 10.8,
2H), 2.93 (m, 1 H), 1.91 (d, J = 12.5, 2H), 1.69 (m, 2H).
DMSO δ 9.20 (s, 2H), 8.67 (s, 1H), 7.83 (s, 1 H), 4.26 (m, 4H), 3.78 (m, 4H), 3.68 (s,
2-196 2.58 473.2 2 0.021
2H), 3.12 (m, 4H), 2.87 (s, 3H), 2.66 (s, 3H), 2.56 (m, 4H).
DMSO δ 13.13 (s, 1H), 8.64 (s, 1 H), 8.16 (s, 1H), 8.08 (s, 1H), 7.85 (s, 1H), 7.81 (d,
2-197 2.96 497.2 2 - J = 8.6, 1H), 7.69 (d, J = 8.5, 1H), 4.28 (m,
4H), 3.81 (m, 4H), 3.68 (s, 2H), 3.12 (s, 4H), 2.87 (s, 3H), 2.57 (s, 4H).
DMSO δ 8.39 (s, 1H), 8.35 (s, 1H), 7.76 (s,
2-198 0.37 487.2 2 - 2H), 5.96 (s, 2H), 4.22 (m, 4H), 3.77 (m,
4H), 3.66 (s, 2H), 3.11 (m, 4H), 2.87 (s, PI3Ka
Cpd. 1H NMR (300 MHz; δ in ppm, J in
Rt [M+1]+ Meth. IC50
Nr. Hz)
(μΜ)
3H), 2.56 (m, 4H), 2.11 (s, 3H).
DMSO δ 8.82 (s, 2H), 8.40 (s, 1H), 7.77 (s,
0.37 1H), 7.31 (q, J = 4.9, 1 H), 4.23 (m, 4H), -199 and 488.2 2 - 3.76 (m, 4H), 3.66 (s, 2H), 3.10 (m, 4H), 2.47 2.87 (s, 3H), 2.84 (d, J = 4.8, 3H), 2.53 (m,
4H).
0.36 DMSO δ 8.24 (s, 1H), 8.05 (s, 1H), 7.81 (s,
1H), 6.67 (s, 2H), 4.17 (m, 4H), 3.75 (m,
2-200 and 488.2 2 0.032
4H), 3.67 (s, 2H), 3.11 (m, 4H), 2.87 (s, 1.99 3H), 2.55 (m, 4H), 2.39 (s, 3H).
DMSO δ 9.33 (d, J = 2.3, H), 8.84 (s, 1H),
0.35 8.56 (dd, J = 8.2, 2.2, 1 H), 8.13 (d, J = 8.2,
2-201 and 483.2 2 3.3 1H), 7.86 (s, 1 H), 4.28 (s, 4H), 3.78 (m,
2.88 4H), 3.69 (s, 2H), 3.12 (m, 4H), 2.87 (s,
3H), 2.56 (m, 4H).
0.36 DMSO δ 8.56 (s, 1H), 8.08 (s, 1 H), 7.86 (s,
1H), 7.45 (s, 2H), 4.16 (m, 4H), 3.72 (m,
2-202 and 542.2 2 - 4H), 3.67 (s, 2H), 3.11 (m, 4H), 2.87 (s, 2.75 3H), 2.52 (m, 4H).
DMSO δ 8.55 (s, 1H), 7.94 (d, J = 5.4, 1H), 7.86 (s, 1H), 7.07 (s, 1H), 6.97 (d, J = 6.9,
2-203 0.36 473.2 2 - 1H), 5.97 (s, 2H), 4.26 (m, 4H), 3.78 (m,
4H), 3.67 (s, 2H), 3.12 (m, 4H), 2.87 (s, 3H), 2.56 (m, 4H).
DMSO δ 9.11 (s, 1H), 8.60 (s, 1H), 8.43 (d, J = 5.7, 1H), 7.95 (s, 1H), 7.18 (d, J = 5.8,
2-204 0.35 488.2 2 10 1H), 4.21 (m, 4H), 3.99 (s, 3H), 3.79 (m,
4H), 3.67 (s, 2H), 3.12 (m, 4H), 2.87 (s, 3H), 2.56 (m, 4H).
0.36 DMSO δ 8.43 (s, 1H), 8.38 (s, 1 H), 7.85 (d,
J = 12.7, 1H), 7.75 (s, 1H), 6.39 (s, 2H),
2-205 and 491.2 2 - 4.23 (m, 4H), 3.77 (m, 4H), 3.66 (s, 2H), 2.23 3.11 (m, 4H), 2.87 (s, 3H), 2.52 (m, 4H).
DMSO δ 9.16 (d, J = 1.4, 1 H), 8.44 (dd, J = 8.1, 2.2, 1H), 8.18 (d, J = 8.2, 1H), 8.05 (s,
2-206 3.20 517.2 2 3.7 1H), 4.22 (m, 4H), 3.76 (m, 4H), 3.73 (s,
2H), 3.12 (m, 4H), 2.87 (s, 3H), 2.56 (m, 4H). PI3Ka
Cpd. 1H NMR (300 MHz; δ in ppm, J in
Rt [M+1]+ Meth. IC50
Nr. Hz)
(μΜ)
2.72 DMSO δ 8.70 (s, 2H), 7.95 (s, 1H), 7.45
(m, 1H), 4.19 (m, 4H), 3.75 (m, 4H), 3.71 -207 and 522.2 2 0.011
(s, 2H), 3.12 (m, 4H), 2.86 (s, 3H), 2.83 (d, 2.85 J = 6.3, 3H), 2.56 (m, 4H).
0.36 DMSO δ 8.15 (s, 1H), 7.93 (s, 1H), 6.76 (s,
2H), 4.15 (m, 4H), 3.74 (m, 4H), 3.72 (s, -208 and 522.2 2 - 2H), 3.12 (m, 4H), 2.87 (s, 3H), 2.57 (m, 2.32 4H), 2.19 (s, 3H).
2.96 DMSO δ 8.56 (s, 1H), 7.96 (s, 1H), 7.59 (s,
2H), 4.14 (m, 4H), 3.72 (m, 6H), 3.12 (m,
2-209 and 576.2 2 - 4H), 2.87 (s, 3H), 2.54 (m, 4H).
3.09
0.37 DMSO δ 7.98 (m, 2H), 6.84 (m, 2H), 6.04
(s, 2H), 4.20 (m, 4H), 3.76 (m, 4H), 3.72 (s,
2-210 and 507.2 2 - 2H), 3.12 (m, 4H), 2.87 (s, 3H), 2.53 (m, 1.70 4H).
DMSO δ 8.53 (d, J = 5.8, H), 8.40 (s, 1 H), 7.94 (s, 1H), 7.20 (d, J = 5.9, 1H), 4.14 (m,
2-211 0.36 522.2 2 - 4H), 3.86 (s, 3H), 3.73 (m, 6H), 3.12 (m, 4H), 2.87 (s, 3H), 2.57 (m, 4H).
MeOD δ 9.13 (s, 2H), 8.02 (s, 1H), 4.30 (m, 4H), 3.85 (dd, J = 9.2, 4.5, 4H), 3.82 (s,
2-212 2.85 507.2 2 - 2H), 3.27 (m, 4H), 2.86 (s, 3H), 2.77 (s, 3H), 2.71 (m, 4H).
MeOD δ 8.10 (s, 1H), 7.99 (s, 1H), 7.92 (s, 1 H), 7.84 (d, J = 8.4, 1H), 7.56 (d, J = 8.2,
2-213 3.24 531.2 2 - 1H), 4.27 (m, 4H), 3.83 (m, 6H), 3.27 (m, 4H), 2.84 (s, 3H), 2.68 (m, 4H).
DMSO δ 8.91 (s, 2H), 8.23 (s, 1H), 6.89 (s,
2-214 4.16 384.2 2 - 2H), 4.32 (m, 6H), 3.78 (m, 4H), 2.74 (s,
3H), 1.33 (t, J = 7.1, 31-1).
DMSO δ 8.90 (s, 2H), 8.27 (s, 1H), 8.20 (s, 1H), 6.86 (s, 2H), 4.28 (m, 4H), 3.78 (m,
2-215 0.35 413.2 2 - 4H), 3.45 (m, 4H), 3.28 (s, 3H), 2.75 (s, 3H).
DMSO δ 8.91 (s, 2H), 8.44 (s, 1H), 8.20 (s,
2-216 3.76 433.2 2 - 1H), 6.92 (s, 2H), 4.29 (s, 4H), 3.79 (s, 4H),
3.45 (m, 4H), 3.25 (s, 3H).
2-217 4.79 355.2 3 - DMSO δ 8.90 (s, 2H), 8.18 (s, 1H), 7.77 (s, PI3Kcc
Cpd. H NMR (300 MHz; δ in ppm, J in
t [M+1]+ Meth. IC50
Nr. Hz)
(μΜ)
1H), 7.35 (s, 1H), 6.85 (s, 2H), 4.28 (s, 4H), 3.77 (m, 4H), 2.74 (s, 3H).
3.53 DMSO δ 8.75 (s, 2H), 8.38 (s, 1H), 7.78 (s,
1H), 6.82 (s, 2H), 4.25 (s, 4H), 4.00 (s, 2H), -218 and 524.3 2 0.028
3.76 (s, 6H), 2.36 (s, 2H), 1.34 (s, 9H), 3.76 1.15 (d, J = 5.8, 6H).
DMSO δ 8.76 (s, 2H), 8.39 (s, 1H), 7.80 (s, 1H), 6.82 (s, 2H), 4.25 (s, 4H), 4.02 (s, 2H),
2-219 0.39 502.2 3 0.003
3.76 (m, 4H), 3.34 (m, 2H), 2.84 (s, 3H), 2.53 (m, 2H), 1.20 (d, J = 5.8, 6H).
DMSO δ 8.77 (s, 2H), 8.41 (s, 1H), 7.76 (s, 1H), 6.83 (s, 2H), 4.23 (m, 4H), 3.77 (m,
2-220 0.43 488.2 3 0.013
4H), 3.65 (s, 2H), 3.18 (m, 4H), 3.04 (q, J = 7.4, 2H), 2.51 (m, 4H), 1.20 (t, J = 7.4, 3H).
DMSO δ 8.76 (s, 2H), 8.41 (s, 1H), 7.76 (s,
3.73 1H), 6.83 (s, 2H), 4.22 (m, 4H), 3.76 (m,
2-221 and 516.3 3 0.011 4H), 3.66 (s, 2H), 3.14 (m, 4H), 2.88 (m,
4.03 2H), 2.51 (m, 4H), 2.11 (m, 1H), 1.01 (d, J
= 6.5, 6H).
DMSO δ 8.57 (s, 2H), 8.21 (s, 1H), 7.60 (s,
2-222 4.07 445.1 3 0.082 1 H), 6.63 (s, 2H), 4.03 (s, 4H), 3.61 (s, 2H),
3.56 (m, 4H), 2.89 (m, 4H), 2.76 (m, 4H).
