WO2009097233A1 - Imidazopyrazines as protein kinase inhibitors - Google Patents

Imidazopyrazines as protein kinase inhibitors Download PDF

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WO2009097233A1
WO2009097233A1 PCT/US2009/031972 US2009031972W WO2009097233A1 WO 2009097233 A1 WO2009097233 A1 WO 2009097233A1 US 2009031972 W US2009031972 W US 2009031972W WO 2009097233 A1 WO2009097233 A1 WO 2009097233A1
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compound
alkyl
heteroaryl
group
aryl
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PCT/US2009/031972
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WO2009097233A9 (en
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Matthew Paul Rainka
Matthew Ernst Voss
Lisa Helen Peterson
Mike Fleming
David B. Belanger
Patrick J. Curran
Bheemashankar A. Kulkarni
Tao Yu
Yonglian Zhang
Yushi Xiao
Angela D. Kerekes
Jayaram R. Tagat
Ronald J. Doll
M. Arshad Siddiqui
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Schering Corporation
Albany Molecular Research, Inc.
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Publication of WO2009097233A9 publication Critical patent/WO2009097233A9/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to imidazo[1 ,2-a]pyrazine compounds useful as protein kinase inhibitors, regulators or modulators, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds and compositions to treat diseases such as, for example, cancer, inflammation, arthritis, viral diseases, neurodegenerative diseases such as Alzheimer's disease, cardiovascular diseases, and fungal diseases.
  • the present compounds are especially useful as Aurora kinase inhibitors.
  • Protein kinases are a family of enzymes that catalyze phosphorylation of proteins, in particular the hydroxyl group of specific tyrosine, serine, or threonine residues in proteins. Protein kinases are pivotal in the regulation of a wide variety of cellular processes, including metabolism, cell proliferation, cell differentiation, and cell survival. Uncontrolled proliferation is a hallmark of cancer cells, and can be manifested by a deregulation of the cell division cycle in one of two ways - making stimulatory genes hyperactive or inhibitory genes inactive.
  • Protein kinase inhibitors, regulators or modulators alter the function of kinases such as cyclin-dependent kinases (CDKs), mitogen activated protein kinase (MAPK/ERK), glycogen synthase kinase 3 (GSK3beta), Checkpoint (Chk) (e.g., CHK-1 , CHK-2 etc.) kinases, AKT kinases, JNK, and the like.
  • CDKs cyclin-dependent kinases
  • MAPK/ERK mitogen activated protein kinase
  • GSK3beta glycogen synthase kinase 3
  • Checkpoint (Chk) e.g., CHK-1 , CHK-2 etc.
  • Examples of protein kinase inhibitors are described in WO02/22610 A1 and by Y. Mettey et a ⁇ in J. Med. Chern., (2003) 46 222-236.
  • the cyclin-dependent kinases are serine/threonine protein kinases, which are the driving force behind the cell cycle and cell proliferation. Misregulation of CDK function occurs with high frequency in many important solid tumors. Individual CDK's, such as, CDK1 , CDK2, CDK3, CDK4, CDK5, CDK6 and CDK7, CDK8 and the like, perform distinct roles in cell cycle progression and can be classified as either G1 , S, or G2M phase enzymes. CDK2 and CDK4 are of particular interest because their activities are frequently misregulated in a wide variety of human cancers. CDK2 activity is required for progression through G1 to the S phase of the cell cycle, and CDK2 is one of the key components of the G1 checkpoint.
  • CDK2 pathway influences tumorgenesis at the level of tumor suppressor function (e.g. p52, RB, and p27) and oncogene activation (cyclin E).
  • tumor suppressor function e.g. p52, RB, and p27
  • cyclin E oncogene activation
  • Many reports have demonstrated that both the coactivator, cyclin E, and the inhibitor, p27, of CDK2 are either over- or underexpressed, respectively, in breast, colon, nonsmall cell lung, gastric, prostate, bladder, non-Hodgkin's lymphoma, ovarian, and other cancers. Their altered expression has been shown to correlate with increased CDK2 activity levels and poor overall survival. This observation makes CDK2 and its regulatory pathways compelling targets for the development of cancer treatments.
  • adenosine ⁇ '-triphosphate (ATP) competitive small organic molecules as well as peptides have been reported in the literature as CDK inhibitors for the potential treatment of cancers.
  • U.S. 6,413,974, col. 1 , line 23- col. 15, line 10 offers a good description of the various CDKs and their relationship to various types of cancer.
  • Flavopiridol (shown below) is a nonselective CDK inhibitor that is currently undergoing human clinical trials, A. M. Senderowicz et al, J. Clin. Oncol. (1998) 16, 2986-2999.
  • CDK inhibitors include, for example, olomoucine (J. Vesely et al, Eur. J. Biochem., (1994) 224, 771-786) and roscovitine (I. Meijer et al, Eur. J. Biochem., (1997) 243, 527-536).
  • U.S. 6,107,305 describes certain pyrazolo[3,4-b] pyridine compounds as CDK inhibitors.
  • An illustrative compound from the '305 patent is:
  • Imidazopyrazines are known.
  • U.S. 6,919,341 (the disclosure of which is incorporated herein by reference) and US2005/0009832 disclose various imidazopyrazines.
  • R is H, CN, -NR 5 R 6 , cycloalkyl, cycloalkenyl, heterocyclenyl, heteroaryl,
  • NR 5 R 6 unsubstituted alkyl, or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR 5 , heterocyclyi,
  • R 1 is H, halo, aryl or heteroaryl, wherein each of said aryl and heteroaryl can be unsubstituted or substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyi, -CH 2 OR 5 , -C(O)NR 5 R 6 , -C(O)OH, -C(O)NH 2 , -NR 5 R 6 (wherein the R 5 and R 6 , together with the N of said
  • -NR°R b form a heterocyclyi ring
  • -S(O)R 0 -S(O 2 )R 0
  • -CN -CHO, -SR 0 , - C(O)OR 5 , -C(O)R 5 and -OR 5 ;
  • R 2 is H, halo, aryl, arylalkyl or heteroaryl, wherein each of said aryl, arylalkyl and heteroaryl can be unsubstituted or optionally independently be substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
  • R 3 is H, alkyl, cycloalkyl, heterocyclyi, aryl or heteroaryl, wherein:
  • said alkyl shown above for R 3 can be unsubstituted or substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR 5 , alkoxy, heteroaryl, and -NR 5 R 6 ;
  • - said aryl shown above for R 3 is unsubstituted, or optionally substituted, or optionally fused, with halo, heteroaryl, heterocyclyi, cycloalkyl or heteroarylalkyl, wherein each of said heteroaryl, heterocyclyi, cycloalkyl and heteroarylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different each moiety being independently selected from alky!, -OR 5 , -N(R 5 R 6 ) and
  • R 3 can be unsubstituted or optionally substituted, or optionally fused, with one or more moieties which can be the same or different with each moiety being independently selected from the group consisting of halo, amino, alkoxycarbonyl, -OR 5 , alkyl, - CHO, - NR 5 R 6 , -S(O 2 )N(R 5 R 6 ), -C(O)N(R 5 R 6 ), -SR 5 , alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclenyl, and heterocyclyl;
  • R 5 is H, alkyl, aminoalkyl, aryl, heteroaryl, heterocyclyl or cycloalkyl
  • R 6 is H, alkyl, aryl, arylalkyl, heteroaryl, heterocyclyl or cycloalkyl; further wherein in any -NR 5 R 6 in Formula I, said R 5 and R 6 can optionally be joined together with the N of said -NR 5 R 6 to form a cyclic ring.
  • Another series of protein kinases are those that play an important role as a checkpoint in cell cycle progression.
  • Checkpoints prevent cell cycle progression at inappropriate times, such as in response to DNA damage, and maintain the metabolic balance of cells while the cell is arrested, and in some instances can induce apoptosis (programmed cell death) when the requirements of the checkpoint have not been met.
  • Checkpoint control can occur in the G1 phase (prior to DNA synthesis) and in G2, prior to entry into mitosis.
  • Tyrosine kinases can be of the receptor type (having extracellular, transmembrane and intracellular domains) or the non-receptor type (being wholly intracellular).
  • Receptor-type tyrosine kinases are comprised of a large number of transmembrane receptors with diverse biological activity. In fact, about 20 different subfamilies of receptor-type tyrosine kinases have been identified.
  • One tyrosine kinase subfamily, designated the HER subfamily is comprised of EGFR (HER1 ), HER2, HER3 and HER4.
  • Ligands of this subfamily of receptors identified so far include epithelial growth factor, TGF-alpha, amphiregulin,
  • HB-EGF betacellulin and heregulin.
  • Another subfamily of these receptor-type tyrosine kinases is the insulin subfamily, which includes INS-R, IGF-IR, IR, and IR-R.
  • the PDGF subfamily includes the PDGF-alpha and beta receptors, CSFIR, c-kit and FLK-II.
  • the FLK family is comprised of the kinase insert domain receptor (KDR), fetal liver kinase-1(FLK-1), fetal liver kinase-4 (FLK-4) and the fms-like tyrosine kinase-1 (flt-1 ).
  • KDR kinase insert domain receptor
  • FLK-1 fetal liver kinase-1
  • FLK-4 fetal liver kinase-4
  • flt-1 fms-like tyrosine kinase-1
  • At least one of the non-receptor protein tyrosine kinases is believed to mediate the transduction in T-cells of a signal from the interaction of a cell- surface protein (Cd4) with a cross-linked anti-Cd4 antibody.
  • Cd4 cell- surface protein
  • the non-receptor type of tyrosine kinases is also comprised of numerous subfamilies, including Src, Frk, Btk, Csk, AbI, Zap70, Fes/Fps, Fak, Jak, Ack, and LIMK.
  • Src subfamily is one of the largest and includes Src, Yes, Fyn, Lyn, Lck, BIk, Hck, Fgr, and Yrk.
  • the Src subfamily of enzymes has been linked to oncogenesis.
  • protein kinases In addition to its role in cell-cycle control, protein kinases also play a crucial role in angiogenesis, which is the mechanism by which new capillaries are formed from existing vessels.
  • angiogenesis is fairly limited, occurring only in the process of wound healing and neovascularization of the endometrium during menstruation.
  • unwanted angiogenesis is a hallmark of several diseases, such as retinopathies, psoriasis, rheumatoid arthritis, age-related macular degeneration, and cancer (solid tumors).
  • Protein kinases which have been shown to be involved in the angiogenic process include three members of the growth factor receptor tyrosine kinase family; VEGF-R2 (vascular endothelial growth factor receptor 2, also known as KDR (kinase insert domain receptor) and as FLK 1); FGF-R (fibroblast growth factor receptor); and TEK (also known as Tie-2).
  • VEGF-R2 vascular endothelial growth factor receptor 2, also known as KDR (kinase insert domain receptor) and as FLK 1
  • FGF-R fibroblast growth factor receptor
  • TEK also known as Tie-2
  • VEGF-R2 which is expressed only on endothelial cells, binds the potent angiogenic growth factor VEGF and mediates the subsequent signal transduction through activation of its intracellular kinase activity.
  • VEGF-R2 direct inhibition of the kinase activity of VEGF-R2 will result in the reduction of angiogenesis even in the presence of exogenous VEGF (see Strawn et al, Cancer Research, 56, 3540-3545 (1996)), as has been shown with mutants of VEGF-R2 which fail to mediate signal transduction. Millauer et al, Cancer Research, 56, 1615-1620 (1996).
  • VEGF-R2 appears to have no function in the adult beyond that of mediating the angiogenic activity of VEGF. Therefore, a selective inhibitor of the kinase activity of VEGF-R2 would be expected to exhibit little toxicity.
  • FGFR binds the angiogenic growth factors aFGF and bFGF and mediates subsequent intracellular signal transduction.
  • growth factors such as bFGF may play a critical role in inducing angiogenesis in solid tumors that have reached a certain size.
  • FGF-R is expressed in a number of different cell types throughout the body and may or may not play important roles in other normal physiological processes in the adult. Nonetheless, systemic administration of a small molecule inhibitor of the kinase activity of FGF-R has been reported to block bFGF-induced angiogenesis in mice without apparent toxicity.
  • TEK also known as Tie-2
  • Tie-2 is another receptor tyrosine kinase expressed only on endothelial cells which has been shown to play a role in angiogenesis.
  • the binding of the factor angiopoietin-1 results in autophosphorylation of the kinase domain of
  • TEK peri-endothelial support cells
  • angiopoietin-2 appears to antagonize the action of angiopoietin-1 on TEK and disrupts angiogenesis.
  • the kinase, JNK belongs to the mitogen-activated protein kinase (MAPK) superfamily. JNK plays a crucial role in inflammatory responses, stress responses, cell proliferation, apoptosis, and tumorigenesis.
  • JNK kinase activity can be activated by various stimuli, including the proinflammatory cytokines (TNF-alpha and interleukin- 1 ), lymphocyte costimulatory receptors (CD28 and CD40), DNA-damaging chemicals, radiation, and Fas signaling.
  • results from the JNK knockout mice indicate that JNK is involved in apoptosis induction and T helper cell differentiation.
  • Pim-1 is a small serine/threonine kinase. Elevated expression levels of Pim-1 have been detected in lymphoid and myeloid malignancies, and recently Pim-1 was identified as a prognostic marker in prostate cancer.
  • K. Peltola "Signaling in Cancer: Pim-1 Kinase and its Partners", Annales Universitatis Turkuensis, Sarja - Ser. D Osa
  • Pim-1 acts as a cell survival factor and may prevent apoptosis in malignant cells.
  • Aurora kinases are serine/threonine protein kinases that have been implicated in human cancer, such as colon, breast and other solid tumors.
  • Aurora-A also sometimes referred to as AIK
  • Aurora-A is believed to be involved in protein phosphorylation events that regulate the cell cycle.
  • Aurora-A may play a role in controlling the accurate segregation of chromosomes during mitosis. Misregulation of the cell cycle can lead to cellular proliferation and other abnormalities.
  • Aurora-A, Aurora-B, Aurora-C have been found to be over-expressed (see, Bischoff et al., EMBO J., 17:3052-3065 (1998); Schumacher et al., J. Cell Biol. 143:1635-1646 (1998); Kimura et al., J. Biol. Chem., 272:13766-13771 (1997)).
  • kinase inhibitors especially small- molecule compounds that may be readily synthesized.
  • the present invention provides a novel class of imidazo[1 ,2-a]pyrazine compounds, methods of preparing such compounds, pharmaceutical compositions comprising one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition or amelioration of one or more diseases associated with protein kinases using such compounds or pharmaceutical compositions.
  • the present invention provides compounds represented by Formula Z:
  • R is H, halo or alkyl
  • R 3 is heteroaryl-X, wherein X is (heterocyclyl)alkyl- wherein said heterocyclyl can be unsubstituted or optionally substituted with 1-4 alkyl moieties;
  • A is -aryl- , -heteroaryl-, -N(R 1 )-aryl- or -N(R 1 )-heteroaryl- , wherein each of said aryl and heteroaryl can be independently unsubstituted or optionally substituted with one or more substituents, which substituents can be the same or different, each substituent being independently selected from the group consisting of alkyi, -NO 2 , halo, hydroxy, trihaloalkyl, alkoxy, and dialkylamino; ,
  • R A is -(CH 2 )i- 4 -heteroaryl, wherein said heteroaryl can optionally be fused with an aryl, wherein each of said aryl and heteroaryl can independently be optionally substituted with one or more moieties each moiety being independently selected from the group consisting of trihaloalkyl, -NO 2 , halo, hydroxyalkyl, alkoxyalkyl and dialkylamino; R 1 is H or alkyl;
  • R 2 is H, hydroxyalkyl-, arylalkyl-, heteroaryl, aryl, heteroarylalkyl-, alkyl, dialkylaminoalkyl-, alkylaminoalkyl-, cycloalkylalkyl-, cycloalkyl, heterocyclylalkyl- or heterocyclyl, wherein said aryl and aryl of arylalkyl can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of trihaioalkyi, -NO 2 , halo, hydroxyalkyl, alkoxyalkyl, dialkylamino and heterocyclylalkyl-, wherein said heterocyclylalkyl can be unsubstituted or substituted with alkyl Or -SO 2 NH 2 ; said heteroaryl and heteroaryl of heteroarylalkyl can be unsubstituted or substituted with one or more moieties, each moiety being
  • heterocyclic group selected from the group consisting of
  • Y is alkoxyalkyl, hydroxyalkyl, dialkylaminoalkyl or alkyl, further wherein
  • Y is hydroxyl
  • the present invention provides compounds represented by
  • R is halo or alkyl
  • R 3 is heteroaryl-X, wherein X is heterocyclylalkyl- wherein said heterocyclyl can be unsubstituted or optionally substituted with 1-4 alkyl moieties;
  • A is heteroaryl, wherein said heteroaryl can be unsubstituted or optionally substituted with one or more substituents, which substituents can be the same or different, each substituent being independently selected from the group consisting of alkyl, -NO 2 , halo, hydroxy, trihaloalkyl, alkoxy, and dialkyiamino;
  • R A is -(CH 2 )i- 4 -heteroaryl, wherein said heteroaryl can optionally be fused with an aryl, wherein each of said aryl and heteroaryl can independently be optionally substituted with one or more moieties each moiety being independently selected from the group consisting of trihaloalkyl, -NO 2 , halo, hydroxyalkyl, alkoxyalkyl and dialkyiamino;
  • R 1 is H or alkyl;
  • R 2 is H, hydroxyalkyl-, arylalkyl-, heteroaryl, aryl, heteroarylalkyl-, alkyl, dialkylaminoalkyl-, alkylaminoalkyl-, cycloalkylalkyl-, cycloalkyl, heterocyclylalkyl- or heterocyclyl, wherein said aryl and aryl of arylalkyl can be unsubstituted or substituted with one or more moieties
  • heterocyclic group selected from the group consisting of
  • Y is alkoxyalkyl, hydroxyalkyl, dialkylaminoalkyl or alkyl, further wherein Y is hydroxyl.
  • the compounds of Formulas I and Z can be useful as protein kinase inhibitors.
  • the compounds of Formulas I and Z can also be useful as Aurora kinase inhibitors.
  • the compounds of Formulas I and Z can be useful in the treatment and prevention of proliferative diseases, for example, cancer, inflammation and arthritis, neurodegenerative diseases such Alzheimer's disease, cardiovascular diseases, viral diseases and fungal diseases.
  • the present invention provides imidazopyrazine compounds, especially imidazo[1 ,2-a]pyrazine compounds, which are represented by structural
  • the present invention provides imidazopyrazine compounds, especially imidaz ⁇ [1 ,2-a]pyrazine compounds, which are represented by structural Formula I, or pharmaceutically acceptable salts, solvates, esters or prodrug thereof, wherein the various moieties are as described above.
  • A is heteroaryl, as described above.
  • A is -NR 1 -heteroaryl, as described above.
  • A is heteroaryl, as described above.
  • A is aryl, as described above.
  • R A is -(CH 2 )- ⁇ - 4 -heteroaryl.
  • R A is aryl, as described above.
  • R is H
  • R is alkyl. In another embodiment, R is methyl.
  • R is halo
  • R 1 is H.
  • R 1 is alkyl
  • R is methyl
  • R is halo
  • R 3 is heteroaryl-(unsubstituted heterocyclyl).
  • R 3 is heteroaryl-(heterocyclyl(methyl)).
  • R 3 is heteroaryl-(heterocyclyl(methyl) 2 ).
  • R 3 is thiazolyl substituted with heterocyclyl which is substituted with 1 -3 alkyl.
  • R 3 is thiazolyl substituted with heterocyclyl which is un substituted.
  • R 3 is thiazolyl substituted with piperidyl which may be optionally substituted with 1-3 alkyl.
  • Non-limiting examples of compounds of Formulas I and Z include the various compounds shown in the Tables below, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
  • “Patient” includes both human and animals.
  • “Mammal” means humans and other mammalian animals.
  • Alkyl means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more, lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain.
  • “Lower alkyl” means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched.
  • suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.
  • alkenyl means an aliphatic hydrocarbon group containing at least one carbon- carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about
  • Branched means that one or more, lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain.
  • Lower alkenyl means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
  • Alkenyl may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl. aryl, cycloalkyl, cyano, alkoxy and -S(alkyl).
  • suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut- 2-enyl, n-pentenyl, octenyl and decenyl.
  • Alkylene means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above.
  • alkylene include methylene, ethylene and propylene.
  • Alkynyl means an aliphatic hydrocarbon group containing at least one carbon- carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain.
  • Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain.
  • Branched means that one or more, lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain.
  • Lower alkynyl means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
  • alkynyl groups include ethynyl, propynyl, 2-butynyl and 3- methylbutynyl.
  • Alkynyl may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.
  • Aryl means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms.
  • the aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • suitable aryl groups include phenyl and naphthyl.
  • Bridged cyclic ring is a hydrocarbon ring such as cycloalkyl, cyclenyl, or aryl or heteroatom containing ring such as, heterocyclyl, heterocyclenyl, or heteroaryl as described herein, that contains a bridge, which is a valence bond or an atom or an unbranched chain of atoms connecting two different parts of the ring.
  • bridgeheads The two tertiary carbon atoms connected through the bridge.
  • Heteroaryl means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms.
  • the "heteroaryl” can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • the prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom.
  • heteroaryl may also include a heteroaryl as defined above fused to an aryl as defined above.
  • suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1 ,2,4- thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1 ,2- ajpyridinyl, imidazo[2,1-b]thiazolyl,
  • heteroaryl also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.
  • “Aralkyl” or “arylalkyl” means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.
  • Alkylaryl means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non-limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl.
  • Cycloalkyl means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms.
  • Preferred cycloalkyl rings contain about 5 to about 7 ring atoms.
  • the cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above.
  • suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like.
  • Cycloalkylalkyl means a cycloalkyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • suitable cycloalkylalkyls include cyclohexyl methyl, adamantylmethyl and the like.
  • Cycloalkenyl means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contain at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms.
  • the cycloalkenyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above.
  • suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-1 ,3-dienyl, and the like.
  • Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.
  • Cycloalkenylalkyl means a cycloalkenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • suitable cycloalkenylalkyls include cyclopentenylmethyl, cyclohexenylmethyl and the like.
  • Halogen means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.
  • Ring system substituent means a substituent attached to an aromatic or non- aromatic ring system which, for example, replaces an available hydrogen on the ring system.
  • Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, amide, -CHO, -O-C(O)-alkyl
  • Yi and Y 2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl.
  • Ring system substituent may also mean a single moiety which simultaneously replaces two available hydrogen on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moiety are methylene dioxy, ethylenedioxy, -C(CH 3 ) 2 - and the like which form moieties such as, for example:
  • Heteroarylalkyl means a heteroaryl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl and the like.
  • Heterocyclyl means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocyclyls contain about 5 to about 6 ring atoms.
  • the prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), -N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention.
  • the heterocyclyl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S, S- dioxide.
  • heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4- dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like.
  • Heterocyclyl may also mean a single moiety (e.g., carbonyl) which simultaneously replaces two available hydrogen on the same carbon atom on a ring system. Example of such moiety is pyrrolidone:
  • Heterocyclylalkyl means a heterocyclyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • suitable heterocyclylalkyls include piperidinylmethyl, piperazinylmethyl and the like.
  • Heterocyclenyl means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms.
  • the prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • the heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above.
  • the nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • heterocyclenyl groups include 1 ,2,3,4- tetrahydropyridinyl, 1 ,2-dihydropyridinyl, 1 ,4-dihydropyridinyl, 1 ,2,3,6- tetrahydropyridinyl, 1 ,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2- imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, 7- oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like.
  • Heterocyclenyl may also mean a single moiety (
  • Heterocyclenylalkyl means a heterocyclenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • hetero-atom containing ring systems of this invention there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom.
  • N, O or S there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom.
  • Alkynylalkyl means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl.
  • Heteroaralkyl means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin-3- ylmethyl. The bond to the parent moiety is through the alkyl.
  • Spiro ring systems have two or more rings linked by one common atom.
  • Preferred spiro ring systems include spiroheteroaryl, spiroheterocyclenyl, spiroheterocyclyl, spirocycloalkyl, spirocyclenyl, and spiroaryl.
  • the spiro ring systems can be optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above.
  • Hydroxyalkyl means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
  • acyl means an H-C(O)-, alkyl-C(O)- or cycloalkyl-C(O)-, group in which the various groups are as previously described.
  • the bond to the parent moiety is through the carbonyl.
  • Preferred acyls contain a lower alkyl.
  • suitable acyl groups include formyl, acetyl and propanoyl.
  • Aroyl means an aryl-C(O)- group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl.
  • suitable groups include benzoyl and 1- naphthoyl.
  • Alkoxy means an alkyl-O- group in which the alkyl group is as previously described.
  • suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Aryloxy means an aryl-O- group in which the aryl group is as previously described.
  • suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen.
  • Alkyloxy means an aralkyl-O- group in which the aralkyl group is as previously described.
  • suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthaIenemethoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Alkylthio means an alkyl-S- group in which the alkyl group is as previously described.
  • suitable alkylthio groups include methylthio and ethylthio.
  • the bond to the parent moiety is through the sulfur.
  • Arylthio means an aryl-S- group in which the aryl group is as previously described.
  • suitable arylthio groups include phenylthio and naphthylthio.
  • the bond to the parent moiety is through the sulfur.
  • Aralkylthio means an aralkyl-S- group in which the aralkyl group is as previously described.
  • Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur.
  • Alkoxycarbonyl means an alkyl-O-CO- group.
  • suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl.
  • the bond to the parent moiety is through the carbonyl.
  • Aryloxycarbonyl means an aryl-O-C(O)- group.
  • suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.
  • the bond to the parent moiety is through the carbonyl.
  • Alkoxycarbonyl means an aralkyl-O-C(O)- group.
  • a suitable aralkoxycarbonyl group is benzyloxycarbonyl.
  • the bond to the parent moiety is through the carbonyl.
  • Alkylsulfonyl means an alkyl-S(O 2 )- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.
  • Arylsulfonyl means an aryl-S(O 2 )- group. The bond to the parent moiety is through the sulfonyl.
  • substituted means that one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • optionally substituted means optional substitution with the specified groups, radicals or moieties.
  • purified refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof.
  • purified refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like) , in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
  • any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.
  • a functional group in a compound is termed "protected”
  • Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et a/, Protective Groups in organic Synthesis (1991 ), Wiley, New York.
  • variable e.g., aryl, heterocycle, R 2 , etc.
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • Prodrugs and solvates of the compounds of the invention are also contemplated herein.
  • a discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987)
  • the term "prodrug” means a compound (e.g., a drug precursor) that is transformed in vivo to yield a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood.
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (C-i-C 8 )alkyl, (C 2 - C-i 2 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1- methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alk)alkyl, (C 2 - C-i 2 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (CrC- 6 )alkanoyloxymethyl, 1-((Ci- C 6 )alkanoyloxy)ethyl, 1-methyl-1-((Ci-C 6 )alkanoyloxy)ethyl, (Cr C- 6 )alkoxycarbonyloxymethyl, N-(Ci-C 6 )alkoxycarbonylaminomethyl, succinoyl, (C 1 - C- 6 )alkanoyl, ⁇ -amino(Ci-C 4 )alkanyl, arylacyl and ⁇ -aminoacyl, or ⁇ -aminoacyl- ⁇ - aminoacyl, where each ⁇ -aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH) 2 ,
  • a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (C- t -Cio)alkyl, (C3-C 7 ) cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ -aminoacyl or natural ⁇ -aminoacyl, — C(OH)C(O)OY 1 wherein Y 1 is H, (Cr C 6 )alkyl or benzyl, — C(OY 2 )Y 3 wherein Y 2 is (C 1 -C 4 ) alkyl and Y 3 is (C r C 6 )alkyl, carboxy (C r C 6 )alkyl, amino(CrC 4 )alkyl or mono-N — or
  • One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.
  • “Hydrate” is a solvate wherein the solvent molecule is H 2 O.
  • One or more compounds of the invention may optionally be converted to a solvate.
  • Preparation of solvates is generally known.
  • M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describes the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water.
  • Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., 5(1 ⁇ , article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001 ).
  • a typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.
  • Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
  • Effective amount or “therapeutically effective amount” is meant to describe an amount of compound or a composition of the present invention effective in inhibiting the above-noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.
  • the compounds of Formulas I and Z can form salts which are also within the scope of this invention.
  • salts denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
  • a compound of Formulas I and Z contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term “salt(s)” as used herein.
  • Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful.
  • Salts of the compounds of the Formulas I and Z may be formed, for example, by reacting a compound of Formulas I and Z with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
  • Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g.
  • esters of the present compounds include the following groups: (1 ) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n- propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, Ci ⁇ alkyl, or C ⁇ alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphoric acid
  • the compounds of Formula (I) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula (I) as well as mixtures thereof, including racemic mixtures, form part of the present invention.
  • the present invention embraces all geometric and positional isomers. For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention.
  • Enantiomers can also be separated by use of chiral HPLC column
  • All stereoisomers for example, geometric isomers, optical isomers and the like
  • of the present compounds including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs
  • those which may exist due to asymmetric carbons on various substituents including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl).
  • salt is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
  • the present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 CI, respectively.
  • Certain isotopically-labelled compounds of Formula (I) e.g., those labeled with
  • 3 H and 14 C are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such strictly as deuterium (i.e., H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances, lsotopically labeled compounds of Formula (I) can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an appropriate isotopically labeled reagent for a non-isotopically labeled reagent.
  • Polymorphic forms of the compounds of Formula I, and of the salts, solvates, esters and prodrugs of the compounds of Formula I, are intended to be included in the present invention.
  • the compounds according to the invention have pharmacological properties; in particular, the compounds of Formulas I and Z can be inhibitors, regulators or modulators of protein kinases.
  • Non-limiting examples of protein kinases that can be inhibited, regulated or modulated include cyclin-dependent kinases (CDKs), such as, CDK1 , CDK2, CDK3, CDK4, CDK5, CDK6 and CDK7, CDK8, mitogen activated protein kinase (MAPK/ERK), glycogen synthase kinase 3 (GSK3beta), Pim-1 kinases,
  • CDKs cyclin-dependent kinases
  • Chk kinases such as Chk1 and Chk2
  • tyrosine kinases such as the HER subfamily
  • EGFR HER1, HER2, HER3 and HER4
  • the insulin subfamily including, for example, INS-R, IGF-IR, IR, and IR-R
  • the PDGF subfamily including, for example, PDGF-alpha and beta receptors, CSFIR, c-kit and FLK-II
  • the FLK family including, for example, kinase insert domain receptor (KDR), fetal liver kinase-1(FLK-1 ), fetal liver kinase-4 (FLK-4) and the fms-like tyrosine kinase-1 (flt-1)
  • non-receptor protein tyrosine kinases for example LCK, Src, Frk, Btk, Csk, AbI, Zap70, Fes/Fps, Fak, Jak, Ack, and LIMK
  • growth factor receptor tyrosine kinases such as VEGF-R2, F
  • the compounds of Formulas I and Z can be inhibitors of protein kinases such as, for example, the inhibitors of the checkpoint kinases such as Chk1 , Chk2 and the like.
  • Preferred compounds can exhibit IC 5O values of less than about 5//m, preferably about 0.001 to about 1.0 ⁇ m, and more preferably about 0.001 to about 0.1 ⁇ m.
  • the assay methods are described in the Examples set forth below.
  • the compounds of Formulas I and Z can be useful in the therapy of proliferative diseases such as cancer, autoimmune diseases, viral diseases, fungal diseases, neurological/neurodegenerative disorders, arthritis, inflammation, antiproliferative (e.g., ocular retinopathy), neuronal, alopecia and cardiovascular disease.
  • proliferative diseases such as cancer, autoimmune diseases, viral diseases, fungal diseases, neurological/neurodegenerative disorders, arthritis, inflammation, antiproliferative (e.g., ocular retinopathy), neuronal, alopecia and cardiovascular disease.
  • proliferative diseases such as cancer, autoimmune diseases, viral diseases, fungal diseases, neurological/neurodegenerative disorders, arthritis, inflammation, antiproliferative (e.g., ocular retinopathy), neuronal, alopecia and cardiovascular disease.
  • the compounds of Formulas I and Z can be useful in the treatment of a variety of cancers, including (but not limited to) the following: tumor of the bladder, breast (including BRCA-mutated breast cancer, colorectal, colon, kidney, liver, lung, small cell lung cancer, non-small cell lung cancer, head and neck, esophagus, bladder, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T- cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma and Burkett's lymphoma; chronic lymphocytic leukemia ("CLL”), acute and chronic myelogenous leukemia, myelodysplastic syndrome and promyelocy
  • inhibitors could act as reversible cytostatic agents which may be useful in the treatment of any disease process which features abnormal cellular proliferation, e.g., benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, endotoxic shock, and fungal infections.
  • Compounds of Formulas I and Z may also be useful in the treatment of Alzheimer's disease, as suggested by the recent finding that CDK5 is involved in the phosphorylation of tau protein (J. Biochem, (1995) 117, 741-749).
  • Compounds of Formulas I and Z may induce or inhibit apoptosis.
  • the apoptotic response is aberrant in a variety of human diseases.
  • Compounds of Formula I, as modulators of apoptosis, will be useful in the treatment of cancer (including but not limited to those types mentioned hereinabove), viral infections
  • autoimmune diseases including but not limited to systemic lupus, erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes mellitus
  • neurodegenerative disorders including but not limited to Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration
  • myelodysplastic syndromes including but not limited to Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration
  • myelodysplastic syndromes including but not limited to Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration
  • Compounds of Formula I can modulate the level of cellular RNA and DNA synthesis. These agents would therefore be useful in the treatment of viral infections (including but not limited to HIV, human papilloma virus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus).
  • Compounds of Formulas I and Z may also be useful in the chemoprevention of cancer. Chemoprevention is defined as inhibiting the development of invasive cancer by either blocking the initiating mutagenic event or by blocking the progression of pre- malignant cells that have already suffered an insult or inhibiting tumor relapse.
  • Compounds of Formulas I and Z may also be useful in inhibiting tumor angiogenesis and metastasis.
  • Compounds of Formulas I and Z may also act as inhibitors of cyclin dependent kinases and other protein kinases, e.g., protein kinase C, her2, raf 1 , MEK1 , MAP kinase, EGF receptor, PDGF receptor, IGF receptor, PI3 kinase, weel kinase, Src, AbI and thus be effective in the treatment of diseases associated with other protein kinases.
  • protein kinase C her2, raf 1 , MEK1 , MAP kinase, EGF receptor, PDGF receptor, IGF receptor, PI3 kinase, weel kinase, Src, AbI and thus be effective in the treatment of diseases associated with other protein kinases.
  • Another aspect of this invention is a method of treating a mammal (e.g., human) having a disease or condition associated with kinases (e.g., CDKs, CHK and Aurora kinases) by administering a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound to the mammal.
  • a mammal e.g., human
  • kinases e.g., CDKs, CHK and Aurora kinases
  • a preferred dosage is about 0.001 to 1000 mg/kg of body weight/day of the compound of Formula I.
  • An especially preferred dosage is about 0.01 to 25 mg/kg of body weight/day of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound.
  • the compounds of this invention may also be useful in combination (administered together or sequentially) with one or more of anti-cancer treatments such as radiation therapy, and/or one or more anti-cancer agents different from the compound of
  • the compounds of the present invention can be present in the same dosage unit as the anti-cancer agent or in separate dosage units.
  • Another aspect of the present invention is a method of treating one or more diseases associated with a kinase (such as CDK, CHK and Aurora), comprising administering to a mammal in need of such treatment: an amount of a first compound, which is a compound of Formula 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; and an amount of at least one second compound, the second compound being an anti-cancer agent different from the compound of Formula 1 , wherein the amounts of the first compound and the second compound result in a therapeutic effect.
  • a kinase such as CDK, CHK and Aurora
  • Non-limiting examples of suitable anti-cancer agent is selected from the group consisting of a cytostatic agent, cisplatin, doxorubicin, liposomal doxorubicin (e.g., Caelyx ® , Myocet ® , Doxil ® ), taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, R115777 ® , L778,123 ® , BMS 214662 ® , Iressa ® , Tarceva ® , antibodies to EGFR 1 antibodies to IGFR (including, for example, those published in US 2005/0136063 published June 23, 2005), KSP inhibitors (such as, for example, those published in
  • Aminoglutethimide Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole,
  • the CDC2 inhibitor olomucine has been found to act synergistically with known cytotoxic agents in inducing apoptosis (J, Cell ScL, (1995) 108, 2897.
  • Compounds of Formulas I and Z may also be administered sequentially with known anticancer or cytotoxic agents when a combination formulation is inappropriate.
  • the invention is not limited in the sequence of administration; compounds of Formulas I and Z may be administered either prior to or after administration of the known anticancer or cytotoxic agent.
  • the cytotoxic activity of the cyclin-dependent kinase inhibitor flavopiridol is affected by the sequence of administration with anticancer agents. Cancer Research, (1997) 57, 3375.
  • this invention includes combinations comprising an amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an amount of one or more anti-cancer treatments and anti-cancer agents listed above wherein the amounts of the compounds/ treatments result in desired therapeutic effect.
  • Another aspect of the present invention is a method of inhibiting one or more
  • Aurora kinases in a patient in need thereof comprising administering to the patient a therapeutically effective amount of at least one compound of Formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
  • Another aspect of the present invention is a method of treating, or slowing the progression of, a disease associated with one or more Aurora kinases in a patient in need thereof, comprising administering a therapeutically effective amount of at least one compound of Formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
  • Yet another aspect of the present invention is a method of treating one or more diseases associated with Aurora kinase, comprising administering to a mammal in need of such treatment an amount of a first compound, which is a compound of Formula 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; and an amount of at least one second compound, the second compound being an anti-cancer agent, wherein the amounts of the first compound and the second compound result in a therapeutic effect.
  • a first compound which is a compound of Formula 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof
  • Another aspect of the present invention is a method of treating, or slowing the progression of, a disease associated with one or more Aurora kinases in a patient in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising in combination at least one pharmaceutically acceptable carrier and at least one compound according to Formula 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
  • the Aurora kinase to be inhibited can be Aurora A, Aurora B and/or Aurora C.
  • Another aspect of the present invention is a method of inhibiting one or more Checkpoint kinases in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
  • Another aspect of the present invention is a method of treating, or slowing the progression of, a disease associated with one or more Checkpoint kinases in a patient in need thereof, comprising administering a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
  • Yet another aspect of the present invention is a method of treating one or more diseases associated with Checkpoint kinase, comprising administering to a mammal in need of such treatment an amount of a first compound, which is a compound of formula 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; and an amount of at least one second compound, the second compound being an anti- cancer agent, wherein the amounts of the first compound and the second compound result in a therapeutic effect.
  • a first compound which is a compound of formula 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof
  • Another aspect of the present invention is a method of treating, or slowing the progression of, a disease associated with one or more Checkpoint kinases in a patient in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising in combination at least one pharmaceutically acceptable carrier and at least one compound according to formula 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
  • the checkpoint kinase to be inhibited can be Chk1 and/or Chk2.
  • Another aspect of the present invention is a method of inhibiting one or more cyclin dependent kinases in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
  • Another aspect of the present invention is a method of treating, or slowing the progression of, a disease associated with one or more cyclin dependent kinases in a patient in need thereof, comprising administering a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
  • Yet another aspect of the present invention is a method of treating one or more diseases associated with cyclin dependent kinase, comprising administering to a mammal in need of such treatment an amount of a first compound, which is a compound of formula 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; and an amount of at least one second compound, the second compound being an anti-cancer agent, wherein the amounts of the first compound and the second compound result in a therapeutic effect.
  • a first compound which is a compound of formula 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof
  • an amount of at least one second compound the second compound being an anti-cancer agent
  • Another aspect of the present invention is a method of treating, or slowing the progression of, a disease associated with one or more cyclin dependent kinases in a patient in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising in combination at least one pharmaceutically acceptable carrier and at least one compound according to formula 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
  • the checkpoint kinase to be inhibited can be CDK1 and/or CDK2.
  • Another aspect of the present invention is a method of inhibiting one or more tyrosine kinases in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of at least one compound of Formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
  • Yet another aspect of the present invention is a method of treating, or slowing the progression of, a disease associated with one or more tyrosine kinases in a patient in need thereof, comprising administering a therapeutically effective amount of at least one compound of Formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
  • Another aspect of the present invention is a method of treating one or more diseases associated with tyrosine kinase, comprising administering to a mammal in need of such treatment an amount of a first compound, which is a compound of Formula 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; and an amount of at least one second compound, the second compound being an anti-cancer agent, wherein the amounts of the first compound and the second compound result in a therapeutic effect.
  • a first compound which is a compound of Formula 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof
  • an amount of at least one second compound the second compound being an anti-cancer agent
  • Another aspect of the present invention is a method of treating, or slowing the progression of, a disease associated with one or more tyrosine kinases in a patient in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising in combination at least one pharmaceutically acceptable carrier and at least one compound according to Formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
  • a pharmaceutical composition comprising in combination at least one pharmaceutically acceptable carrier and at least one compound according to Formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
  • the tyrosine kinase can be VEGFR (VEGF-R2), EGFR,
  • HER2 HER2, SRC, JAK and/or TEK.
  • Another aspect of the present invention is a method of inhibiting one or more Pim-1 kinases in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of at least one compound of Formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
  • Yet another aspect of the present invention is a method of treating, or slowing the progression of, a disease associated with one or more Pim-1 kinases in a patient in need thereof, comprising administering a therapeutically effective amount of at least one compound of Formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
  • Another aspect of the present invention is a method of treating one or more diseases associated with Pim-1 kinase, comprising administering to a mammal in need of such treatment an amount of a first compound, which is a compound of
  • Formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; and an amount of at least one second compound, the second compound being an anti-cancer agent, wherein the amounts of the first compound and the second compound result in a therapeutic effect.
  • Another aspect of the present invention is a method of treating, or slowing the progression of, a disease associated with one or more Pim-1 kinases in a patient in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising in combination at least one pharmaceutically acceptable carrier and at least one compound according to Formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
  • a pharmaceutical composition comprising in combination at least one pharmaceutically acceptable carrier and at least one compound according to Formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
  • compositions which comprise at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound and at least one pharmaceutically acceptable carrier.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.
  • the powders and tablets may be comprised of from about 5 to about 95 percent active ingredient.
  • Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18 th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania.
  • Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration. Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.
  • a pharmaceutically acceptable carrier such as an inert compressed gas, e.g. nitrogen.
  • solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • the compounds of the invention may also be deliverable transdermally.
  • the transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • the compounds of this invention may also be delivered subcutaneously.
  • the compound is administered orally or intravenously.
  • the pharmaceutical preparation is in a unit dosage form.
  • the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
  • the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg, according to the particular application.
  • the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
  • a typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two to four divided doses.
  • kits comprising a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound and a pharmaceutically acceptable carrier, vehicle or diluent.
  • kits comprising an amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound and an amount of at least one anticancer therapy and/or anti-cancer agent listed above, wherein the amounts of the two or more ingredients result in desired therapeutic effect.
  • VXR-200 (200 MHz, 1 H), Varian Gemini-300 (300 MHz) or XL-400 (400 MHz) and are reported as ppm down field from Me4Si with number of protons, multiplicities, and coupling constants in Hertz indicated parenthetically.
  • analyses was performed using an Applied Biosystems API-100 mass spectrometer and Shimadzu SCL-10A LC column: Altech platinum C18, 3 micron,
  • Part A The title compound was prepared according to US20060106023 (A1 ).
  • Part B To a solution of compound from Example 1 , Part A (2.00 g, 8.19 mmol) in DMF (50 ml_) was added N-iodosuccinimide (1.84 g, 8.19 mmol). The reaction mixture was stirred at 6OC for 16 hours. The mixture was cooled to 25C and concentrated. The residue was dissolved in DCM with a small amount of methanol and then loaded on the column. Purification by column chromatography (SiO 2 , 40% ethyl acetate/hexanes) afforded compound as a white solid 2.30 g (76%). 1 H-NMR (400
  • Part C A suspension of bromide from Part A (45.6 g), Pd(PPh3)4 (10.8 g), potassium carbonate (77.4 g), trimethylboroxine (46.9 g) and potassium carbonate (77.4 g) in DMF (410 (T)L) was heated overnight under nitrogen at 105C. After cooling, the mixture was diluted with ethyl acetate (1 L), washed with brine (2 x 500 mL), dried (magnesium sulfate), filtered, concentrated and purified by chromatography on silica gel. The title compound was obtained as a pale yellow solid (21.4 g, 64%).
  • the crude sulfoxide (220 mg, 0.48 mmol) in dimethylsulfoxide (2.5 mL) was added to a premixed solution of sodium hydride (106 mg, 1.45 mmol) and 2-amino-4-methylisothiazole (78 mg, 0.68 mmol) in dimethylsulfoxide (2.5 mL).
  • the reaction was stirred for 20 minutes then quenched with saturated aqueous ammonium chloride (50 mL).
  • the aqueous layer was extracted with diethyl ether (2 * 50 mL) and ethyl acetate (2 * 50 mL).
  • Example 5 was prepared in a similar manner to Example 4.
  • 1 H NMR 300 MHz, CD 3 OD
  • ⁇ 8.34 s, 1 H
  • 8.26 s, 1 H
  • 8.08 s, 1 H
  • 8.01 s, 1 H
  • 7.36 s, 1 H
  • 5.15 s, 2H
  • 4.43 s, 2H
  • 3.17-2.99 m, 2H
  • 2.71-2.55 m, 2H
  • 2.64 (s, 3H) 2.06- 1.71 (m, 5H), 1.65-1.46 (m, 1 H).
  • HPLC t R 3.82 min (UV 25 4 nm )- Mass calculated for formula C 2I H 24 N 8 O 2 S 452.17; observed MH + (ESI MS) 453.1 (m/z).
  • Part A To a solution of 4-(4,4,5,5-Tetramethyl-1 ,3 ) 2-dioxaborolan-2-yl)-1 H-pyrazole (2.2 g, 11.32) and bromide (2.83 g, 11.32 mmol) in DMA (5 ml_) was added potassium carbonate (1.9 g, 13.6 mmol). The mixture was heated at 6OC for 20 hr. To the reaction mixture was added half sat'd ammonium chloride and ethyl acetate. The organic phase was washed with water (2x), brine and dried (sodium sulfate).
  • Part B A mixture of Example 1 , Part D (1.49 g), boronate from Example 7, Part A (2.13 g), PdCI2(dppf) (0.398 g), potassium phosphate (2.07 g), in DME (45 ml_) and water (5 ml_) was heated at 95C overnight. The reaction was allowed to cool, diluted with ethyl acetate and filtered through Celite. The filtrate was washed with water, brine and dried (sodium sulfate). Chromatography afforded the title compound. Part C: A solution of the compound from Example 7, Part B (260 mg) in THF (25 ml_) at rt was added MCPBA (288 mg) in one portion.
  • Part D A solution of the compound from Example 7, Part C (1 equiv), amine (5 equiv), DIEA (5 equiv) in NMP was heated at 5OC overnight. The reaction mixture was concentrated and purified by Prep-LC. Using this general procedure compounds listed in Table 2 were prepared.
  • Part B A mixture of the boronate from example 10 part A (250 mg, 1.00 equiv), sodium azide (108 mg, 2.00 equiv), and sodium iodide (124 mg, 1.00 equiv) in DMSO (2 mL) was stirred at 50 0 C for 2 hours at which time TLC indicated no starting material remained. The reaction was allowed to cool to room temperature, then quenched with water (8 mL) and extracted with ethyl acetate (3 x 15 mL).
  • Part C To a mixture of aryl iodide from Part B (315 mg, 1.00 equiv), PdCI 2 (dppf) (39 mg, 0.10 equiv), and potassium phosphate (228 mg, 2.00 equiv) under nitrogen was added a solution of the boronate from Part B (170 mg, 1.20 equiv) in 1 ,4-dioxane (1.5 mL), followed by water (0.15 mL). The mixture was stirred at 90 0 C for 17 hours at which time TLC indicated no starting material remained.
  • N-Methyl morpholine 14 mg, 2.00 equiv was added to a stirring mixture of carboxylic acid (14 mg, 1.50 equiv) and HATU (39 mg, 1.50 equiv) in DMF (0.5 mL). After 30 minutes, the amine from example 10 (38.5 mg, 1.00 equiv) was added as a
  • Part B A mixture of the benzimidazole from example 14 part A (4.18 g, 1.00 equiv), potassium carbonate (8.53 g, 3.00 equiv) in DMF (50 mL) was stirred at room temperature for 5 minutes at which time 2-(trimethylsilyl)ethoxymethyl chloride (4.0 mL, 1.1 equiv) was added. After stirring at room temperature for 18 hours the reaction was quenched with a saturated aqueous solution of sodium bicarbonate (40 mL) and concentrated under reduced pressure to a residue.
  • Part C To a solution of 4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (1.65 g, 1 equiv), benzimidazole from Example 14 part B (3.11 g, 1.1 equiv) in DMA (57 mL) was added potassium carbonate (3.51 g, 3 equiv). The mixture was heated at 50 0 C for 18 hours.
  • reaction mixture was poured into water (250 mL), extracted with ethyl acetate (500 mL), the organic layer washed with brine (250 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purification by silica gel chromatography (80 g SiO2, hexanes to 50% of ethyl acetate in hexanes) afforded the desired boronate as a off-white solid 2.67 g (64%).
  • reaction was allowed to cool to room then diluted with ethyl acetate (700 mt_) and washed with water (250 ml_), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purification by silica gel chromatography (120 g SiO 2 , hexanes to 100% ethyl acetate) afforded the desired coupled product as a brown foam 2.04 g (66%).
  • Part A To a stirring solution of the coupled product from Example 16 (2.04 g, 1 equiv) in tetrahydrofuran (63 mL) at -78 0 C was added DIBAL-H (1 M in dichloromethane, 6.5 mL, 2.5 equiv) dropwise. The mixture was stirred at -78 0 C for 5 hours at which time thin layer chromatography (30% ethyl acetate/hexanes) indicated the reaction was complete. The mixture was quickly poured into stirring saturated aqueous sodium potassium tartrate and stirred at room temperature for 14 hours. The mixture was extracted with ethyl acetate (500 ml_), the organic layer separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure affording the aldehyde as a brown foam 1.96 g (100%).
  • Part B Sodium triacetoxyborohydride (1.50 equiv) was added to a stirring mixture of aldehyde (1.00 equiv), amine (1.20 equiv), and acetic acid (1.00 equiv) in 1 ,2- dichloroethane at room temperature. The mixture was stirred until no starting material remained as judged by TLC. The reaction was then quenched with 1 N NaOH and extracted three times with chloroform. The combined organics were dried over sodium sulfate, filtered, and concentrated. This material was dissolved in 1 ,4- dioxane, HCI (4N in dioxane) was added and the mixture was sonicated until such time that HPLC indicated no starting material remained. The mixture was concentrated under reduced pressure, purified by prep-HPLC, and conversion to the hydrochloride salt afforded the title compounds as off-white solids in Table 6.
  • Part A Sodium borohydride (2.0 equiv) was added to a stirring mixture of aldehyde from Example 17 part A (1.00 equiv) in acetic acid (5.7 ml_) in 1 ,2-dichloromethane (17 ml_) at room temperature. The mixture was stirred until no starting material remained as judged by TLC. The reaction was then quenched with 2N NaOH (11 mL) and a saturated solution of aqueous sodium bicarbonate (35 mL). After stirring at room temperature for 15 minutes, the phases were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the alcohol as a brown foam 1.01 g (100%).
  • the desired intermediate was then dissolved in dioxane (2 mL) and treated with 4 N HCI in dioxane (2 mL). The reaction was sonicated at room temperature for 1 hour. The solvent was removed and the residue was purified by prep-HPLC (95:5 to 5:95 water/acetonitrile with 0.1% trifluoroacetic acid). The fractions were collected and dried and the residue treated with 0.2 N HCI and freeze-dried to afford the title compound as a white solid 6.9 mg (28%).
  • Example 24 was prepared in a similar manner to Example 15.
  • 1 H NMR 300 MHz, CD 3 OD
  • HPLC t R 7.36 min (UV 2 54nm)- Mass calculated for formula C 24 H 30 N 8 O 2 S 494.2; observed MH + (ESI MS) 495.8 (m/z).
  • EXAMPLE 24 7.36 min (UV 2 54nm)- Mass calculated for formula C 24
  • Example 25 was prepared in a similar manner to Example 6.
  • 1 H NMR 300 MHz, CD 3 OD
  • ⁇ 8.20 s, 1 H
  • 7.94 s, 1 H
  • 7.85 s, 1 H
  • 7.77 s, 1 H
  • 7.18 s, 1 H
  • 4.98 s, 2H
  • 4.37 br s, 2H
  • 4.17-3.81 m, 2H
  • 3.71-3.40 m, 2H
  • 3.20-3.05 m, 1H
  • 3.03- 2.84 m, 2H
  • 2.79-2.62 m, 1 H
  • 2.52 s, 3H
  • 2.06-1.97 m, 4H
  • 1.97-1.69 m, 5H
  • 1.46 s, 9H
  • 1.32-1.14 m, 1H
  • Trifluoroacetic acid (2 mL) was added to a solution of amide (20 mg, 0.02 mmol) in methylene chloride (2 mL). The reaction was allowed to stir at room temperature for 2 hours. The solvent was removed and the resultant residue placed onto a prep-HPLC (95:5 to 40:60 water/acetonitrile with 0.1% trifluoroacetic acid). The collected fractions were concentrated then treated with 0.2 N HCI and freeze-dried to afford the title compound as a white solid 3.2 mg (23%).
  • Part B To a mixture of alcohol from Part A (80 mg, 0.15 mmol), boronate from Example 7, Part A (84 mg, 0.23 mmol) and Pd(PPh 3 ) 4 (17.8 mg, 0.015 mmol) was added 2 mL of DMF followed by 3 M aqueous K 3 PO 4 solution (0.21 mL, 0.63 mmol). The reaction mixture was heated at 65 0 C for 18 h. It was diluted with 30 ml_ of EtOAc and washed with 1 N aqueous NH 4 CI solution (20 mL x 2). The organic layer was concentrated under vacuum.
  • Part C To a solution of alcohol from Part B (31 mg, 0.049 mmol) in 1.5 mL of THF, was added 3 CL of water followed by Dess-Martin periodinane (64 mg, 0.15 mmol). The reaction mixture was stirred at room temperature for 30 min. It was diluted with 5 mL of THF. The mixture was filtered. The filtrate was diluted with 20 mL of CH 2 CI 2 and washed with 10 mL of saturated aqueous NaHCO 3 solution. It was dried over anhydrous Na 2 SO 4 and then concentrated to give 30 mg of the title compound which was used in the subsequent reactions without further purification. Part D: A solution of aldehyde (12 mg, 0.019 mmol), 3,3-dimethylpiperidine (22 mg,
  • Part B A mixture of mesylate from Part A (9.6 mg, 0.014 mmol), N, N- diethylisopropylamine (6.0 mg, 0.068 mmol) and NaI (4.1 mg, 0.027 mmol) in 1 mL of THF was stirred at 60 0 C for 3 h. It was diluted with 10 mL of CH 2 CI 2 and washed with water. The organic was concentrated under vacuum.
  • Part A To a solution of 4-amino-3-fluoro pyridine (560 mg, 5.0 mmol) and Et 3 N (760 mg, 7.5 mmol) in 20 ml_ of THF, was added chloroacetyl chloride (622 mg, 5.5 mmol). The reaction was stirred at room temperature and monitored by thin layer chromatography. More chloroacetyl chloride was added until 4-amino-3-fluoro pyridine was consumed. It was quenched by adding 20 ml_ of saturated aqueous NaHC ⁇ 3 . The mixture was diluted with 150 ml_ of CH 2 CI 2 .
  • Part B A mixture of amide from Part A (106 mg, 0.55 mmol) and Cs 2 CO 3 (326 mg, 1.0 mmol) in 2 rnL of DMSO was heated at 100 0 C for 5 min. To the mixture was added 4- pyrazoleboronic acid pinacol ester (94 mg, 0.50 mmol). The reaction was stirred at 100 0 C for 20 min. It was cooled to room temperature and diluted with 30 ml_ of CH 2 Cl 2 . The mixture was washed with water. The organic was concentrated and purified by running a quick column eluting with 2% MeOH/EtOAc to give 52 mg of the title compound.
  • Part A To a mixture of iodide (43 mg, 0.083 mmol), boronate from Example 29, Part B (43 mg, 0.124 mmol) and Pd(PPh 3 ) 4 (14 mg, 0.012 mmol) in a vial, was added 1.1 mL of DMF, followed by adding 0.11 mL of 3 M aqueous KsPO 4 solution (0.33 mmol). The vial was sealed and stirred at 65 0 C overnight. It was diluted with 30 mL of EtOAc and washed with water. It was concentrated and purified by flash chromatography eluting with 7% MeOH/DCM to give 24 mg of the title compound.
  • Part B To a solution of alcohol from Part A (102 mg, 0.17 mmol) in 5 mL of THF, was added NEt 3 (0.094 mL, 0.67 mmol), followed by methanesulfonylchloride (0.029 mL, 0.37 mmol). The reaction was stirred at room temperature for 15 min. It was monitored by thin layer chromatography and found starting alcohol was not totally consumed. Additional methanesulfonylchloride (0.0035 mL, 0.039 mmol) was added. The stirring was continued for 5 min. It was quenched by adding 2 mL of saturated NH 4 Cl (aq.) and 2 mL of water. The organic layer was collected.
  • Part C A mixture of mesylate from Part B (24.7 mg, 0.036 mmol), N, N- diethylisopropylamine (7.8 mg, 0.089 mmol) and NaI (1 mg, 0.007 mmol) in 1.5 ml_ of THF was stirred at 80 0 C for 4 h. It was diluted with 10 ml_ of CH 2 CI 2 and washed with water and brine. It was dried over anhydrous Na 2 SO 4 . The organic was concentrated under vacuum.
  • Aurora A Assay An in vitro assay was developed that utilizes recombinant Aurora A or Aurora B as an enzyme source and a peptide based on PKA as the substrate.
  • Aurora A kinase assays were performed in low protein binding 384-well plates (Corning Inc). All reagents were thawed on ice. Compounds were diluted in 100% DMSO to desirable concentrations. Each reaction consisted of 8 nM enzyme (Aurora A, Upstate cat#14-511), 100 nM Tamra-PKAtide (Molecular Devices, 5TAMRA- GRTGRRNSICOOH ), 25 ⁇ M ATP (Roche), 1 mM DTT (Pierce), and kinase buffer (10 mM Tris, 10 mM MgCI2, 0.01% Tween 20).
  • Aurora B kinase assays were performed in low protein binding 384-well plates
  • DMSO DMSO to desirable concentrations.
  • Each reaction consisted of 26 nM enzyme (Aurora B, Invitrogen cat#pv3970), 100 nM Tamra-PKAtide (Molecular Devices, 5TAMRA-GRTGRRNSICOOH ), 50 ⁇ M ATP (Roche), 1 mM DTT (Pierce), and kinase buffer (10 mM Tris, 10 mM MgCI2, 0.01% Tween 20).
  • 14 ⁇ l containing TAMRA-PKAtide, ATP, DTT and kinase buffer were combined with 1 ⁇ l diluted compound.
  • the kinase reaction was started by the addition of 5 ⁇ l diluted enzyme. The reaction was allowed to run for 2 hours at room temperature.
  • Dose-response curves were plotted from inhibition data generated each in duplicate, from 8 point serial dilutions of inhibitory compounds. Concentration of compound was plotted against kinase activity, calculated by degree of fluorescent polarization. To generate IC 50 values, the dose-response curves were then fitted to a standard sigmoidal curve and IC 50 values were derived by nonlinear regression analysis.
  • Several compounds of the present invention exhibit Aurora A IC 50 values of about 0.0001 nm to about 4 nm, Aurora B IC 50 values of about 0.0001 nm to about 13 nM, and p-HH3 IC 50 values of about 1 nM to about 10,000 nM. Additional compounds exhibit Aurora A IC 50 values of about 0.0001 nm to about 3000 nm, Aurora B IC 50 values of about 0.0001 nm to about 3000 nM, and p-HH3 IC 50 values of about 1 nM to about 10,00O nM.

Abstract

In its many embodiments, the present invention provides a novel class of imidazopyrazine compounds as inhibitors of protein and/or Aurora kinases, methods of preparing such compounds, pharmaceutical compositions including one or more such compounds, methods of preparing pharmaceutical formulations including one or more such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with the protein or Aurora kinases using such compounds or pharmaceutical compositions.

Description

IMIDAZOPYRAZINES AS PROTEIN KINASE INHIBITORS
Field of the Invention
The present invention relates to imidazo[1 ,2-a]pyrazine compounds useful as protein kinase inhibitors, regulators or modulators, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds and compositions to treat diseases such as, for example, cancer, inflammation, arthritis, viral diseases, neurodegenerative diseases such as Alzheimer's disease, cardiovascular diseases, and fungal diseases. The present compounds are especially useful as Aurora kinase inhibitors.
Background of the Invention
Protein kinases are a family of enzymes that catalyze phosphorylation of proteins, in particular the hydroxyl group of specific tyrosine, serine, or threonine residues in proteins. Protein kinases are pivotal in the regulation of a wide variety of cellular processes, including metabolism, cell proliferation, cell differentiation, and cell survival. Uncontrolled proliferation is a hallmark of cancer cells, and can be manifested by a deregulation of the cell division cycle in one of two ways - making stimulatory genes hyperactive or inhibitory genes inactive. Protein kinase inhibitors, regulators or modulators alter the function of kinases such as cyclin-dependent kinases (CDKs), mitogen activated protein kinase (MAPK/ERK), glycogen synthase kinase 3 (GSK3beta), Checkpoint (Chk) (e.g., CHK-1 , CHK-2 etc.) kinases, AKT kinases, JNK, and the like. Examples of protein kinase inhibitors are described in WO02/22610 A1 and by Y. Mettey et a\ in J. Med. Chern., (2003) 46 222-236. The cyclin-dependent kinases are serine/threonine protein kinases, which are the driving force behind the cell cycle and cell proliferation. Misregulation of CDK function occurs with high frequency in many important solid tumors. Individual CDK's, such as, CDK1 , CDK2, CDK3, CDK4, CDK5, CDK6 and CDK7, CDK8 and the like, perform distinct roles in cell cycle progression and can be classified as either G1 , S, or G2M phase enzymes. CDK2 and CDK4 are of particular interest because their activities are frequently misregulated in a wide variety of human cancers. CDK2 activity is required for progression through G1 to the S phase of the cell cycle, and CDK2 is one of the key components of the G1 checkpoint. Checkpoints serve to maintain the proper sequence of cell cycle events and allow the cell to respond to insults or to proliferative signals, while the loss of proper checkpoint control in cancer cells contributes to tumorgenesis. The CDK2 pathway influences tumorgenesis at the level of tumor suppressor function (e.g. p52, RB, and p27) and oncogene activation (cyclin E). Many reports have demonstrated that both the coactivator, cyclin E, and the inhibitor, p27, of CDK2 are either over- or underexpressed, respectively, in breast, colon, nonsmall cell lung, gastric, prostate, bladder, non-Hodgkin's lymphoma, ovarian, and other cancers. Their altered expression has been shown to correlate with increased CDK2 activity levels and poor overall survival. This observation makes CDK2 and its regulatory pathways compelling targets for the development of cancer treatments.
A number of adenosine δ'-triphosphate (ATP) competitive small organic molecules as well as peptides have been reported in the literature as CDK inhibitors for the potential treatment of cancers. U.S. 6,413,974, col. 1 , line 23- col. 15, line 10 offers a good description of the various CDKs and their relationship to various types of cancer. