WO2009021083A1 - Quinoxaline derivatives as pi3 kinase inhibitors - Google Patents

Quinoxaline derivatives as pi3 kinase inhibitors Download PDF

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WO2009021083A1
WO2009021083A1 PCT/US2008/072401 US2008072401W WO2009021083A1 WO 2009021083 A1 WO2009021083 A1 WO 2009021083A1 US 2008072401 W US2008072401 W US 2008072401W WO 2009021083 A1 WO2009021083 A1 WO 2009021083A1
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substituted
amino
heteroaryl
6alkyl
cancer
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WO2009021083A8 (en
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Steven David Knight
Cynthia A. Parrish
Lance H. Ridgers
Martha A. Sarpong
Amita M. Chaudhari
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Smithkline Beecham Corporation
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Priority to EP08797323A priority Critical patent/EP2173354A4/en
Priority to JP2010520295A priority patent/JP2010535804A/en
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Publication of WO2009021083A8 publication Critical patent/WO2009021083A8/en

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Definitions

  • PB kinases phosphoinositide 3 ' OH kinase family
  • the present invention relates to the use of quinoxalines in the treatment of one or more disease states selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries.
  • PB kinases e.g. PBKalpha
  • PBKalpha membrane phospholipid pools
  • PBKalpha dual-specificity kinase enzymes, meaning they display both: lipid kinase (phosphorylation of phosphoinositides) as well as protein kinase activity, shown to be capable of phosphorylation of protein as substrate, including auto-phosphorylation as intramolecular regulatory mechanism.
  • phospholipids signaling are activated in response to a variety of extra-cellular signals such as growth factors, mitogens, integrins (cell-cell interactions) hormones, cytokines, viruses and neurotransmitters such as described in Scheme I hereinafter and also by intracellular regulation by other signaling molecules (cross-talk, where the original signal can activate some parallel pathways that in a second step transmit signals to PBKs by intra-cellular signaling events), such as small GTPases, kinases or phosphatases for example. Intracellular regulation can also occur as a result of aberrant expression or lack of expression of cellular oncogenes or tumor suppressors.
  • extra-cellular signals such as growth factors, mitogens, integrins (cell-cell interactions) hormones, cytokines, viruses and neurotransmitters such as described in Scheme I hereinafter and also by intracellular regulation by other signaling molecules (cross-talk, where the original signal can activate some parallel pathways that in a second step transmit signals to PBKs by intra-cellular signaling events
  • the inositol phospholipid (phosphoinositides) intracellular signaling pathways begin with activation of signaling molecules (extra cellular ligands, stimuli, receptor dimerization, transactivation by heterologous receptor (e.g. receptor tyrosine kinase) and the recruitment and activation of PBK including the involvement of G-protein linked transmembrane receptor integrated into the plasma membrane.
  • PBK converts the membrane phospholipid PI(4,5)P 2 into PI(3,4,5)P 3 that functions as a second messenger.
  • PI and PI(4)P are also substrates of PBK and can be phosphorylated and converted into PBP and PI(3,4)P 2 , respectively.
  • PBK enzymatic activity results either directly or indirectly in the generation of two 3 ' -phosphoinositide subtypes that function as 2 nd messengers in intra-cellular signal transduction pathways (Trends Biochem. Sci. 22(7) p.267-72 (1997) by Vanhaesebroeck et al: Chem. Rev. 101(8) p.2365-80 (2001) by Leslie et al (2001); Annu. Rev. Cell.Dev. Biol. 17p, 615-75 (2001) by Katso et al. and Cell. MoI. Life Sci.
  • PBK isoforms categorized by their catalytic subunits, their regulation by corresponding regulatory subunits, expression patterns and signaling-specific functions (pl lO ⁇ , ⁇ , ⁇ and ⁇ ) perform this enzymatic reaction (Exp. Cell. Res. 25 (1) p. 239-54 (1999) by Vanhaesebroeck and Katso et al., 2001, above).
  • the closely related isoforms pi 10a and ⁇ are ubiquitously expressed, while ⁇ and ⁇ are more specifically expressed in the haematopoietic cell system, smooth muscle cells, myocytes and endothelial cells (Trends Biochem. Sci. 22(7) p.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. Inducibility of protein expression includes synthesis of protein as well as protein stabilization that is in part regulated by association with regulatory subunits.
  • class I PBKs can phosphorylate phosphatidylinositol (PI), phosphatidylinositol-4-phosphate (PI4P), and phosphatidylinositol-4,5-bisphosphate (PI(4,5)P 2 ) to produce phosphatidylinositol-3- phosphate (PBP), phosphatidylinositol-3,4-bisphosphate (PI(3,4)P 2 , and phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P 3 , respectively.
  • PI phosphatidylinositol
  • P4P phosphatidylinositol-4-phosphate
  • PI(4,5)P 2 phosphatidylinositol-4,5-bisphosphate
  • Class II PBKs phosphorylate PI and phosphatidylinositol-4-phosphate.
  • Class III PBKs can only phosphorylate PI (Vanhaesebrokeck et al., 1997, above; Vanhaesebroeck et al., 1999, above and Leslie et al, 2001, above)
  • phosphoinositide 3-kinases phosphorylate the hydroxyl of the third carbon of the inositol ring.
  • the phosphorylation of phosphoinositides that generate Ptdlns to 3,4,5-trisphosphate (PtdIns(3,4,5)P3), PtdIns(3,4)P2 and PtdIns(3)P produce second messengers for a variety of signal transduction pathways, including those essential to cell proliferation, cell differentiation, cell growth, cell size, cell survival, apoptosis, adhesion, cell motility, cell migration, chemotaxis, invasion, cytoskeletal rearrangement, cell shape changes, vesicle trafficking and metabolic pathway (Katso et al, 2001, above and MoI.
  • G-protein coupled receptors mediate phosphoinositide 3'OH-kinase activation via small GTPases such as G ⁇ and Ras, and consequently PI3K signaling plays a central role in establishing and coordinating cell polarity and dynamic organization of the cytoskeleton - which together provides the driving force of cells to move.
  • Chemotaxis the directed movement of cells toward a concentration gradient of chemical attractants, also called chemokines is involved in many important diseases such as inflammation/auto-immunity, neurodegeneration, antiogenesis, invasion/metastasis and wound healing (Immunol. Today 21(6) p.
  • PI3-Kinase responsible for generating these phosphorylated signalling products, was originally identified as an activity associated with viral oncoproteins and growth factor receptor tyrosine kinases that phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at the 3'- hydroxyl of the inositol ring (Panayotou et al., Trends Cell Biol. 2 p. 358-60 (1992)).
  • PI phosphatidylinositol
  • class I PI3 kinases e.g. class IB isoform PI3K ⁇
  • class IB isoform PI3K ⁇ are dual-specific kinase enzymes, meaning they display both lipid kinase and protein kinase activity, shown to be capable of phosphorylation of other proteins as substrates, as well as auto-phosphorylation as an intra-molecular regulatory mechanism.
  • PI3-kinase activation is therefore believed to be involved in a range of cellular responses including cell growth, differentiation, and apoptosis (Parker et al., Current Biology, 5 p. 577-99 (1995); Yao et al., Science, 267 p. 2003-05 (1995)).
  • PI3-kinase appears to be involved in a number of aspects of leukocyte activation.
  • a p85-associated PI3 -kinase activity has been shown to physically associate with the cytoplasmic domain of CD28, which is an important costimulatory molecule for the activation of T-cells in response to antigen (Pages et al., Nature, 369 p.
  • PI3K ⁇ has been identified as a mediator of G beta-gamma-dependent regulation of JNK activity, and G beta-gamma are subunits of heterotrimeric G proteins (Lopez- Ilasaca et al., J. Biol. Chem. 273(5) p. 2505-8 (1998)).
  • Cellular processes in which PBKs play an essential role include suppression of apoptosis, reorganization of the actin skeleton, cardiac myocyte growth, glycogen synthase stimulation by insulin, TNF ⁇ -mediated neutrophil priming and superoxide generation, and leukocyte migration and adhesion to endothelial cells. Recently, (Laffargue et al, Immunity 16(3) p.
  • PBK ⁇ relays inflammatory signals through various G(i)-coupled receptors and its central to mast cell function, stimuli in context of leukocytes, immunology includes cytokines, chemokines, adenosines, antibodies, integrins, aggregation factors, growth factors, viruses or hormones for example (J. Cell. Sci. 114(Pt 16) p. 2903-10 (2001) by Lawlor et al.; Laffargue et al., 2002, above and Curr. Opinion Cell Biol. 14(2) p. 203-13 (2002) by Stephens et al.).
  • PI3-kinase inhibitors Two compounds, LY294002 and wortmannin (cf. hereinafter), have been widely used as PI3-kinase inhibitors. These compounds are non-specific PI3K inhibitors, as they do not distinguish among the four members of Class I PI3-kinases.
  • the IC50 values of wortmannin against each of the various Class I PI3 -kinases are in the range of 1-10 nM.
  • the IC50 values for LY294002 against each of these PI3-kinases is about 15-20 ⁇ M (Fruman et al., Ann. Rev. Biochem., 67, p.
  • wortmannin is a fungal metabolite which irreversibly inhibits PI3K activity by binding covalently to the catalytic domain of this enzyme. Inhibition of PI3K activity by wortmannin eliminates subsequent cellular response to the extracellular factor.
  • neutrophils respond to the chemokine fMet-Leu-Phe (fMLP) by stimulating PI3K and synthesizing Ptdlns (3, 4, 5)P3. This synthesis correlates with activation of the respirators burst involved in neutrophil destruction of invading microorganisms.
  • Class I PBK is a heterodimer consisting of a pi 10 catalytic subunit and a regulatory subunit, and the family is further divided into class Ia and Class Ib enzymes on the basis of regulatory partners and mechanism of regulation.
  • Class Ia enzymes consist of three distinct catalytic subunits (pl lO ⁇ , pl lO ⁇ , and pl lO ⁇ ) that dimerise with five distinct regulatory subunits (p85 ⁇ , p55 ⁇ , p50 ⁇ , p85 ⁇ , and p55 ⁇ ), with all catalytic subunits being able to interact with all regulatory subunits to form a variety of heterodimers.
  • Class Ia PBK are generally activated in response to growth factor-stimulation of receptor tyrosine kinases, via interaction of the regulatory subunit SH2 domains with specific phospho- tyrosine residues of the activated receptor or adaptor proteins such as IRS-I.
  • Small GTPases (ras as an example) are also involved in the activation of PBK in conjunction with receptor tyrosine kinase activation. Both pl lO ⁇ and pl lO ⁇ are constitutively expressed in all cell types, whereas pl lO ⁇ expression is more restricted to leukocyte populations and some epithelial cells.
  • the single Class Ib enzyme consists of a pl lO ⁇ catalytic subunit that interacts with a plOl regulatory subunit. Furthermore, the Class Ib enzyme is activated in response to G-protein coupled receptor (GPCR) systems and its expression appears to be limited to leukocytes.
  • GPCR G-protein coupled receptor
  • Tumor-related mutations in p85 ⁇ have also been identified in cancers such as those of the ovary and colon (Philp et al, Cancer Research, 2001, 61_, 7426-7429).
  • activation of Class Ia PI3K contributes to tumourigenic events that occur upstream in signaling pathways, for example by way of ligand-dependent or ligand-independent activation of receptor tyrosine kinases, GPCR systems or integrins (Vara et al, Cancer Treatment Reviews, 2004, 30, 193-204).
  • upstream signaling pathways examples include over-expression of the receptor tyrosine kinase Erb2 in a variety of tumors leading to activation of PI3K-mediated pathways (Harari et al., Oncogene, 2000, 19, 6102-6114) and over-expression of the oncogene Ras (Kauffmann-Zeh et al., Nature, 1997, 385, 544-548).
  • Class Ia PBKs may contribute indirectly to tumourigenesis caused by various downstream signaling events.
  • loss of function of the PTEN tumor-suppressor phosphatase that catalyses conversion of PI(3,4,5)P3 back to PI(4,5)P2 is associated with a very broad range of tumors via deregulation of PBK-mediated production of PI(3,4,5)P3 (Simpson and Parsons, Exp. Cell Res., 2001, 264, 29-41).
  • augmentation of the effects of other PBK-mediated signaling events is believed to contribute to a variety of cancers, for example by activation of AKT (Nicholson and Andeson, Cellular Signaling, 2002, 14, 381-395).
  • PBK signaling is known to play an important role in mediating angiogenic events in endothelial cells in response to pro-angiogenic factors such as VEGF (abid et al., Arterioscler, Thromb. Vase. Biol., 2004,
  • PBK inhibitors are anticipated to provide therapeutic benefit via inhibition of tumor cell invasion and metastasis.
  • This invention relates to novel compounds of Formula (I):
  • Rl is a ring system containing 1 to 2 double bonds represented by Formula (II):
  • This invention also relates to a method of treating cancer, which comprises administering to a subject in need thereof an effective amount of a compound of Formula
  • This invention also relates to a method of treating one or more disease states selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, sperm motility, transplantation rejection, graft rejection and lung injuries, which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I).
  • Included in the present invention are methods of co-administering the present PB kinase inhibiting compounds with further active ingredients.
  • This invention relates to novel compounds of Formula (I). This invention also relates to novel compounds of Formula (I)(A):
  • Rl is represented by a formula selected from a group consisting of: formulas (III), (IV)
  • X is O, N or S
  • Y is O or S; each R2, R3, R4 and R5 is independently selected from: hydrogen, halogen, acyl, sulfonyl, amino, formyl, substituted amino, Cl-6alkyl, substituted Cl-6alkyl, C3-
  • This invention also relates to novel compounds of Formula (I)(B):
  • Rl is represented by a formula selected from a group consisting of: formulas (III) (IV), (V) and (VI):
  • This invention also relates to novel compounds of Formulas (I)(A) or (I)(B), wherein Rl, and R2 and R5 are defined as above; and n is 0;
  • R4 is hydrogen or amino; or a pharmaceutically acceptable salt thereof.
  • This invention also relates to novel compounds of Formulas (I)(A) or (I)(B), wherein X is N or O;
  • Rl, and R2 and R5 are otherwise defined as above; n is 0;
  • R4 is hydrogen or amino; or a pharmaceutically acceptable salt thereof.
  • This invention also relates to novel compounds of Formulas (I)(A) or (I)(B), wherein
  • R2 is selected from a group consisting of:
  • X is N or O
  • R5 is selected from a group consisting of: formyl, halogen, acyl, sulfonyl, amino, substituted amino, Cl-6alkyl, substituted Cl-6alkyl, C3-7cycloalkyl, substituted C3-
  • Rl is otherwise defined as above; n is O;
  • R4 is hydrogen or amino; or a pharmaceutically acceptable salt thereof.
  • This invention also relates to novel compounds of Formulas (I)(A) or (I)(B), wherein R2 is selected from a group consisting of:
  • Rl is a ring selected from a group consisting of: pyrazole, oxazole, thiadiazole, oxadiazole, isooxazole and isothiazole, optionally substituted with 1 to 2 substituentss, each of which is independently selected from a group consisting of: formyl, halogen, acyl, sulfonyl, amino, substituted amino, Cl-6alkyl, substituted Cl-6alkyl, C3-
  • R4 is hydrogen or amino; or a pharmaceutically acceptable salt thereof.
  • This invention also relates to novel compounds of Formulas (I)(A) or (I)(B), wherein R2 is selected from a group consisting of:
  • Rl is a pyrazole optionally substituted with 1 to 2 groups, each of which is independently selected from a group consisting of: formyl, halogen, acyl, sulfonyl, amino, substituted amino, Cl-6alkyl, substituted Cl-6alkyl, C3-7cycloalkyl, substituted C3-7cycloalkyl, C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cyano, hydroxyl and alkoxy; n is 0;
  • R4 is hydrogen or amino; or a pharmaceutically acceptable salt thereof.
  • This invention also relates to novel compounds of Formulas (I)(A) or (I)(B), wherein
  • R2 is selected from a group consisting of:
  • Rl is a pyrazole optionally substituted with 1 to 2 groups, each of which is independently selected from a group consisting of: formyl, halogen, sulfonyl, amino, substituted amino, Cl-6alkyl, substituted Cl-6alkyl, C3-7cycloalkyl, substituted C3-
  • This invention also relates to novel compounds of Formula (I)(C):
  • Rl is an aromatic ring system of formula (II):
  • X is C, O, N or S; each R2, R3, R4 and R5 is independently selected from: hydrogen, halogen, acyl, sulfonyl, amino, formyl, substituted amino, Cl-6alkyl, substituted Cl-6alkyl, C3- 7cycloalkyl, substituted C3-7cycloalkyl, C3-7heterocycloalkyl, substituted C3- 7heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, alkoxy, nitro, acyloxy, and aryloxy; n is 0-2; m is 0-3; two adjacent R5 groups may form an additional five or six-membered
  • This invention also relates to novel compounds of Formula (I)(D):
  • Rl is an aromatic ring system of formula (II):
  • X is C, O, N or S; each R2, R3 and R5 is independently selected from: hydrogen, halogen, acyl, sulfonyl, amino, formyl, substituted amino, Cl-6alkyl, substituted Cl-6alkyl, C3-7cycloalkyl, substituted C3-7cycloalkyl, C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, alkoxy, nitro, acyloxy, and aryloxy;
  • R4 is hydrogen or amino; n is 0-2; m is 0-3; two adjacent R5 groups may form an additional five or six-membered ring containing 0-2 hetero atoms, wherein said additional ring is optionally substituted with 1 to 2 substituents selected from a group consisting of: Cl-3alkyl, halogen, amino and alkoxy; or a pharmaceutically acceptable salt thereof; that when Rl is thiophene, R4 is not piperazine;
  • This invention also relates to novel compounds of Formula (I)(E):
  • Rl is an aromatic ring system of formula (II):
  • X is C, O, N or S; each R2, R4 and R5 is independently selected from: hydrogen, halogen, acyl, sulfonyl, amino, formyl, substituted amino, Cl-6alkyl, substituted Cl-6alkyl, C3-7cycloalkyl, substituted C3-7cycloalkyl, C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, alkoxy, nitro, acyloxy, and aryloxy;
  • R3 is selected from a group consisting of: hydrogen, halogen, acyl, amino, formyl, substituted amino, Cl-6alkyl, substituted Cl-6alkyl, C3-7cycloalkyl, substituted C3- 7cycloalkyl; n is 0-2; m is 0-3; two adjacent R5 groups may form an additional five or six-membered ring containing
  • This invention also relates to the following compounds:
  • This invention also relates to a method of treating cancer, which comprises coadministering to a subject in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof; and at least one anti-neoplastic agent such as one selected from the group consisting of: anti-microtubule agents, plantinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I hinibitors, hormones and hormonal anlogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, and cell cycle signaling inhibitors.
  • anti-neoplastic agent such as one selected from the group consisting of: anti-microtubule agents, plantinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I hinibitors, hormones and hormonal anlogues, signal transduction pathway
  • This invention also relates to a method of treating cancer, which comprises co- administering to a subject in need thereof an effective amount of a compound of Formula
  • receptor tyrosine kinase inhibitor such as one selected from the group consisting of: receptor tyrosine kinase inhibitor, non-receptor tyrosine kinase inhibitor, S ⁇ 2/S ⁇ 3 domain blocker, serine/threonine kinase inhibitor, phosphotidyl inositol-3 kinase inhibitor, myo-inositol singaling inhibitor, and Ras oncogene inhibitor.
  • the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • substituted amino as used herein, is meant -NR30R40 wherein each R30 and R40 is independently selected from a group including hydrogen, Cl-6alkyl, acyl, sulfonyl, C3-C7cycloalkyl, wherein at least one of R30 and R40 is not hydrogen.
  • acyl as used herein, unless otherwise defined, is meant
  • sulfonyl as used herein is meant -SO2R35, wherein R35 is Cl- ⁇ alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl.
  • aryl as used herein, unless otherwise defined, is meant aromatic, hydrocarbon, ring system.
  • the ring system may be monocyclic or fused polycyclic (e.g. bicyclic, tricyclic, etc.).
  • the monocyclic aryl ring is C5-C10, or
  • a C6 ring system i.e. a phenyl ring is a suitable aryl group.
  • the polycyclic ring is a bicyclic aryl group, where suitable bicyclic aryl groups are C8-C12, or C9-C10.
  • a naphthyl ring, which has 10 carbon atoms, is a suitable polycyclic aryl group.
  • heteroaryl an aromatic ring system containing carbon(s) and at least one heteroatom.
  • Heteroaryl may be monocyclic or polycyclic.
  • a monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 10 hetero atoms.
  • a polycyclic heteroaryl ring may contain fused, spiro or bridged ring junctions, for example, bicyclic heteroaryl is a polycyclic heteroaryl.
  • Bicyclic heteroaryl rings may contain from 8 to 12 member atoms.
  • Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (carbons and heteroatoms).
  • heteroaryl groups include but are not limited to: benzofuran, benzothiophene, furan, imidazole, indole, isothiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinoline, quinazoline, quinoxaline, thiazole, and thiophene.
  • monocyclic heteroaryl as used herein, unless otherwise defined, is meant a monocyclic heteroaryl ring containing 1-5 carbon atoms and 1-4 hetero atoms.
  • alkylcarboxy as used herein, unless otherwise defined, is meant -
  • alkoxy as used herein is meant -O(alkyl) including -OCH3, - OCH 2 CH 3 and -OC(CH3)3 where alkyl is as described herein.
  • alkylthio as used herein is meant -S(alkyl) including -SCH3, - SCH 2 CH 3 where where alkyl is as described herein.
  • cycloalkyl as used herein unless otherwise defined, is meant a nonaromatic, unsaturated or saturated, cyclic or polycyclic C3-C ⁇ 2-
  • cycloalkyl and substituted cycloalkyl substituents as used herein include: cyclohexyl, aminocyclohexyl, cyclobutyl, aminocyclobutyl, 4-hydroxy- cyclohexyl, 2-ethylcyclohexyl, propyW-methoxycyclohexyl, 4-methoxycyclohexyl, A- carboxycyclohexyl, cyclopropyl, aminocyclopentyl, and cyclopentyl.
  • heterocycloalkyl as used herein is meant a non-aromatic, unsaturated or saturated, monocyclic or polycyclic, heterocyclic ring containing at least one carbon and at least one heteroatom.
  • exemplary monocyclic heterocyclic rings include: piperidine, piperazine, pyrrolidine, and morpholine.
  • exemplary polycyclic heterocyclic rings include quinuclidine.
  • substituted is meant that the subject chemical moiety has one to five substituents, suitably from one to three, selected from the group consisting of: hydrogen, halogen, Cl-C6alkyl, amino, trifluoromethyl, - (CH 2 ) n COOH, C3-C7cycloalkyl, substituted amino, aryl, heteroaryl, arylalkyl, arylcycloalkyl, heteroarylalkyl, heterocycloalkyl, cyano, hydroxyl, alkoxy, alkylthio, aryloxy, acyloxy, acyl, acylamino, arylamino, nitro, oxo, -CO2R50, -SO2R70, -NR50SO2R70, NR 5 oC(0)R 75 and -CONR 55 R 60 , wherein R50 and R55 are each independently selected from: hydrogen, alkyl, and C3-
  • arylamino and “aryloxy” is meant that the subject chemical moiety has one to five substituents, suitably from one to three, selected from the group consisting of: hydrogen, Cl-C6alkyl, halogen, trifluoromethyl, -(CH 2 ) n COOH, amino, substituted amino, cyano, hydroxyl, alkoxy, alkylthio, aryloxy, acyloxy, acyl, acylamino, and nitro, n is 0-6.
  • acyloxy as used herein is meant -OC(O)alkyl where alkyl is as described herein.
  • acyloxy substituents as used herein include: -OC(O)CH3, - OC(O)CH(CH 3 ) 2 and -OC(O)(CH 2 )3CH 3 .
  • acylamino as used herein is meant -N(H)C(O)alkyl, -
  • substituents selected from a group consisting of: halogen, Cl-3alkyl, alkoxy, amino and acyl.
  • Examples of N-acylamino substituents as used herein include: -N(H)C(O)CH 3 , -N(H)C(O)CH(CH 3 ) 2 and -N(H)C(O)(CH 2 )3CH 3 .
  • aryloxy as used herein is meant -O(aryl), -O(substituted aryl), - O(heteroaryl) or -O(substituted heteroaryl).
  • arylamino as used herein is meant -NRgo(aryl), -NRgo(substituted aryl), -NRgo(heteroaryl) or -NRgo(substituted heteroaryl), wherein R80 is H, Cl-6alkyl or C3-C7cycloalkyl.
  • heteroatom oxygen, nitrogen or sulfur.
  • halogen as used herein is meant a substituent selected from bromide, iodide, chloride and fluoride.
  • alkyl and derivatives thereof and in all carbon chains as used herein, including alkyl chains defined by the term “-(CH 2 V, “-(CH 2 ) m “ and the like, is meant a linear or branched, saturated or unsaturated hydrocarbon chain, and unless otherwise defined, the carbon chain will contain from 1 to 12 carbon atoms.
  • substituted alkyl an alkyl group substituted with one to six substituents selected from the group consisting of: halogen, trifluoromethyl, alkylcarboxy, amino, substituted amino, cyano, hydroxyl, alkoxy, alkylthio, aryloxy, acyloxy, acyl, acylamino, carbamate, urea, sulfonyl, C3-7cycloheteralkyl, C3-7cycloalkyl and nitro.
  • alkyl and substituted alkyl substituents as used herein include: -CH 3 , -CH 2 -CH 3 , -CH 2 -CH 2 -CH 3 , -CH(CH 3 ) 2 , -CH 2 -CH 2 -C(CH 3 ) 3 , -CH 2 -CF 3 , C ⁇ C-C(CH 3 ) 3 , -C ⁇ C-CH 2 -OH, cyclopropylmethyl, -CH 2 -C(CH 3 ) 2 -CH 2 -NH 2 , C ⁇ C-C 6 H 5 , -C ⁇ C-C(CH 3 ) 2 -OH, -CH 2 -CH(OH)-CH(OH)-CH(OH)-CH(OH)-CH(OH)-CH 2 -OH, piperidinylmethyl, methoxyphenylethyl, -C(CH 3 ) 3 , -(CH 2 ) 3 -CH 3 , -CH 2
  • prophylatic therapy is meant the institution of measures to protect a person from a disease to which he or she has been, or may be, exposed. Also called preventive treatment.
  • co-administering and derivatives thereof as used herein is meant either simultaneous administration or any manner of separate sequential administration of a PB kinase inhibiting compound, as described herein, and a further active ingredient or ingredients.
  • further active ingredient or ingredients includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of treatment.
  • the compounds are administered in a close time proximity to each other.
  • the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.
  • Such isomers include: enantiomers, tautomers, rotamers.
  • enantiomers tautomers
  • rotamers In formulas where a "dotted" bond is drawn between two atoms, it is meant that such bond can be either single or double bond.
  • a ring system containing such bonds can be aromatic or non-aromatic.
  • Certain compounds described herein may contain one or more chiral atoms, or may otherwise be capable of existing as two enantiomers, or two or more diastereoisomers.
  • the compounds of this invention include mixtures of enantiomers/diastereoisomers as well as purified enantiomers/diastereoisomers or enantiomerically/diastereoisomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds represented by formula I or II above as well as any wholly or partially equilibrated mixtures thereof. The present invention also covers the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted.
  • tautomer is an oxo substituent in place of a hydroxy substituent. Also, as stated above, it is understood that all tautomers and mixtures of tautomers are included within the scope of the compounds of Formula I or II.
  • esters can be employed, for example methyl, ethyl, pivaloyloxymethyl, and the like for -COOH, and acetate maleate and the like for -OH, and those esters known in the art for modifying solubility or hydrolysis characteristics, for use as sustained release or prodrug formulations. It has now been found that compounds of the present invention are inhibitors of the Phosphatoinositides 3-kinases (PBKs).
  • PBKs Phosphatoinositides 3-kinases
  • PBK phosphatoinositides 3-kinase
  • the compounds of the present invention are therefore useful in the treatment of autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries.
  • the compounds of Formula (I) are useful as medicaments in particular for the treatment of autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries.
  • the compounds of Formula (I) are inhibitors of one or more phosphatoinositides 3-kinases (PBKs), suitably, Phosphatoinositides 3-kinase ⁇ (PBK ⁇ ), Phosphatoinositides 3-kinase ⁇ (PBK ⁇ ), Phosphatoinositides 3-kinase ⁇ (PBK ⁇ ), or Phosphatoinositides 3-kinase ⁇ (PBK ⁇ ).
  • PBKs phosphatoinositides 3-kinases
  • Compounds according to Formula (I) are suitable for the modulation, notably the inhibition of the activity of phosphatoinositides 3-kinases (PBK), suitably phosphatoinositides 3-kinase (PBK ⁇ ). Therefore the compounds of the present invention are also useful for the treatment of disorders which are mediated by PBKs. Said treatment involves the modulation - notably the inhibition or the down regulation - of the phosphatoinositides 3-kinases.
  • the compounds of the present invention are used for the preparation of a medicament for the treatment of a disorder selected from multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosis, inflammatory bowel disease, lung inflammation, thrombosis or brain infection/inflammation, such as meningitis or encephalitis, Alzheimer's disease, Huntington's disease, CNS trauma, stroke or ischemic conditions, cardiovascular diseases such as athero-sclerosis, heart hypertrophy, cardiac myocyte dysfunction, elevated blood pressure or vasoconstriction.
  • a disorder selected from multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosis, inflammatory bowel disease, lung inflammation, thrombosis or brain infection/inflammation, such as meningitis or encephalitis, Alzheimer's disease, Huntington's disease, CNS trauma, stroke or ischemic conditions, cardiovascular diseases such as at
  • the compounds of Formula (I) are useful for the treatment of autoimmune diseases or inflammatory diseases such as multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosis, inflammatory bowel disease, lung inflammation, thrombosis or brain infection/inflammation such as meningitis or encephalitis.
  • autoimmune diseases or inflammatory diseases such as multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosis, inflammatory bowel disease, lung inflammation, thrombosis or brain infection/inflammation such as meningitis or encephalitis.
  • the compounds of Formula (I) are useful for the treatment of neurodegenerative diseases including multiple sclerosis, Alzheimer's disease, Huntington's disease, CNS trauma, stroke or ischemic conditions.
  • the compounds of Formula (I) are useful for the treatment of cardiovascular diseases such as atherosclerosis, heart hypertrophy, cardiac myocyte dysfunction, elevated blood pressure or vasoconstriction.
  • the compounds of Formula (I) are useful for the treatment of chronic obstructive pulmonary disease, anaphylactic shock fibrosis, psoriasis, allergic diseases, asthma, stroke, ischemic conditions, ischemia-reperfusion, platelets aggregation/activation, skeletal muscle atrophy/hypertrophy, leukocyte recruitment in cancer tissue, angiogenesis, invasion metastasis, in particular melanoma, Karposi's sarcoma, acute and chronic bacterial and virual infections, sepsis, transplantation rejection, graft rejection, glomerulo sclerosis, glomerulo nephritis, progressive renal fibrosis, endothelial and epithelial injuries in the lung, and lung airway inflammation.
  • the pharmaceutically active compounds of the present invention are active as PB kinase inhibitors, particularly the compounds that inhibit PBK ⁇ , either selectively or in conjunction with one or more of PBK ⁇ , PBK ⁇ , or PBK ⁇ , they exhibit therapeutic utility in treating cancer.
  • the invention relates to a method of treating cancer in a mammal, including a human, wherein the cancer is selected from: brain (gliomas), glioblastomas, leukemias, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma, osteosarcoma, giant cell tumor of bone and thyroid.
  • brain gliomas
  • glioblastomas leukemias
  • Bannayan-Zonana syndrome Cowden disease
  • Lhermitte-Duclos disease breast
  • inflammatory breast cancer Wilm's tumor
  • Ewing's sarcoma Rhabdomyosarcoma
  • the invention relates to a method of treating cancer in a mammal, including a human, wherein the cancer is selected from: Lymphoblastic T cell leukemia,
  • Chronic myelogenous leukemia Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, Acute megakaryocyte leukemia, promyelocytic leukemia and Erythroleukemia.
  • the invention relates to a method of treating cancer in a mammal, including a human, wherein the cancer is selected from: malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma and follicular lymphoma.
  • the invention relates to a method of treating cancer in a mammal, including a human, wherein the cancer is selected from: neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer.
  • the cancer is selected from: neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer.
  • a compound of Formula (I) When a compound of Formula (I) is administered for the treatment of cancer, the term “co-administering" and derivatives thereof as used herein is meant either simultaneous administration or any manner of separate sequential administration of a PB kinase inhibiting compound, as described herein, and a further active ingredient or ingredients, known to be useful in the treatment of cancer, including chemotherapy and radiation treatment.
  • the term further active ingredient or ingredients, as used herein includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of treatment for cancer.
  • the compounds are administered in a close time proximity to each other.
  • the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.
  • any anti-neoplastic agent that has activity versus a susceptible tumor being treated may be co-administered in the treatment of cancer in the present invention.
  • examples of such agents can be found in Cancer Principles and Practice f Oncology by V. T. Devita and S. Hellman (editors), 6 th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers.
  • a person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved.
  • Typical anti-neoplastic agents useful in the present invention include, but are not limited to, anti-microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclins, actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and anti- folate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; and cell cycle signaling inhibitors.
  • anti-microtubule agents such as diterpenoids and vinca alkaloids
  • Anti-microtubule or anti-mitotic agents are phase specific agents active against the microtubules of tumor cells during M or the mitosis phase of the cell cycle.
  • anti-microtubule agents include, but are not limited to, diterpenoids and vinca alkaloids.
  • Diterpenoids which are derived from natural sources, are phase specific anti - cancer agents that operate at the G 2 ZM phases of the cell cycle. It is believed that the diterpenoids stabilize the ⁇ -tubulin subunit of the microtubules, by binding with this protein. Disassembly of the protein appears then to be inhibited with mitosis being arrested and cell death following. Examples of diterpenoids include, but are not limited to, paclitaxel and its analog docetaxel.
  • Paclitaxel 5 ⁇ ,20-epoxy-l,2 ⁇ ,4,7 ⁇ ,10 ⁇ ,13 ⁇ -hexa-hydroxytax-l l-en-9-one 4,10- diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine; is a natural diterpene product isolated from the Pacific yew tree Taxus brevifolia and is commercially available as an injectable solution TAXOL®. It is a member of the taxane family of terpenes. It was first isolated in 1971 by Wani et al. J. Am. Chem, Soc, 93:2325. 1971), who characterized its structure by chemical and X-ray crystallographic methods.
  • Paclitaxel has been approved for clinical use in the treatment of refractory ovarian cancer in the United States (Markman et al., Yale Journal of Biology and Medicine, 64:583, 1991; McGuire et al., Ann. Intern, Med., 111 :273,1989) and for the treatment of breast cancer (Holmes et al., J. Nat. Cancer Inst., 83:1797,1991.) It is a potential candidate for treatment of neoplasms in the skin (Einzig et. al., Proc. Am. Soc. Clin. Oncol., 20:46) and head and neck carcinomas (Forastire et. al., Sem. Oncol., 20:56, 1990).
  • the compound also shows potential for the treatment of polycystic kidney disease (Woo et. al., Nature, 368:750. 1994), lung cancer and malaria.
  • Treatment of patients with paclitaxel results in bone marrow suppression (multiple cell lineages, Ignoff, R.J. et. al, Cancer Chemotherapy Pocket Guid ⁇ i 1998) related to the duration of dosing above a threshold concentration (5OnM) (Kearns, CM. et. al., Seminars in Oncology, 3(6) p.16-23, 1995).
  • Docetaxel is indicated for the treatment of breast cancer.
  • Docetaxel is a semisynthetic derivative of paclitaxel q.v., prepared using a natural precursor, 10-deacetyl-baccatin III, extracted from the needle of the European Yew tree.
  • the dose limiting toxicity of docetaxel is neutropenia.
  • Vinca alkaloids are phase specific anti-neoplastic agents derived from the periwinkle plant. Vinca alkaloids act at the M phase (mitosis) of the cell cycle by binding specifically to tubulin. Consequently, the bound tubulin molecule is unable to polymerize into microtubules. Mitosis is believed to be arrested in metaphase with cell death following. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, and vinorelbine.
  • Vinblastine vincaleukoblastine sulfate
  • VELBAN® an injectable solution.
  • Myelosuppression is the dose limiting side effect of vinblastine.
  • Vincristine vincaleukoblastine, 22-oxo-, sulfate
  • ONCOVIN® an injectable solution.
  • Vincristine is indicated for the treatment of acute leukemias and has also found use in treatment regimens for Hodgkin's and non-Hodgkin's malignant lymphomas.
  • Alopecia and neurologic effects are the most common side effect of vincristine and to a lesser extent myelosupression and gastrointestinal mucositis effects occur.
  • Vinorelbine 3',4'-didehydro -4'-deoxy-C'-norvincaleukoblastine [R-(R*,R*)-2,3- dihydroxybutanedioate (l :2)(salt)], commercially available as an injectable solution of vinorelbine tartrate (NAVELBINE®), is a semisynthetic vinca alkaloid.
  • Vinorelbine is indicated as a single agent or in combination with other chemotherapeutic agents, such as cisplatin, in the treatment of various solid tumors, particularly non-small cell lung, advanced breast, and hormone refractory prostate cancers. Myelosuppression is the most common dose limiting side effect of vinorelbine.
  • Platinum coordination complexes are non-phase specific anti-cancer agents, which are interactive with DNA.
  • the platinum complexes enter tumor cells, undergo, aquation and form intra- and interstrand crosslinks with DNA causing adverse biological effects to the tumor.
  • Examples of platinum coordination complexes include, but are not limited to, cisplatin and carboplatin.
  • Cisplatin cis-diamminedichloroplatinum
  • PLATINOL® an injectable solution.
  • Cisplatin is primarily indicated in the treatment of metastatic testicular and ovarian cancer and advanced bladder cancer.
  • the primary dose limiting side effects of cisplatin are nephrotoxicity, which may be controlled by hydration and diuresis, and ototoxicity.
  • Carboplatin platinum, diammine [l,l-cyclobutane-dicarboxylate(2-)-O,O'], is commercially available as PARAPLATIN® as an injectable solution.
  • Carboplatin is primarily indicated in the first and second line treatment of advanced ovarian carcinoma. Bone marrow suppression is the dose limiting toxicity of carboplatin.
  • Alkylating agents are non-phase anti-cancer specific agents and strong electrophiles. Typically, alkylating agents form covalent linkages, by alkylation, to DNA through nucleophilic moieties of the DNA molecule such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazole groups. Such alkylation disrupts nucleic acid function leading to cell death.
  • alkylating agents include, but are not limited to, nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; and triazenes such as dacarbazine.
  • Cyclophosphamide 2-[bis(2-chloroethyl)amino]tetrahydro-2H- 1 ,3 ,2- oxazaphosphorine 2-oxide monohydrate, is commercially available as an injectable solution or tablets as CYTOXAN®. Cyclophosphamide is indicated as a single agent or in combination with other chemotherapeutic agents, in the treatment of malignant lymphomas, multiple myeloma, and leukemias. Alopecia, nausea, vomiting and leukopenia are the most common dose limiting side effects of cyclophosphamide.
  • Melphalan 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commercially available as an injectable solution or tablets as ALKERAN®. Melphalan is indicated for the palliative treatment of multiple myeloma and non-resectable epithelial carcinoma of the ovary. Bone marrow suppression is the most common dose limiting side effect of melphalan. Chlorambucil, 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, is commercially available as LEUKERAN® tablets.
  • Chlorambucil is indicated for the palliative treatment of chronic lymphatic leukemia, and malignant lymphomas such as lymphosarcoma, giant follicular lymphoma, and Hodgkin's disease. Bone marrow suppression is the most common dose limiting side effect of chlorambucil. Busulfan, 1 ,4-butanediol dimethanesulfonate, is commercially available as
  • Busulfan is indicated for the palliative treatment of chronic myelogenous leukemia. Bone marrow suppression is the most common dose limiting side effects of busulfan.
  • Carmustine, l,3-[bis(2-chloroethyl)-l -nitrosourea, is commercially available as single vials of lyophilized material as BiCNU®.
  • Carmustine is indicated for the palliative treatment as a single agent or in combination with other agents for brain tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphomas. Delayed myelosuppression is the most common dose limiting side effects of carmustine.
  • dacarbazine 5-(3,3-dimethyl-l-triazeno)-imidazole-4-carboxamide, is commercially available as single vials of material as DTIC-Dome®.
  • dacarbazine is indicated for the treatment of metastatic malignant melanoma and in combination with other agents for the second line treatment of Hodgkin's Disease. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dacarbazine.
  • Antibiotic anti-neoplasties are non-phase specific agents, which bind or intercalate with DNA. Typically, such action results in stable DNA complexes or strand breakage, which disrupts ordinary function of the nucleic acids leading to cell death.
  • antibiotic anti-neoplastic agents include, but are not limited to, actinomycins such as dactinomycin, anthrocyclins such as daunorubicin and doxorubicin; and bleomycins.
  • Dactinomycin also know as Actinomycin D, is commercially available in injectable form as COSMEGEN®. Dactinomycin is indicated for the treatment of Wilm's tumor and rhabdomyosarcoma. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dactinomycin.
  • Daunorubicin (8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy- ⁇ -L-lyxo- hexopyranosyl)oxy]-7,8,9, 10-tetrahydro-6,8, 11 -trihydroxy- 1 -methoxy-5 , 12 naphthacenedione hydrochloride, is commercially available as a liposomal injectable form as DAUNOXOME® or as an injectable as CERUBIDINE®. Daunorubicin is indicated for remission induction in the treatment of acute nonlymphocytic leukemia and advanced HIV associated Kaposi's sarcoma.
  • Doxorubicin is primarily indicated for the treatment of acute lymphoblastic leukemia and acute myeloblastic leukemia, but is also a useful component in the treatment of some solid tumors and lymphomas. Myelosuppression is the most common dose limiting side effect of doxorubicin.
  • Bleomycin a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of Streptomyces verticillus, is commercially available as BLENOXANE®. Bleomycin is indicated as a palliative treatment, as a single agent or in combination with other agents, of squamous cell carcinoma, lymphomas, and testicular carcinomas. Pulmonary and cutaneous toxicities are the most common dose limiting side effects of bleomycin.
  • Topoisomerase II inhibitors include, but are not limited to, epipodophyllotoxins.
  • Epipodophyllotoxins are phase specific anti-neoplastic agents derived from the mandrake plant. Epipodophyllotoxins typically affect cells in the S and G 2 phases of the cell cycle by forming a ternary complex with topoisomerase II and DNA causing DNA strand breaks. The strand breaks accumulate and cell death follows.
  • Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide.
  • Etoposide 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R )-ethylidene- ⁇ -D- glucopyranoside]
  • VePESID® an injectable solution or capsules
  • VP-16 an injectable solution or capsules
  • Etoposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of testicular and non-small cell lung cancers. Myelosuppression is the most common side effect of etoposide. The incidence of leucopenia tends to be more severe than thrombocytopenia.
  • Teniposide 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R )-thenylidene- ⁇ -D- glucopyranoside], is commercially available as an injectable solution as VUM ON® and is commonly known as VM-26.
  • Teniposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia in children. Myelosuppression is the most common dose limiting side effect of teniposide.
  • Teniposide can induce both leucopenia and thrombocytopenia.
  • Antimetabolite neoplastic agents are phase specific anti-neoplastic agents that act at
  • S phase DNA synthesis of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis. Consequently, S phase does not proceed and cell death follows.
  • antimetabolite anti-neoplastic agents include, but are not limited to, fluorouracil, methotrexate, cytarabine, mecaptopurine, thioguanine, and gemcitabine.
  • 5 -fluorouracil 5-fluoro-2,4- (1H,3H) pyrimidinedione
  • fluorouracil is commercially available as fluorouracil.
  • Administration of 5 -fluorouracil leads to inhibition of thymidylate synthesis and is also incorporated into both RNA and DNA. The result typically is cell death.
  • 5 -fluorouracil is indicated as a single agent or in combination with other chemotherapy agents in the treatment of carcinomas of the breast, colon, rectum, stomach and pancreas. Myelosuppression and mucositis are dose limiting side effects of 5- fluorouracil.
  • Other fluoropyrimidine analogs include 5-fluoro deoxyuridine (floxuridine) and 5-fluorodeoxyuridine monophosphate.
  • Cytarabine 4-amino-l- ⁇ -D-arabinofuranosyl-2 (lH)-pyrimidinone, is commercially available as CYTOSAR-U® and is commonly known as Ara-C. It is believed that cytarabine exhibits cell phase specificity at S-phase by inhibiting DNA chain elongation by terminal incorporation of cytarabine into the growing DNA chain. Cytarabine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Other cytidine analogs include 5-azacytidine and 2',2'- difluorodeoxycytidine (gemcitabine).
  • Cytarabine induces leucopenia, thrombocytopenia, and mucositis.
  • Mercaptopurine 1 ,7-dihydro-6H-purine-6-thione monohydrate, is commercially available as PURINETHOL®.
  • Mercaptopurine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism.
  • Mercaptopurine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Myelosuppression and gastrointestinal mucositis are expected side effects of mercaptopurine at high doses.
  • a useful mercaptopurine analog is azathioprine.
  • Thioguanine 2-amino-l,7-dihydro-6H-purine-6-thione, is commercially available as TABLOID®.
  • Thioguanine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism.
  • Thioguanine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia.
  • Myelosuppression including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of thioguanine administration. However, gastrointestinal side effects occur and can be dose limiting.
  • Other purine analogs include pentostatin, erythrohydroxynonyladenine, fludarabine phosphate, and cladribine.
  • Gemcitabine 2'-deoxy-2', 2'-difluorocytidine monohydrochloride ( ⁇ -isomer), is commercially available as GEMZ AR®. Gemcitabine exhibits cell phase specificity at S- phase and by blocking progression of cells through the Gl /S boundary. Gemcitabine is indicated in combination with cisplatin in the treatment of locally advanced non-small cell lung cancer and alone in the treatment of locally advanced pancreatic cancer. Myelosuppression, including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of gemcitabine administration.
  • Methotrexate N-[4[[(2,4-diamino-6-pteridinyl) methyljmethylamino] benzoyl]-L- glutamic acid, is commercially available as methotrexate sodium. Methotrexate exhibits cell phase effects specifically at S-phase by inhibiting DNA synthesis, repair or replication through the inhibition of dyhydrofolic acid reductase which is required for synthesis of purine nucleotides and thymidylate.
  • Methotrexate is indicated as a single agent or in combination with other chemotherapy agents in the treatment of choriocarcinoma, meningeal leukemia, non-Hodgkin's lymphoma, and carcinomas of the breast, head, neck, ovary and bladder.
  • Myelosuppression (leucopenia, thrombocytopenia, and anemia) and mucositis are expected side effect of methotrexate administration.
  • Camptothecins including, camptothecin and camptothecin derivatives are available or under development as Topoisomerase I inhibitors. Camptothecins cytotoxic activity is believed to be related to its Topoisomerase I inhibitory activity. Examples of camptothecins include, but are not limited to irinotecan, topotecan, and the various optical forms of 7-(4-methylpiperazino-methylene)-10,l l-ethylenedioxy-20-camptothecin described below.
  • Irinotecan HCl, (4S)-4,l l-diethyl-4-hydroxy-9-[(4-piperidinopiperidino) carbonyloxy]-lH-pyrano[3',4',6,7]indolizino[l,2-b]quinoline-3,14(4H,12H)-dione hydrochloride, is commercially available as the injectable solution CAMPTOSAR®.
  • Irinotecan is a derivative of camptothecin which binds, along with its active metabolite SN-38, to the topoisomerase I - DNA complex. It is believed that cytotoxicity occurs as a result of irreparable double strand breaks caused by interaction of the topoisomerase I : DNA : irintecan or SN-38 ternary complex with replication enzymes. Irinotecan is indicated for treatment of metastatic cancer of the colon or rectum. The dose limiting side effects of irinotecan HCl are myelosuppression, including neutropenia, and GI effects, including diarrhea.
  • Topotecan HCl (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-lH- pyrano [3 ' ,4 ' ,6,7]indolizino [ 1 ,2-b] quinoline-3 , 14-(4H, 12H)-dione monohydrochloride, is commercially available as the injectable solution HYCAMTIN®.
  • Topotecan is a derivative of camptothecin which binds to the topoisomerase I - DNA complex and prevents religation of singles strand breaks caused by Topoisomerase I in response to torsional strain of the DNA molecule.
  • Topotecan is indicated for second line treatment of metastatic carcinoma of the ovary and small cell lung cancer.
  • the dose limiting side effect of topotecan HCl is myelosuppression, primarily neutropenia.
  • camptothecin derivative of formula A following, currently under development, including the racemic mixture (R, S) form as well as the R and S enantiomers:
  • Hormones and hormonal analogues are useful compounds for treating cancers in which there is a relationship between the hormone(s) and growth or lack of growth of the cancer.
  • hormones and hormonal analogues useful in cancer treatment include, but are not limited to, adrenocorticosteroids such as prednisone and prednisolone which are useful in the treatment of malignant lymphoma and acute leukemia in children ; aminoglutethimide and other aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane useful in the treatment of adrenocortical carcinoma and hormone dependent breast carcinoma containing estrogen receptors; progestrins such as megestrol acetate useful in the treatment of hormone dependent breast cancer and endometrial carcinoma; estrogens, androgens, and anti-androgens such as flutamide, nilutamide, bicalutamide, cyproterone acetate and 5 ⁇ -reductases such as
  • GnRH gonadotropin-releasing hormone
  • LH leutinizing hormone
  • FSH follicle stimulating hormone
  • Signal transduction pathway inhibitors are those inhibitors, which block or inhibit a chemical process which evokes an intracellular change. As used herein this change is cell proliferation or differentiation.
  • Signal tranduction inhibitors useful in the present invention include inhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases, SH2/SH3domain blockers, serine/threonine kinases, phosphotidyl inositol-3 kinases, myoinositol signaling, and Ras oncogenes.
  • protein tyrosine kinases catalyse the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth.
  • protein tyrosine kinases can be broadly classified as receptor or non-receptor kinases.
  • Receptor tyrosine kinases are transmembrane proteins having an extracellular ligand binding domain, a transmembrane domain, and a tyrosine kinase domain. Receptor tyrosine kinases are involved in the regulation of cell growth and are generally termed growth factor receptors. Inappropriate or uncontrolled activation of many of these kinases, i.e. aberrant kinase growth factor receptor activity, for example by over-expression or mutation, has been shown to result in uncontrolled cell growth. Accordingly, the aberrant activity of such kinases has been linked to malignant tissue growth. Consequently, inhibitors of such kinases could provide cancer treatment methods.
  • Growth factor receptors include, for example, epidermal growth factor receptor (EGFr), platelet derived growth factor receptor (PDGFr), erbB2, erbB4, vascular endothelial growth factor receptor (VEGFr), tyrosine kinase with immunoglobulin-like and epidermal growth factor homology domains (TIE-2), insulin growth factor -I (IGFI) receptor, macrophage colony stimulating factor (cfms), BTK, ckit, cmet, fibroblast growth factor (FGF) receptors, Trk receptors (TrkA, TrkB, and TrkC), ephrin (eph) receptors, and the RET protooncogene.
  • EGFr epidermal growth factor receptor
  • PDGFr platelet derived growth factor receptor
  • erbB2 erbB4
  • VEGFr vascular endothelial growth factor receptor
  • TIE-2 vascular endothelial growth factor receptor
  • TIE-2 t
  • inhibitors of growth receptors include ligand antagonists, antibodies, tyrosine kinase inhibitors and anti-sense oligonucleotides.
  • Growth factor receptors and agents that inhibit growth factor receptor function are described, for instance, in Kath, John C, Exp. Opin. Ther. Patents (2000) 10(6):803-818; Shawver et al DDT VoI 2, No. 2 February 1997; and Lofts, F. J. et al, "Growth factor receptors as targets", New Molecular Targets for Cancer Chemotherapy, ed. Workman, Paul and Kerr, David, CRC press 1994, London.
  • Non-receptor tyrosine kinases which are not growth factor receptor kinases are termed nonreceptor tyrosine kinases.
  • Non-receptor tyrosine kinases useful in the present invention include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (Focal adhesion kinase), Brutons tyrosine kinase, and Bcr-Abl.
  • Such nonreceptor kinases and agents which inhibit non-receptor tyrosine kinase function are described in Sinh, S. and Corey, S. J., (1999) Journal of Hematotherapy and Stem Cell Research 8 (5): 465 - 80; and Bolen, J.B., Brugge, J.S., (1997) Annual review of
  • SH2/SH3 domain blockers are agents that disrupt SH2 or SH3 domain binding in a variety of enzymes or adaptor proteins including, PI3-K p85 subunit, Src family kinases, adaptor molecules (She, Crk, Nek, Grb2) and Ras-GAP.
  • SH2/SH3 domains as targets for anti-cancer drugs are discussed in Smithgall, T. E. (1995), Journal of Pharmacological and
  • Inhibitors of Serine/Threonine Kinases including MAP kinase cascade blockers which include blockers of Raf kinases (rafk), Mitogen or Extracellular Regulated Kinase (MEKs), and Extracellular Regulated Kinases (ERKs); and Protein kinase C family member blockers including blockers of PKCs (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta).
  • IkB kinase family IKKa, IKKb
  • PKB family kinases AKT kinase family members
  • TGF beta receptor kinases TGF beta receptor kinases.
  • Serine/Threonine kinases and inhibitors thereof are described in Yamamoto, T., Taya, S., Kaibuchi, K., (1999), Journal of Biochemistry. 126 (5) 799-803; Brodt, P, Samani, A., and Navab, R. (2000), Biochemical
  • Patent No. 6,268,391 and Martinez-Iacaci, L., et al, Int. J. Cancer (2000), 88(1), 44-52.
  • Inhibitors of Phosphotidyl inositol-3 Kinase family members including blockers of PI3- kinase, ATM, DNA-PK, and Ku are also useful in the present invention.
  • Such kinases are discussed in Abraham, R.T. (1996), Current Opinion in Immunology. 8 (3) 412-8; Canman, C.E., Lim, D.S. (1998), Oncogene 17 (25) 3301-3308; Jackson, S.P. (1997), International Journal of Biochemistry and Cell Biology. 29 (7):935-8; and Zhong, H. et al, Cancer res, (2000) 60(6), 1541-1545.
  • Myo-inositol signaling inhibitors such as phospho lipase C blockers and Myoinositol analogues.
  • signal inhibitors are described in Powis, G., and Kozikowski A., (1994) New Molecular Targets for Cancer Chemotherapy ed., Paul Workman and David Kerr, CRC press 1994, London.
  • Ras Oncogene Another group of signal transduction pathway inhibitors are inhibitors of Ras Oncogene.
  • Such inhibitors include inhibitors of farnesyltransferase, geranyl-geranyl transferase, and CAAX proteases as well as anti-sense oligonucleotides, ribozymes and immunotherapy.
  • Such inhibitors have been shown to block ras activation in cells containing wild type mutant ras , thereby acting as antiproliferation agents.
  • Ras oncogene inhibition is discussed in Scharovsky, O. G., Rozados, V.R., Gervasoni, S.I. Matar, P. (2000), Journal of Biomedical Science. 7(4) 292-8; Ashby, M.N. (1998), Current Opinion in Lipidology. 9 (2) 99 - 102; and BioChim. Biophys. Acta, (19899) 1423(3): 19-30.
  • antibody antagonists to receptor kinase ligand binding may also serve as signal transduction inhibitors.
  • This group of signal transduction pathway inhibitors includes the use of humanized antibodies to the extracellular ligand binding domain of receptor tyrosine kinases.
  • Imclone C225 EGFR specific antibody see Green, M. C. et al, Monoclonal Antibody Therapy for Solid Tumors, Cancer Treat.
  • Herceptin ® erbB2 antibody see Tyrosine Kinase Signalling in Breast cance ⁇ erbB Family Receptor Tyrosine Kniases, Breast cancer Res., 2000, 2(3), 176-183
  • 2CB VEGFR2 specific antibody see Brekken, R. A. et al, Selective Inhibition of VEGFR2 Activity by a monoclonal Anti-VEGF antibody blocks tumor growth in mice, Cancer Res. (2000) 60, 5117-5124).
  • Non-receptor kinase angiogenesis inhibitors may also find use in the present invention.
  • Inhibitors of angiogenesis related VEGFR and TIE2 are discussed above in regard to signal transduction inhibitors (both receptors are receptor tyrosine kinases).
  • Angiogenesis in general is linked to erbB2/EGFR signaling since inhibitors of erbB2 and EGFR have been shown to inhibit angiogenesis, primarily VEGF expression.
  • the combination of an erbB2/EGFR inhibitor with an inhibitor of angiogenesis makes sense.
  • non-receptor tyrosine kinase inhibitors may be used in combination with the EGFR/erbB2 inhibitors of the present invention.
  • anti-VEGF antibodies which do not recognize VEGFR (the receptor tyrosine kinase), but bind to the ligand; small molecule inhibitors of integrin (alpha v beta 3 ) that will inhibit angiogenesis; endostatin and angiostatin (non-RTK) may also prove useful in combination with the disclosed erb family inhibitors.
  • VEGFR the receptor tyrosine kinase
  • small molecule inhibitors of integrin alpha v beta 3
  • endostatin and angiostatin non-RTK
  • Agents used in immunotherapeutic regimens may also be useful in combination with the compounds of formula (I).
  • immunologic strategies to generate an immune response against erbB2 or EGFR. These strategies are generally in the realm of tumor vaccinations.
  • the efficacy of immunologic approaches may be greatly enhanced through combined inhibition of erbB2/EGFR signaling pathways using a small molecule inhibitor. Discussion of the immunologic/tumor vaccine approach against erbB2/EGFR are found in Reilly RT et al. (2000), Cancer Res. 60: 3569-3576; and Chen Y, Hu D, Eling DJ, Robbins J, and Kipps TJ. (1998), Cancer Res. 58: 1965-1971.
  • Agents used in proapoptotic regimens may also be used in the combination of the present invention.
  • Members of the Bcl-2 family of proteins block apoptosis. Upregulation of bcl-2 has therefore been linked to chemoresistance.
  • EGF epidermal growth factor
  • Cell cycle signalling inhibitors inhibit molecules involved in the control of the cell cycle.
  • a family of protein kinases called cyclin dependent kinases (CDKs) and their interaction with a family of proteins termed cyclins controls progression through the eukaryotic cell cycle. The coordinate activation and inactivation of different cyclin/CDK complexes is necessary for normal progression through the cell cycle.
  • CDKs cyclin dependent kinases
  • Several inhibitors of cell cycle signalling are under development. For instance, examples of cyclin dependent kinases, including CDK2, CDK4, and CDK6 and inhibitors for the same are described in, for instance, Rosania et al, Exp. Opin. Ther. Patents (2000) 10(2):215-230.
  • the cancer treatment method of the claimed invention includes the co-administration a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate or pro-drug thereof and at least one anti-neoplastic agent, such as one selected from the group consisting of anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, and cell cycle signaling inhibitors.
  • anti-neoplastic agent such as one selected from the group consisting of anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine
  • the pharmaceutically active compounds of the present invention are active as PI3 kinase inhibitors, particularly the compounds that modulate/inhibit PI3K ⁇ , either selectively or in conjunction with one or more of PI3K ⁇ , PI3K ⁇ , or PI3K ⁇ , they exhibit therapeutic utility in treating a disease state selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, cancer, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, sperm motility, transplantation rejection, graft rejection and lung injuries.
  • a disease state selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, cancer, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, sperm motility, transplantation rejection, graft rejection and lung injuries.
  • a disease state selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, cancer, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, sperm motility, transplantation rejection, graft rejection or lung injuries
  • co-administering and derivatives thereof as used herein is meant either simultaneous administration or any manner of separate sequential administration of a PB kinase inhibiting compound, as described herein, and a further active ingredient or ingredients, known to be useful in the treatment of autoimmune disorders, inflammatory diseases, cardiovascular diseases, cancer, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, sperm motility, transplantation rejection, graft rejection and/or lung injuries.
  • PBK ⁇ PB kinases
  • the exemplified compounds were tested and found active against PBK ⁇ .
  • the ICso's ranged from about 1 nM to 10 ⁇ M. The majority of the compounds were under 500 nM; the more active compounds were under 100 nM, the most active compounds can be found under 10 nM.
  • Example 2 The compound of Example 2 was tested generally according to the assays described herein and in at least one experimental run exhibited a IC50 value: equal to 100 nM against PBK ⁇ .
  • Example 5 The compound of Example 5 was tested generally according to the assays described herein and in at least one experimental run exhibited a IC50 value: equal to 32 nM against PBK ⁇ .
  • Example 9 The compound of Example 9 was tested generally according to the assays described herein and in at least one experimental run exhibited a IC50 value: equal to 25 nM against PBK ⁇ .
  • Example 42 The compound of Example 42 was tested generally according to the assays described herein and in at least one experimental run exhibited a IC50 value: equal to 100 nM against PBK ⁇ .
  • the PB -Kinase assay has been developed and optimized from a kit produced by Upstate (Millipore). Briefly, this kit contains a biotinylated PIP3 which forms a HTRF (homogeneous time-resolved fluorescence energy transfer) complex when mixed with a Europium labeled anti-GST monoclonal antibody, a GST tagged pleckstrin homology (PH) domain, and Streptavidin-Allophycocyanin (APC).
  • the unlabeled PIP3 produced by PI 3- Kinase activity displaces biotin-PIP3 from the complex resulting in a loss of energy transfer and thus a decrease in signal.
  • Millipore, PI 3 -Kinase (human) HTRFTM Assay technical document associated with catalog# 33-017
  • the wortmannin control is dispensed from a Greiner polypropylene 120 ⁇ L mother plate containing > 20 ⁇ L of ImM wortmannin into the assay plate via the hummingbird or comparable instrument in wells 18 A, C, E, G, I, K, M, O (0.1 ⁇ L of ImM wortmannin in 100% DMSO).
  • the PIP3 control is dispensed into the plate manually via a matrix pipettor, l ⁇ L of 200 ⁇ M PIP3 in IX Reaction buffer to wells 18 B, D, F, H, J, L, N, P.
  • the PI3 -Kinase assay has been developed and optimized from a kit produced by Upstate (Millipore).
  • the assay kit (cat: 33-017) contains seven reagents: 1) 4X Reaction Buffer, 2) PIP2 (ImM), 3) Stop A, 4) Stop B, 5) Detection Mix A, 6) Detection Mix B, 7) Detection Mix C.
  • PBKinase prepared in-house
  • 4X PI3K Detection Buffer Millipore
  • dithiothreitol Sigma, D-5545
  • Adenosine-5 '-triphosphate ATP, Sigma, A-6419
  • PIP3 l,2-dioctanoyl-sn-glycero-3- [phosphoinositil-3,4,5-triphosphate] tetraammonium salt (Avanti polar lipids, 850186P)
  • DMSO Sigma, 472301)
  • Wortmannin Sigma, W-1628
  • IX PBKinase Reaction Buffer by diluting stock 1 :4 with de-ionized water, freshly prepared DTT is added at a final concentration of 5 mM on the day of use.
  • Enzyme addition and compound preincubation is initiated by the addition of 2.5 ⁇ L of 2X enzyme solution, PBK alpha in IX reaction buffer, to all wells using a Multidrop Combi. Plates are incubated at room temperature for 15 minutes. Substrate addition and reaction initiation is completed by the addition of 2.5 ⁇ L of 2X substrate solution, PIP2 and ATP in IX reaction buffer, to all wells using a Multidrop Combi. Plates are incubated at room temperature for one hour.
  • Reactions are quenched by the addition of 2.5 ⁇ L of stop solution (mix Stop A and Stop B in a ratio of 5:1, respectively, i.e.: for a 6000 ⁇ L total volume, mix 5000 ⁇ L Stop A and lOOO ⁇ L Stop B) to all wells using the Multidrop Combi.
  • stop solution mix Stop A and Stop B in a ratio of 5:1, respectively, i.e.: for a 6000 ⁇ L total volume, mix 5000 ⁇ L Stop A and lOOO ⁇ L Stop B
  • the loss of PI3 -kinase signal due to product formation leading to biotinylated-PIP3 displacement is nonlinear with respect to both increasing product and time. This non- linear detection will impact accuracy of IC50 calculations; therefore, there is a need for a correction factor or back calculation to obtain a more accurate IC50.
  • the correction varies based on the standard wells of the assay plates (column 6 and 18) of product formed in each assay plate.
  • %inhibition min + (max-min)/(l + ([inhibitor]/IC50) ⁇ n) where min is the %inhibition with no inhibitor (typically 0%), max is the %inhibition with saturating inhibitor (typically 100%), and n is the Hill slope (typically 1).
  • pIC50 -log(IC50)
  • SPA imaging beads are microspheres containing scintillant which emit light in the red region of the visible spectrum. As a result, these beads are ideally suited to use with a CCD imager such as the Viewlux.
  • the Leadseeker beads used in this system are polystyrene beads that have been coupled with polyethyleneimine. When added to the assay mixture, the beads absorb both the substrate (PIP2) and product (PIP3). Adsorbed P 33 -PIP3 will cause an increase in signal, measured as ADUs (analog to digital units).
  • This protocol details the use of the PEI-PS Leadseeker beads for assays using His-pl 10/p85 PBK alpha.
  • Solid compounds are typically plated with 0.1 ⁇ l of 100% DMSO in all wells (except column 6 and 18) of a 384-well, flat bottom, low volume plate (Greiner 784075).
  • the compounds are serially diluted (3-fold in 100% DMSO) across the plate from column 1 to column 12 and column 13 to column 24 and leave column 6 and 18 containing only DMSO to yield 1 lconcentraions for each test compound.
  • the assay buffer contains MOPS (pH 6.5), CHAPS, and DTT.
  • PI3K alpha and PIP2 L- alpha-D-myo-Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]3-O-phospho linked, D(+)- sn-l,2-di-O-octanoylglyceryl, CellSignals # 901) are mixed and incubated in the plate with compound for 30min prior to starting the reaction with the addition of P 33 -ATP and MgCl 2 (reagents added using Zoom). Enzyme-free wells (column 18) are typically done to determine the low control.
  • PEI-PS Leadseeker beads in PBS/EDTA/CHAPS are added (by Multidrop) to quench the reaction, and the plates are allowed to incubate for at least one hour (typically overnight) before centrifugation.
  • the signal is determined using a Viewlux detector and is then imported into curve fitting software (Activity Base) for construction of concentration response curves.
  • the percent inhibition of activity was calculated relative to high controls (Cl, 0.1 ⁇ l DMSO in column 6, rows A-P)) and low controls (C2, 5 ⁇ l of 40 uM PIP2 in buffer in column 18, rows A-P) using, 1OO*(1-(U1-C2)/(C1-C2)).
  • the IC50 values were converted to pIC50 values, i.e., -log IC50 in Molar concentration.
  • Block MSD plates o Make 2OmL 3% blocking solution/plate (600mg blocker A in 2OmL WB), add 150ul/well and incubate at RT for at least 1 hr
  • AKT duplex assay o Wash plates (4x with 200ul/well WB in plate washer); tap plates on paper towel to blot o Add 60ul of lysates/well, incubate on shaker at RT for lhr o During incubation prepare detection Ab (3mL/plate; 2mL WB and ImL blocking solution w/ Ab at 1OnM); repeat wash step as above o Add 25ul of Ab/well, incubate on shaker at RT for lhr; repeat wash step as above o Add 150ul/well Ix Read Buffer (dilute 4x stock in ddH2O, 20mL/plate), read immediately
  • BT474, HCC 1954 and T-47D (human breast) were cultured in RPMI- 1640 containing 10% fetal bovine serum at 37 0 C in 5% CO 2 incubator.
  • Cells were split into T75 flask (Falcon #353136) two to three days prior to assay set up at density which yields approximately 70-80% confluence at time of harvest for assay.
  • Cells were harvested using 0.25% trypsin-EDTA (Sigma #4049). Cell counts were performed on cell suspension using Trypan Blue exclusion staining. Cells were then plated in 384 well black flat bottom polystyrene (Greiner #781086) in 48 ⁇ l of culture media per well at 1,000 cells/well.
  • test compounds were added the following day.
  • the test compounds were prepared in clear bottom polypropylene 384 well plates (Greiner#781280) with consecutive two fold dilutions. 4 ⁇ l of these dilutions were added to 105 ⁇ l culture media, after mixing the solution, 2 ⁇ l of these dilutions were added into each well of the cell plates. The final concentration of DMSO in all wells was 0.15%. Cells were incubated at 37 0 C, 5% CO 2 for 72 hours.
  • the pharmaceutically active compounds within the scope of this invention are useful as PI3 Kinase inhibitors in mammals, particularly humans, in need thereof.
  • the present invention therefore provides a method of treating diseases associated with PI3 kinase inhibition, particularly: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries and other conditions requiring PI3 kinase modulation/inhibition, which comprises administering an effective compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate or pro-drug thereof.
  • the compounds of Formula (I) also provide for a method of treating the above indicated disease states because of their ability to act as PI3 inhibitors.
  • the drug may be administered to a patient in need thereof by any conventional route of administration, including, but not limited to, intravenous, intramuscular, oral, subcutaneous, intradermal, and parenteral.
  • the pharmaceutically active compounds of the present invention are incorporated into convenient dosage forms such as capsules, tablets, or injectable preparations.
  • Solid or liquid pharmaceutical carriers are employed.
  • Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • Liquid carriers include syrup, peanut oil, olive oil, saline, and water.
  • the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit.
  • the preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.
  • the pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to give the desired oral or parenteral products.
  • Doses of the presently invented pharmaceutically active compounds in a pharmaceutical dosage unit as described above will be an efficacious, nontoxic quantity preferably selected from the range of 0.001 - 100 mg/kg of active compound, preferably 0.001 - 50 mg/kg.
  • the selected dose is administered preferably from 1-6 times daily, orally or parenterally.
  • Preferred forms of parenteral administration include topically, rectally, transdermally, by injection and continuously by infusion.
  • Oral dosage units for human administration preferably contain from 0.05 to 3500 mg of active compound. Oral administration, which uses lower dosages is preferred. Parenteral administration, at high dosages, however, also can be used when safe and convenient for the patient.
  • Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular PB kinase inhibitor in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition.
  • the method of this invention of inducing PB kinase inhibitory activity in mammals, including humans, comprises administering to a subject in need of such activity an effective PB kinase modulating/inhibiting amount of a pharmaceutically active compound of the present invention.
  • the invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use as a PB kinase inhibitor.
  • the invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use in therapy.
  • the invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use in treating autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries.
  • the invention also provides for a pharmaceutical composition for use as a PB inhibitor which comprises a compound of Formula (I) and a pharmaceutically acceptable carrier.
  • the invention also provides for a pharmaceutical composition for use in the treatment of autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries, which comprises a compound of Formula (I) and a pharmaceutically acceptable carrier. No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention.
  • the pharmaceutically active compounds of the present invention can be co-administered with further active ingredients, including compounds known to have utility when used in combination with a PB kinase inhibitor.
  • Quinoxalines such as represented by compounds of Formula I can be prepared from, for example, bromoquinoxalinols (2) which have been prepared in the literature (Journal of Medicinal Chemistry, 1981, 24( ⁇ ), 93-101).
  • bromoquinoxalinols such as compound 2 may be converted to a bromochloroquinoxaline such as compound 3 by for example, treatment with phosphorous oxychloride at elevated temperatures (typically 120 0 C).
  • the resulting chlorinated compound (3) may undergo a variety of coupling reactions as delineated by steps C, D or E.
  • the coupling step is for instance a nucleophilic displacement reaction such as for steps C or D
  • suitable nucleophiles such as amines, or alkoxides are commercially available or easily prepared by methods known to those skilled in the art.
  • such a displacement may be carried out at room temperature or further facilitated by heating to temperatures such as 70-100 0 C either in neat reagent or in a suitable polar solvent such as N,N'- dimethy formamide .
  • the coupling step to prepare compounds of formula 4 may be a transition metal (such as palladium) catalyzed cross-coupling reaction of an aryl or heteroaryl boronate ester or boronic acid with compound 3, such as in step E.
  • a transition metal such as palladium
  • An optionalrary coupling reaction such as a Suzuki cross-coupling depicted in step E can be acheived by treating compound 3 with an appropriate palladium catalyst (typically 1,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1 :1)), in the presence of inorganic base (such as potassium carbonate, sodium carbonate or sodium bicabonate) and a suitable solvent (such as 1,4-dioxane or N,N'- dimethyformamide) at elevated temperatures (typically 100 0 C).
  • an appropriate palladium catalyst typically 1,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1 :1)
  • inorganic base such as potassium carbonate, sodium carbonate or sodium bicabonate
  • a suitable solvent such as 1,4-dioxane or N,N'- dimethyformamide
  • the resulting compounds of formula (4) may undergo another palladium catalyzed coupling reaction as described above with an aryl or heteroaryl boronate ester or boronic acid to furnish compounds of the present invention such as 6.
  • a palladium catalyst such as 1,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1 :1)
  • base such as potassium acetate
  • solvent such as dioxane
  • Such boronate esters can undergo typical Suzuki cross-coupling reactions (as described above) with approariate aryl or heteroaryl halides to provide compounds of the present invention, such as compound 6.
  • an amine or hydroxyl deprotecting step may be included. These include examples such as removal of a tosylsulfonyl protecting group with aqueous base (such as sodium hydroxide) in a polar solvent such as ethanol at elevated temperature (typically 5O 0 C) or the removal of a sily protecting group with fluoride ion or aqueous acid (such as acetic acid).
  • R2 N or O-node
  • Scheme 2 describes the removal of an amine protecting group when it is necessary to protect an amine before a coupling reaction (such as in steps C, D, E, G or H in Sheme 1 above ) can be carried out.
  • a Boc-protected amine such as compound 7 can be treated with trifluoroacetic acid in a suitable solvent (such as acetonitrile) at room temperature to furnish compounds of the present invention such as compound 8.
  • a tosylsulfonyl protected pyrazole amine such as compound 9 can be converted to the free pyrazole compound 10 by treating with aqueous base (such as aqueous sodium hydroxide) in a polar solvent, typically ethanol and elevated temperatures, for instance 5O 0 C.
  • silylethers may be deprotected using standard methods involving fluoride ion or aqueous acid, for instance acetic acid to furnish hydroxyl compounds such as 12.
  • a carbonyl containing compound such as 13 (Scheme 3) can be reduced to the corresponding alcohol using a hydride based reducing agent such as sodium borohydride in a polar protic solvent to furnish hydroxyl containing compounds such as 14.
  • Scheme 3
  • Pyrazoles such as compound 9 can be prepared from the Suzuki coupling of an aryl bromide such as compound 17 (Scheme 4) with compounds such as 5 (Scheme 1).
  • Compounds of formula 17 can be prepared from substituted pyrazoles such as 15, some of which are commercially available and the preparation of which is described in the literature (Inorganic Chemistry 2002, 41(1), 1889-1896).
  • the reaction was cooled to room temperature.
  • the reaction was diluted with ethyl acetate (100 mL) and water (50 mL), and the layers were separated.
  • the aqueous layer was back-extracted with ethyl acetate (20 mL).
  • the combined organic layers were washed with brine (30 mL), dried over magnesium sulfate and concentrated in vacuo to give a brown solid.
  • the solid was triturated in dichloromethane to give a yellow solid following vacuum filtration. The yellow solid was washed with methanol to give the title compound (92% pure).
  • reaction mixture was cooled to room temperature, diluted with water (50 mL) and brine (10 mL), and extracted with (3 x 50 mL) ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo.
  • An oral dosage form for administering the present invention is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table II, below.
  • An injectable form for administering the present invention is produced by stirring
  • sucrose, calcium sulfate dihydrate and an PBK inhibitor as shown in Table III below are mixed and granulated in the proportions shown with a 10% gelatin solution.
  • the wet granules are screened, dried, mixed with the starch, talc and stearic acid;, screened and compressed into a tablet.

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Abstract

Invented is a method of inhibiting the activity/function of PI3 kinases using quinoxaline derivatives. Also invented is a method of treating one or more disease states selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries by the administration of quinoxaline derivatives.

Description

OUINOXALINE DERIVATIVES AS PI3 KINASE INHIBITORS
Field of the invention
This invention relates to the use of quinoxaline derivatives for the modulation, notably the inhibition of the activity or function of the phosphoinositide 3 ' OH kinase family (hereinafter PB kinases), suitably, PBKα, PBKδ, PBKβ, or PBKγ. Suitably, the present invention relates to the use of quinoxalines in the treatment of one or more disease states selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries.
Background of the invention
Cellular membranes represent a large store of second messengers that can be enlisted in a variety of signal transduction pathways. In regards function and regulation of effector enzymes in phospholipids signaling pathways, these enzymes generate second messengers from the membrane phospholipid pools (class I PB kinases (e.g. PBKalpha) are dual-specificity kinase enzymes, meaning they display both: lipid kinase (phosphorylation of phosphoinositides) as well as protein kinase activity, shown to be capable of phosphorylation of protein as substrate, including auto-phosphorylation as intramolecular regulatory mechanism. These enzymes of phospholipids signaling are activated in response to a variety of extra-cellular signals such as growth factors, mitogens, integrins (cell-cell interactions) hormones, cytokines, viruses and neurotransmitters such as described in Scheme I hereinafter and also by intracellular regulation by other signaling molecules (cross-talk, where the original signal can activate some parallel pathways that in a second step transmit signals to PBKs by intra-cellular signaling events), such as small GTPases, kinases or phosphatases for example. Intracellular regulation can also occur as a result of aberrant expression or lack of expression of cellular oncogenes or tumor suppressors. The inositol phospholipid (phosphoinositides) intracellular signaling pathways begin with activation of signaling molecules (extra cellular ligands, stimuli, receptor dimerization, transactivation by heterologous receptor (e.g. receptor tyrosine kinase) and the recruitment and activation of PBK including the involvement of G-protein linked transmembrane receptor integrated into the plasma membrane. PBK converts the membrane phospholipid PI(4,5)P2 into PI(3,4,5)P3 that functions as a second messenger. PI and PI(4)P are also substrates of PBK and can be phosphorylated and converted into PBP and PI(3,4)P2, respectively. In addition, these phosphoinositides can be converted into other phosphoinositides by 5 '-specific and 3'- specific phophatases, thus PBK enzymatic activity results either directly or indirectly in the generation of two 3 ' -phosphoinositide subtypes that function as 2nd messengers in intra-cellular signal transduction pathways (Trends Biochem. Sci. 22(7) p.267-72 (1997) by Vanhaesebroeck et al: Chem. Rev. 101(8) p.2365-80 (2001) by Leslie et al (2001); Annu. Rev. Cell.Dev. Biol. 17p, 615-75 (2001) by Katso et al. and Cell. MoI. Life Sci. 59(5) p.761-79 (2002) by Toker et al.). Multiple PBK isoforms categorized by their catalytic subunits, their regulation by corresponding regulatory subunits, expression patterns and signaling-specific functions (pl lOα, β, δ and γ) perform this enzymatic reaction (Exp. Cell. Res. 25 (1) p. 239-54 (1999) by Vanhaesebroeck and Katso et al., 2001, above).
The closely related isoforms pi 10a 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 (Trends Biochem. Sci. 22(7) p.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. Inducibility of protein expression includes synthesis of protein as well as protein stabilization that is in part regulated by association with regulatory subunits.
To date, eight mammalian PBKs have been identified, divided into three main classes (I, II, and III) on the basis of sequence homology, structure, binding partners, mode of activation, and substrate preference. In vitro, class I PBKs can phosphorylate phosphatidylinositol (PI), phosphatidylinositol-4-phosphate (PI4P), and phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) to produce phosphatidylinositol-3- phosphate (PBP), phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2, and phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3, respectively. Class II PBKs phosphorylate PI and phosphatidylinositol-4-phosphate. Class III PBKs can only phosphorylate PI (Vanhaesebrokeck et al., 1997, above; Vanhaesebroeck et al., 1999, above and Leslie et al, 2001, above)
Scheme I: Conversion of PI(4.5)P2 to PIP3
Figure imgf000004_0001
PtdIns(4,5)P2
Figure imgf000004_0002
PtdIns(3,4,5)P3
As illustrated in Scheme I above, phosphoinositide 3-kinases (PBKs) phosphorylate the hydroxyl of the third carbon of the inositol ring. The phosphorylation of phosphoinositides that generate Ptdlns to 3,4,5-trisphosphate (PtdIns(3,4,5)P3), PtdIns(3,4)P2 and PtdIns(3)P produce second messengers for a variety of signal transduction pathways, including those essential to cell proliferation, cell differentiation, cell growth, cell size, cell survival, apoptosis, adhesion, cell motility, cell migration, chemotaxis, invasion, cytoskeletal rearrangement, cell shape changes, vesicle trafficking and metabolic pathway (Katso et al, 2001, above and MoI. Med. Today 6(9) p. 347-57 (2000) by Stein). G-protein coupled receptors mediate phosphoinositide 3'OH-kinase activation via small GTPases such as Gβγ and Ras, and consequently PI3K signaling plays a central role in establishing and coordinating cell polarity and dynamic organization of the cytoskeleton - which together provides the driving force of cells to move. Chemotaxis - the directed movement of cells toward a concentration gradient of chemical attractants, also called chemokines is involved in many important diseases such as inflammation/auto-immunity, neurodegeneration, antiogenesis, invasion/metastasis and wound healing (Immunol. Today 21(6) p. 260-4 (2000) by Wyman et al.; Science 287(5455) p. 1049-53 (2000) by Hirsch et al.; FASEB J. 15(11) p. 2019-21 (2001) by Hirsch et al. and Nat. Immunol. 2(2) p. 108-15 (2001) by Gerard et al.).
Advances using genetic approaches and pharmacological tools have provided insights into signalling and molecular pathways that mediate chemotaxis in response to chemoattractant activated G-protein coupled receptors. PI3-Kinase, responsible for generating these phosphorylated signalling products, was originally identified as an activity associated with viral oncoproteins and growth factor receptor tyrosine kinases that phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at the 3'- hydroxyl of the inositol ring (Panayotou et al., Trends Cell Biol. 2 p. 358-60 (1992)). However, more recent biochemical studies revealed that class I PI3 kinases (e.g. class IB isoform PI3Kγ) are dual-specific kinase enzymes, meaning they display both lipid kinase and protein kinase activity, shown to be capable of phosphorylation of other proteins as substrates, as well as auto-phosphorylation as an intra-molecular regulatory mechanism.
PI3-kinase activation, is therefore believed to be involved in a range of cellular responses including cell growth, differentiation, and apoptosis (Parker et al., Current Biology, 5 p. 577-99 (1995); Yao et al., Science, 267 p. 2003-05 (1995)). PI3-kinase appears to be involved in a number of aspects of leukocyte activation. A p85-associated PI3 -kinase activity has been shown to physically associate with the cytoplasmic domain of CD28, which is an important costimulatory molecule for the activation of T-cells in response to antigen (Pages et al., Nature, 369 p. 327-29 (1994); Rudd, Immunity 4 p. 527- 34 (1996)). Activation of T cells through CD28 lowers the threshold for activation by antigen and increases the magnitude and duration of the proliferative response. These effects are linked to increases in the transcription of a number of genes including interleukin-2 (IL2), an important T cell growth factor (Fraser et al., Science 251 p. 313-16 (1991)). Mutation of CD28 such that it can no longer interact with PI3-kinase leads to a failure to initiate IL2 production, suggesting a critical role for PI3 -kinase in T cell activation. PI3Kγ has been identified as a mediator of G beta-gamma-dependent regulation of JNK activity, and G beta-gamma are subunits of heterotrimeric G proteins (Lopez- Ilasaca et al., J. Biol. Chem. 273(5) p. 2505-8 (1998)). Cellular processes in which PBKs play an essential role include suppression of apoptosis, reorganization of the actin skeleton, cardiac myocyte growth, glycogen synthase stimulation by insulin, TNFα-mediated neutrophil priming and superoxide generation, and leukocyte migration and adhesion to endothelial cells. Recently, (Laffargue et al, Immunity 16(3) p. 441-51 (2002)) it has been described that PBKγ relays inflammatory signals through various G(i)-coupled receptors and its central to mast cell function, stimuli in context of leukocytes, immunology includes cytokines, chemokines, adenosines, antibodies, integrins, aggregation factors, growth factors, viruses or hormones for example (J. Cell. Sci. 114(Pt 16) p. 2903-10 (2001) by Lawlor et al.; Laffargue et al., 2002, above and Curr. Opinion Cell Biol. 14(2) p. 203-13 (2002) by Stephens et al.).
Specific inhibitors against individual members of a family of enzymes provide invaluable tools for deciphering functions of each enzyme. Two compounds, LY294002 and wortmannin (cf. hereinafter), have been widely used as PI3-kinase inhibitors. These compounds are non-specific PI3K inhibitors, as they do not distinguish among the four members of Class I PI3-kinases. For example, the IC50 values of wortmannin against each of the various Class I PI3 -kinases are in the range of 1-10 nM. Similarly, the IC50 values for LY294002 against each of these PI3-kinases is about 15-20 μM (Fruman et al., Ann. Rev. Biochem., 67, p. 481-507 (1998)), also 5-10 microM on CK2 protein kinase and some inhibitory activity on phospholipases. Wortmannin is a fungal metabolite which irreversibly inhibits PI3K activity by binding covalently to the catalytic domain of this enzyme. Inhibition of PI3K activity by wortmannin eliminates subsequent cellular response to the extracellular factor. For example, neutrophils respond to the chemokine fMet-Leu-Phe (fMLP) by stimulating PI3K and synthesizing Ptdlns (3, 4, 5)P3. This synthesis correlates with activation of the respirators burst involved in neutrophil destruction of invading microorganisms. Treatment of neutrophils with wortmannin prevents the fMLP-induced respiratory burst response (Thelen et al., Proc. Natl. Acad. Sci. USA, 91, p. 4960-64 (1994)). Indeed, these experiments with wortmannin, as well as other experimental evidence, shows that PI3K activity in cells of hematopoietic lineage, particularly neutrophils, monocytes, and other types of leukocytes, is involved in many of the non-memory immune response associated with acute and chronic inflammation.
Figure imgf000007_0001
LY294002 Wortmannin
Based on studies using wortmannin, there is evidence that PB -kinase function is also required for some aspects of leukocyte signaling through G-protein coupled receptors (Thelen et al., 1994, above). Moreover, it has been shown that wortmannin and LY294002 block neutrophil migration and superoxide release. Cyclooxygenase inhibiting benzofuran derivatives are disclosed by John M. Janusz et al., in J. Med. Chem. 1998; Vol. 41, No. 18.
It is now well understood that deregulation of onocogenes and tumour-suppressor genes contributes to the formation of malignant tumours, for example by way of increase cell growth and proliferation or increased cell survival. It is also now known that signaling pathways mediated by the PBK family have a central role in a number of cell processes including proliferation and survival, and deregulation of these pathways is a causative factor a wide spectrum of human cancers and other diseases (Katso et al., Annual Rev. Cell Dev. Biol. 2001, JJ: 615-617 and Foster et al, J. Cell Science. 2003, H6: 3037-3040). Class I PBK is a heterodimer consisting of a pi 10 catalytic subunit and a regulatory subunit, and the family is further divided into class Ia and Class Ib enzymes on the basis of regulatory partners and mechanism of regulation. Class Ia enzymes consist of three distinct catalytic subunits (pl lOα, pl lOβ, and pl lOδ) that dimerise with five distinct regulatory subunits (p85α, p55α, p50α, p85β, and p55γ), with all catalytic subunits being able to interact with all regulatory subunits to form a variety of heterodimers. Class Ia PBK are generally activated in response to growth factor-stimulation of receptor tyrosine kinases, via interaction of the regulatory subunit SH2 domains with specific phospho- tyrosine residues of the activated receptor or adaptor proteins such as IRS-I. Small GTPases (ras as an example) are also involved in the activation of PBK in conjunction with receptor tyrosine kinase activation. Both pl lOα and pl lOβ are constitutively expressed in all cell types, whereas pl lOδ expression is more restricted to leukocyte populations and some epithelial cells. In contrast, the single Class Ib enzyme consists of a pl lOγ catalytic subunit that interacts with a plOl regulatory subunit. Furthermore, the Class Ib enzyme is activated in response to G-protein coupled receptor (GPCR) systems and its expression appears to be limited to leukocytes.
There is now considerable evidence indicating that Class Ia PBK enzymes contribute to tumourigenesis in a wide variety of human cancers, either directly or indirectly (Vivanco and Sawyers, Nature Reviews Cancer, 2002, 2, 489-501). For example, the pi 10a subunit is amplified in some tumours such as those of the ovary (Shayesteh, et al, Nature Genetics. 1999, 21 : 99-102) and cervix (Ma et al, Oncogene. 2000, 19: 2739- 2744). More recently, activating mutations within pl lOα (PIK3CA gene) have been associated with various other tumors such as those of the colon and of the breast and lung (Samuels, et al., Science, 2004, 304, 554). Tumor-related mutations in p85α have also been identified in cancers such as those of the ovary and colon (Philp et al, Cancer Research, 2001, 61_, 7426-7429). In addition to direct effects, it is believed that activation of Class Ia PI3K contributes to tumourigenic events that occur upstream in signaling pathways, for example by way of ligand-dependent or ligand-independent activation of receptor tyrosine kinases, GPCR systems or integrins (Vara et al, Cancer Treatment Reviews, 2004, 30, 193-204). Examples of such upstream signaling pathways include over-expression of the receptor tyrosine kinase Erb2 in a variety of tumors leading to activation of PI3K-mediated pathways (Harari et al., Oncogene, 2000, 19, 6102-6114) and over-expression of the oncogene Ras (Kauffmann-Zeh et al., Nature, 1997, 385, 544-548). In addition, Class Ia PBKs may contribute indirectly to tumourigenesis caused by various downstream signaling events. For example, loss of function of the PTEN tumor-suppressor phosphatase that catalyses conversion of PI(3,4,5)P3 back to PI(4,5)P2 is associated with a very broad range of tumors via deregulation of PBK-mediated production of PI(3,4,5)P3 (Simpson and Parsons, Exp. Cell Res., 2001, 264, 29-41). Furthermore, augmentation of the effects of other PBK-mediated signaling events is believed to contribute to a variety of cancers, for example by activation of AKT (Nicholson and Andeson, Cellular Signaling, 2002, 14, 381-395).
In addition to a role in mediating proliferative and survival signaling in tumor cells, there is also good evidence that class Ia PBK enzymes also contributes to tumourigenesis via its function in tumor-associated stromal cells. For examples, PBK signaling is known to play an important role in mediating angiogenic events in endothelial cells in response to pro-angiogenic factors such as VEGF (abid et al., Arterioscler, Thromb. Vase. Biol., 2004,
24, 294-300). As Class I PBK enzymes are also involved in motility and migration (Sawyer, Expert Opinion investing. Drugs, 2004, J_3, 1-19), PBK inhibitors are anticipated to provide therapeutic benefit via inhibition of tumor cell invasion and metastasis. Summary of the Invention
This invention relates to novel compounds of Formula (I):
Figure imgf000009_0001
in which
Rl is a ring system containing 1 to 2 double bonds represented by Formula (II):
Figure imgf000009_0002
(H) . each X is independently C, O, N or S; each R2, R3, R4 and R5 is independently selected from: hydrogen, halogen, acyl, sulfonyl, amino, formyl, substituted amino, Cl-6alkyl, substituted Cl-6alkyl, C3- 7cycloalkyl, substituted C3-7cycloalkyl, C3-7heterocycloalkyl, substituted C3- 7heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, alkoxy, nitro, acyloxy, and aryloxy; n is 0-2; m is 0-3; two adjacent R5 groups may form an additional five or six-membered ring containing 0-2 hetero atoms, wherein said additional ring is optionally substituted with 1 to 2 substituents selected from a group consisting of: Cl-3alkyl, halogen, amino and alkoxy; or a pharmaceutically acceptable salt thereof; provided that when Rl is thiophene, R4 is not piperazine.
This invention also relates to a method of treating cancer, which comprises administering to a subject in need thereof an effective amount of a compound of Formula
(I)-
This invention also relates to a method of treating one or more disease states selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, sperm motility, transplantation rejection, graft rejection and lung injuries, which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I).
Included in the present invention are methods of co-administering the present PB kinase inhibiting compounds with further active ingredients.
Detailed Description of the Invention
This invention relates to novel compounds of Formula (I). This invention also relates to novel compounds of Formula (I)(A):
Figure imgf000010_0001
(I)(A)
in which
Rl is represented by a formula selected from a group consisting of: formulas (III), (IV)
, (V) and (VI):
Figure imgf000011_0001
(ill) (IV)
Figure imgf000011_0002
(V) (Vl)
wherein X is O, N or S;
Y is O or S; each R2, R3, R4 and R5 is independently selected from: hydrogen, halogen, acyl, sulfonyl, amino, formyl, substituted amino, Cl-6alkyl, substituted Cl-6alkyl, C3-
7cycloalkyl, substituted C3-7cycloalkyl, C3-7heterocycloalkyl, substituted C3-
7heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, alkoxy, nitro, acyloxy, and aryloxy; n is 0-2; m is 0-2; two adjacent R5 groups may form an additional five or six-membered ring containing
0-2 hetero atoms, wherein said additional ring is optionally substituted with 1 to 2 substituents selected from a group consisting of: Cl-3alkyl, halogen, amino and alkoxy; or a pharmaceutically acceptable salt thereof; provided that when Rl is thiophene, R4 is not piperazine.
This invention also relates to novel compounds of Formula (I)(B):
Figure imgf000011_0003
in which
Rl is represented by a formula selected from a group consisting of: formulas (III) (IV), (V) and (VI):
Figure imgf000012_0001
(IV)
Figure imgf000012_0002
(V) (Vl)
X is O, N or S; Y is 0 or S; each R2, R3, R4 and R5 is independently selected from: hydrogen, halogen, acyl, sulfonyl, amino, formyl, substituted amino, Cl-6alkyl, substituted Cl-6alkyl, C3- 7cycloalkyl, substituted C3-7cycloalkyl, C3-7heterocycloalkyl, substituted C3- 7heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, alkoxy, nitro, acyloxy, and aryloxy; n is 0-2; m is 0-3; or a pharmaceutically acceptable salt thereof; provided that when Rl is thiophene, R4 is not piperazine.
This invention also relates to novel compounds of Formulas (I)(A) or (I)(B), wherein Rl, and R2 and R5 are defined as above; and n is 0;
R4 is hydrogen or amino; or a pharmaceutically acceptable salt thereof.
This invention also relates to novel compounds of Formulas (I)(A) or (I)(B), wherein X is N or O;
Rl, and R2 and R5 are otherwise defined as above; n is 0;
R4 is hydrogen or amino; or a pharmaceutically acceptable salt thereof. This invention also relates to novel compounds of Formulas (I)(A) or (I)(B), wherein
R2 is selected from a group consisting of:
C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl, heteroaryl and substituted heteroaryl;
X is N or O;
R5 is selected from a group consisting of: formyl, halogen, acyl, sulfonyl, amino, substituted amino, Cl-6alkyl, substituted Cl-6alkyl, C3-7cycloalkyl, substituted C3-
7cycloalkyl, C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, hydroxyl, alkoxy, nitro, acyloxy, and aryloxy; m is
0-3;
Rl is otherwise defined as above; n is O;
R4 is hydrogen or amino; or a pharmaceutically acceptable salt thereof.
This invention also relates to novel compounds of Formulas (I)(A) or (I)(B), wherein R2 is selected from a group consisting of:
C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl, heteroaryl and substituted heteroaryl;
Rl is a ring selected from a group consisting of: pyrazole, oxazole, thiadiazole, oxadiazole, isooxazole and isothiazole, optionally substituted with 1 to 2 substituentss, each of which is independently selected from a group consisting of: formyl, halogen, acyl, sulfonyl, amino, substituted amino, Cl-6alkyl, substituted Cl-6alkyl, C3-
7cycloalkyl, substituted C3-7cycloalkyl, C3-7heterocycloalkyl, substituted C3-
7heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cyano, hydroxyl and alkoxy; n is 0;
R4 is hydrogen or amino; or a pharmaceutically acceptable salt thereof.
This invention also relates to novel compounds of Formulas (I)(A) or (I)(B), wherein R2 is selected from a group consisting of:
C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl, heteroaryl and substituted heteroaryl; Rl is a pyrazole optionally substituted with 1 to 2 groups, each of which is independently selected from a group consisting of: formyl, halogen, acyl, sulfonyl, amino, substituted amino, Cl-6alkyl, substituted Cl-6alkyl, C3-7cycloalkyl, substituted C3-7cycloalkyl, C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cyano, hydroxyl and alkoxy; n is 0;
R4 is hydrogen or amino; or a pharmaceutically acceptable salt thereof.
This invention also relates to novel compounds of Formulas (I)(A) or (I)(B), wherein
R2 is selected from a group consisting of:
C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl, heteroaryl and substituted heteroaryl;
Rl is a pyrazole optionally substituted with 1 to 2 groups, each of which is independently selected from a group consisting of: formyl, halogen, sulfonyl, amino, substituted amino, Cl-6alkyl, substituted Cl-6alkyl, C3-7cycloalkyl, substituted C3-
7cycloalkyl, C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hydroxyl and alkoxy; n is 0; R4 is hydrogen; or a pharmaceutically acceptable salt thereof.
This invention also relates to novel compounds of Formula (I)(C):
Figure imgf000014_0001
(I)(C)
in which
Rl is an aromatic ring system of formula (II):
Figure imgf000015_0001
(H) .
X is C, O, N or S; each R2, R3, R4 and R5 is independently selected from: hydrogen, halogen, acyl, sulfonyl, amino, formyl, substituted amino, Cl-6alkyl, substituted Cl-6alkyl, C3- 7cycloalkyl, substituted C3-7cycloalkyl, C3-7heterocycloalkyl, substituted C3- 7heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, alkoxy, nitro, acyloxy, and aryloxy; n is 0-2; m is 0-3; two adjacent R5 groups may form an additional five or six-membered ring containing 0-2 hetero atoms, wherein said additional ring is optionally substituted with 1 to 2 substituents selected from a group consisting of: Cl-3alkyl, halogen, amino and alkoxy; or a pharmaceutically acceptable salt thereof; provided that the fϊve-membered ring as drawn in formula (II) contains 0-2 nitrogens; provided that when Rl is thiophene, R4 is not piperazine.
This invention also relates to novel compounds of Formula (I)(D):
Figure imgf000015_0002
in which
Rl is an aromatic ring system of formula (II):
Figure imgf000016_0001
(H) .
X is C, O, N or S; each R2, R3 and R5 is independently selected from: hydrogen, halogen, acyl, sulfonyl, amino, formyl, substituted amino, Cl-6alkyl, substituted Cl-6alkyl, C3-7cycloalkyl, substituted C3-7cycloalkyl, C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, alkoxy, nitro, acyloxy, and aryloxy;
R4 is hydrogen or amino; n is 0-2; m is 0-3; two adjacent R5 groups may form an additional five or six-membered ring containing 0-2 hetero atoms, wherein said additional ring is optionally substituted with 1 to 2 substituents selected from a group consisting of: Cl-3alkyl, halogen, amino and alkoxy; or a pharmaceutically acceptable salt thereof; that when Rl is thiophene, R4 is not piperazine;
This invention also relates to novel compounds of Formula (I)(E):
Figure imgf000016_0002
in which
Rl is an aromatic ring system of formula (II):
Figure imgf000017_0001
(H) .
X is C, O, N or S; each R2, R4 and R5 is independently selected from: hydrogen, halogen, acyl, sulfonyl, amino, formyl, substituted amino, Cl-6alkyl, substituted Cl-6alkyl, C3-7cycloalkyl, substituted C3-7cycloalkyl, C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, alkoxy, nitro, acyloxy, and aryloxy;
R3 is selected from a group consisting of: hydrogen, halogen, acyl, amino, formyl, substituted amino, Cl-6alkyl, substituted Cl-6alkyl, C3-7cycloalkyl, substituted C3- 7cycloalkyl; n is 0-2; m is 0-3; two adjacent R5 groups may form an additional five or six-membered ring containing
0-2 hetero atoms, wherein said additional ring is optionally substituted with 1 to 2 substituents selected from a group consisting of: Cl-3alkyl, halogen, amino and alkoxy;; or a pharmaceutically acceptable salt thereof; provided that when Rl is thiophene, R4 is not piperazine;
This invention also relates to the following compounds:
5-[3-(4-morpholinyl)-6-quinoxalinyl]-2-furancarbaldehyde;
{5 - [3 -(4-morpholinyl)-6-quinoxalinyl] -2-furanyl} methanol; {5-[3-(4-pyridinyl)-6-quinoxalinyl]-2-furanyl}methanol;
7-(2,3-dihydrothieno[3,4-δ][l,4]dioxin-5-yl)-2-(4-morpholinyl)quinoxaline;
2-(4-morpholinyl)-7-(3 -phenyl- lH-pyrazol-4-yl)quinoxaline;
7- {3-cyclohexyl- 1 -[(4-methylphenyl)sulfonyl]- lH-pyrazol-4-yl} -2-(4- morpholinyl)quinoxaline; 7-(3-cyclohexyl-lH-pyrazol-4-yl)-2-(4-morpholinyl)quinoxaline; l-[7-(3-cyclohexyl-lH-pyrazol-4-yl)-2-quinoxalinyl]-N,Λ/-dimethyl-4-piperidinamine;
7-(3 -cyclohexyl- lH-pyrazol-4-yl)-2-(4-methyl- 1 -piperazinyl)quinoxaline; l-[7-(5-cyclohexyl-lH-pyrazol-4-yl)-2-quinoxalinyl]-N,Λ/-dimethyl-3-pyrrolidinamine; 7-(5-cyclohexyl-lH-pyrazol-4-yl)-2-{4-[3-(methyloxy)phenyl]-l-piperazinyl}quinoxaline;
7-(5-cyclohexyl-lH-pyrazol-4-yl)-2-{4-[2-(methyloxy)phenyl]-l-piperazinyl}quinoxaline;
2-(4-morpholinyl)-7-pyrazolo[l,5-α]pyridin-3-ylquinoxaline;
7- {3-methyl- 1 -[(4-methylphenyl)sulfonyl]- lH-pyrazol-4-yl} -2-(4- morpholinyl)quinoxaline;
7-(3 -methyl- lH-pyrazol-4-yl)-2-(4-morpholinyl)quinoxaline;
7- {3-cyclohexyl- 1 -[(4-methylphenyl)sulfonyl]- lΗ-pyrazol-4-yl} -2-(4- morpholinyl)quinoxaline;
7-{l-[(4-methylphenyl)sulfonyl]-3-phenyl-lH-pyrazol-4-yl}-2-(4- morpholinyl)quinoxaline;
7-(3 -methyl- lH-pyrazol-4-yl)-2-(4-morpholinyl)quinoxaline;
7-[3-(l,l-dimethylethyl)-lΗ-pyrazol-4-yl]-2-(4-morpholinyl)quinoxaline;
7-(5-cyclohexyl-l -methyl- lH-pyrazol-4-yl)-2-(4-morpholinyl)quinoxaline;
7-(3-cyclohexyl-l -methyl- lH-pyrazol-4-yl)-2-(4-morpholinyl)quinoxaline; 7-(3-cyclohexyl- 1 -methyl- 1 H-pyrazol-4-yl)-2-(4-morpholinyl)quinoxaline;
2-(4-morpholinyl)-7-(l,3,5-trimethyl-lH-pyrazol-4-yl)quinoxaline;
3 - { 1 -methyl-4- [3 -(4-morpholinyl)-6-quinoxalinyl] - 1 H-pyrazol-3 -yl} aniline;
4-[3-(4-morpholinyl)-6-quinoxalinyl]-3-phenyl-lH-pyrazol-5-amine;
7- (3-(4-chlorophenyl)- 1 -[(4-methylphenyl)sulfonyl]- lH-pyrazol-4-yl} -2-(4- morpholinyl)quinoxaline;
7-[3-(4-chlorophenyl)-lH-pyrazol-4-yl]-2-(4-morpholinyl)quinoxaline;
7-{3-[4-(methyloxy)phenyl]-lH-pyrazol-4-yl}-2-(4-morpholinyl)quinoxaline;
7-(3-cyclopropyl-lH-pyrazol-4-yl)-2-(4-morpholinyl)quinoxaline;
2-(4-morpholinyl)-7-[3-(3-nitrophenyl)-lH-pyrazol-4-yl]quinoxaline; 7-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-(4-morpholinyl)quinoxaline;
7-[3-(4-methylphenyl)-lH-pyrazol-4-yl]-2-(4-morpholinyl)quinoxaline;
7-(3-cyclopentyl-lH-pyrazol-4-yl)-2-(4-morpholinyl)quinoxaline;
7-[l-methyl-3-(4-nitrophenyl)-lH-pyrazol-4-yl]-2-(4-morpholinyl)quinoxaline;
7-(5-cyclohexyl-l -methyl- lH-pyrazol-4-yl)-2-(4-morpholinyl)quinoxaline; 3- {4-[3-(4-morpholinyl)-6-quinoxalinyl]-lH-pyrazol-3-yl}benzoic acid;
1 -methyl-4- [3 -(I -methyl- lH-pyrazol-4-yl)-6-quinoxalinyl]-lH-pyrazol-5 -amine;
N- {1 -methyl-4- [3 -(I -methyl- lH-pyrazol-4-yl)-6-quinoxalinyl]-lH-pyrazol-5- yl}benzenesulfonamide;
N- {1 -methyl-4- [3 -(I -methyl- lH-pyrazol-4-yl)-6-quinoxalinyl]-lH-pyrazol-5- yl}benzamide;
7-(l -methyl- lH-imidazol-5-yl)-2-(4-morpholinyl)quinoxaline;
7-(l -methyl- lH-imidazol-5-yl)-2-(l -methyl- lH-pyrazol-4-yl)quinoxaline; 4- {l-methyl-4-[3-(4-morpholinyl)-6-quinoxalinyl]-lH-pyrazol-3-yl} aniline;
7- [ 1 -methyl-5 -( 1 -piperazinylcarbonyl)- 1 H-pyrazol-4-yl] -2-(4-morpholinyl)quinoxaline;
2-(l -methyl- lH-pyrazol-4-yl)-7-(5-phenyl-l,3,4-oxadiazol-2-yl)quinoxaline;
2-(l -methyl- lH-pyrazol-4-yl)-7-(4-phenyl- IH- l,2,3-triazol-5-yl)quinoxaline;
2-(l -methyl- lH-pyrazol-4-yl)-7-(l -phenyl- IH-1, 2, 3-triazol-5-yl)quinoxaline;
2-(l -methyl- lH-pyrazol-4-yl)-7-[l-(phenylsulfonyl)-lH-pyrazol-4-yl]quinoxaline and
2-(l -methyl- lH-pyrazol-4-yl)-7-(lH-pyrazol-4-yl)quinoxaline;
This invention also relates to a method of treating cancer, which comprises coadministering to a subject in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof; and at least one anti-neoplastic agent such as one selected from the group consisting of: anti-microtubule agents, plantinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I hinibitors, hormones and hormonal anlogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, and cell cycle signaling inhibitors.
This invention also relates to a method of treating cancer, which comprises co- administering to a subject in need thereof an effective amount of a compound of Formula
(I), or a pharmaceutically acceptable salt thereof; and at least one signal transduction pathway inhibitor such as one selected from the group consisting of: receptor tyrosine kinase inhibitor, non-receptor tyrosine kinase inhibitor, SΗ2/SΗ3 domain blocker, serine/threonine kinase inhibitor, phosphotidyl inositol-3 kinase inhibitor, myo-inositol singaling inhibitor, and Ras oncogene inhibitor.
As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.
Compounds of Formula (I) are included in the pharmaceutical compositions of the invention. Definitions
By the term "substituted amino" as used herein, is meant -NR30R40 wherein each R30 and R40 is independently selected from a group including hydrogen, Cl-6alkyl, acyl, sulfonyl, C3-C7cycloalkyl, wherein at least one of R30 and R40 is not hydrogen. By the term "acyl" as used herein, unless otherwise defined, is meant
-C(O)(alkyl), -C(O)(cycloalkyl), or -C(O)(heterocycloalkyl).
By the term "sulfonyl" as used herein is meant -SO2R35, wherein R35 is Cl- βalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl.
By the term "aryl" as used herein, unless otherwise defined, is meant aromatic, hydrocarbon, ring system. The ring system may be monocyclic or fused polycyclic (e.g. bicyclic, tricyclic, etc.). In various embodiments, the monocyclic aryl ring is C5-C10, or
C5-C7, or C5-C6, where these carbon numbers refer to the number of carbon atoms that form the ring system. A C6 ring system, i.e. a phenyl ring is a suitable aryl group. In various embodiments, the polycyclic ring is a bicyclic aryl group, where suitable bicyclic aryl groups are C8-C12, or C9-C10. A naphthyl ring, which has 10 carbon atoms, is a suitable polycyclic aryl group.
By the term "heteroaryl" as used herein, unless otherwise defined, is meant an aromatic ring system containing carbon(s) and at least one heteroatom. Heteroaryl may be monocyclic or polycyclic. A monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 10 hetero atoms. A polycyclic heteroaryl ring may contain fused, spiro or bridged ring junctions, for example, bicyclic heteroaryl is a polycyclic heteroaryl. Bicyclic heteroaryl rings may contain from 8 to 12 member atoms. Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (carbons and heteroatoms). Exemplary heteroaryl groups include but are not limited to: benzofuran, benzothiophene, furan, imidazole, indole, isothiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinoline, quinazoline, quinoxaline, thiazole, and thiophene.
By the term "monocyclic heteroaryl" as used herein, unless otherwise defined, is meant a monocyclic heteroaryl ring containing 1-5 carbon atoms and 1-4 hetero atoms. By the term "alkylcarboxy" as used herein, unless otherwise defined, is meant -
(CH2)nCOOR8o, wherein R80 is hydrogen or Cl-C6alkyl, n is 0-6.
By the term "alkoxy" as used herein is meant -O(alkyl) including -OCH3, - OCH2CH3 and -OC(CH3)3 where alkyl is as described herein.
By the term "alkylthio" as used herein is meant -S(alkyl) including -SCH3, - SCH2CH3 where where alkyl is as described herein.
The term "cycloalkyl" as used herein unless otherwise defined, is meant a nonaromatic, unsaturated or saturated, cyclic or polycyclic C3-C^2- Examples of cycloalkyl and substituted cycloalkyl substituents as used herein include: cyclohexyl, aminocyclohexyl, cyclobutyl, aminocyclobutyl, 4-hydroxy- cyclohexyl, 2-ethylcyclohexyl, propyW-methoxycyclohexyl, 4-methoxycyclohexyl, A- carboxycyclohexyl, cyclopropyl, aminocyclopentyl, and cyclopentyl. By the term "heterocycloalkyl" as used herein is meant a non-aromatic, unsaturated or saturated, monocyclic or polycyclic, heterocyclic ring containing at least one carbon and at least one heteroatom. Exemplary monocyclic heterocyclic rings include: piperidine, piperazine, pyrrolidine, and morpholine. Exemplary polycyclic heterocyclic rings include quinuclidine. By the term "substituted" as used herein, unless otherwise defined, is meant that the subject chemical moiety has one to five substituents, suitably from one to three, selected from the group consisting of: hydrogen, halogen, Cl-C6alkyl, amino, trifluoromethyl, - (CH2)nCOOH, C3-C7cycloalkyl, substituted amino, aryl, heteroaryl, arylalkyl, arylcycloalkyl, heteroarylalkyl, heterocycloalkyl, cyano, hydroxyl, alkoxy, alkylthio, aryloxy, acyloxy, acyl, acylamino, arylamino, nitro, oxo, -CO2R50, -SO2R70, -NR50SO2R70, NR5oC(0)R75 and -CONR55R60, wherein R50 and R55 are each independently selected from: hydrogen, alkyl, and C3-C7cycloalkyl; R55 and R60 can optionally form a heterocycloalkyl ring; n is 0 to 6; R75 is selected from a group consisting of: Cl-C6alkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, amino, substituted amino, arylamino, Cl-C6heterocycloalkyl, substituted Cl-C6heterocycloalkyl; each R60 and R70 is independently selected from a group consisting of: Cl-C6alkyl, C3-C7cycloalkyl, substituted Cl-C6heterocycloalkyl, Cl-C6heterocycloalkyl, halogen, amino, substituted amino, arylamino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo, -(CH2)nCOOH, aryl optionally fused with a five-membered ring or substituted with one to five groups selected from a group consisting of: Cl-C6alkyl, C3-C7cycloalkyl, halogen, amino, substituted amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo, or -(CH2)nCOOH, or heteroaryl optionally fused with a five-membered ring or substituted with one to five groups selected from a group consisting of: Cl-C6alkyl, C3-C7cycloalkyl, halogen, amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo, or -(CH2)nCOOH. By the term "substituted", when referred in the definition of R35, R60, R70, R75,
"arylamino", and "aryloxy", is meant that the subject chemical moiety has one to five substituents, suitably from one to three, selected from the group consisting of: hydrogen, Cl-C6alkyl, halogen, trifluoromethyl, -(CH2)nCOOH, amino, substituted amino, cyano, hydroxyl, alkoxy, alkylthio, aryloxy, acyloxy, acyl, acylamino, and nitro, n is 0-6. By the term "acyloxy" as used herein is meant -OC(O)alkyl where alkyl is as described herein. Examples of acyloxy substituents as used herein include: -OC(O)CH3, - OC(O)CH(CH3)2 and -OC(O)(CH2)3CH3. By the term "acylamino" as used herein is meant -N(H)C(O)alkyl, -
N(H)C(O)(cycloalkyl), N(H)C(O)(aryl) where alkyl is as described herein, and aryl is optionally substituted with one to three substituents selected from a group consisting of: halogen, Cl-3alkyl, alkoxy, amino and acyl. Examples of N-acylamino substituents as used herein include: -N(H)C(O)CH3, -N(H)C(O)CH(CH3)2 and -N(H)C(O)(CH2)3CH3.
By the term "aryloxy" as used herein is meant -O(aryl), -O(substituted aryl), - O(heteroaryl) or -O(substituted heteroaryl).
By the term "arylamino" as used herein is meant -NRgo(aryl), -NRgo(substituted aryl), -NRgo(heteroaryl) or -NRgo(substituted heteroaryl), wherein R80 is H, Cl-6alkyl or C3-C7cycloalkyl.
By the term "heteroatom" as used herein is meant oxygen, nitrogen or sulfur.
By the term "halogen" as used herein is meant a substituent selected from bromide, iodide, chloride and fluoride.
By the term "alkyl" and derivatives thereof and in all carbon chains as used herein, including alkyl chains defined by the term "-(CH2V, "-(CH2)m" and the like, is meant a linear or branched, saturated or unsaturated hydrocarbon chain, and unless otherwise defined, the carbon chain will contain from 1 to 12 carbon atoms.
By the term "substituted alkyl" as used herein is meant an alkyl group substituted with one to six substituents selected from the group consisting of: halogen, trifluoromethyl, alkylcarboxy, amino, substituted amino, cyano, hydroxyl, alkoxy, alkylthio, aryloxy, acyloxy, acyl, acylamino, carbamate, urea, sulfonyl, C3-7cycloheteralkyl, C3-7cycloalkyl and nitro.
Examples of alkyl and substituted alkyl substituents as used herein include: -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2, -CH2-CH2-C(CH3)3, -CH2-CF3, C≡C-C(CH3)3, -C≡C-CH2-OH, cyclopropylmethyl, -CH2-C(CH3)2-CH2-NH2, C≡C-C6H5 , -C≡C-C(CH3)2-OH, -CH2-CH(OH)-CH(OH)-CH(OH)-CH(OH)-CH2-OH, piperidinylmethyl, methoxyphenylethyl, -C(CH3)3, -(CH2)3-CH3, -CH2-CH(CH3)2, -CH(CH3)-CH2-CH3, -CH=CH2, and -C≡C-CH3.
By the term "treating" and derivatives thereof as used herein, is meant prophylatic and therapeutic therapy. Prophylatic therapy is meant the institution of measures to protect a person from a disease to which he or she has been, or may be, exposed. Also called preventive treatment.
By the term "co-administering" and derivatives thereof as used herein is meant either simultaneous administration or any manner of separate sequential administration of a PB kinase inhibiting compound, as described herein, and a further active ingredient or ingredients. The term further active ingredient or ingredients, as used herein, includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of treatment. Suitably, if the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.
The term "compound" as used herein includes all isomers of the compound.
Examples of such isomers include: enantiomers, tautomers, rotamers. In formulas where a "dotted" bond is drawn between two atoms, it is meant that such bond can be either single or double bond. A ring system containing such bonds can be aromatic or non-aromatic.
Certain compounds described herein may contain one or more chiral atoms, or may otherwise be capable of existing as two enantiomers, or two or more diastereoisomers.
Accordingly, the compounds of this invention include mixtures of enantiomers/diastereoisomers as well as purified enantiomers/diastereoisomers or enantiomerically/diastereoisomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds represented by formula I or II above as well as any wholly or partially equilibrated mixtures thereof. The present invention also covers the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted.
Further, an example of a possible tautomer is an oxo substituent in place of a hydroxy substituent. Also, as stated above, it is understood that all tautomers and mixtures of tautomers are included within the scope of the compounds of Formula I or II.
Compounds of Formula (I) are included in the pharmaceutical compositions of the invention. Where a -COOH or -OH group is present, pharmaceutically acceptable esters can be employed, for example methyl, ethyl, pivaloyloxymethyl, and the like for -COOH, and acetate maleate and the like for -OH, and those esters known in the art for modifying solubility or hydrolysis characteristics, for use as sustained release or prodrug formulations. It has now been found that compounds of the present invention are inhibitors of the Phosphatoinositides 3-kinases (PBKs). When the phosphatoinositides 3-kinase (PBK) enzyme is inhibited by a compound of the present invention, PBK is unable to exert its enzymatic, biological or pharmacological effects. The compounds of the present invention are therefore useful in the treatment of autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries.
The compounds of Formula (I) are useful as medicaments in particular for the treatment of autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries. According to one embodiment of the present invention, the compounds of Formula (I) are inhibitors of one or more phosphatoinositides 3-kinases (PBKs), suitably, Phosphatoinositides 3-kinase γ (PBKγ), Phosphatoinositides 3-kinase γ (PBKα), Phosphatoinositides 3-kinase γ (PBKβ), or Phosphatoinositides 3-kinase γ (PBKδ).
Compounds according to Formula (I) are suitable for the modulation, notably the inhibition of the activity of phosphatoinositides 3-kinases (PBK), suitably phosphatoinositides 3-kinase (PBKα). Therefore the compounds of the present invention are also useful for the treatment of disorders which are mediated by PBKs. Said treatment involves the modulation - notably the inhibition or the down regulation - of the phosphatoinositides 3-kinases.
Suitably, the compounds of the present invention are used for the preparation of a medicament for the treatment of a disorder selected from multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosis, inflammatory bowel disease, lung inflammation, thrombosis or brain infection/inflammation, such as meningitis or encephalitis, Alzheimer's disease, Huntington's disease, CNS trauma, stroke or ischemic conditions, cardiovascular diseases such as athero-sclerosis, heart hypertrophy, cardiac myocyte dysfunction, elevated blood pressure or vasoconstriction.
Suitably, the compounds of Formula (I) are useful for the treatment of autoimmune diseases or inflammatory diseases such as multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosis, inflammatory bowel disease, lung inflammation, thrombosis or brain infection/inflammation such as meningitis or encephalitis.
Suitably, the compounds of Formula (I) are useful for the treatment of neurodegenerative diseases including multiple sclerosis, Alzheimer's disease, Huntington's disease, CNS trauma, stroke or ischemic conditions.
Suitably, the compounds of Formula (I) are useful for the treatment of cardiovascular diseases such as atherosclerosis, heart hypertrophy, cardiac myocyte dysfunction, elevated blood pressure or vasoconstriction.
Suitably, the compounds of Formula (I) are useful for the treatment of chronic obstructive pulmonary disease, anaphylactic shock fibrosis, psoriasis, allergic diseases, asthma, stroke, ischemic conditions, ischemia-reperfusion, platelets aggregation/activation, skeletal muscle atrophy/hypertrophy, leukocyte recruitment in cancer tissue, angiogenesis, invasion metastasis, in particular melanoma, Karposi's sarcoma, acute and chronic bacterial and virual infections, sepsis, transplantation rejection, graft rejection, glomerulo sclerosis, glomerulo nephritis, progressive renal fibrosis, endothelial and epithelial injuries in the lung, and lung airway inflammation.
Because the pharmaceutically active compounds of the present invention are active as PB kinase inhibitors, particularly the compounds that inhibit PBKα, either selectively or in conjunction with one or more of PBKδ, PBKβ, or PBKγ, they exhibit therapeutic utility in treating cancer.
Suitably, the invention relates to a method of treating cancer in a mammal, including a human, wherein the cancer is selected from: brain (gliomas), glioblastomas, leukemias, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma, osteosarcoma, giant cell tumor of bone and thyroid.
Suitably, the invention relates to a method of treating cancer in a mammal, including a human, wherein the cancer is selected from: Lymphoblastic T cell leukemia,
Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, Acute megakaryocyte leukemia, promyelocytic leukemia and Erythroleukemia.
Suitably, the invention relates to a method of treating cancer in a mammal, including a human, wherein the cancer is selected from: malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma and follicular lymphoma.
Suitably, the invention relates to a method of treating cancer in a mammal, including a human, wherein the cancer is selected from: neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer.
When a compound of Formula (I) is administered for the treatment of cancer, the term "co-administering" and derivatives thereof as used herein is meant either simultaneous administration or any manner of separate sequential administration of a PB kinase inhibiting compound, as described herein, and a further active ingredient or ingredients, known to be useful in the treatment of cancer, including chemotherapy and radiation treatment. The term further active ingredient or ingredients, as used herein, includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of treatment for cancer. Preferably, if the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.
Typically, any anti-neoplastic agent that has activity versus a susceptible tumor being treated may be co-administered in the treatment of cancer in the present invention. Examples of such agents can be found in Cancer Principles and Practice f Oncology by V. T. Devita and S. Hellman (editors), 6th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved. Typical anti-neoplastic agents useful in the present invention include, but are not limited to, anti-microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclins, actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and anti- folate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; and cell cycle signaling inhibitors. Examples of a further active ingredient or ingredients for use in combination or coadministered with the present PB kinase inhibiting compounds are chemotherapeutic agents.
Anti-microtubule or anti-mitotic agents are phase specific agents active against the microtubules of tumor cells during M or the mitosis phase of the cell cycle. Examples of anti-microtubule agents include, but are not limited to, diterpenoids and vinca alkaloids.
Diterpenoids, which are derived from natural sources, are phase specific anti - cancer agents that operate at the G2ZM phases of the cell cycle. It is believed that the diterpenoids stabilize the β-tubulin subunit of the microtubules, by binding with this protein. Disassembly of the protein appears then to be inhibited with mitosis being arrested and cell death following. Examples of diterpenoids include, but are not limited to, paclitaxel and its analog docetaxel.
Paclitaxel, 5β,20-epoxy-l,2α,4,7β,10β,13α-hexa-hydroxytax-l l-en-9-one 4,10- diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine; is a natural diterpene product isolated from the Pacific yew tree Taxus brevifolia and is commercially available as an injectable solution TAXOL®. It is a member of the taxane family of terpenes. It was first isolated in 1971 by Wani et al. J. Am. Chem, Soc, 93:2325. 1971), who characterized its structure by chemical and X-ray crystallographic methods. One mechanism for its activity relates to paclitaxel's capacity to bind tubulin, thereby inhibiting cancer cell growth. Schiff et al., Proc. Natl, Acad, Sci. USA, 77:1561-1565 (1980); Schiff et al., Nature, 277:665-667 (1979); Kumar, J. Biol, Chem, 256: 10435-10441 (1981). For a review of synthesis and anticancer activity of some paclitaxel derivatives see: D. G. I. Kingston et al., Studies in Organic Chemistry vol. 26, entitled "New trends in Natural Products Chemistry 1986", Attaur-Rahman, P. W. Le Quesne, Eds. (Elsevier, Amsterdam, 1986) pp 219-235.
Paclitaxel has been approved for clinical use in the treatment of refractory ovarian cancer in the United States (Markman et al., Yale Journal of Biology and Medicine, 64:583, 1991; McGuire et al., Ann. Intern, Med., 111 :273,1989) and for the treatment of breast cancer (Holmes et al., J. Nat. Cancer Inst., 83:1797,1991.) It is a potential candidate for treatment of neoplasms in the skin (Einzig et. al., Proc. Am. Soc. Clin. Oncol., 20:46) and head and neck carcinomas (Forastire et. al., Sem. Oncol., 20:56, 1990). The compound also shows potential for the treatment of polycystic kidney disease (Woo et. al., Nature, 368:750. 1994), lung cancer and malaria. Treatment of patients with paclitaxel results in bone marrow suppression (multiple cell lineages, Ignoff, R.J. et. al, Cancer Chemotherapy Pocket Guidβi 1998) related to the duration of dosing above a threshold concentration (5OnM) (Kearns, CM. et. al., Seminars in Oncology, 3(6) p.16-23, 1995). Docetaxel, (2R,3S)- N-carboxy-3-phenylisoserine,N-te/t-butyl ester, 13 -ester with
5β-20-epoxy-l,2α,4,7β,10β,13α-hexahydroxytax-l l-en-9-one 4-acetate 2-benzoate, trihydrate; is commercially available as an injectable solution as TAXOTERE®. Docetaxel is indicated for the treatment of breast cancer. Docetaxel is a semisynthetic derivative of paclitaxel q.v., prepared using a natural precursor, 10-deacetyl-baccatin III, extracted from the needle of the European Yew tree. The dose limiting toxicity of docetaxel is neutropenia.
Vinca alkaloids are phase specific anti-neoplastic agents derived from the periwinkle plant. Vinca alkaloids act at the M phase (mitosis) of the cell cycle by binding specifically to tubulin. Consequently, the bound tubulin molecule is unable to polymerize into microtubules. Mitosis is believed to be arrested in metaphase with cell death following. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, and vinorelbine.
Vinblastine, vincaleukoblastine sulfate, is commercially available as VELBAN® as an injectable solution. Although, it has possible indication as a second line therapy of various solid tumors, it is primarily indicated in the treatment of testicular cancer and various lymphomas including Hodgkin's Disease; and lymphocytic and histiocytic lymphomas. Myelosuppression is the dose limiting side effect of vinblastine.
Vincristine, vincaleukoblastine, 22-oxo-, sulfate, is commercially available as ONCOVIN® as an injectable solution. Vincristine is indicated for the treatment of acute leukemias and has also found use in treatment regimens for Hodgkin's and non-Hodgkin's malignant lymphomas. Alopecia and neurologic effects are the most common side effect of vincristine and to a lesser extent myelosupression and gastrointestinal mucositis effects occur.
Vinorelbine, 3',4'-didehydro -4'-deoxy-C'-norvincaleukoblastine [R-(R*,R*)-2,3- dihydroxybutanedioate (l :2)(salt)], commercially available as an injectable solution of vinorelbine tartrate (NAVELBINE®), is a semisynthetic vinca alkaloid. Vinorelbine is indicated as a single agent or in combination with other chemotherapeutic agents, such as cisplatin, in the treatment of various solid tumors, particularly non-small cell lung, advanced breast, and hormone refractory prostate cancers. Myelosuppression is the most common dose limiting side effect of vinorelbine.
Platinum coordination complexes are non-phase specific anti-cancer agents, which are interactive with DNA. The platinum complexes enter tumor cells, undergo, aquation and form intra- and interstrand crosslinks with DNA causing adverse biological effects to the tumor. Examples of platinum coordination complexes include, but are not limited to, cisplatin and carboplatin.
Cisplatin, cis-diamminedichloroplatinum, is commercially available as PLATINOL® as an injectable solution. Cisplatin is primarily indicated in the treatment of metastatic testicular and ovarian cancer and advanced bladder cancer. The primary dose limiting side effects of cisplatin are nephrotoxicity, which may be controlled by hydration and diuresis, and ototoxicity.
Carboplatin, platinum, diammine [l,l-cyclobutane-dicarboxylate(2-)-O,O'], is commercially available as PARAPLATIN® as an injectable solution. Carboplatin is primarily indicated in the first and second line treatment of advanced ovarian carcinoma. Bone marrow suppression is the dose limiting toxicity of carboplatin.
Alkylating agents are non-phase anti-cancer specific agents and strong electrophiles. Typically, alkylating agents form covalent linkages, by alkylation, to DNA through nucleophilic moieties of the DNA molecule such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazole groups. Such alkylation disrupts nucleic acid function leading to cell death. Examples of alkylating agents include, but are not limited to, nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; and triazenes such as dacarbazine.
Cyclophosphamide, 2-[bis(2-chloroethyl)amino]tetrahydro-2H- 1 ,3 ,2- oxazaphosphorine 2-oxide monohydrate, is commercially available as an injectable solution or tablets as CYTOXAN®. Cyclophosphamide is indicated as a single agent or in combination with other chemotherapeutic agents, in the treatment of malignant lymphomas, multiple myeloma, and leukemias. Alopecia, nausea, vomiting and leukopenia are the most common dose limiting side effects of cyclophosphamide.
Melphalan, 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commercially available as an injectable solution or tablets as ALKERAN®. Melphalan is indicated for the palliative treatment of multiple myeloma and non-resectable epithelial carcinoma of the ovary. Bone marrow suppression is the most common dose limiting side effect of melphalan. Chlorambucil, 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, is commercially available as LEUKERAN® tablets. Chlorambucil is indicated for the palliative treatment of chronic lymphatic leukemia, and malignant lymphomas such as lymphosarcoma, giant follicular lymphoma, and Hodgkin's disease. Bone marrow suppression is the most common dose limiting side effect of chlorambucil. Busulfan, 1 ,4-butanediol dimethanesulfonate, is commercially available as
MYLERAN® TABLETS. Busulfan is indicated for the palliative treatment of chronic myelogenous leukemia. Bone marrow suppression is the most common dose limiting side effects of busulfan.
Carmustine, l,3-[bis(2-chloroethyl)-l -nitrosourea, is commercially available as single vials of lyophilized material as BiCNU®. Carmustine is indicated for the palliative treatment as a single agent or in combination with other agents for brain tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphomas. Delayed myelosuppression is the most common dose limiting side effects of carmustine.
Dacarbazine, 5-(3,3-dimethyl-l-triazeno)-imidazole-4-carboxamide, is commercially available as single vials of material as DTIC-Dome®. Dacarbazine is indicated for the treatment of metastatic malignant melanoma and in combination with other agents for the second line treatment of Hodgkin's Disease. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dacarbazine.
Antibiotic anti-neoplasties are non-phase specific agents, which bind or intercalate with DNA. Typically, such action results in stable DNA complexes or strand breakage, which disrupts ordinary function of the nucleic acids leading to cell death. Examples of antibiotic anti-neoplastic agents include, but are not limited to, actinomycins such as dactinomycin, anthrocyclins such as daunorubicin and doxorubicin; and bleomycins.
Dactinomycin, also know as Actinomycin D, is commercially available in injectable form as COSMEGEN®. Dactinomycin is indicated for the treatment of Wilm's tumor and rhabdomyosarcoma. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dactinomycin.
Daunorubicin, (8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo- hexopyranosyl)oxy]-7,8,9, 10-tetrahydro-6,8, 11 -trihydroxy- 1 -methoxy-5 , 12 naphthacenedione hydrochloride, is commercially available as a liposomal injectable form as DAUNOXOME® or as an injectable as CERUBIDINE®. Daunorubicin is indicated for remission induction in the treatment of acute nonlymphocytic leukemia and advanced HIV associated Kaposi's sarcoma. Myelosuppression is the most common dose limiting side effect of daunorubicin. Doxorubicin, (8S, 10S)-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo- hexopyranosyl)oxy]-8-glycoloyl, 7,8,9,10-tetrahydro-6,8,l l-trihydroxy-l-methoxy-5,12 naphthacenedione hydrochloride, is commercially available as an injectable form as RUBEX® or ADRI AMYCIN RDF®. Doxorubicin is primarily indicated for the treatment of acute lymphoblastic leukemia and acute myeloblastic leukemia, but is also a useful component in the treatment of some solid tumors and lymphomas. Myelosuppression is the most common dose limiting side effect of doxorubicin.
Bleomycin, a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of Streptomyces verticillus, is commercially available as BLENOXANE®. Bleomycin is indicated as a palliative treatment, as a single agent or in combination with other agents, of squamous cell carcinoma, lymphomas, and testicular carcinomas. Pulmonary and cutaneous toxicities are the most common dose limiting side effects of bleomycin.
Topoisomerase II inhibitors include, but are not limited to, epipodophyllotoxins. Epipodophyllotoxins are phase specific anti-neoplastic agents derived from the mandrake plant. Epipodophyllotoxins typically affect cells in the S and G2 phases of the cell cycle by forming a ternary complex with topoisomerase II and DNA causing DNA strand breaks. The strand breaks accumulate and cell death follows. Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide.
Etoposide, 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R )-ethylidene-β-D- glucopyranoside], is commercially available as an injectable solution or capsules as VePESID® and is commonly known as VP-16. Etoposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of testicular and non-small cell lung cancers. Myelosuppression is the most common side effect of etoposide. The incidence of leucopenia tends to be more severe than thrombocytopenia.
Teniposide, 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R )-thenylidene-β-D- glucopyranoside], is commercially available as an injectable solution as VUM ON® and is commonly known as VM-26. Teniposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia in children. Myelosuppression is the most common dose limiting side effect of teniposide. Teniposide can induce both leucopenia and thrombocytopenia. Antimetabolite neoplastic agents are phase specific anti-neoplastic agents that act at
S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis. Consequently, S phase does not proceed and cell death follows. Examples of antimetabolite anti-neoplastic agents include, but are not limited to, fluorouracil, methotrexate, cytarabine, mecaptopurine, thioguanine, and gemcitabine.
5 -fluorouracil, 5-fluoro-2,4- (1H,3H) pyrimidinedione, is commercially available as fluorouracil. Administration of 5 -fluorouracil leads to inhibition of thymidylate synthesis and is also incorporated into both RNA and DNA. The result typically is cell death. 5 -fluorouracil is indicated as a single agent or in combination with other chemotherapy agents in the treatment of carcinomas of the breast, colon, rectum, stomach and pancreas. Myelosuppression and mucositis are dose limiting side effects of 5- fluorouracil. Other fluoropyrimidine analogs include 5-fluoro deoxyuridine (floxuridine) and 5-fluorodeoxyuridine monophosphate.
Cytarabine, 4-amino-l-β-D-arabinofuranosyl-2 (lH)-pyrimidinone, is commercially available as CYTOSAR-U® and is commonly known as Ara-C. It is believed that cytarabine exhibits cell phase specificity at S-phase by inhibiting DNA chain elongation by terminal incorporation of cytarabine into the growing DNA chain. Cytarabine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Other cytidine analogs include 5-azacytidine and 2',2'- difluorodeoxycytidine (gemcitabine). Cytarabine induces leucopenia, thrombocytopenia, and mucositis. Mercaptopurine, 1 ,7-dihydro-6H-purine-6-thione monohydrate, is commercially available as PURINETHOL®. Mercaptopurine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism. Mercaptopurine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Myelosuppression and gastrointestinal mucositis are expected side effects of mercaptopurine at high doses. A useful mercaptopurine analog is azathioprine.
Thioguanine, 2-amino-l,7-dihydro-6H-purine-6-thione, is commercially available as TABLOID®. Thioguanine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism. Thioguanine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Myelosuppression, including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of thioguanine administration. However, gastrointestinal side effects occur and can be dose limiting. Other purine analogs include pentostatin, erythrohydroxynonyladenine, fludarabine phosphate, and cladribine. Gemcitabine, 2'-deoxy-2', 2'-difluorocytidine monohydrochloride (β-isomer), is commercially available as GEMZ AR®. Gemcitabine exhibits cell phase specificity at S- phase and by blocking progression of cells through the Gl /S boundary. Gemcitabine is indicated in combination with cisplatin in the treatment of locally advanced non-small cell lung cancer and alone in the treatment of locally advanced pancreatic cancer. Myelosuppression, including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of gemcitabine administration. Methotrexate, N-[4[[(2,4-diamino-6-pteridinyl) methyljmethylamino] benzoyl]-L- glutamic acid, is commercially available as methotrexate sodium. Methotrexate exhibits cell phase effects specifically at S-phase by inhibiting DNA synthesis, repair or replication through the inhibition of dyhydrofolic acid reductase which is required for synthesis of purine nucleotides and thymidylate. Methotrexate is indicated as a single agent or in combination with other chemotherapy agents in the treatment of choriocarcinoma, meningeal leukemia, non-Hodgkin's lymphoma, and carcinomas of the breast, head, neck, ovary and bladder. Myelosuppression (leucopenia, thrombocytopenia, and anemia) and mucositis are expected side effect of methotrexate administration.
Camptothecins, including, camptothecin and camptothecin derivatives are available or under development as Topoisomerase I inhibitors. Camptothecins cytotoxic activity is believed to be related to its Topoisomerase I inhibitory activity. Examples of camptothecins include, but are not limited to irinotecan, topotecan, and the various optical forms of 7-(4-methylpiperazino-methylene)-10,l l-ethylenedioxy-20-camptothecin described below. Irinotecan HCl, (4S)-4,l l-diethyl-4-hydroxy-9-[(4-piperidinopiperidino) carbonyloxy]-lH-pyrano[3',4',6,7]indolizino[l,2-b]quinoline-3,14(4H,12H)-dione hydrochloride, is commercially available as the injectable solution CAMPTOSAR®.
Irinotecan is a derivative of camptothecin which binds, along with its active metabolite SN-38, to the topoisomerase I - DNA complex. It is believed that cytotoxicity occurs as a result of irreparable double strand breaks caused by interaction of the topoisomerase I : DNA : irintecan or SN-38 ternary complex with replication enzymes. Irinotecan is indicated for treatment of metastatic cancer of the colon or rectum. The dose limiting side effects of irinotecan HCl are myelosuppression, including neutropenia, and GI effects, including diarrhea. Topotecan HCl, (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-lH- pyrano [3 ' ,4 ' ,6,7]indolizino [ 1 ,2-b] quinoline-3 , 14-(4H, 12H)-dione monohydrochloride, is commercially available as the injectable solution HYCAMTIN®. Topotecan is a derivative of camptothecin which binds to the topoisomerase I - DNA complex and prevents religation of singles strand breaks caused by Topoisomerase I in response to torsional strain of the DNA molecule. Topotecan is indicated for second line treatment of metastatic carcinoma of the ovary and small cell lung cancer. The dose limiting side effect of topotecan HCl is myelosuppression, primarily neutropenia. Also of interest, is the camptothecin derivative of formula A following, currently under development, including the racemic mixture (R, S) form as well as the R and S enantiomers:
Figure imgf000034_0001
known by the chemical name "7-(4-methylpiperazino-methylene)-10,l l-ethylenedioxy- 20(R,S)-camptothecin (racemic mixture) or "7-(4-methylpiperazino-methylene)-10,l l- ethylenedioxy-20(R)-camptothecin (R enantiomer) or "7-(4-methylpiperazino-methylene)- 10,l l-ethylenedioxy-20(S)-camptothecin (S enantiomer). Such compound as well as related compounds are described, including methods of making, in U.S. Patent Nos. 6,063,923; 5,342,947; 5,559,235; 5,491,237 and pending U.S. patent Application No. 08/977,217 filed November 24, 1997.
Hormones and hormonal analogues are useful compounds for treating cancers in which there is a relationship between the hormone(s) and growth or lack of growth of the cancer. Examples of hormones and hormonal analogues useful in cancer treatment include, but are not limited to, adrenocorticosteroids such as prednisone and prednisolone which are useful in the treatment of malignant lymphoma and acute leukemia in children ; aminoglutethimide and other aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane useful in the treatment of adrenocortical carcinoma and hormone dependent breast carcinoma containing estrogen receptors; progestrins such as megestrol acetate useful in the treatment of hormone dependent breast cancer and endometrial carcinoma; estrogens, androgens, and anti-androgens such as flutamide, nilutamide, bicalutamide, cyproterone acetate and 5α-reductases such as finasteride and dutasteride, useful in the treatment of prostatic carcinoma and benign prostatic hypertrophy; anti- estrogens such as tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, as well as selective estrogen receptor modulators (SERMS) such those described in U.S. Patent Nos. 5,681,835, 5,877,219, and 6,207,716, useful in the treatment of hormone dependent breast carcinoma and other susceptible cancers; and gonadotropin-releasing hormone (GnRH) and analogues thereof which stimulate the release of leutinizing hormone (LH) or follicle stimulating hormone (FSH) for the treatment prostatic carcinoma, for instance, LHRH agonists and antagagonists such as goserelin acetate and luprolide.
Signal transduction pathway inhibitors are those inhibitors, which block or inhibit a chemical process which evokes an intracellular change. As used herein this change is cell proliferation or differentiation. Signal tranduction inhibitors useful in the present invention include inhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases, SH2/SH3domain blockers, serine/threonine kinases, phosphotidyl inositol-3 kinases, myoinositol signaling, and Ras oncogenes.
Several protein tyrosine kinases catalyse the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth. Such protein tyrosine kinases can be broadly classified as receptor or non-receptor kinases.
Receptor tyrosine kinases are transmembrane proteins having an extracellular ligand binding domain, a transmembrane domain, and a tyrosine kinase domain. Receptor tyrosine kinases are involved in the regulation of cell growth and are generally termed growth factor receptors. Inappropriate or uncontrolled activation of many of these kinases, i.e. aberrant kinase growth factor receptor activity, for example by over-expression or mutation, has been shown to result in uncontrolled cell growth. Accordingly, the aberrant activity of such kinases has been linked to malignant tissue growth. Consequently, inhibitors of such kinases could provide cancer treatment methods. Growth factor receptors include, for example, epidermal growth factor receptor (EGFr), platelet derived growth factor receptor (PDGFr), erbB2, erbB4, vascular endothelial growth factor receptor (VEGFr), tyrosine kinase with immunoglobulin-like and epidermal growth factor homology domains (TIE-2), insulin growth factor -I (IGFI) receptor, macrophage colony stimulating factor (cfms), BTK, ckit, cmet, fibroblast growth factor (FGF) receptors, Trk receptors (TrkA, TrkB, and TrkC), ephrin (eph) receptors, and the RET protooncogene. Several inhibitors of growth receptors are under development and include ligand antagonists, antibodies, tyrosine kinase inhibitors and anti-sense oligonucleotides. Growth factor receptors and agents that inhibit growth factor receptor function are described, for instance, in Kath, John C, Exp. Opin. Ther. Patents (2000) 10(6):803-818; Shawver et al DDT VoI 2, No. 2 February 1997; and Lofts, F. J. et al, "Growth factor receptors as targets", New Molecular Targets for Cancer Chemotherapy, ed. Workman, Paul and Kerr, David, CRC press 1994, London.
Tyrosine kinases, which are not growth factor receptor kinases are termed nonreceptor tyrosine kinases. Non-receptor tyrosine kinases useful in the present invention, which are targets or potential targets of anti-cancer drugs, include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (Focal adhesion kinase), Brutons tyrosine kinase, and Bcr-Abl. Such nonreceptor kinases and agents which inhibit non-receptor tyrosine kinase function are described in Sinh, S. and Corey, S. J., (1999) Journal of Hematotherapy and Stem Cell Research 8 (5): 465 - 80; and Bolen, J.B., Brugge, J.S., (1997) Annual review of
Immunology. 15: 371-404.
SH2/SH3 domain blockers are agents that disrupt SH2 or SH3 domain binding in a variety of enzymes or adaptor proteins including, PI3-K p85 subunit, Src family kinases, adaptor molecules (She, Crk, Nek, Grb2) and Ras-GAP. SH2/SH3 domains as targets for anti-cancer drugs are discussed in Smithgall, T. E. (1995), Journal of Pharmacological and
Toxicological Methods. 34(3) 125-32.
Inhibitors of Serine/Threonine Kinases including MAP kinase cascade blockers which include blockers of Raf kinases (rafk), Mitogen or Extracellular Regulated Kinase (MEKs), and Extracellular Regulated Kinases (ERKs); and Protein kinase C family member blockers including blockers of PKCs (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta). IkB kinase family (IKKa, IKKb), PKB family kinases, AKT kinase family members, and TGF beta receptor kinases. Such Serine/Threonine kinases and inhibitors thereof are described in Yamamoto, T., Taya, S., Kaibuchi, K., (1999), Journal of Biochemistry. 126 (5) 799-803; Brodt, P, Samani, A., and Navab, R. (2000), Biochemical
Pharmacology, 60. 1101-1107; Massague, J., Weis-Garcia, F. (1996) Cancer Surveys.
27:41-64; Philip, P.A., and Harris, AX. (1995), Cancer Treatment and Research. 78: 3-27,
Lackey, K. et al Bioorganic and Medicinal Chemistry Letters, (10), 2000, 223-226; U.S.
Patent No. 6,268,391; and Martinez-Iacaci, L., et al, Int. J. Cancer (2000), 88(1), 44-52.
Inhibitors of Phosphotidyl inositol-3 Kinase family members including blockers of PI3- kinase, ATM, DNA-PK, and Ku are also useful in the present invention. Such kinases are discussed in Abraham, R.T. (1996), Current Opinion in Immunology. 8 (3) 412-8; Canman, C.E., Lim, D.S. (1998), Oncogene 17 (25) 3301-3308; Jackson, S.P. (1997), International Journal of Biochemistry and Cell Biology. 29 (7):935-8; and Zhong, H. et al, Cancer res, (2000) 60(6), 1541-1545.
Also useful in the present invention are Myo-inositol signaling inhibitors such as phospho lipase C blockers and Myoinositol analogues. Such signal inhibitors are described in Powis, G., and Kozikowski A., (1994) New Molecular Targets for Cancer Chemotherapy ed., Paul Workman and David Kerr, CRC press 1994, London.
Another group of signal transduction pathway inhibitors are inhibitors of Ras Oncogene. Such inhibitors include inhibitors of farnesyltransferase, geranyl-geranyl transferase, and CAAX proteases as well as anti-sense oligonucleotides, ribozymes and immunotherapy. Such inhibitors have been shown to block ras activation in cells containing wild type mutant ras , thereby acting as antiproliferation agents. Ras oncogene inhibition is discussed in Scharovsky, O. G., Rozados, V.R., Gervasoni, S.I. Matar, P. (2000), Journal of Biomedical Science. 7(4) 292-8; Ashby, M.N. (1998), Current Opinion in Lipidology. 9 (2) 99 - 102; and BioChim. Biophys. Acta, (19899) 1423(3): 19-30.
As mentioned above, antibody antagonists to receptor kinase ligand binding may also serve as signal transduction inhibitors. This group of signal transduction pathway inhibitors includes the use of humanized antibodies to the extracellular ligand binding domain of receptor tyrosine kinases. For example Imclone C225 EGFR specific antibody (see Green, M. C. et al, Monoclonal Antibody Therapy for Solid Tumors, Cancer Treat. Rev., (2000), 26(4), 269-286); Herceptin ® erbB2 antibody (see Tyrosine Kinase Signalling in Breast canceπerbB Family Receptor Tyrosine Kniases, Breast cancer Res., 2000, 2(3), 176-183); and 2CB VEGFR2 specific antibody (see Brekken, R. A. et al, Selective Inhibition of VEGFR2 Activity by a monoclonal Anti-VEGF antibody blocks tumor growth in mice, Cancer Res. (2000) 60, 5117-5124).
Non-receptor kinase angiogenesis inhibitors may also find use in the present invention. Inhibitors of angiogenesis related VEGFR and TIE2 are discussed above in regard to signal transduction inhibitors (both receptors are receptor tyrosine kinases). Angiogenesis in general is linked to erbB2/EGFR signaling since inhibitors of erbB2 and EGFR have been shown to inhibit angiogenesis, primarily VEGF expression. Thus, the combination of an erbB2/EGFR inhibitor with an inhibitor of angiogenesis makes sense. Accordingly, non-receptor tyrosine kinase inhibitors may be used in combination with the EGFR/erbB2 inhibitors of the present invention. For example, anti-VEGF antibodies, which do not recognize VEGFR (the receptor tyrosine kinase), but bind to the ligand; small molecule inhibitors of integrin (alphav beta3) that will inhibit angiogenesis; endostatin and angiostatin (non-RTK) may also prove useful in combination with the disclosed erb family inhibitors. (See Bruns CJ et al (2000), Cancer Res., 60: 2926-2935; Schreiber AB, Winkler ME, and Derynck R. (1986), Science, 232: 1250-1253; Yen L et al. (2000), Oncogene 19: 3460-3469).
Agents used in immunotherapeutic regimens may also be useful in combination with the compounds of formula (I). There are a number of immunologic strategies to generate an immune response against erbB2 or EGFR. These strategies are generally in the realm of tumor vaccinations. The efficacy of immunologic approaches may be greatly enhanced through combined inhibition of erbB2/EGFR signaling pathways using a small molecule inhibitor. Discussion of the immunologic/tumor vaccine approach against erbB2/EGFR are found in Reilly RT et al. (2000), Cancer Res. 60: 3569-3576; and Chen Y, Hu D, Eling DJ, Robbins J, and Kipps TJ. (1998), Cancer Res. 58: 1965-1971. Agents used in proapoptotic regimens (e.g., bcl-2 antisense oligonucleotides) may also be used in the combination of the present invention. Members of the Bcl-2 family of proteins block apoptosis. Upregulation of bcl-2 has therefore been linked to chemoresistance. Studies have shown that the epidermal growth factor (EGF) stimulates anti-apoptotic members of the bcl-2 family (i.e., mcl-1). Therefore, strategies designed to downregulate the expression of bcl-2 in tumors have demonstrated clinical benefit and are now in Phase II/III trials, namely Genta's G3139 bcl-2 antisense oligonucleotide. Such proapoptotic strategies using the antisense oligonucleotide strategy for bcl-2 are discussed in Water JS et al. (2000), J. Clin. Oncol. 18: 1812-1823; and Kitada S et al. (1994), Antisense Res. Dev. 4: 71-79.
Cell cycle signalling inhibitors inhibit molecules involved in the control of the cell cycle. A family of protein kinases called cyclin dependent kinases (CDKs) and their interaction with a family of proteins termed cyclins controls progression through the eukaryotic cell cycle. The coordinate activation and inactivation of different cyclin/CDK complexes is necessary for normal progression through the cell cycle. Several inhibitors of cell cycle signalling are under development. For instance, examples of cyclin dependent kinases, including CDK2, CDK4, and CDK6 and inhibitors for the same are described in, for instance, Rosania et al, Exp. Opin. Ther. Patents (2000) 10(2):215-230.
In one embodiment, the cancer treatment method of the claimed invention includes the co-administration a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate or pro-drug thereof and at least one anti-neoplastic agent, such as one selected from the group consisting of anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, and cell cycle signaling inhibitors.
Because the pharmaceutically active compounds of the present invention are active as PI3 kinase inhibitors, particularly the compounds that modulate/inhibit PI3Kα, either selectively or in conjunction with one or more of PI3Kγ, PI3Kβ, or PI3Kδ, they exhibit therapeutic utility in treating a disease state selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, cancer, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, sperm motility, transplantation rejection, graft rejection and lung injuries.
When a compound of Formula (I) is administered for the treatment of a disease state selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, cancer, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, sperm motility, transplantation rejection, graft rejection or lung injuries, the term "co-administering" and derivatives thereof as used herein is meant either simultaneous administration or any manner of separate sequential administration of a PB kinase inhibiting compound, as described herein, and a further active ingredient or ingredients, known to be useful in the treatment of autoimmune disorders, inflammatory diseases, cardiovascular diseases, cancer, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, sperm motility, transplantation rejection, graft rejection and/or lung injuries.
Biological Assays
Compounds of the present invention were tested according to the following assays and found as inhibitors of PB kinases, particularly PBKα. The exemplified compounds were tested and found active against PBKα. The ICso's ranged from about 1 nM to 10 μM. The majority of the compounds were under 500 nM; the more active compounds were under 100 nM, the most active compounds can be found under 10 nM.
The compound of Example 2 was tested generally according to the assays described herein and in at least one experimental run exhibited a IC50 value: equal to 100 nM against PBKα.
The compound of Example 5 was tested generally according to the assays described herein and in at least one experimental run exhibited a IC50 value: equal to 32 nM against PBKα.
The compound of Example 9 was tested generally according to the assays described herein and in at least one experimental run exhibited a IC50 value: equal to 25 nM against PBKα.
The compound of Example 42 was tested generally according to the assays described herein and in at least one experimental run exhibited a IC50 value: equal to 100 nM against PBKα.
PBK alpha TR-FRET assay Assay Principle
The PB -Kinase assay has been developed and optimized from a kit produced by Upstate (Millipore). Briefly, this kit contains a biotinylated PIP3 which forms a HTRF (homogeneous time-resolved fluorescence energy transfer) complex when mixed with a Europium labeled anti-GST monoclonal antibody, a GST tagged pleckstrin homology (PH) domain, and Streptavidin-Allophycocyanin (APC). The unlabeled PIP3 produced by PI 3- Kinase activity displaces biotin-PIP3 from the complex resulting in a loss of energy transfer and thus a decrease in signal. Millipore, PI 3 -Kinase (human) HTRF™ Assay, technical document associated with catalog# 33-017
Assay protocol
Compounds are serially diluted (3-fold in 100% DMSO) across a polypropylene 120 μL mother plate from column 1 to column 12 and column 13 to column 24, leaving columns 6 and 18 containing only DMSO to yield 11 concentrations for each test compound. Once titrations are made, 0.1 μL is transferred to the assay plates (Greiner 784075). This assay plate contains three controls: column 6 with DMSO, and column 18 with alternating 20 μM wortmannin and 40 μM PIP3. The wortmannin control is dispensed from a Greiner polypropylene 120 μL mother plate containing > 20μL of ImM wortmannin into the assay plate via the hummingbird or comparable instrument in wells 18 A, C, E, G, I, K, M, O (0.1 μL of ImM wortmannin in 100% DMSO). The PIP3 control is dispensed into the plate manually via a matrix pipettor, lμL of 200 μM PIP3 in IX Reaction buffer to wells 18 B, D, F, H, J, L, N, P.
The PI3 -Kinase assay has been developed and optimized from a kit produced by Upstate (Millipore). The assay kit (cat: 33-017) contains seven reagents: 1) 4X Reaction Buffer, 2) PIP2 (ImM), 3) Stop A, 4) Stop B, 5) Detection Mix A, 6) Detection Mix B, 7) Detection Mix C. In addition the following items were obtained or purchased, PBKinase (prepared in-house), 4X PI3K Detection Buffer (Millipore), dithiothreitol (Sigma, D-5545), Adenosine-5 '-triphosphate (ATP, Sigma, A-6419), PIP3 (l,2-dioctanoyl-sn-glycero-3- [phosphoinositil-3,4,5-triphosphate] tetraammonium salt (Avanti polar lipids, 850186P), DMSO (Sigma, 472301), Wortmannin (Sigma, W-1628).
Prepare IX PBKinase Reaction Buffer by diluting stock 1 :4 with de-ionized water, freshly prepared DTT is added at a final concentration of 5 mM on the day of use. Enzyme addition and compound preincubation is initiated by the addition of 2.5μL of 2X enzyme solution, PBK alpha in IX reaction buffer, to all wells using a Multidrop Combi. Plates are incubated at room temperature for 15 minutes. Substrate addition and reaction initiation is completed by the addition of 2.5μL of 2X substrate solution, PIP2 and ATP in IX reaction buffer, to all wells using a Multidrop Combi. Plates are incubated at room temperature for one hour. Reactions are quenched by the addition of 2.5μL of stop solution (mix Stop A and Stop B in a ratio of 5:1, respectively, i.e.: for a 6000μL total volume, mix 5000μL Stop A and lOOOμL Stop B) to all wells using the Multidrop Combi. Followed by the addition of 2.5μL of Detection Reagents Solution (mix Detection mix C, Detection mix A, and Detection mix B together in an 18:1 :1 ratio, i.e.: for a 6000 μL total volume, mix 5400 μL Detection mix C, 30 OμL Detection mix A, and 300 μL Detection mix B, note: this solution should be prepared 2 hours prior to use) to all wells using the Mulitdrop Combi, cover plate to avoid exposure to light. Incubate one hour, evaluate the HTRF signal on the Envision plate reader.
Data analysis
The loss of PI3 -kinase signal due to product formation leading to biotinylated-PIP3 displacement is nonlinear with respect to both increasing product and time. This non- linear detection will impact accuracy of IC50 calculations; therefore, there is a need for a correction factor or back calculation to obtain a more accurate IC50. The correction varies based on the standard wells of the assay plates (column 6 and 18) of product formed in each assay plate. All data were initially normalized by calculating a ratio of acceptor to donor fluorescence, and %inhibition for each compound concentration was calculated as follows: %inhibition = 100*(signal - CtrlB)/(CtrlA - CtrlB) where QrIA= PBKinase alpha + lOμM Wortmannin and CrtlB= PBKinase alpha + DMSO. An IC50 was then calculated fitting the %inhibition data to the equation: %inhibition = min + (max-min)/(l + ([inhibitor]/IC50)Λn) where min is the %inhibition with no inhibitor (typically 0%), max is the %inhibition with saturating inhibitor (typically 100%), and n is the Hill slope (typically 1). Finally, the IC50 was converted to pIC50 (pIC50 = -log(IC50)), and the pIC50 value was corrected by using plate controls and the equation below: pIC50 (corrected) = pIC50 (observed) + loglO((CtrlA-CtrlB)/(CtrlB-CtrlC)), where CtrlA and CtrlB are as defined above and QtIC= lOμM PI(3,4,5)P3, 100% displacement of biotinylated PI(3,4,5)P3.
PBK alpha Leadseeker SPA Assay
Assay principle
SPA imaging beads are microspheres containing scintillant which emit light in the red region of the visible spectrum. As a result, these beads are ideally suited to use with a CCD imager such as the Viewlux. The Leadseeker beads used in this system are polystyrene beads that have been coupled with polyethyleneimine. When added to the assay mixture, the beads absorb both the substrate (PIP2) and product (PIP3). Adsorbed P33-PIP3 will cause an increase in signal, measured as ADUs (analog to digital units). This protocol details the use of the PEI-PS Leadseeker beads for assays using His-pl 10/p85 PBK alpha.
Assay protocol
Solid compounds are typically plated with 0.1 μl of 100% DMSO in all wells (except column 6 and 18) of a 384-well, flat bottom, low volume plate (Greiner 784075). The compounds are serially diluted (3-fold in 100% DMSO) across the plate from column 1 to column 12 and column 13 to column 24 and leave column 6 and 18 containing only DMSO to yield 1 lconcentraions for each test compound.
The assay buffer contains MOPS (pH 6.5), CHAPS, and DTT. PI3K alpha and PIP2 (L- alpha-D-myo-Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]3-O-phospho linked, D(+)- sn-l,2-di-O-octanoylglyceryl, CellSignals # 901) are mixed and incubated in the plate with compound for 30min prior to starting the reaction with the addition of P33-ATP and MgCl2 (reagents added using Zoom). Enzyme-free wells (column 18) are typically done to determine the low control. PEI-PS Leadseeker beads in PBS/EDTA/CHAPS are added (by Multidrop) to quench the reaction, and the plates are allowed to incubate for at least one hour (typically overnight) before centrifugation. The signal is determined using a Viewlux detector and is then imported into curve fitting software (Activity Base) for construction of concentration response curves. The percent inhibition of activity was calculated relative to high controls (Cl, 0.1 μl DMSO in column 6, rows A-P)) and low controls (C2, 5 μl of 40 uM PIP2 in buffer in column 18, rows A-P) using, 1OO*(1-(U1-C2)/(C1-C2)). The concentration of test compound yielding 50% inhibition was determined using the equation, y = ((Vmax*x) / (K+x)) + Y2, where "K" was equal to the IC50. The IC50 values were converted to pIC50 values, i.e., -log IC50 in Molar concentration.
Celluar assays:
DAY l • Plate cells before noon o 1OK cells/well in clear flat-bottomed 96-well plates (f.v. 105ul) o Last four wells in last column receive media only o Place in 37degC incubator overnight • Compound plate o Prepare in polypropylene round-bottomed 96-well plates; 8 compounds per plate, 11 -pt titrations of each (3x serial dilution), DMSO in last column
(0.15% f.c. on cells) o 15ul in first well, lOul DMSO in the rest; take 5ul from first well and mix in next, continue across plate {excluding last column); seal with foil lid and place at 4degC
DAY 2
• Take out Lysis buffer inhibitors (4degC/-20degC) and compound plates (4degC), thaw on bench top; make Ix Tris wash buffer (WB) to fill reservoir on plate washer and top off bench supply (use MiIiQ), turn on centrifuge to allow it to cool
• Block MSD plates o Make 2OmL 3% blocking solution/plate (600mg blocker A in 2OmL WB), add 150ul/well and incubate at RT for at least 1 hr
• Add compound (while blocking) o Add 300ul growth media (RPMI w/ Q, 10% FBS) per well (682x dil of compound) to each compound plate o Add 5ul compound dilution into each well (f.v. 11 OuI) on duplicate plates o Place in 37degC incubator for 30min
• Make lysates o Prepare MSD Lysis buffer; for 1OmL add 200ul protease inhibitor solution, and lOOul each of Phosphatase inhibitors I & II (Keep on ice until ready for use) o Remove plates post-incubation, aspirate media with plate washer, wash Ix with cold PBS, and add 80ul MSD Lysis buffer per well; incubate on shaker at 4degC for >30min o Spin cold at 2500rpm for lOmin; leave plates in 4degC centrifuge until ready for use
• AKT duplex assay o Wash plates (4x with 200ul/well WB in plate washer); tap plates on paper towel to blot o Add 60ul of lysates/well, incubate on shaker at RT for lhr o During incubation prepare detection Ab (3mL/plate; 2mL WB and ImL blocking solution w/ Ab at 1OnM); repeat wash step as above o Add 25ul of Ab/well, incubate on shaker at RT for lhr; repeat wash step as above o Add 150ul/well Ix Read Buffer (dilute 4x stock in ddH2O, 20mL/plate), read immediately
• Analysis o Observe all the data points at each compound concentration. o The data point from highest inhibitor concentration must be equal or greater than 70% of DMSO control. o IC50 for duplicate runs must be within 2-fold of each other (not flagged in summary template). o Y min must be greater than zero; if both mins are red flagged (>35) then compound is listed as inactive (IC50= > highest dose). If only one min is red flagged, but still <50 then call IC50 as listed. o Any data points equal or greater than 30% off the curve will not be considered.
Cell Growth/Death Assay:
BT474, HCC 1954 and T-47D (human breast) were cultured in RPMI- 1640 containing 10% fetal bovine serum at 370C in 5% CO2 incubator. Cells were split into T75 flask (Falcon #353136) two to three days prior to assay set up at density which yields approximately 70-80% confluence at time of harvest for assay. Cells were harvested using 0.25% trypsin-EDTA (Sigma #4049). Cell counts were performed on cell suspension using Trypan Blue exclusion staining. Cells were then plated in 384 well black flat bottom polystyrene (Greiner #781086) in 48 μl of culture media per well at 1,000 cells/well. All plates were placed at 5% CO2, 370C overnight and test compounds were added the following day. One plate was treated with CellTiter-Glo (Promega #G7573) for a day 0 (t=0) measurement and read as described below. The test compounds were prepared in clear bottom polypropylene 384 well plates (Greiner#781280) with consecutive two fold dilutions. 4 μl of these dilutions were added to 105 μl culture media, after mixing the solution, 2 μl of these dilutions were added into each well of the cell plates. The final concentration of DMSO in all wells was 0.15%. Cells were incubated at 370C, 5% CO2 for 72 hours. Following 72 hours of incubation with compounds each plate was developed and read. CellTiter-Glo reagent was added to assay plates using a volume equivalent to the cell culture volume in the wells. Plates were shaken for approximately two minutes and incubated at room temperature for approximately 30 minutes and chemiluminescent signal was read on the Analyst GT (Molecular Devices) reader. Results were expressed as a percent of the t=0 and plotted against the compound concentration. Cell growth inhibition was determined for each compound by fitting the dose response with a 4 or 6 parameter curve fit using XL fit software and determining the concentration that inhibited 50% of the cell growth (gIC50) with the Y min as the t=0 and Y max as the DMSO control. Value from wells with no cells was subtracted from all samples for background correction. Additional references: The compounds of the present invention can also be tested to determine their inhibitory activity at PI3Kα, PI3Kδ, PI3Kβ and PI3Kγ according to the following references: For all PI3K iso forms:
1. Cloning, expression, purification, and characterization of the human Class Ia phosphoinositide 3-kinase isoforms: Meier, T.I.; Cook, J.A.; Thomas, J.E.;
Radding, J.A.; Horn, C; Lingaraj, T.; Smith, M.C. Protein Expr. Purif, 2004, 35(2), 218. 2. Competitive fluorescence polarization assays for the detection of phosphoinositide kinase and phosphatase activity: Drees, B.E.; Weipert, A.; Hudson, H.; Ferguson, C. G.; Chakravarty, L.; Prestwich, G.D. Comb. Chem. High Throughput.Screen., 2003, 6(4), 321. For PI3Kγ: WO 2005/011686 Al
The pharmaceutically active compounds within the scope of this invention are useful as PI3 Kinase inhibitors in mammals, particularly humans, in need thereof.
The present invention therefore provides a method of treating diseases associated with PI3 kinase inhibition, particularly: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries and other conditions requiring PI3 kinase modulation/inhibition, which comprises administering an effective compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate or pro-drug thereof. The compounds of Formula (I) also provide for a method of treating the above indicated disease states because of their ability to act as PI3 inhibitors. The drug may be administered to a patient in need thereof by any conventional route of administration, including, but not limited to, intravenous, intramuscular, oral, subcutaneous, intradermal, and parenteral. The pharmaceutically active compounds of the present invention are incorporated into convenient dosage forms such as capsules, tablets, or injectable preparations. Solid or liquid pharmaceutical carriers are employed. Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline, and water. Similarly, the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.
The pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to give the desired oral or parenteral products. Doses of the presently invented pharmaceutically active compounds in a pharmaceutical dosage unit as described above will be an efficacious, nontoxic quantity preferably selected from the range of 0.001 - 100 mg/kg of active compound, preferably 0.001 - 50 mg/kg. When treating a human patient in need of a PBK inhibitor, the selected dose is administered preferably from 1-6 times daily, orally or parenterally. Preferred forms of parenteral administration include topically, rectally, transdermally, by injection and continuously by infusion. Oral dosage units for human administration preferably contain from 0.05 to 3500 mg of active compound. Oral administration, which uses lower dosages is preferred. Parenteral administration, at high dosages, however, also can be used when safe and convenient for the patient.
Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular PB kinase inhibitor in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition.
Additional factors depending on the particular patient being treated will result in a need to adjust dosages, including patient age, weight, diet, and time of administration.
The method of this invention of inducing PB kinase inhibitory activity in mammals, including humans, comprises administering to a subject in need of such activity an effective PB kinase modulating/inhibiting amount of a pharmaceutically active compound of the present invention. The invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use as a PB kinase inhibitor.
The invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use in therapy.
The invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use in treating autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries.
The invention also provides for a pharmaceutical composition for use as a PB inhibitor which comprises a compound of Formula (I) and a pharmaceutically acceptable carrier.
The invention also provides for a pharmaceutical composition for use in the treatment of autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries, which comprises a compound of Formula (I) and a pharmaceutically acceptable carrier. No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention.
In addition, the pharmaceutically active compounds of the present invention can be co-administered with further active ingredients, including compounds known to have utility when used in combination with a PB kinase inhibitor.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way.
Experimental Details
Schemes
The compounds of the following examples are readily prepared according to the following Schemes or by analogous methods.
Quinoxalines such as represented by compounds of Formula I can be prepared from, for example, bromoquinoxalinols (2) which have been prepared in the literature (Journal of Medicinal Chemistry, 1981, 24(\), 93-101). As outlined in Scheme 1, bromoquinoxalinols such as compound 2 may be converted to a bromochloroquinoxaline such as compound 3 by for example, treatment with phosphorous oxychloride at elevated temperatures (typically 1200C). The resulting chlorinated compound (3) may undergo a variety of coupling reactions as delineated by steps C, D or E. When the coupling step is for instance a nucleophilic displacement reaction such as for steps C or D, suitable nucleophiles such as amines, or alkoxides are commercially available or easily prepared by methods known to those skilled in the art. In the instances where the coupling step is an amine or alkoxide displacement of the chloride in compound 3, such a displacement may be carried out at room temperature or further facilitated by heating to temperatures such as 70-1000C either in neat reagent or in a suitable polar solvent such as N,N'- dimethy formamide . Alternatively, the coupling step to prepare compounds of formula 4 may be a transition metal (such as palladium) catalyzed cross-coupling reaction of an aryl or heteroaryl boronate ester or boronic acid with compound 3, such as in step E. An exemplerary coupling reaction such as a Suzuki cross-coupling depicted in step E can be acheived by treating compound 3 with an appropriate palladium catalyst (typically 1,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1 :1)), in the presence of inorganic base (such as potassium carbonate, sodium carbonate or sodium bicabonate) and a suitable solvent (such as 1,4-dioxane or N,N'- dimethyformamide) at elevated temperatures (typically 1000C). The resulting compounds of formula (4) may undergo another palladium catalyzed coupling reaction as described above with an aryl or heteroaryl boronate ester or boronic acid to furnish compounds of the present invention such as 6. Likewise, in the instances when R2 in compound 4 is N or O, borylation can be achieved with a palladium catalyst (such as 1,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1 :1)) in the presence of base (such as potassium acetate) in solvent (such as dioxane) at elevated temperature (typically 1000C) to provide boronate esters such as compound 5. Such boronate esters can undergo typical Suzuki cross-coupling reactions (as described above) with approariate aryl or heteroaryl halides to provide compounds of the present invention, such as compound 6. If necessary, as shown in scheme 2, an amine or hydroxyl deprotecting step may be included. These include examples such as removal of a tosylsulfonyl protecting group with aqueous base (such as sodium hydroxide) in a polar solvent such as ethanol at elevated temperature (typically 5O0C) or the removal of a sily protecting group with fluoride ion or aqueous acid (such as acetic acid).
Scheme 1
Figure imgf000048_0001
R2= N or O-node
R1 , N^ .R2
J
6 R2= O, N or C-node
Conditions: a) Bromine, acetic acid, rt; b) POCl3, 120 0C; c) HNRiR2, DMF, 25 0C - 120 0C; d) NaH, HORi, DMF, 25 0C - 120 0C; e) aryl or heteroaryl (R2) boronic or boronate ester, palladium catalyst, K2CO3, NaHCO3 or Na2CO3, water, dioxane or DMF, heat; f) bis(pinacolato)diboron, potassium acetate, palladium catalyst, dioxane, heat; g) aryl or heteroaryl (Rl) bromide, palladium catalyst, K2CO3, NaHCO3 or Na2CO3, water, dioxane or DMF, 100 heat; h) aryl or heteroaryl (Rl) boronic or boronate ester, palladium catalyst, K2CO3, NaHCO3 or Na2CO3, water, dioxane or DMF, heat.
Scheme 2 describes the removal of an amine protecting group when it is necessary to protect an amine before a coupling reaction (such as in steps C, D, E, G or H in Sheme 1 above ) can be carried out. For example, a Boc-protected amine such as compound 7 can be treated with trifluoroacetic acid in a suitable solvent (such as acetonitrile) at room temperature to furnish compounds of the present invention such as compound 8. Likewise, a tosylsulfonyl protected pyrazole amine such as compound 9 can be converted to the free pyrazole compound 10 by treating with aqueous base ( such as aqueous sodium hydroxide) in a polar solvent, typically ethanol and elevated temperatures, for instance 5O0C. Similarly, silylethers may be deprotected using standard methods involving fluoride ion or aqueous acid, for instance acetic acid to furnish hydroxyl compounds such as 12.
Scheme 2
Figure imgf000049_0001
Figure imgf000049_0002
C-node
Conditions: a) Trifluoroacetic acid, acetonitrile, rt; b) 1-6N NaOH (aq), EtOH,
5O0C; c) AcOH, water, THF, rt.
Alternatively, a carbonyl containing compound such as 13 (Scheme 3) can be reduced to the corresponding alcohol using a hydride based reducing agent such as sodium borohydride in a polar protic solvent to furnish hydroxyl containing compounds such as 14. Scheme 3
Figure imgf000050_0001
Conditions: a) NaBH4, MeOH, rt.
Pyrazoles such as compound 9 (Scheme 2) can be prepared from the Suzuki coupling of an aryl bromide such as compound 17 (Scheme 4) with compounds such as 5 (Scheme 1). Compounds of formula 17 can be prepared from substituted pyrazoles such as 15, some of which are commercially available and the preparation of which is described in the literature (Inorganic Chemistry 2002, 41(1), 1889-1896).
Scheme 4
Figure imgf000050_0002
Conditions: a) N-bromosuccinimide, N,N-dimethylformamide, RT; b) p- toluenesulfonyl chloride, pyridine, methylene chloride, RT.
Experimental Section:
Compounds of the present invention can be prepared according to Schemes 1 - 4, using different coupling groups in steps C, D, and E (Scheme 1). Alternative coupling groups for step C, D, and E are all commercially available, known in the literature or described in preparations for Intermediates 1 and 2 below.
Exemplary preparations are described in Examples 1 -44. All claimed compounds were or can be prepared by the preparations described in this section.
Example 1
Preparation of 5-r3-(4-morpholinyl)-6-quinoxalinyll-2-furancarbaldehvde
Figure imgf000050_0003
A mixture of 7-bromo-2-(4-morpholinyl)quinoxaline (386 mg, 1.31 mmol), 5- formyl-2-furanboronic acid (220 mg, 1.57 mmol), [1,1 '-bis(diphenylphosphino)- ferrocene]-dichloropalladium(II) dichloromethane adduct (19 mg, 0.03 mmol), and 2M aqueous sodium carbonate (2.6 mL, 5.25 mmol) in 1,4-dioxane (15 mL) was heated at 100 0C for 18 hours. The reaction was cooled and diluted with dichloromethane then treated with decolorizing charcoal and sodium sulfate. Filtration through a pad of celite followed by concentration under reduced pressure gave the crude product. The resulting oil was purified by silica gel chromatography (50% Hexanes in ethyl acetate) to give the title compound (268 mg, 66 %) as a solid. MS(ES)+ m/e 309.8 [M+H]+.
The following compounds were or can be prepared following the procedures used to prepare Example 1 using different heterocyclic boronic acids:
Figure imgf000051_0002
Example 3
Preparation of (5 - [3 -(4-morpholinyl)-6-quinoxalinyll -2-furanyl| methanol
Figure imgf000051_0001
A slurry of 5-[3-(4-morpholinyl)-6-quinoxalinyl]-2-furancarbaldehyde (200 mg,
0.65 mmol) in absolute ethanol (20 mL) was treated with sodium borohydride (35 mg, 1.26 mmol) in one portion. After stirring at ambient temperature for 20 hours, the reaction was evaporated under reduced pressure. The resulting residue was taken into water then extracted into ethy acetate. The extracts were dried over sodium sulfate then evaporated to a residue that was purified by silica gel chromatography (3% methanol in dichloromethane). The obtained product was recrystallized from acetonitrile to give the title compound (45 mg, 22%) as a yellow solid. MS(ES)+ m/e 311.8 [M+H]+.
Example 4 Preparation of { 5 -[3 -(4-pyridinvD-6-quinoxalinyH -2-furanyll methanol
Figure imgf000052_0001
a) 7-[5-({[(l,l-dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-furanyl]-2-(4- pyridinyl)quinoxaline
A mixture of 7-bromo-2-(4-pyridinyl)quinoxaline (170 mg, 0.59 mmol), [5-({[(l,l- dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-furanyl]boronic acid (183 mg, 0.71 mmol), [1,1 '-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) dichloromethane adduct (13 mg, 0.02 mmol), and 2M aqueous sodium carbonate (1.2 mL, 2.38 mmol) in 1,4- dioxane (15 mL) was heated at 100 0C for 4 hours. The reaction was cooled to room temperature then concentrated under reduced pressure. The resulting residue was taken into brine then extracted into ethyl acetate. The extracts were dried over sodium sulfate and evaporated to a residue that was purified by silica gel chromatography (20% hexanes in ethyl acetate) to give the title compound (162 mg, 65%) as a yellow solid. MS(ES)+ m/e 418.4 [M+H]+.
b) {5 - [3 -(4-pyridinyl)-6-quinoxalinyl] -2-furanyl} methanol
A solution of 7-[5-({[(l,l -dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-furanyl]-2- (4-pyridinyl)quinoxaline (162 mg, 0.39 mmol) in a 3:1 :1 mixture of acetic acid, water and tetrahydrofuran, respectively, was stirred at room temperature for 5 days. The reaction was evaporated under reduced pressure. The resulting residue was taken into saturated aqueous sodium bicarbonate, extracted into ethyl acetate, dried over sodium sulfate then evaporated under reduced pressure. The residue was purified by silica gel chromatography (100% ethyl acetate) to give the title compound (57 mg, 48%) as a yellow solid. MS(ES)+ m/e 303.9 [M+H]+.
Example 5
Preparation of 2-(4-morpholinyl)-7-(3 -phenyl- lH-pyrazol-4-yl)quinoxaline
Figure imgf000052_0002
a) 4-bromo-3 -phenyl- lH-pyrazole A solution of commercially available pyrazole or one prepared as described in the literature {Inorganic Chemistry 2002, 41(1), 1889-1896 ) such as 3-phenyl-lH-pyrazole (2.98 g, 20.67 mmol) in anhydrous N,N-dimethylformamide (40 mL) was treated in one portion with N-bromosuccinimide (3.68 g, 20.67 mmol). The reaction stirred at room temperature for 1 hour then was evaporated under reduced pressure. The resulting oil was taken into hot acetonitrile (15 mL) then diluted with water until the product precipitated from the solution. The solids were collected by filtration, rinsed with water and vacuum dried to give the title compound (4.19 g, 91%) as a white solid. MS(ES)+ m/e 222.8,
224.8, bromine pattern [M+Η]+.
b) 4-bromo- 1 - [(4-methylphenyl)sulfonyl] -3 -phenyl- lH-pyrazole
A solution of 4-bromo-3-phenyl-lH-pyrazole (4.15 g, 18.6 mmol) and pyridine (4.5 mL, 55.8 mmol) in anhydrous methylene chloride (40 mL) was treated in one portion with /?-toluenesulfonyl chloride (4.26 g, 22.3 mmol) then stirred at room temperature for 3 days. The reaction was evaporated under reduced pressure and the resulting residue was taken into ethyl acetate and washed with portions of saturated aqueous sodium bicarbonate and brine solution then dried over anhydrous sodium sulfate. This organic solution was evaporated under reduced pressure to a residue then purified by silica chromatography ( 5% ethyl acetate in Ηexanes). The desired fractions were combined and evaporated under reduced pressure to give the title compound (6.90 g, 98%) as a white solid. MS(ES)+ m/e
376.9, 379.0, bromine pattern [M+Η]+.
c) 7-{l-[(4-methylphenyl)sulfonyl]-3-phenyl-lH-pyrazol-4-yl}-2-(4- morpholinyl)quinoxaline
A slurry of 7-bromo-2-(4-morpholinyl)quinoxaline (112 mg, 0.38 mmol) or a related quinoxaline, bis(pinacolato)diboron (106 mg, 0.42 mmol), [1,1 '- bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with CH2Cl2 (16 mg, 0.02 mmol), and potassium acetate (75 mg, 0.76 mmol) in 1,4-dioxane (6.0 mL) was heated at 100 0C for 2 hours. The reaction was cooled briefly then 4-bromo- 1 -[(4- methylphenyl)sulfonyl]-3-phenyl-lH-pyrazole (144 mg, 0.38 mmol), [1,1 '- bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with CH2Cl2 (16 mg, 0.02 mmol) and 2M aqueous solution of sodium carbonate (0.76 mL, 1.52 mmol) were added and the reaction was heated at 100 0C for a further 18 hours. Cooled to room temperature then concentrated under reduced pressure. The resulting wet residue was taken into ethyl acetate (50 mL) then filtered through a short pad of silica gel (20 g) topped with anhydrous sodium sulfate (5 g). The filtrate was evaporated under reduced pressure and the resulting residue was purified by silica chromatography ( 30% hexanes in ethyl acetate). The desired fractions were combined and evaporated under reduced pressure to give the title compound (122 mg, 63 %) as a pale yellow solid. MS(ES)+ m/e 512.2 [M+H]+.
d) 2-(4-morpholinyl)-7-(3 -phenyl- lH-pyrazol-4-yl)quinoxaline
A solution of 7- { 1 -[(4-methylphenyl)sulfonyl]-3-phenyl- lH-pyrazol-4-yl} -2-(4- morpholinyl)quinoxaline (100 mg, 0.20 mmol) in ethanol (15 mL) was treated with a IN solution of NaOH (5 mL) then heated at 50 0C for 18 hours. The reaction was treated with IN HCl (5 mL) then concentrated under reduced pressure. The aqueous concentrate was diluted with a saturated aqueous solution of sodium bicarbonate then extracted into methylene chloride. The extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting orange residue was purified by silica chromatography (20% Ηexanes in ethyl acetate) and the desired fractions were combined and evaporated to give the tittle compound (52 mg, 74 %) as a yellow solid. MS(ES)+ m/e 358.0 [M+Η]+.
The following compounds were or can be prepared following the procedures used to prepare Example 5 using different pyrazole bromides in step b:
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Example 23
Preparation of 7- {3-methyl-l-[(4-methylphenyl)sulfonyll-lH-pyrazol-4-yl|-2-(4- morpholinvDquinoxaline
Figure imgf000056_0002
7- {3-methyl- 1 -[(4-methylphenyl)sulfonyl]- lH-pyrazol-4-yl} -2-(4- morpholinyl)quinoxaline
In a sealed tube, a solution of 2-(4-morpholinyl)-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoxaline (200 mg, 0.586 mmol), 4-bromo-3-methyl-l-[(4- methylphenyl)sulfonyl]-lH-pyrazole (194 mg, 0.615 mmol), and dichloro[l,l '- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (24 mg, 0.029 mmol) in 1 ,4-dioxane (2 mL) and saturated aqueous sodium bicarbonate solution (2 mL) was stirred at 100 0C for 1.5 hr. The reaction was cooled to room temperature. The reaction was diluted with 100 mL ethyl acetate and 50 mL water. The layers were separated and the aqueous layer was back-extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate and concentrated in vacuo to give a brown residue. Purification by silica gel chromatography ( 0-100% ethyl acetate/hexanes) afforded the title compound as a yellow solid (223 mg, 80%). MS(ES)+ m/e 450.1 [M+H]+.
The following compounds were or can be prepared following the procedures used to prepare Example 23 using different pyrazole bromides:
Figure imgf000057_0001
Figure imgf000058_0001
Examples 31 and 32
Preparation of 7-(3-cyclohexyl- 1 -methyl- lH-pyrazol-4-yl)-2-(4-morpholinyl)quinoxaline and 7-(5-cyclohexyl-l -methyl- lH-pyrazol-4-yl)-2-(4-morpholinyl)quinoxaline:
Figure imgf000058_0002
a) 4-bromo-3-cyclohexyl-l-methyl-lH-pyrazole and 4-bromo-5-cyclohexyl-l-methyl-lH- pyrazole
In an oven-dried round bottom flask under nitrogen, 4-bromo-3-cyclohexyl-lΗ- pyrazole (2.876 g, 12.55 mmol) in anhydrous N,N-dimethylformamide (20 mL) at 0 0C was treated with sodium hydride (0.502g, 12.55 mmol). The pale yellow solution bubbled slightly and the reaction was stirred for 30 minutes at room temperature. Iodomethane (0.942 mL, 15.06 mmol) was added and the reaction s stirred at room temperature for 1 hour. The reaction was poured into 100 mL of an ice-water mixture and the product extracted with ethyl acetate (20OmL). The aqueous layer was back-extracted with ethyl acetate (2 x 25 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, and concentrated in vacuo. Purification by silica gel chromatography ( 0-30% ethyl acetate/hexanes) provided a mixture of the title compounds as a colourless liquid. MS(ES)+ m/e 243.0, 245.0 bromine pattern [M+H]+.
b) 7-(3-cyclohexyl-l -methyl- lH-pyrazol-4-yl)-2-(4-morpholinyl)quinoxaline and 7-(5- cyclohexyl- 1 -methyl- lH-pyrazol-4-yl)-2-(4-morpholinyl)quinoxaline
In a sealed tube, a solution of 2-(4-morpholinyl)-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoxaline (702 mg, 2.056 mmol), a mixture of 4-bromo-3-cyclohexyl- 1 -methyl- lH-pyrazole and 4-bromo-5-cyclohexyl-l-methyl-lH-pyrazole (500 mg, 2.056 mmol), and 1 , r-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (84 mg, 0.103 mmol) in 1,4-dioxane (5.14 mL) and saturated aqueous sodium bicarbonate solution (5.14 mL) was stirred at 100 0C for 1.5 hours. The reaction was cooled to room temperature. The reaction was diluted with ethyl acetate (100 mL) and water (50 mL), and the mixture was filtered through Celite. The layers were separated and the aqueous layer was back-extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate and concentrated in vacuo to give a brown residue. Purification by silica gel chromatography ( 30-100% ethyl acetate/hexanes) provided a 1 :1 mixture of the title compounds as a pale yellow foamy solid (318 mg). Purification by reverse phase ΗPLC provided 7-(3-cyclohexyl-l-methyl- lΗ-pyrazol-4-yl)-2-(4-morpholinyl)quinoxaline as a yellow solid (117 mg, 0.310 mmol, 15.07% yield) as the first isomer collected off the column and then 7-(5-cyclohexyl-l- methyl-lH-pyrazol-4-yl)-2-(4-morpholinyl)quinoxaline as a yellow solid (123 mg, 0.326 mmol, 15.85% yield). MS(ES)+ m/e 378.1, 378.0 respectively [M+H]+.
Example 33
Preparation of l-\ 1 -methyl-3-(4-nitrophenyl)- lH-pyrazol-4-yll-2-(4- morpholinvDquinoxaline
Figure imgf000059_0001
In a sealed tube, a solution of l-methyl-3-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazole (560 mg, 1.700 mmol, WO2007024843A2), 7- bromo-2-(4-morpholinyl)quinoxaline (500 mg, 1.700 mmol), and 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (69 mg, 0.084 mmol) in 1,4-dioxane (4.25 mL) and saturated aqueous sodium bicarbonate solution (4.250 mL) was stirred at 100 0C for 1.5 hours. The reaction was cooled to room temperature. The reaction was diluted with ethyl acetate (100 mL) and water (50 mL), and the layers were separated. The aqueous layer was back-extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate and concentrated in vacuo to give a brown solid. The solid was triturated in dichloromethane to give a yellow solid following vacuum filtration. The yellow solid was washed with methanol to give the title compound (92% pure). The solid and filtrate were combined and purified by silica gel chromatography ( 10-100% ethyl acetate/hexanes, 30 minutes) to provide unreacted 7-bromo-2-(4-morpholinyl)quinoxaline (240 mg) and the title compound as a pale yellow solid (231 mg, 33%). MS(ES)+ m/e 417.2 [M+H]+.
Example 34
Preparation of (4- { 1 -methyl-4-r3-(4-morpholinyl)-6-quinoxalinyll- lH-pyrazol-3- yllphenvDamine
Figure imgf000060_0001
In an oven-dried flask under nitrogen, a mixture of 10% palladium on carbon (22 mg, 0.207 mmol) and 7-[l-methyl-3-(4-nitrophenyl)-lΗ-pyrazol-4-yl]-2-(4- morpholinyl)quinoxaline (110 mg, 0.264 mmol) in anhydrous tetrahydrofuran (15 mL) was prepared. The flask was evacuated (vacuum line), backfilled with nitrogen (3 times), evacuated again and finally filled with hydrogen (via balloon 3 times). The reaction was stirred under hydrogen (1 atm via balloon) at room temperature for 4 hours. The reaction was filtered through a pad of Celite, washing with ethyl acetate (50 mL). The filtrate was concentrated in vacuo, the residue purified by silica gel chromatography (30-100% ethyl acetate/hexanes) followed by purification by reverse phase HPLC to provide the title compound as a yellow solid (5%). MS(ES)+ m/e 387.3 [M+H]+.
Example 35
Preparation of 1 -methyl-4-[3-(l -methyl- lH-pyrazol-4-yl)-6-quinoxalinyl"|- lH-pyrazol-5- amine
Figure imgf000060_0002
In a sealed tube, a solution of 2-(l-methyl-lH-pyrazol-4-yl)-7-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)quinoxaline (600 mg, 1.784 mmol), 4-bromo-l -methyl- IH- pyrazol-5 -amine (314 mg, 1.784 mmol), and l,l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (72.8 mg, 0.089 mmol) in 1,4-dioxane (5 mL) and saturated aqueous potassium carbonate solution (5 mL) was stirred at 100 0C for 1.5 hours. The reaction was cooled to room temperature and diluted with ethyl acetate (100 mL) and water (50 mL). The aqueous layer was back-extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate and concentrated in vacuo to give a brown residue. Purification by silica gel chromatography (0-100% ethyl acetate/hexanes, then 100% ethyl acetate then 10% methanol/ethyl acetate) provided the title compound as a yellow solid (37%). MS(ES)+ m/e 306.1 [M+H]+.
The following compounds were or can be prepared following the procedures described in Example 35 using different heteroaryl bromides:
Figure imgf000061_0002
Example 37
Preparation of N-{l-methyl-4-[3-(l-methyl-lH-pyrazol-4-yl)-6-quinoxalinyll-lH-pyrazol- 5 -vU benzenesulfonamide
Figure imgf000061_0001
a) N-{1 -methyl-4-[3-( 1 -methyl- 1 H-pyrazol-4-yl)-6-quinoxalinyl]- 1 H-pyrazol-5-yl} -N- (phenylsulfonyl)benzenesulfonamide
In an oven-dried round bottom flask under nitrogen, a solution of l-methyl-4-[3-(l- methyl-lH-pyrazol-4-yl)-6-quinoxalinyl]-lH-pyrazol-5 -amine (100 mg, 0.328 mmol) and pyridine (0.029 mL, 0.360 mmol) in dichloromethane (1.638 mL) at room temperature was treated with benzenesulfonyl chloride (0.044 mL, 0.344 mmol) by syringe. The reaction was stirred for 30 minutes. Additional benzenesulfonyl chloride (0.044 mL, 0.344 mmol) to drive the reaction to all bis-sulfonylated product). Stirring was continued overnight. The reaction was concentrated in vacuo, the residue diluted with ethyl acetate (100 mL) and neutralized with saturated aqueous sodium ammonium chloride. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification by silica gel chromatography (0-10% methanol/ethyl acetate) provided the title compound as an off-white solid (25 mg, 13%). MS(ES)+ m/e 587.1 [M+H]+. b) N-{l-methyl-4-[3-(l-methyl-lH-pyrazol-4-yl)-6-quinoxalinyl]-lH-pyrazol-5- yl}benzenesulfonamide
A solution of N-{l-methyl-4-[3-(l-methyl-lH-pyrazol-4-yl)-6-quinoxalinyl]-lH- pyrazol-5-yl}-N-(phenylsulfonyl)benzenesulfonamide (25 mg, 0.043 mmol) in anhydrous pyridine (1 rnL) was treated with pyrrolidine (3.53 μL, 0.043 mmol). The reaction was stirred at 70 0C for 1.5 hours. The reaction was cooled to room temperature and concentrated in vacuo. The yellow residue was diluted with ethyl acetate (30 mL) and neutralized using saturated aqueous ammonium chloride solution. The organic layer was washed with brine (15 mL) and then dried over magnesium sulfate and concentrated in vacuo to give a tan solid. Trituration in dichloromethane provided the title compound as an ivory white solid (69%) after drying in a vacuum oven. MS(ES)+ m/e 446.3 [M+H]+.
Example 38
Preparation of Λ/-{l-methyl-4-r3-(l-methyl-lH-pyrazol-4-yl)-6-quinoxalinyll-lH-pyrazol- 5-yl|benzamide
Figure imgf000062_0001
In an oven dried flask under nitrogen, a solution of l-methyl-4-[3-(l-methyl-lH- pyrazol-4-yl)-6-quinoxalinyl]-lH-pyrazol-5 -amine (91 mg, 0.298 mmol) and triethylamine (0.050 mL, 0.358 mmol) in dichloromethane (2.5 mL) was treated with benzoyl chloride (0.036 mL, 0.313 mmol) at room temperature. The reaction was stirred for 2 hours. The reaction was diluted with ethyl acetate (100 mL) and neutralized with saturated aqueous ammonium chloride solution. The aqueous layer was back-extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate and concentrated in vacuo to give a brown residue. The brown residue was treated with methanol and the resultant yellow precipitate was filtered off. The filtrate was concentrated in vacuo. Following two purifications by reverse phase HPLC, the title compound was obtained as a slightly off-white solid (21%). MS(ES)+ m/e 410.2 [M+H]+.
Example 39 Preparation of 7-( 1 -methyl- lH-imidazol-5-yl)-2-( 1 -methyl- lH-pyrazol-4-vDquinoxaline
Figure imgf000063_0001
In an oven-dried sealed tube, a solution of l-methyl-5-tributylstannanyl-lΗ- imidazole (150 mg, 0.404 mmol), 7-bromo-2-(l -methyl- lH-pyrazol-4-yl)quinoxaline (117 mg, 0.404 mmol) and tetrakis(triphenylphosphine)palladium(0) (24 mg, 0.021 mmol) in 1,4-dioxane (2 mL) was stirred at 100 0C for 18 hours. The reaction was cooled to room temperature and LCMS showed that the reaction had not progessed to completion. Additional l-methyl-5-tributylstannanyl-lH-imidazole (150 mg, 0.404 mmol) was added and the reaction was stirred at 100 0C for an additional 7 hours. The reaction was transferred to a round bottom flask and concentrated in vacuo to give a brown residue. Trituration in ethyl acetate provided the title compound as a brown solid (81%). MS(ES)+ m/e 291.1 [M+H]+.
Example 40
Preparation of 7-d -methyl- lH-imidazol-5-yl)-2-(4-morpholinyl)quinoxaline
Figure imgf000063_0002
Following the procedure described in Example 39 using 7-bromo-2-(4- morpholinyl)quinoxaline provided the title compound as a yellow solid (69%). MS(ES)+ ml Q 296.1 [M+H] +"1".
Example 41
Preparation of 2-d -methyl- lH-pyrazol-4-vO-7-(4-phenyl- IH- 1.2.3-triazol-5- vDquinoxaline
Figure imgf000063_0003
In an oven dried microwave vessel under nitrogen, 7-bromo-2-( 1 -methyl- 1Η- pyrazol-4-yl)quinoxaline (150 mg, 0.519 mmol), bis(pinacolato)diboron (158 mg, 0.623 mmol), potassium acetate (153 mg, 1.556 mmol), and 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (18.98 mg, 0.026 mmol) in 1,4-dioxane (2 mL) was stirred at 100 0C in an oil bath for 45 minutes. The reaction was cooled to room temperature. 4-bromo-5-phenyl-lH-l,2,3-triazole (116 mg, 0.519 mmol, US20050153877 Al) and 2M potassium carbonate solution (0.259 mL, 0.519 mmol) were added to the reaction mixture and the vessel was sealed again. The reaction was stirred at 100 0C for 15 hours and then cooled to room temperature. Monitoring by LCMS showed that the reaction had not proceeded - only both starting materials were observed. Additional 1,1'- bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (18.98 mg, 0.026 mmol) was added to the reaction and stirred at 100 0C for an additional 24 hours. The reaction was cooled to room temperature. The reaction was filtered through Celite and the pad washed with ethyl acetate. The bi-phasic mixture was separated in a separatory funnel. The organic layer was washed with brine (20 mL), dried over magnesium sulfate, and concentrated in vacuo to give a brown solid. Trituration of the solid in dichloromethane and ether gave a purple solid after filtration. The filtrate was concentrated in vacuo and the residue triturated in ethyl acetate to give a tan solid after filtration. The purple solid was triturated in dichloromethane and filtered to give another purple solid. All solids above were combined and dissolved in dimethylsulfoxide. This solution were purified by reverse phase HPLC to give a white solid. Trituration in dichloromethane/ethyl acetate (1 :1) an dcollection of the precipitate provided the title compound as a white solid (12.3 mg, 7%). MS(ES)+ m/e 354.1 [M+H]+.
Example 42
Preparation of 2-( 1 -methyl- lH-pyrazol-4-yl)-7-( 1 -phenyl- IH-1 ,2,3-triazol-5- vDquinoxaline
Figure imgf000064_0001
A solution of 5-bromo-l-phenyl-lΗ-l,2,3-triazole (120 mg, 0.428 mmol,
US20070249579A1), 2-(l-methyl-lH-pyrazol-4-yl)-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoxaline (176 mg, 0.471 mmol), 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (31 mg, 0.042 mmol) and 2M potassium carbonate solution (0.643 mL, 1.285 mmol) in 1,4- dioxane (3 niL) was stirred at 100 0C for 90 minutes. The reaction was cooled to room temperature and diluted with ethyl acetate (100 mL) and water (50 mL). The aqueous layer was back-extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate and concentrated in vacuo to give a brown residue. Purification by silica gel chromatography (ethyl acetate/hexanes, 30 minutes) provided the title compound as a yellow solid (92% pure). Recrystallization of the yellow solid in ethanol followed by drying in a vacuum oven provided the title compound as a yellow-brown solid (25 mg, 16.5%). MS(ES)+ m/e 354.1 [M+H]+.
Example 43
Preparation of 2-( 1 -methyl- lH-pyrazol-4-yl)-7-r 1 -(phenylsulfonyl)- lH-pyrazol-4- yllquinoxaline and 2-(l -methyl- lH-pyrazol-4-yl)-7-(lH-pyrazol-4-yl)quinoxaline
Figure imgf000065_0001
a) 1 -(phenylsulfonyl)-4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- lH-pyrazole
To a solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (100 mg, 0.515 mmol) in pyridine (54 μL, 0.670 mmol) and dichloromethane (3 mL) was added benzenesulfonyl chloride (73 μL, 0.567 mmol) dropwise. After 2.5 hours, the reaction mixture was quenched with a little methanol and then dryed in vacuo. Purification of the residue by flash chromatography (15-40% ethyl acetate/hexanes) afforded the title compound as a white solid (76%). 1H NMR (DMSO-J6, 400 MHz) δ: 8.58 (s, IH), 8.04 (d, 2H, J = 8.4 Hz), 7.97 (s, IH), 7.81 (t, IH, J = 7.6 Hz), 7.68 (t, 2H, J = 7.8 Hz), 1.26 (s, 12H).
b) 2-(l-methyl-lH-pyrazol-4-yl)-7-[l -(phenylsulfonyl)- lH-pyrazol-4-yl]quinoxaline and 2-(l -methyl- lH-pyrazol-4-yl)-7-(lH-pyrazol-4-yl)quinoxaline
A mixture of 7-bromo-2-(l -methyl- lH-pyrazol-4-yl)quinoxaline (100 mg, 0.346 mmol), 1 -(phenylsulfonyl)-4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- lH-pyrazole (138 mg, 0.413 mmol), and [l,l '-bis(diphenylphosphino)-ferrocene]- dichloropalladium(II)-dichloromethane adduct (8 mg, 9.80 μmol) in 2M aqueous sodium carbonate (0.500 mL, 1.00 mmol) and 1,4-dioxane (2.5 mL) was heated at 100 0C for 20.5 h. The reaction mixture was cooled to room temperature, diluted with water (50 mL) and brine (10 mL), and extracted with (3 x 50 mL) ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (45-100% ethyl acetate/hexanes) provided two products, 2-(l -methyl- lH-pyrazol-4-yl)-7-[ 1 -(phenylsulfonyl)- lH-pyrazol-4-yl]quinoxaline as a yellow solid in 16% yield (MS(ES)+ m/e 417 [M+Η]+) and 2-(l -methyl- lH-pyrazol-4-yl)- 7-(lH-pyrazol-4-yl)quinoxaline as a yellow solid in 42% yield (MS(ES)+ m/e 277 [M+Η]+).
Some non-commercially available intermediates such as heteroaryls, heteroaryl (Rl or R2) bromides, boronic acids (Rl or R2) and boronate esters (Rl or R2) were or can be prepared following Schemes 3 and 4 and the procedures below or by methods known in the literature.
Intermediate 1
Preparation of 2-(4-Morpholinyl)-7-(4 A5,5-tetramethyl-l ,3,2-dioxaborolan-2- vDquinoxaline
Figure imgf000066_0001
a) 7-bromo-2(lH)-quinoxalinone:
Prepared according to the procedure described in Journal of Medicinal Chemistry, 1981, 24(1), 93-101.
b) 7-Bromo-2-chloroquinoxaline
A slurry of 7-bromo-2(lH)-quinoxalinone (22.2 mmol) in neat phosphorus oxy chloride (50 mL) was heated at 120 0C for 20 hours. The reaction was cooled to ambient temperature then concentrated under reduced pressure to a purple residue. The residue was taken into ethyl acetate then slowly poured into ice-cold, saturated aqueous sodium bicarbonate solution (-100 mL) and extracted with ethyl acetate. The extracts were washed with saturated aqueous sodium bicarbonate and brine then dried over anhydrous sodium sulfate and decolorizing charcoal. The slurry was filtered through Celite then concentrated under reduced pressure to give the title compound (3.0 g, 55%) as white solid. MS(ES)+ m/e 242.9; 244.8 [M+]+.
c) 7-Bromo-2-(4-morpholinyl)quinoxaline
A solution of 7-bromo-2-chloroquinoxaline (6.16mmol) in N,N-dimethylformamide
(20 mL) was treated with an amine such as neat morpholine (18.5 mmol) then heated at 80 0C for 1 hour. The reaction was cooled to ambient temperature then concentrated under reduced pressure to a yellow residue. The residue was taken into ethyl acetate and washed with portions of saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate and decolorizing charcoal then filtered through Celite. The filtrate was concentrated under reduced pressure to give (1.43 g, 95 %) as a yellow solid. MS(ES)+ m/e 293.7; 295.9 [M+]+ .
Similar quinoxalines were or can be prepared following the procedures used to prepare Intermediate 1 by varying the choice of amine in displacement step c.
Intermediate 2
2-(4-morpholinyl)-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoxaline
Figure imgf000067_0001
2-(4-Morpholinyl)-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoxaline
A slurry of 7-bromo-2-(4-morpholinyl)quinoxaline (0.67mmol), bis(pinacolato)diboron (0.87 mmol), potassium acetate (1.33 mmol) and [1,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1 :1) (0.03 mmol) in anhydrous 1,4-dioxane (10 mL) was heated at HO0C for 18 hours. The reaction mixture was cooled to ambient temperature then filtered through a short pad of silica (~15 g) topped with anhydrous sodium sulfate (~5 g), rinsing with ethyl acetate. The filtrate was concentrated under reduced pressure to a brown residue then purified by column chromatography on silica (15 % hexanes in ethyl acetate). The desired fractions were combined and concentrated to give the title compound (186 mg, 81 %) as a yellow solid. MS(ES)+ m/e 342.0 [M+]+.
Other similar quinoxalineboronates were or can be prepared following the procedures used to prepare Intermediate 2 by varying the choice of starting quinoxaline bromide.
Intermediate 3
Preparation of 4-bromo- 14(4-methylphenv0sulfonyl1-3-phenyl- lH-pyrazole
Figure imgf000067_0002
a) 4-bromo-3 -phenyl- lH-pyrazole A solution of 3-phenyl-lH-pyrazole (20.67 mmol) in anhydrous N ,N- dimethylformamide (40 mL) was treated in one portion with N-bromosuccinimide (20.67 mmol). The reaction stirred at room temperature for 1 hour then was evaporated under reduced pressure. The resulting oil was taken into hot acetonitrile (15 mL) then diluted with water until the product precipitated from the solution. The solids were collected by filtration, rinsed with water and vacuum dried to give the title compound (4.19 g, 91%) as a white solid. MS(ES)+ m/e 222.8, 224.8, bromine pattern [M+Η]+.
b) 4-bromo- 1 - [(4-methylphenyl)sulfonyl] -3 -phenyl- lH-pyrazole A solution of 4-bromo-3-phenyl-lH-pyrazole (18.6 mmol) and pyridine (4.5 mL) in anhydrous methylene chloride (40 mL) was treated in one portion with/?-toluenesulfonyl chloride (22.3 mmol) then stirred at room temperature for 3 days. The reaction was evaporated under reduced pressure and the resulting residue was taken into ethyl acetate and washed with portions of saturated aqueous sodium bicarbonate and brine solution then dried over anhydrous sodium sulfate. This organic solution was evaporated under reduced pressure to a residue then purified by silica chromatography ( 5% ethyl acetate in Ηexanes). The desired fractions were combined and evaporated under reduced pressure to give the title compound (6.90 g, 98%) as a white solid. MS(ES)+ m/e 376.9, 379.0, bromine pattern [M+Η]+.
* Other substituted pyrazole bromides can be prepared using this procedure by varying the choice of starting substituted pyrazole, which are either commercially available or prepared using methods described in the literature {Inorganic Chemistry 2002, 41(7), 1889-1896 ).
Intermediate 4
Preparation of 4-bromo-3-cvclopropyl- 1 -r(4-methylphenyl)sulfonvH- lH-pyrazole
Figure imgf000068_0001
In an oven dried flask under nitrogen, a solution of 3-cyclopropyl-l-[(4- methylphenyl)sulfonyl]-lΗ-pyrazole (500 mg, 1.906 mmol) in anhydrous N5N- dimethylformamide (10 mL) was treated with N-bromosuccinimide (339 mg, 1.906 mmol) in one portion at room temperature. The reaction was stirred at room temperature overnight. LCMS showed 30% starting material remained. Additional N- bromosuccinimide (68 mg, 0.2 equiv) was added to the reaction mixture and the reaction was stirred overnight at room temperature. The reaction mixture was poured into ice-water (100 niL) and a white precipitate formed. The precipitate was collected by filtration, washed with water (100 mL) and dried in vacuo overnight to give the title compound as a white solid (487 mg, 75%). MS(ES)+ m/e 340.6, 342.7 bromine pattern [M+H]+.
Intermediate 5
Preparation of 3-cvclopentyl-lH-pyrazole
Figure imgf000069_0001
In an oven dried round bottom flask under nitrogen, sodium methoxide (0.482 g,
8.92 mmol) was suspended in anhydrous toluene (8.92 mL) then treated with a mixture of 1-cyclopentylethanone (1 g, 8.92 mmol) and ethyl formate (1.045 mL, 12.84 mmol) in one portion. The reaction became orange-yellow and was stirred at room temperature for 3 hours. The reaction was extracted into cold water (2 x 50 mL) and the water extracts (in a 250 mL erlenmeyer flask) were treated with hydrazine monohydrate (0.430 mL, 8.92 mmol) followed by glacial acetic acid (0.510 mL, 8.92 mmol) to give a resultant acidic solution. The mixture was stirred for 30 minutes then ice was added and it was treated with 6N sodium hydroxide to give a basic solution. An orange oil separated, which was extracted with dichloromethane (2 x 150 mL). The extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as orange oil (292 mg, 17%). MS(ES)+ m/e 136.8 [M+Η]+.
Intermediate 6 Preparation of 7-bromo-2-( 1 -methyl- lH-pyrazol-4-yl)quinoxaline
Figure imgf000069_0002
In a sealed pressure tube under nitrogen, 7-bromo-2-chloroquinoxaline (5 g, 20.53 mmol), l-methylpyrazole-4-boronic acid pinacol ester (4.49 g, 21.56 mmol) and 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.838 g, 1.027 mmol), 2M potassium carbonate solution (30.8 mL, 61.6 mmol) and 1,4-dioxane (82 mL) was combined and stirred at 100 0C for 1 hour. The reaction was cooled to room temperature. The reaction was diluted with ethyl acetate (100 mL) and water (100 mL), and the layers were separated. The aqueous layer was back-extracted with ethyl acetate (50 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate and concentrated in vacuo to give a red-brown residue. Trituration in dichloromethane provided the title compound as a cream colored solid (4.52g, 76%). MS(ES)+ m/e 288.7, 290.9 bromine pattern [M+H]+.
Intermediate 7
Preparation of 2-(l-methyl-lH-pyrazol-4-yl)-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- vDquinoxaline
Figure imgf000070_0001
A solution of 7-bromo-2-(l -methyl- lΗ-pyrazol-4-yl)quinoxaline (1 g, 3.46 mmol), bis(pinacolato)diboron (1.054 g, 4.15 mmol), potassium acetate (1.018 g, 10.38 mmol), and
1 , 1 '-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex
(0.141 g, 0.173 mmol) in anhydrous 1,4-dioxane (14.1 mL) was stirred at 100 0C for 90 minutes. The reaction was cooled to room temperature and filtered through a pad of Celite, washing with 100 mL of ethyl acetate. The filtrate was concentrated in vacuo to give a dark brown solid. The solid was dissolved in ethyl acetate (30 mL) and hexanes (60 mL) was added to the solution to make it cloudy. A precipitate formed within 15 minutes, which was collected by suction filtration, washing with ethyl acetate (20 mL). The dark brown solid was discarded and the light brown/yellow filtrate was concentrated in vacuo to give a light brown solid. Trituration in hexanes (20 mL) and ethyl acetate (4 mL) provided the title compound as a tan brown solid after collection by filtration (1.29 g, 90% pure, 100% yield). MS(ES)+ m/e 337.3 for ester; 255.1 for acid [M+H]+.
Exemplary capsule composition
An oral dosage form for administering the present invention is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table II, below.
Table II
INGREDIENTS AMOUNTS
Compound of example 1 25 mg
Lactose 55 mg
Talc 16 mg
Magnesium Stearate 4 mg Exemplary Injectable Parenteral Composition An injectable form for administering the present invention is produced by stirring
1.5% by weight of compound of example 1 in 10% by volume propylene glycol in water.
Exemplary Tablet Composition
The sucrose, calcium sulfate dihydrate and an PBK inhibitor as shown in Table III below, are mixed and granulated in the proportions shown with a 10% gelatin solution. The wet granules are screened, dried, mixed with the starch, talc and stearic acid;, screened and compressed into a tablet.
Table III
INGREDIENTS AMOUNTS
Compound of example 1 20 mg calcium sulfate dehydrate 30 mg
Sucrose 4 mg
Starch 2 mg
Talc 1 mg stearic acid 0.5 mg
While the preferred embodiments of the invention are illustrated by the above, it is to be understood that the invention is not limited to the precise instructions herein disclosed and that the right to all modifications coming within the scope of the following claims is reserved.

Claims

What is claimed is:
1. A compound of Formula (I) :
Figure imgf000072_0001
(I)
in which
Rl is a ring system containing 1 to 2 double bonds represented by formula (II):
Figure imgf000072_0002
(H) each X is independently C, O, N or S; each R2, R3, R4 and R5 is independently selected from: hydrogen, halogen, acyl, sulfonyl amino, formyl, substituted amino, Cl-6alkyl, substituted Cl-6alkyl, C3-
7cycloalkyl, substituted C3-7cycloalkyl, C3-7heterocycloalkyl, substituted C3-
7heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, alkoxy, nitro, acyloxy, and aryloxy; n is 0-2; m is 0-3; two adjacent R5 groups may form an additional five or six-membered ring containing
0-2 hetero atoms, wherein said additional ring is optionally substituted with 1 to 2 substituents selected from a group consisting of: Cl-3alkyl, halogen, amino and alkoxy; or a pharmaceutically acceptable salt thereof; provided that R2 is not H, and when Rl is thiophene, R4 is not piperazine.
2. A compound according to claim 1, wherein the fϊve-membered ring as drawn in formula (II) contains 0-2 nitrogens; or pharmaceutically acceptable salts thereof.
3. A compound according to claim 1, in which Rl is represented by a formula selected from a group consisting of: formulas (III), (IV) , (V) and (VI):
Figure imgf000073_0001
(ill) (IV)
Figure imgf000073_0002
(V) (Vl)
X is O, N or S; Y is O or S; each R2, R3, R4 and R5 is independently selected from: hydrogen, halogen, acyl, sulfonyl, amino, formyl, substituted amino, Cl-6alkyl, substituted Cl-6alkyl, C3- 7cycloalkyl, substituted C3-7cycloalkyl, C3-7heterocycloalkyl, substituted C3- 7heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, alkoxy, nitro, acyloxy, and aryloxy; n is 0-2; m is 0-3; two adjacent R5 groups may form an additional six-membered ring containing 0-2 hetero atoms, wherein said additional ring is optionally substituted with 1 to 2 substituents selected from a group consisting of: Cl-3alkyl, halogen, amino and alkoxy; or a pharmaceutically acceptable salt thereof; provided that R2 is not H, and when Rl is thiophene, R4 is not piperazine.
4. A compound according to claim 1, in which Rl is represented by a formula selected from a group consisting of: formulas (III), (IV), (V) and (VI):
Figure imgf000074_0001
(in) (IV)
Figure imgf000074_0002
(V) (Vl)
X is O, N or S; Y is O or S; each R2, R3, R4 and R5 is independently selected from: hydrogen, halogen, acyl, amino, formyl, substituted amino, Cl-6alkyl, substituted Cl-6alkyl, C3-7cycloalkyl, substituted C3-7cycloalkyl, C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, alkoxy, nitro, acyloxy, and aryloxy; n is 0-2; m is 0-3; or a pharmaceutically acceptable salt thereof; provided that R2 is not H, and when Rl is thiophene, R4 is not piperazine.
5. A compound according to any one of claim 1 to 4, in which each R2, R3 and R5 is independently selected from: halogen, acyl, amino, formyl, substituted amino, Cl-6alkyl, substituted Cl-6alkyl, C3-7cycloalkyl, substituted C3-7cycloalkyl, C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, alkoxy, nitro, acyloxy, and aryloxy; n is 0; m is 0-3; R4 is hydrogen or amino.
6. A compound according to any one of claim 1 to 5 in which R5 is selected from a group consisting of: hydrogen, halogen, acyl, amino, formyl, substituted amino,
Cl-6alkyl, substituted Cl-6alkyl, C3-7cycloalkyl, substituted C3-7cycloalkyl.
7. A compound according to any one of claim 1 to 6, wherein n is 0; m is 0 to 3; and R4 is hydrogen or amino.
8. A compound according to any one of claim 1 to 6, wherein n is 0; m is 0 to 3; X is N or O; and R4 is hydrogen or amino.
9. A compound according to any one of claim 1 to 6, wherein R2 is selected from a group consisting of:
C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl, heteroaryl and substituted heteroaryl;
X is N or O;
R5 is selected from a group consisting of: formyl, halogen, acyl, sulfonyl, amino, substituted amino, Cl-6alkyl, substituted Cl-6alkyl, C3-7cycloalkyl, substituted C3-
7cycloalkyl, C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, hydroxyl, alkoxy, nitro, acyloxy, and aryloxy; Rl is otherwise defined as above; n is 0; m is 0-3; and
R4 is hydrogen or amino.
10. A compound according to any one of claim 1 to 4, wherein R2 is selected from a group consisting of:
C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl, heteroaryl and substituted heteroaryl;
Rl is a ring selected from a group consisting of: pyrazole, oxazole, thiadiazole, oxadiazole, isooxazole and isothiazole, optionally substituted with 1 to 2 substituents, each of which is independently selected from a group consisting of: formyl, halogen, acyl, sulfonyl, amino, substituted amino, Cl-6alkyl, substituted Cl-6alkyl, C3-
7cycloalkyl, substituted C3-7cycloalkyl, C3-7heterocycloalkyl, substituted C3-
7heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cyano, hydroxyl and alkoxy; n is 0;
R4 is hydrogen or amino; or a pharmaceutically acceptable salt thereof.
11. A compound of claim 10, wherein Rl is a pyrazole optionally substituted with 1 to 2 substituents, each of which is independently selected from a group consisting of: formyl, halogen, acyl, sulfonyl, amino, substituted amino, Cl-6alkyl, substituted Cl-6alkyl, C3-7cycloalkyl, substituted C3-7cycloalkyl, C3- 7heterocycloalkyl, substituted CS-Vheterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cyano, hydroxyl and alkoxy; n is 0; and
R4 is hydrogen.
12. A pharmaceutical composition comprising a compound according to any one of claim 1 to 11 and a pharmaceutically acceptable carrier.
13. A method of inhibiting one or more phosphatoinositides 3-kinases (PBKs) in a human; comprising administering to the human a therapeutically effective amount of a compound of Formula (I) as defined in claim 1 or a pharmaceutically acceptable salt.
14. A method of treating one or more disease states selected from a group consisting of: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries, in a human, which method comprises administering to such human, a therapeutically effective amount of a compound according to claim 2.
15. A method of treating cancer comprises co-administration a compound according to claim 1 ; and/or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof; and at least one anti-neoplastic agent, such as one selected from a group consisting of anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, and cell cycle signaling inhibitors.
16. A method of claim 14 wherein the disease is cancer.
17. A method of claim 16 wherein the cancer is selected from a group consisting of: brain (gliomas), glioblastomas, leukemias, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid,
18. A method of claim 16 wherein the disease is selected from a group consisting of: ovarian cancer, renal cancer, pancreatic cancer, breast cancer, prostate cancer and leukemia.
19. A method of claim 13, wherein said PB kinase is a PI3α.
20. A method of claim 13, wherein said PI3 kinase is a PI3γ.
21. A method of claim 13 wherein the compound according to claim 1, or a pharmaceutically acceptable salt thereof, is administered in a pharmaceutical composition.
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