DMSO δ 8.80 (s, 2H), 8.35 (s, 1H), 7.60 (s, 1H), 6.79 (s, 2H), 5.43 (s, 1H), 4.83 (t, J =
2-223 2.74 342.2 2 - 5.2, 1 H), 4.07 (d, J = 11.5, 1 H), 3.95 (d, J =
8.9, 1H), 3.80 (m, 1H), 3.59 (m, 3H), 3.36 (m, 2H), 2.33 (s, 3H).
DMSO δ 8.77 (s, 2H), 8.39 (s, 1H), 7.62 (s, 1H), 6.80 (s, 2H), 5.51 (s, 2H), 3.93 (m,
2-224 3.60 384.2 2 25.4 1H), 3.80 (m, 1H), 3.70 (m, 1H), 3.59 (m,
1H), 3.46 (s, 3H), 3.34 (m, 1H), 2.86 (m, 1H), 2.72 (m, 1H), 2.32 (s, 3H).
DMSO δ 8.74 (s, 2H), 8.35 (s, 1H), 7.70 (m, 6H), 6.82 (s, 2H), 4.20 (s, 4H), 3.74 (m,
2-225 4.23 536.3 3 - 4H), 3.60 (s, 2H), 2.90 (s, 4H), 2.50 (m, 4H).
DMSO δ 8.76 (s, 2H), 8.40 (s, 1H), 7.72 (s,
2-226 0.36 396.3 4 0.077 1H), 6.82 (s, 2H), 4.22 (s, 4H), 3.76 (m,
4H), 3.55 (s, 2H), 3.35 (s, 1 H), 2.69 (m, PI3Ka
Cpd. 1H N R (300 MHz; δ in ppm, J in
Rt [M+1f Meth. IC50
Nr. Hz)
(μΜ)
4H), 2.37 (m, 4H).
CDCI3 δ 8.74 (s, 2H), 7.77 (s, 1H), 7.27 (s, 1H), 5.59 (s, 2H), 4.53 (d, J = 11.7, 1H), -227 3.58 370.2 2 6.09 4.05 (t, J = 12.2, 1H), 3.95 (dd, J = 11.8,
3.7, 1H), 3.81 (m, 1H), 3.76 (s, 3H), 3.63 (m, 1H), 2.42 (s, 3H).
DMSO δ 8.77 (s, 2H), 8.40 (s, 1H), 7.80 (s,
0.35 1H), 6.83 (s, 2H), 4.21 (m, 4H), 3.76 (m,
4H), 3.63 (s, 2H), 3.38 (s, 2H), 3.19 (dd, J
2-228 and 500.4 3 0.108
= 10.7, 2.3, 2H), 2.96 (d, J = 10.0, 2H), 2.84 2.85 (s, 3H), 1.99 (m, 2H), 1.66 (q, J = 6.1 ,
2H).
DMSO δ 8.76 (s, 2H), 8.40 (s, 1H), 7.72 (s,
0.35 1H), 6.82 (s, 2H), 4.52 (d, J = 4.1 , 1H),
2-229 and 411.3 3 0.114 4.22 (s, 4H), 3.76 (m, 4H), 3.56 (s, 2H),
0.87 3.42 (m, 1 H), 2.75 (m, 2H), 2.10 (t, J = 9.7,
2H), 1.69 (m, 2H), 1.40 (m, 2H).
DMSO δ 8.77 (s, 2H), 8.41 (s, 1H), 7.76 (s, 1H), 6.83 (s, 2H), 4.23 (s, 4H), 3.76 (m,
2-230 0.34 481.4 3 0.034 4H), 3.62 (s, 2H), 3.52 (m, 2H), 3.44 (m,
2H), 3.05 (s, 2H), 2.43 (m, 4H), 2.16 (s, 6H).
DMSO δ 8.77 (s, 2H), 8.41 (s, 1H), 7.77 (s, 1H), 6.83 (s, 2H), 5.34 (q, J = 6.8, 1H),
2-231 0.34 510.4 3 0.085 4.23 (s, 4H), 3.77 (m, 4H), 3.64 (s, 2H),
3.45 (m, 4H), 2.49 (m, 2H), 2.41 (m, 2H), 2.02 (s, 3H), 1.28 (d, J = 6.7, 3H).
0.42 524.2 MeOD δ 8.80 (s, 2H), 8.18 (s, H), 7.70 (s,
1H), 7.54 (m, 2H), 4.31 (s, 4H), 3.85 (s,
2-232 and and 2 - 4H), 3.40 (s, 4H), 2.52 (s, 4H), 1.54 (s, 6H), 3.03 424.2 1.42 (s, 9H).
DMSO δ 8.80 (s, 2H), 8.44 (s, 1H), 7.77 (s,
2.40 1H), 6.86 (s, 2H), 4.25 (m, 4H), 3.79 (m,
2-233 and 502.2 3 - 6H), 3.59 (s, 3H), 2.87 (m, 3H), 2.72 (m,
2.87 2H), 2.28 (s, 3H), 1.91 (m, 2H), 1.54 (m,
2H).
DMSO δ 8.77 (s, 2H), 8.42 (s, 1H), 7.77 (s,
2-234 0.39 468.2 3 - 1H), 6.85 (s, 2H), 4.85 (d, J = 7.0, 1H),
4.40 (m, 1H), 4.23 (m, 4H), 3.78 (m, 4H), PI3Ka
Cpd. 1H NMR (300 MHz; 6 in ppm, J in
t [M+1]+ Meth. IC50
Nr. Hz)
(μΜ)
3.64 (s, 2H), 3.44 (m, 4H), 2.40 (m, 4H), 1.16 (d, J = 6.5, 3H).
0.41 DMSO δ 8.76 (s, 2H), 8.42 (s, H), 7.76 (s,
1H), 6.84 (s, 2H), 4.23 (m, 4H), 3.78 (m, -235 and 488.2 3 - 6H), 3.34 (m, 4H), 2.89 (s, 3H), 2.73 (m, 2.71 4H), 1.79 (m, 2H).
eOD δ 8.71 (s, 2H), 8.07 (s, 1H), 7.58 (s, 1H), 4.20 (m, 4H), 3.75 (m, 4H), 3.21 (s,
2-236 0.41 424.2 3 - 2H), 2.73 (m, 4H), 2.50 (m, 4H), 1.39 (s, 6H).
DMSO δ 13.29 (s, 1H), 9.17 (s, 1H), 8.45 (s, 1H), 7.63 (m, 2H), 7.47 (m, 1H), 4.42 (q,
2-237 4.70 407.1 5 - J = 7.1, 2H), 4.28 (m, 4H), 3.82 (m, 4H), 2.64 (s, 3H), 1.40 (t, J = 7.1 , 3H).
2-238 4.07 379.1 5 -
2-239 3.92 349.1 5 -
2-240 3.65 423.2 5 -
2-241 4.34 486.3 5 -
0.40 DMSO δ 8.77 (s, 2H), 8.37 (s, 1 H), 7.72 (s,
1H), 6.82 (s, 2H), 4.25 (s, 4H), 3.77 (m,
2-242 and 502.3 3 0.016
4H), 3.07 (s, 4H), 2.84 (s, 3H), 2.54 (m, 3.01 4H), 1.47 (s, 6H).
DMSO δ 8.89 (d, J = 10.8, 2H), 8.18 (s, 1H), 8.02 (d, J = 8.7, 2H), 7.54 (dd, J = 8.5,
2-243 2.97 555.1 2 - 6.5, 4H), 7.34 (d, J = 8.9, 2H), 4.27 (m,
4H), 3.78 (m, 4H), 3.49 (m, 4H), 2.50 (s, 3H), 2.31 (m, 4H), 2.19 (s, 3H).
DMSO δ 9.22 (s, 1H), 9.07 (s, 1H), 8.22 (s, 1H), 8.03 (d, J = 8.6, 2H), 7.88 (d, J = 8.7,
2-244 4.58 473.4 2 0.144
2H), 7.57 (m, 5H), 7.41 (s, 1H), 4.24 (m, 4H), 3.78 (m, 4H), 2.50 (s, 3H).
DMSO δ 9.14 (s, 1H), 8.96 (s, 1H), 8.19 (s, 1H), 8.02 (d, J = 8.7, 2H), 7.90 (d, J = 8.7,
2-245 5.33 487.3 2 - 2H), 7.58 (m, 5H), 7.36 (s, 1H), 4.27 (m,
4H), 3.81 (s, 3H), 3.78 (m, 4H), 2.50 (s, 3H). Table 5. IC50 of AKT Phosphorylation Inhibition of some representative compounds of the examples (μΜ), as tested in the cell assay procedure described above.
Figure imgf000214_0001
Example C1
The individual measured EC50 values against the particular cell of the exemplary compounds and of the chemotherapeutic agents are compared to the combination EC50 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. These data are provided in Tables 6, 7 and 8, below.
Last column on Tables 6, 7 and 8 represent the CI, where (++++) represents a combination index lower than 0.1 , (+++) represents a combination index greater than 0.1 but lower than 0.3, (++) represents a combination index greater than 0.3 but lower than 0.7, (+) represents a combination index greater than 0.7 but lower than 1.2, (-) represents a combination Index greater than 1.2. Table 6 In vitro cell proliferation assays of combination of Product No. 2-50 and various chemotherapeutics agents.
Figure imgf000215_0001
Table 7 In vitro cell proliferation assays of combination of Product No. 2-108 and various chemotherapeutics agents.
Figure imgf000216_0001
Table 8 In vitro cell proliferation assays of combination of Product No. 2-215 and various chemotherapeutics agents.
Figure imgf000216_0002

Claims

Claims
1. A combination comprising:
(A) a compound of formula I,
Figure imgf000217_0001
wherein:
R1 represents:
(a) -N(R a)R1b,
in which R1a and R1b 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, optionally containing one or two double bonds, and which ring is optionally substituted by one or more substituents selected from =0 and B1; a heterocycloalkyi group (attached to the requisite imidazopyrazine via a carbon atom), optionally substituted by one or more substituents selected from =0 and B2; a monocyclic heteroaryl group optionally substituted by one or more substituents selected from B3;
R2 and R3 independently represent:
(i) hydrogen;
(ii) Q1;
(iii) C1-12 alkyl optionally substituted by one or more substituents selected from =0, =S, =N(R10a) and Q2; or R2 or R3 may represent a fragment of formula IA,
Figure imgf000218_0001
m represents 0, 1 , 2, 3, 4, 5 or 6; each R15 represents hydrogen, halo or C -6 alkyl optionally substituted by one or more substituents selected from E ; or
the two R15 groups may linked together to form (along with the requisite carbon atom to which those R15 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 E2; Ra and Rb 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, a 3- to 12-membered saturated carbocyclic ring, or an unsaturated 5- to 12-membered carbocyclic or heterocyclic ring; (b) comprises a linker group -(C(RX)2)P- and/or -(C(Rx)2)r-0-(C(Rx)2)s- (wherein p is 1 or 2; r is 0 or 1 ; s is 0 or 1 ; and each Rx independently represents hydrogen or Ci-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. forming a spiro-cycle), all of which cyclic groups, defined by the linkage of Ra and Rb, are optionally substituted by one or more substituents selected from =0 and E3;
R4 represents hydrogen or a substituent selected from halo, -CN, -OR 0b, -N(R10 )R11b, -C(O)N(R 0b)R11b, -C(O)R 0b, C1-6 alkyl and heterocycloalkyl, which latter two groups are optionally substituted by one or more substituents selected from E4 and =0; but wherein at least one of R2, R3 and R4 represents a substituent other than hydrogen; R5 represents aryl or heteroaryl (both of which are optionally substituted by one or more substituents selected from E5); each Q1 and Q2 independently represents, on each occasion when used herein: halo, -CN, -N02, -N(R10a)R 1a, -OR 0a, -C(=Y)-R10a, -C(=Y)-OR 0a, -C(=Y)N(R10a)R11a, -OC(=Y)-R 0a, -OC(=Y)-OR10a, -OC(=Y)N(R10a)R 1a, -OS(O)2OR 0a, -OP(=Y)(OR 0a)(OR a), -OP(OR10a)(OR11a), -N(R12a)C(=Y)R11a, -N(R12a)C(=Y)OR11a, -N(R12a)C(=Y)N(R 0a)R11a, -NR 2aS(O)2R10a,
-NR12aS(O)2N(R10a)R a, -S(O)2N(R10a)R11a, -SC(=Y)R10a, -S(O)2R 0a, -SR 0a, -S(O)R 0a, C -12 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0, =S, =N(R10a) and E6), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E7); each B1, B2 and B3 independently represent halo, -N02, -CN, -N(R10a)R a, -OR10a, -C(=Y)-R10a, -C(=Y)-OR10a, -C(=Y)N(R10a)R1 a, -N(R12a)C(=Y)R 1a, -N(R 2a)C(=Y)OR11a, -N(R12a)C(=Y)N(R10a)R 1a, -NR12aS(O)2R10a,
-NR12aS(O)2N(R10a)R11a, -S(O)2N(R10a)R11a, -SC(=Y)R10a, -SC(=Y)OR 0a, -S(O)2R10a, C 12 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0 and E8), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E9); or, any two B1 substituents, when attached to the same carbon atom (thereby forming a spiro-cycle), may be linked together to form, a 3- to 12- membered ring, optionally containing one or more heteroatoms, which ring optionally contains one or more double bonds, and which ring is itself optionally substituted by one or more substituents selected from halo, =0 and C1-3 alkyl optionally substituted by one or more fluoro atoms; each R 0a, R1 a, R12a, R 0b and R 1b independently represent, on each occasion when used herein, hydrogen, C -12 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0, =S, =N(R20) and E10), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E11); or any relevant pair of R10a, R11a and R12a and/or any pair of R10b and R11b may be linked together to form a 3- to 20-membered ring, optionally containing one or more heteroatoms, optionally containing one or more unsaturations, and which ring is optionally substituted by one or more substituents selected from =0, =S, =N(R20) and E 2; each E1, E2, E3, E4, E5, E6, E7, E8, E9, E 0, E 1 and E12 independently represents, on each occasion when used herein:
(i) Q4;
(ii) Ci-12 alkyl optionally substituted by one or more substituents selected from =0 and Q5; or any two E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11 or E12 groups may be linked together to form a 3- to 12-membered ring, optionally containing one or more unsaturations, and which ring is optionally substituted by one or more substituents selected from =0 and J1; each Q4 and Q5 independently represent, on each occasion when used herein: halo, -CN, -N02, -N(R U)R 1, -OR , -C(=Y)-R20, -C(=Y)-OR20, -C(=Y)N(R20)R21, -OC(=Y)-R20, -OC(=Y)-OR20, -OC(=Y)N(R20)R21, -OS(0)2OR20, -OP(=Y)(OR20)(OR21), -OP(OR20)(OR21), -N(R22)C(=Y)R21, -N(R22)C(=Y)OR21, -N(R22)C(=Y)N(R20)R21, -NR22S(0)2R20, -NR22S(O)2N(R20)R21, -S(O)2N(R20)R21, -SC(=Y)R20, -S(0)2R20, -SR20, -S(0)R20, C1-6 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0 and J2), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from J3); each Y independently represents, on each occasion when used herein, =0, =S, =NR23 or =N-CN; each R20, R2 , R22 and R23 independently represent, on each occasion when used herein, hydrogen, C1-6 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from J4 and =0), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from J5); or any relevant pair of R20, R2 and R22, may be linked together to form a 3- to 20- membered ring, optionally containing one or more heteroatoms, optionally containing one or more unsaturations, and which ring is optionally substituted by one or more substituents selected from J6 and =0; each J1, J2, J3, J4, J5 and J6 independently represents, on each occasion when used herein:
(') Q7;
(ii) C1-6 alkyl or heterocycloalkyl, both of which are optionally substituted by one or more substituents selected from =0 and Q8; each Q7 and Q8 independently represents, on each occasion when used herein: -CN, halo, -N(R50)R51, -OR50, -C(=Ya)-R50, -C(=Ya)-OR50, -C(=Ya)N(R50)R51, -N(R52)C(=Ya)R51, -NR52S(0)2R50, -S(0)2R50, -SR50, -S(0)R50 or C1-6 alkyl optionally substituted by one or more fluoro atoms; each Ya independently represents, on each occasion when used herein, =0, =S, =NR53 or =N-CN; each R50, R51, R52 and R53 independently represents, on each occasion when used herein, hydrogen or Ci_6 alkyl optionally substituted by one or more substituents selected from fluoro, -OR60 and -N(R61)R62; or
any relevant pair of R50, R51 and R52 may be linked together to form, a 3- to 8- membered ring, optionally containing one or more heteroatoms, optionally containing one or more unsaturations, and which ring is optionally substituted by one or more substituents selected from =0 and C -3 alkyl;
R60, R61 and R62 independently represent hydrogen or C1-6 alkyl optionally substituted by one or more fluoro atoms; or a pharmaceutically acceptable ester, amide, solvate or salt thereof; and
(B) one or more (e.g. one) therapeutic agent(s) selected from:
(i) targeted kinase inhibitors;
(ii) receptor tyrosine kinase (RTK) inhibitors;
(iii) PIM family kinase inhibitors (e.g. a PIM-1 , PIM-2 and/or PIM-3 inhibitor);
(iv) Flt-3 inhibitors;
(v) EGFR or HER2 inhibitors;
(vi) therapeutic monoclonal antibodies;
(vii) MEK inhibitors;
(vii) BRaf inhibitors;
(viii) anthracyclins;
(ix) taxanes;
(x) platins;
(xi) nucleotide analogs;
(xii) alkylating agents;
(xiii) hormone therapeutic agents;
(xiv) anti-tumour compounds that have potential radiosensitising and/or chemosensitising effects;
(xv) JAK inhibitors; and/or (xvi) 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.
2. A combination comprising component (A) as defined in Claim 1 , and component (B), wherein component (B) is selected from:
(i) specific targeted kinase inhibitors;
(ii) specific receptor tyrosine kinase (RTK) inhibitors;
(iii) specific PIM family kinase inhibitors (e.g. PIM-1 inhibitor PIM-1 , PIM-2 and/or PIM-3), such as SGI-1776;
(iv) specific Flt-3 inhibitors;
(v) specific EGFR or HER2 inhibitors, such as lapatanib;
(vi) specific therapeutic monoclonal antibodies, such as the HER2 inhibitor trastuzumab;
(vii) specific MEK inhibitors, such as PD-0325901 ;
(vii) specific BRaf inhibitors, such as GDC-0879;
(viii) specific anthracyclins, such as doxorubicin;
(ix) specific taxanes, such as paclitaxel or, particularly, docetaxel;
(x) specific platins, such as carboplatin or, particularly, cisplatin;
(xi) specific nucleotide analogs, such as 5-fluorouracil (5-FU) or gemcitabine;
(xii) specific alkylating agents, such as temozolomide;
(xiii) specific hormone therapeutic agents, such as an estrogen receptor antagonist e.g. tamoxifen;
(xiv) specific anti-tumour compounds that have potential radiosensitising and/or chemosensitising effects, such as chloroquine;
(xv) specific JAK inhibitors;
(xvi) specific 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- B;
(xvii) specific mTOR inhibitors, such as rapamycin; and/or
(xviii) specific Akt or PI3-K inhibitors, such as GDC-0941.
3. A combination as claimed in Claim 1 or Claim 2, wherein component (B) represents rapamycin, GDC-0941 or, preferably, SGI-1776, lapatanib, trastuzumab, PD-0325901 , GDC-0879, doxorubicin, paclitaxel, docetaxel, carboplatin, cisplatin, 5-fluorouracil, gemcitabine, temozolomide, tamoxifen and/or chloroquine.
4. A combination as claimed in any one of the preceding claims wherein, in the compound of formula I:
R4 represents hydrogen or a substituent selected from halo, -CN, -OR10b, -N(R10b)R11b, -C(O)N(R10b)R b, C1-e alkyl and heterocycloalkyi, which latter two groups are optionally substituted by one or more substituents selected from E4 and =0; and
each Q7 and Q8 independently represents, on each occasion when used herein halo, -N(R50)R51, -OR50, -C(=Ya)-R50, -C(=Ya)-OR50, -C(=Ya)N(R50)R51, -N(R52)C(=Ya)R51, -NR52S(0)2R50, -S(0)2R50, -SR50, -S(0)R50 or C1-6 alkyl optionally substituted by one or more fluoro atoms.
5. A combination as claimed in any one of the preceding claims, wherein, in the compound of formula I:
R1 represents -N(R1a)R1b, in which R1a and R1b 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 groups (such groups are preferably unsubstituted); R2 and R3 independently represent(s) hydrogen or a substituent selected from halo (e.g. bromo, chloro, iodo) -CN,-N(R10a)R11a, -C(=Y)OR10a, -C(=Y)-R10a, -C(=Y)-N(R 0a)R11a, C1-6 alkyl (optionally substituted by one or more (e.g. one) substituent(s) selected from E6) and heterocycloalkyi (e.g. a 5- or, preferably, a 6-membered heterocycloalkyi group, which preferably contains one heteroatom (e.g. nitrogen), and which may contain one unsaturation, e.g a double bond, so forming e.g. a piperidinyl ring, e.g. 4-piperidinyl, for example in which the 1 ,2-position optionally contains a double bond), which heterocycloalkyi group is optionally substituted by one or more substituents selected from =0 and, preferably, E6 (e.g. in which the E6 substituent is located on a nitrogen heteroatom); R4 represents hydrogen, chloro, bromo, iodo or -CN; R5 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 R5 groups are optionally substituted by one or more (e.g. one or two) substituents selected from E5; each R10a, R 1a, R 2a, R10b and R b (e.g. each R10a and R11a) independently represents hydrogen or C -6 (e.g. C -4) alkyl optionally substituted by one or more substituents selected from =0 and E10; or any relevant pair of R 0a, R a and R12a (e.g. R10a and R 1a) may (e.g. when both are attached to the same nitrogen atom) be linked together to form a 4- to 8-membered ring, optionally containing a further heteroatom, and optionally substituted by one or more substituents selected from =0 and E 2; and/or each E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11 and E12 (independently represents C1-12 alkyl optionally substituted by one or more substituents selected from =0 and Q5, or, preferably (each E to E 2 independently represent) Q4.
6. A combination as claimed in any one of the preceding claims, wherein, in the compound of formula I: each Q4 and Q5 (e.g. each Q4) independently represent halo, -N(R20)R21, -OR20, -C(=Y)-OR20, -C(=Y)N(R20)R21, -N(R22)C(=Y)R21, -N(R22)C(=Y)N(R20)R21, -NR 2S(0)2R2°, -S(0)2R20 and/or C1-6 alkyl (optionally substituted by one or more substituents selected from =0 and J2); each R20, R2 , R22 and R23 (e.g. each R20 and R21) independently represents hydrogen or C^e (e.g. C1-4) alkyl optionally substituted by one or more substituents selected from =0 and J4; or any relevant pair of R20, R21 and R22 (e.g. R20 and R21) may (e.g. when both are attached to the same nitrogen atom) may be linked together to form a 4- to 8-membered ring, optionally containing a further heteroatom, and optionally substituted by one or more substituents selected from =0 and J6; each J1, J2, J3, J4, J5 and J6 independently represent C-i-6 (e.g. Ci_3) alkyl optionally substituted by one or more substituents selected from Q8, or, J1 to J6 more preferably represent a substituent selected from Q7; each Q7 and Q8 independently represent halo, -N(R50)R51, -OR50, -C(=Ya)-OR50, -C(=Ya)-R50, -S(0)2R50 or C1-3 alkyl optionally substituted by one or more fluoro atoms; each R50, R5 , R52 and R53 independently represents hydrogen or C1-6 (e.g. C1- ) alkyl optionally substituted by one or more fluoro atoms; and/or each R60, R61 and R62 independently represents hydrogen or C1-2 alkyl (e.g. methyl).
7. A combination as defined in any one of Claims 1 to 6, for use as a pharmaceutical.
8. A pharmaceutical formulation including a combination, as defined in any one of Claims 1 to 6, or a pharmaceutically acceptable ester, amide, solvate or salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
9. A combination product as claimed in any one of Claims 1 to 6, wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
10. A combination, as defined in any one of Claims 1 to 6 or 9, or a pharmaceutical formulation as claimed in Claim 8, for use in the treatment of a disease in which inhibition of a PI3-K and/or mTOR is desired and/or required.
11. Use of a combination, as defined in any one of Claims 1 to 6 or 9, or a pharmaceutical formulation as claimed in Claim 8, for the manufacture of a medicament for the treatment of a disease in which inhibition of a PI3-K and/or mTOR is desired and/or required.
12. A method of treatment of a disease in which inhibition of a PI3-K and/or mTOR is desired and/or required, which method comprises administration of a therapeutically effective amount of a combination as defined in any one of Claims 1 to 6 or 9, or a pharmaceutical formulation as claimed in Claim 8, to a patient suffering from, or susceptible to, such a condition.
13. A combination as claimed in Claim 10, a use as claimed in Claim 1, or a method as claimed in Claim 12, wherein the disease is cancer, an immune disorder, a cardiovascular disease, a viral infection, inflammation, a metabolism/endocrine function disorder, a neurological disorder, an obstructive airways disease, an allergic disease, an inflammatory disease, immunosuppression, a disorder commonly connected with organ transplantation, an AIDS-related disease, benign prostate hyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis, psoriasis, a bone disorder, atherosclerosis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis, restenosis, stroke, diabetes, hepatomegaly, Alzheimer's disease, cystic fibrosis, a hormone-related disease, an immunodeficiency disorder, a destructive bone disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukaemia, liver disease, a pathologic immune condition involving T cell activation, CNS disorders, and other associated diseases.
14. A process for the preparation of a formulation as defined in Claim 8, which process comprises bringing into association components (A) and (B) of the combination as defined in any one of Claims 1 to 6, and at least one pharmaceutically-acceptable adjuvant, diluent or carrier.
PCT/GB2011/051998 2010-10-21 2011-10-14 Combinations of pi3k inhibitors with a second anti -tumor agent WO2012052745A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP10380132 2010-10-21
EP10380132.0 2010-10-21

Publications (1)

Publication Number Publication Date
WO2012052745A1 true WO2012052745A1 (en) 2012-04-26

Family

ID=43708896

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2011/051998 WO2012052745A1 (en) 2010-10-21 2011-10-14 Combinations of pi3k inhibitors with a second anti -tumor agent

Country Status (1)

Country Link
WO (1) WO2012052745A1 (en)

Cited By (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104016990A (en) * 2014-06-19 2014-09-03 山东大学 Imidazopyrazine derivatives as well as preparation method and application thereof
JP2015518011A (en) * 2012-06-01 2015-06-25 南京▲薬▼石▲薬▼物研▲発▼有限公司Ｐｈａｒｍａｂｌｏｃｋ （Ｎａｎｊｉｎｇ） Ｒ＆Ｄ Ｃｏ． Ｌｔｄ． Pyrrolo [2,1-f] [1,2,4] triazine derivatives and their antitumor applications
CN105622526A (en) * 2016-02-24 2016-06-01 湖北工业大学 Preparation method of 2-aminopyrazine derivatives
US9370515B2 (en) 2013-03-07 2016-06-21 Califia Bio, Inc. Mixed lineage kinase inhibitors and method of treatments
US9493442B2 (en) 2014-02-13 2016-11-15 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9493450B2 (en) 2014-02-13 2016-11-15 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9527835B2 (en) 2014-02-13 2016-12-27 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
WO2016209895A1 (en) * 2015-06-26 2016-12-29 Dow Global Technologies Llc Imidazopyrazine derived compounds for electronic devices
US9670210B2 (en) 2014-02-13 2017-06-06 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9695180B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted imidazo[1,2-a]pyrazines as LSD1 inhibitors
US9695168B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted imidazo[1,5-α]pyridines and imidazo[1,5-α]pyrazines as LSD1 inhibitors
US9695167B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted triazolo[1,5-a]pyridines and triazolo[1,5-a]pyrazines as LSD1 inhibitors
US9758523B2 (en) 2014-07-10 2017-09-12 Incyte Corporation Triazolopyridines and triazolopyrazines as LSD1 inhibitors
US9944647B2 (en) 2015-04-03 2018-04-17 Incyte Corporation Heterocyclic compounds as LSD1 inhibitors
CN108570011A (en) * 2018-06-14 2018-09-25 枣庄九星生物科技有限公司 A kind of preparation method of 2- Aminopyrazine derivatives
US10166221B2 (en) 2016-04-22 2019-01-01 Incyte Corporation Formulations of an LSD1 inhibitor
WO2019073031A1 (en) 2017-10-13 2019-04-18 INSERM (Institut National de la Santé et de la Recherche Médicale) Combination treatment of pancreatic cancer
WO2019101871A1 (en) 2017-11-23 2019-05-31 Inserm (Institut National De La Sante Et De La Recherche Medicale) A new marker for predicting the sensitivity to pi3k inhibitors
US10308644B2 (en) 2016-12-22 2019-06-04 Incyte Corporation Heterocyclic compounds as immunomodulators
US10329255B2 (en) 2015-08-12 2019-06-25 Incyte Corporation Salts of an LSD1 inhibitor
US10618916B2 (en) 2018-05-11 2020-04-14 Incyte Corporation Heterocyclic compounds as immunomodulators
US10669271B2 (en) 2018-03-30 2020-06-02 Incyte Corporation Heterocyclic compounds as immunomodulators
US10793565B2 (en) 2016-12-22 2020-10-06 Incyte Corporation Heterocyclic compounds as immunomodulators
US10806785B2 (en) 2016-12-22 2020-10-20 Incyte Corporation Immunomodulator compounds and methods of use
WO2021001431A1 (en) 2019-07-02 2021-01-07 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of pi3ka-selective inhibitors for treating metastatic disease in patients suffering from pancreatic cancer
WO2021001427A1 (en) 2019-07-02 2021-01-07 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the prophylactic treatment of cancer in patients suffering from pancreatitis
WO2021001426A1 (en) 2019-07-02 2021-01-07 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of ultrafast elasticity imaging for detecting pancreatic cancers
US10968200B2 (en) 2018-08-31 2021-04-06 Incyte Corporation Salts of an LSD1 inhibitor and processes for preparing the same
EP3842554A1 (en) 2014-05-09 2021-06-30 Memorial Sloan Kettering Cancer Center Biomarkers for response to pi3k inhibitors
US11248229B2 (en) 2016-11-10 2022-02-15 Memorial Sloan-Kettering Cancer Center Inhibition of KMT2D for the treatment of cancer
WO2022064458A1 (en) * 2020-09-28 2022-03-31 1ST Biotherapeutics, Inc. Indazoles as hematopoietic progenitor kinase 1 (hpk1) inhibitors and methods of using same
US11401279B2 (en) 2019-09-30 2022-08-02 Incyte Corporation Pyrido[3,2-d]pyrimidine compounds as immunomodulators
US11407749B2 (en) 2015-10-19 2022-08-09 Incyte Corporation Heterocyclic compounds as immunomodulators
US11465981B2 (en) 2016-12-22 2022-10-11 Incyte Corporation Heterocyclic compounds as immunomodulators
US11535615B2 (en) 2015-12-22 2022-12-27 Incyte Corporation Heterocyclic compounds as immunomodulators
US11572366B2 (en) 2015-11-19 2023-02-07 Incyte Corporation Heterocyclic compounds as immunomodulators
US11608337B2 (en) 2016-05-06 2023-03-21 Incyte Corporation Heterocyclic compounds as immunomodulators
US11613536B2 (en) 2016-08-29 2023-03-28 Incyte Corporation Heterocyclic compounds as immunomodulators
US11673883B2 (en) 2016-05-26 2023-06-13 Incyte Corporation Heterocyclic compounds as immunomodulators
US11718605B2 (en) 2016-07-14 2023-08-08 Incyte Corporation Heterocyclic compounds as immunomodulators
US11753406B2 (en) 2019-08-09 2023-09-12 Incyte Corporation Salts of a PD-1/PD-L1 inhibitor
US11760756B2 (en) 2020-11-06 2023-09-19 Incyte Corporation Crystalline form of a PD-1/PD-L1 inhibitor
US11780836B2 (en) 2020-11-06 2023-10-10 Incyte Corporation Process of preparing a PD-1/PD-L1 inhibitor
US11866451B2 (en) 2019-11-11 2024-01-09 Incyte Corporation Salts and crystalline forms of a PD-1/PD-L1 inhibitor
US11866434B2 (en) 2020-11-06 2024-01-09 Incyte Corporation Process for making a PD-1/PD-L1 inhibitor and salts and crystalline forms thereof
US11873309B2 (en) 2016-06-20 2024-01-16 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2023250431A3 (en) * 2022-06-22 2024-02-08 Children's Hospital Medical Center Multi-cyclic irak and flt3 inhibiting compounds and uses thereof

Citations (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0253738A1 (en) 1986-07-17 1988-01-20 Rhone-Poulenc Sante Taxol derivatives, their preparation and pharmaceutical compositions containing them
WO1988004298A1 (en) 1986-12-05 1988-06-16 Byk Gulden Lomberg Chemische Fabrik Gmbh 8-alkylaminoimidazo[1,2-a]pyrazines and derivatives, their preparation and their application in therapy
US5438072A (en) 1992-12-02 1995-08-01 Rhone-Poulenc Rorer S.A. Taxoid-based compositions
US5698582A (en) 1991-07-08 1997-12-16 Rhone-Poulenc Rorer S.A. Compositions containing taxane derivatives
US5714512A (en) 1991-07-08 1998-02-03 Rhone-Poulenc Rorer, S.A. Compositions containing taxane derivatives
US5750561A (en) 1991-07-08 1998-05-12 Rhone-Poulenc Rorer, S.A. Compositions containing taxane derivatives
WO1999064401A2 (en) 1998-06-12 1999-12-16 Societe De Conseils De Recherches Et D'applications Scientifiques Sas Imidazolyl derivatives and their use as somatostatin receptor ligands
WO2002010140A2 (en) 2000-08-01 2002-02-07 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) Imidazolyl derivatives
WO2002060492A1 (en) 2001-01-30 2002-08-08 Cytopia Pty Ltd Methods of inhibiting kinases
WO2002062800A1 (en) 2001-02-08 2002-08-15 Eisai Co., Ltd. Bicyclic nitrogenous fused-ring compound
WO2004022562A1 (en) 2002-09-09 2004-03-18 Cellular Genomics, Inc. 6-ARYL-IMIDAZO[1,2-a]PYRAZIN-8-YLAMINES, METHOD OF MAKING, AND METHOD OF USE THEREOF
US6713485B2 (en) 1998-01-12 2004-03-30 Smithkline Beecham Corporation Heterocyclic compounds
US20040147478A1 (en) 2002-11-15 2004-07-29 Pfizer Inc. Combination chemotherapy
WO2004072080A1 (en) 2003-02-10 2004-08-26 Cellular Genomics, Inc. Certain 8-heteroaryl-6-phenyl-imidazo[1,2-a]pyrazines as modulators of hsp90 complex activity
US20050085550A1 (en) 2003-10-21 2005-04-21 Warner-Lambert Company Polymorphic form of N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide
US6933299B1 (en) 1999-07-09 2005-08-23 Smithkline Beecham Corporation Anilinoquinazolines as protein tyrosine kinase inhibitors
US6960614B2 (en) 2000-07-19 2005-11-01 Warner-Lambert Company Oxygenated esters of 4-lodo phenylamino benzhydroxamic acids
US6972298B2 (en) 2001-05-09 2005-12-06 Warner-Lambert Company Method of treating or inhibiting neutrophil chemotaxis by administering a MEK inhibitor
US7084147B2 (en) 1999-07-09 2006-08-01 Smithkline Beecham Corporation Anilinoquinazaolines as protein tyrosine kinase inhibitors
US7141576B2 (en) 2001-01-16 2006-11-28 Smithkline Beecham (Cork) Limited Cancer treatment method
US7157466B2 (en) 2000-06-30 2007-01-02 Smithkline Beecham (Cork) Limited Quinazoline ditosylate salt compounds
WO2007028051A2 (en) 2005-09-02 2007-03-08 Abbott Laboratories Novel imidazo based heterocycles
WO2007044515A1 (en) 2005-10-07 2007-04-19 Exelixis, Inc. Azetidines as mek inhibitors for the treatment of proliferative diseases
WO2008156614A2 (en) 2007-06-14 2008-12-24 Schering Corporation Imidazopyrazines as protein kinase inhibitors
WO2009007029A1 (en) 2007-07-11 2009-01-15 Bayer Schering Pharma Aktiengesellschaft Imidazo-, pyrazolopyrazines and imidazotriazines and their use
WO2010105008A2 (en) 2009-03-12 2010-09-16 Genentech, Inc. Combinations of phosphoinositide 3-kinase inhibitor compounds and chemotherapeutic agents for the treatment of hematopoietic malignancies
WO2010119264A1 (en) 2009-04-16 2010-10-21 Centro Nacional De Investigaciones Oncólogicas (Cnio) Imidazopyrazines for use as kinase inhibitors

Patent Citations (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4814470A (en) 1986-07-17 1989-03-21 Rhone-Poulenc Sante Taxol derivatives, their preparation and pharmaceutical compositions containing them
EP0253738A1 (en) 1986-07-17 1988-01-20 Rhone-Poulenc Sante Taxol derivatives, their preparation and pharmaceutical compositions containing them
WO1988004298A1 (en) 1986-12-05 1988-06-16 Byk Gulden Lomberg Chemische Fabrik Gmbh 8-alkylaminoimidazo[1,2-a]pyrazines and derivatives, their preparation and their application in therapy
US5698582A (en) 1991-07-08 1997-12-16 Rhone-Poulenc Rorer S.A. Compositions containing taxane derivatives
US5714512A (en) 1991-07-08 1998-02-03 Rhone-Poulenc Rorer, S.A. Compositions containing taxane derivatives
US5750561A (en) 1991-07-08 1998-05-12 Rhone-Poulenc Rorer, S.A. Compositions containing taxane derivatives
US5438072A (en) 1992-12-02 1995-08-01 Rhone-Poulenc Rorer S.A. Taxoid-based compositions
US6713485B2 (en) 1998-01-12 2004-03-30 Smithkline Beecham Corporation Heterocyclic compounds
US7109333B2 (en) 1998-01-12 2006-09-19 Smithkline Beecham Corporation Heterocyclic compounds
US6727256B1 (en) 1998-01-12 2004-04-27 Smithkline Beecham Corporation Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
WO1999064401A2 (en) 1998-06-12 1999-12-16 Societe De Conseils De Recherches Et D'applications Scientifiques Sas Imidazolyl derivatives and their use as somatostatin receptor ligands
US7084147B2 (en) 1999-07-09 2006-08-01 Smithkline Beecham Corporation Anilinoquinazaolines as protein tyrosine kinase inhibitors
US6933299B1 (en) 1999-07-09 2005-08-23 Smithkline Beecham Corporation Anilinoquinazolines as protein tyrosine kinase inhibitors
US7157466B2 (en) 2000-06-30 2007-01-02 Smithkline Beecham (Cork) Limited Quinazoline ditosylate salt compounds
US6960614B2 (en) 2000-07-19 2005-11-01 Warner-Lambert Company Oxygenated esters of 4-lodo phenylamino benzhydroxamic acids
WO2002010140A2 (en) 2000-08-01 2002-02-07 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) Imidazolyl derivatives
US7141576B2 (en) 2001-01-16 2006-11-28 Smithkline Beecham (Cork) Limited Cancer treatment method
WO2002060492A1 (en) 2001-01-30 2002-08-08 Cytopia Pty Ltd Methods of inhibiting kinases
WO2002062800A1 (en) 2001-02-08 2002-08-15 Eisai Co., Ltd. Bicyclic nitrogenous fused-ring compound
US6972298B2 (en) 2001-05-09 2005-12-06 Warner-Lambert Company Method of treating or inhibiting neutrophil chemotaxis by administering a MEK inhibitor
WO2004022562A1 (en) 2002-09-09 2004-03-18 Cellular Genomics, Inc. 6-ARYL-IMIDAZO[1,2-a]PYRAZIN-8-YLAMINES, METHOD OF MAKING, AND METHOD OF USE THEREOF
US20040147478A1 (en) 2002-11-15 2004-07-29 Pfizer Inc. Combination chemotherapy
WO2004072081A1 (en) 2003-02-10 2004-08-26 Cellular Genomics, Inc. Certain 8-heteroaryl-6-phenyl-imidazo[1,2-a]pyrazines as modulators of kinase activity
WO2004072080A1 (en) 2003-02-10 2004-08-26 Cellular Genomics, Inc. Certain 8-heteroaryl-6-phenyl-imidazo[1,2-a]pyrazines as modulators of hsp90 complex activity
US20050085550A1 (en) 2003-10-21 2005-04-21 Warner-Lambert Company Polymorphic form of N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide
WO2007028051A2 (en) 2005-09-02 2007-03-08 Abbott Laboratories Novel imidazo based heterocycles
WO2007044515A1 (en) 2005-10-07 2007-04-19 Exelixis, Inc. Azetidines as mek inhibitors for the treatment of proliferative diseases
WO2008156614A2 (en) 2007-06-14 2008-12-24 Schering Corporation Imidazopyrazines as protein kinase inhibitors
WO2009007029A1 (en) 2007-07-11 2009-01-15 Bayer Schering Pharma Aktiengesellschaft Imidazo-, pyrazolopyrazines and imidazotriazines and their use
WO2010105008A2 (en) 2009-03-12 2010-09-16 Genentech, Inc. Combinations of phosphoinositide 3-kinase inhibitor compounds and chemotherapeutic agents for the treatment of hematopoietic malignancies
WO2010119264A1 (en) 2009-04-16 2010-10-21 Centro Nacional De Investigaciones Oncólogicas (Cnio) Imidazopyrazines for use as kinase inhibitors

Non-Patent Citations (50)

* Cited by examiner, † Cited by third party
Title
A. M. ABDEL MAGIB ET AL., J. ORG. CHEM., vol. 61, 1996, pages 3849
A.F. ABDEL-MAGID; C.A MARYANOFF, SYNTHESIS, 1990, pages 537
ANDANAPPA K. GADAD ET AL., BIOORG. MED. CHEM., vol. 12, 2004, pages 5651 - 5659
ASUNCI6N MARIN ET AL., FARMACO, vol. 47, no. 1, 1992, pages 63 - 75
BISSERY ET AL., CANCER RES., vol. 51, 1991, pages 4845
BRETONNET ET AL., J. MED. CHEM., vol. 50, 2007, pages 1872
BUNDEGAARD, H.: "Design of Prodrugs", 1985, ELESEVIER, pages: 1 - 92
CURRENT OPINION IN CHEMICAL BIOLOGY, vol. 3, 1999, pages 459 - 465
DAVIES ET AL., EXPERT. OPIN. PHARMACOTHER, vol. 4, 2003, pages 553 - 565
E. ABIGNENTE ET AL., FARMACO, vol. 45, 1990, pages 1075
EASTON ET AL.: "mTOR and cancer therapy", ONCOGENE, vol. 25, no. 48, 2006, pages 6436 - 46
F.D. BELLAMY; K. OU, TETRAHEDRON LETT., vol. 25, 1985, pages 839
HENNESSEY ET AL., NATURE REV. DRUG DISCOVERY, vol. 4, 2005, pages 988 - 1004
HERBST ET AL., CANCER TREAT. REV., vol. 29, 2003, pages 407 - 415
J. A. H. LAINTON, J. COMB. CHEM., vol. 5, 2003, pages 400
J. KOBE ET AL., TETRAHEDRON, vol. 24, 1968, pages 239
J. ORG.CHEM., vol. 55, 1990, pages 3209 - 3213
J.ORG.CHEM, vol. 68, 2003, pages 4935 - 4937
KATSO, ANNU. REV. CELL. DEV. BOIL., vol. 17, 2001, pages 615 - 75
L. WENGWEI ET AL., TETRAHEDRON LETT., vol. 47, 2006, pages 1941
LESLIE ET AL., CHEM. REV., vol. 101, no. 8, 2001, pages 2365 - 80
M. KUWAHARA ET AL., CHEM. PHARM BULL., vol. 44, 1996, pages 122
M. PLOTKIN ET AL., TETRAHEDRON LETT., vol. 41, 2000, pages 2269
M. SCHLOSSER ET AL.: "Organometallics in Synthesis. A Manual", 2002, WILEY &SONS LTD
M.A. EI-SHERBENY ET AL., BOLL. CHIM. FARM., vol. 136, 1997, pages 253 - 256
MANGATAL ET AL., TETRAHEDRON, vol. 45, 1989, pages 4177
N. DEFACQZ ET AL., TETRAHEDRON LETT., vol. 44, 2003, pages 9111
NICOLAOU, K. C.; BULGER, P. G.; SARLAH, D., ANGEW. CHEM. INT ED., vol. 44, 2005, pages 2 - 49
NICOLAOU, K. C.; BULGER, P. G.; SARLAH, D., ANGEW. CHEM. INT. ED., vol. 44, 2005, pages 2 - 49
O. C. DERMER, CHEM. REV., vol. 14, 1934, pages 385
P.F. FABIO; A.F. LANZILOTTI; S.A. LANG, JOURNAL OF LABELLED COMPOUNDS ANDPHARMACEUTICALS, vol. 15, 1978, pages 407
PARSONS ET AL., NATURE, vol. 436, 2005, pages 792
PAUL HEINZ ET AL., MONATSHEFTE FUR CHEMIE, vol. 108, 1977, pages 665 - 680
RINGEL ET AL., J. NATL. CANCER INST., vol. 83, 1991, pages 288
S. Y. HAN; Y.-A. KIM, TETRAHEDRON, vol. 60, 2004, pages 2447
S.J. GREGSON ET AL., J. MED. CHEM., vol. 47, 2004, pages 1161
SEVERINSEN, R. ET AL., TETRAHEDRON, vol. 61, 2005, pages 5565 - 5575
SEYDEN-PENNE, J.: "Reductions by the Alumino and Borohydrides", 1991, VCH
SHINTANI, R.; OKAMOTO, K., ORG. LETT., vol. 7, no. 21, 2005, pages 4757 - 4759
T. IKEMOTO ET AL., TETRAHEDRON, vol. 56, 2000, pages 7915
T. IKEMOTO; M. WAKIMASU, HETEROCYCLES, vol. 55, 2001, pages 99
T. W. GREENE; P. G. M. WUTS, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 1999
T.W. GREENE; P.G.M. WUTZ: "Protective Groups in Organic Synthesis", 3rd edition", 1999, WILEY-INTERSCIENCE
TOKER, CELL. MOL. LIFE SCI., vol. 59, no. 5, 2002, pages 761 - 79
VANHAESEBROECK, EXP. CELL. RES., vol. 25, no. 1, 1999, pages 239 - 54
VANHAESEBROECK, TRENDS BIOCHEM. SCI, vol. 22, no. 87, 1997, pages 267 - 72
VANHAESEBROECK, TRENDS BIOCHEM. SCI., vol. 22, no. 7, 1997, pages 267 - 72
WERBER,G. ET AL., J. HETEROCYCL. CHEM., vol. 14, 1977, pages 823 - 827
WIGGINS, J. M., SYNTH. COMMUN., vol. 18, 1988, pages 741
WIPF, P.; JUNG, J.-K., J. ORG. CHEM., vol. 65, no. 20, 2000, pages 6319 - 6337

Cited By (78)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015518011A (en) * 2012-06-01 2015-06-25 南京▲薬▼石▲薬▼物研▲発▼有限公司Ｐｈａｒｍａｂｌｏｃｋ （Ｎａｎｊｉｎｇ） Ｒ＆Ｄ Ｃｏ． Ｌｔｄ． Pyrrolo [2,1-f] [1,2,4] triazine derivatives and their antitumor applications
US9370515B2 (en) 2013-03-07 2016-06-21 Califia Bio, Inc. Mixed lineage kinase inhibitors and method of treatments
US9670210B2 (en) 2014-02-13 2017-06-06 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US11247992B2 (en) 2014-02-13 2022-02-15 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9493442B2 (en) 2014-02-13 2016-11-15 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9493450B2 (en) 2014-02-13 2016-11-15 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9527835B2 (en) 2014-02-13 2016-12-27 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US10300051B2 (en) 2014-02-13 2019-05-28 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US10174030B2 (en) 2014-02-13 2019-01-08 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US11155532B2 (en) 2014-02-13 2021-10-26 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US10513493B2 (en) 2014-02-13 2019-12-24 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9994546B2 (en) 2014-02-13 2018-06-12 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US10717737B2 (en) 2014-02-13 2020-07-21 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US10676457B2 (en) 2014-02-13 2020-06-09 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US11142797B2 (en) 2014-05-09 2021-10-12 Memorial Sloan-Kettering Cancer Center Biomarkers for response to PI3K inhibitors
EP3842554A1 (en) 2014-05-09 2021-06-30 Memorial Sloan Kettering Cancer Center Biomarkers for response to pi3k inhibitors
CN104016990A (en) * 2014-06-19 2014-09-03 山东大学 Imidazopyrazine derivatives as well as preparation method and application thereof
US9695167B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted triazolo[1,5-a]pyridines and triazolo[1,5-a]pyrazines as LSD1 inhibitors
US10047086B2 (en) 2014-07-10 2018-08-14 Incyte Corporation Imidazopyridines and imidazopyrazines as LSD1 inhibitors
US10138249B2 (en) 2014-07-10 2018-11-27 Incyte Corporation Triazolopyridines and triazolopyrazines as LSD1 inhibitors
US9758523B2 (en) 2014-07-10 2017-09-12 Incyte Corporation Triazolopyridines and triazolopyrazines as LSD1 inhibitors
US10112950B2 (en) 2014-07-10 2018-10-30 Incyte Corporation Substituted imidazo[1,2-a]pyrazines as LSD1 inhibitors
US10968221B2 (en) 2014-07-10 2021-04-06 Incyte Corporation Substituted [1,2,4]triazolo[1,5-a]pyrazines as LSD1 inhibitors
US9695180B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted imidazo[1,2-a]pyrazines as LSD1 inhibitors
US10640503B2 (en) 2014-07-10 2020-05-05 Incyte Corporation Imidazopyridines and imidazopyrazines as LSD1 inhibitors
US10125133B2 (en) 2014-07-10 2018-11-13 Incyte Corporation Substituted [1,2,4]triazolo[1,5-a]pyridines and substituted [1,2,4]triazolo[1,5-a]pyrazines as LSD1 inhibitors
US9695168B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted imidazo[1,5-α]pyridines and imidazo[1,5-α]pyrazines as LSD1 inhibitors
US10556908B2 (en) 2014-07-10 2020-02-11 Incyte Corporation Substituted imidazo[1,2-a]pyrazines as LSD1 inhibitors
US9944647B2 (en) 2015-04-03 2018-04-17 Incyte Corporation Heterocyclic compounds as LSD1 inhibitors
US10800779B2 (en) 2015-04-03 2020-10-13 Incyte Corporation Heterocyclic compounds as LSD1 inhibitors
US11401272B2 (en) 2015-04-03 2022-08-02 Incyte Corporation Heterocyclic compounds as LSD1 inhibitors
WO2016209895A1 (en) * 2015-06-26 2016-12-29 Dow Global Technologies Llc Imidazopyrazine derived compounds for electronic devices
US11498900B2 (en) 2015-08-12 2022-11-15 Incyte Corporation Salts of an LSD1 inhibitor
US10723700B2 (en) 2015-08-12 2020-07-28 Incyte Corporation Salts of an LSD1 inhibitor
US10329255B2 (en) 2015-08-12 2019-06-25 Incyte Corporation Salts of an LSD1 inhibitor
US11407749B2 (en) 2015-10-19 2022-08-09 Incyte Corporation Heterocyclic compounds as immunomodulators
US11572366B2 (en) 2015-11-19 2023-02-07 Incyte Corporation Heterocyclic compounds as immunomodulators
US11866435B2 (en) 2015-12-22 2024-01-09 Incyte Corporation Heterocyclic compounds as immunomodulators
US11535615B2 (en) 2015-12-22 2022-12-27 Incyte Corporation Heterocyclic compounds as immunomodulators
CN105622526A (en) * 2016-02-24 2016-06-01 湖北工业大学 Preparation method of 2-aminopyrazine derivatives
US10166221B2 (en) 2016-04-22 2019-01-01 Incyte Corporation Formulations of an LSD1 inhibitor
US11608337B2 (en) 2016-05-06 2023-03-21 Incyte Corporation Heterocyclic compounds as immunomodulators
US11673883B2 (en) 2016-05-26 2023-06-13 Incyte Corporation Heterocyclic compounds as immunomodulators
US11873309B2 (en) 2016-06-20 2024-01-16 Incyte Corporation Heterocyclic compounds as immunomodulators
US11718605B2 (en) 2016-07-14 2023-08-08 Incyte Corporation Heterocyclic compounds as immunomodulators
US11613536B2 (en) 2016-08-29 2023-03-28 Incyte Corporation Heterocyclic compounds as immunomodulators
US11248229B2 (en) 2016-11-10 2022-02-15 Memorial Sloan-Kettering Cancer Center Inhibition of KMT2D for the treatment of cancer
US10806785B2 (en) 2016-12-22 2020-10-20 Incyte Corporation Immunomodulator compounds and methods of use
US11787793B2 (en) 2016-12-22 2023-10-17 Incyte Corporation Heterocyclic compounds as immunomodulators
US10793565B2 (en) 2016-12-22 2020-10-06 Incyte Corporation Heterocyclic compounds as immunomodulators
US11566026B2 (en) 2016-12-22 2023-01-31 Incyte Corporation Heterocyclic compounds as immunomodulators
US10800768B2 (en) 2016-12-22 2020-10-13 Incyte Corporation Heterocyclic compounds as immunomodulators
US11339149B2 (en) 2016-12-22 2022-05-24 Incyte Corporation Heterocyclic compounds as immunomodulators
US11465981B2 (en) 2016-12-22 2022-10-11 Incyte Corporation Heterocyclic compounds as immunomodulators
US10308644B2 (en) 2016-12-22 2019-06-04 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2019073031A1 (en) 2017-10-13 2019-04-18 INSERM (Institut National de la Santé et de la Recherche Médicale) Combination treatment of pancreatic cancer
US11351156B2 (en) 2017-10-13 2022-06-07 Inserm Combination treatment of pancreatic cancer
WO2019101871A1 (en) 2017-11-23 2019-05-31 Inserm (Institut National De La Sante Et De La Recherche Medicale) A new marker for predicting the sensitivity to pi3k inhibitors
US11124511B2 (en) 2018-03-30 2021-09-21 Incyte Corporation Heterocyclic compounds as immunomodulators
US10669271B2 (en) 2018-03-30 2020-06-02 Incyte Corporation Heterocyclic compounds as immunomodulators
US11414433B2 (en) 2018-05-11 2022-08-16 Incyte Corporation Heterocyclic compounds as immunomodulators
US10906920B2 (en) 2018-05-11 2021-02-02 Incyte Corporation Heterocyclic compounds as immunomodulators
US10618916B2 (en) 2018-05-11 2020-04-14 Incyte Corporation Heterocyclic compounds as immunomodulators
CN108570011A (en) * 2018-06-14 2018-09-25 枣庄九星生物科技有限公司 A kind of preparation method of 2- Aminopyrazine derivatives
US11512064B2 (en) 2018-08-31 2022-11-29 Incyte Corporation Salts of an LSD1 inhibitor and processes for preparing the same
US10968200B2 (en) 2018-08-31 2021-04-06 Incyte Corporation Salts of an LSD1 inhibitor and processes for preparing the same
WO2021001426A1 (en) 2019-07-02 2021-01-07 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of ultrafast elasticity imaging for detecting pancreatic cancers
WO2021001431A1 (en) 2019-07-02 2021-01-07 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of pi3ka-selective inhibitors for treating metastatic disease in patients suffering from pancreatic cancer
WO2021001427A1 (en) 2019-07-02 2021-01-07 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the prophylactic treatment of cancer in patients suffering from pancreatitis
US11753406B2 (en) 2019-08-09 2023-09-12 Incyte Corporation Salts of a PD-1/PD-L1 inhibitor
US11401279B2 (en) 2019-09-30 2022-08-02 Incyte Corporation Pyrido[3,2-d]pyrimidine compounds as immunomodulators
US11866451B2 (en) 2019-11-11 2024-01-09 Incyte Corporation Salts and crystalline forms of a PD-1/PD-L1 inhibitor
US11834467B2 (en) 2020-09-28 2023-12-05 1ST Biotherapeutics, Inc. Substituted indazoles as hematopoietic progenitor kinase 1 (HPK1) inhibitors
WO2022064458A1 (en) * 2020-09-28 2022-03-31 1ST Biotherapeutics, Inc. Indazoles as hematopoietic progenitor kinase 1 (hpk1) inhibitors and methods of using same
US11760756B2 (en) 2020-11-06 2023-09-19 Incyte Corporation Crystalline form of a PD-1/PD-L1 inhibitor
US11780836B2 (en) 2020-11-06 2023-10-10 Incyte Corporation Process of preparing a PD-1/PD-L1 inhibitor
US11866434B2 (en) 2020-11-06 2024-01-09 Incyte Corporation Process for making a PD-1/PD-L1 inhibitor and salts and crystalline forms thereof
WO2023250431A3 (en) * 2022-06-22 2024-02-08 Children's Hospital Medical Center Multi-cyclic irak and flt3 inhibiting compounds and uses thereof

Similar Documents

Publication Publication Date Title
WO2012052745A1 (en) Combinations of pi3k inhibitors with a second anti -tumor agent
EP2526102B1 (en) Inhibitors of PI3 kinase
EP2710018B1 (en) Macrocyclic compounds as protein kinase inhibitors
EP2419429B1 (en) Imidazopyrazines as inhibitors of protein kinases
EP2524918A1 (en) Imidazopyrazines derivates as kinase inhibitors
EP2480549B1 (en) Fused imidazo[3,2-d]pyrazines as PI3 kinase inhibitors
EP2758397A1 (en) Imidazopyridine compounds, compositions and methods of use
AU2016313263B2 (en) Condensed tricyclic compounds as protein kinase inhibitors
WO2011121317A9 (en) Imidazothiadiazoles for use as kinase inhibitors

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11782657

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11782657

Country of ref document: EP

Kind code of ref document: A1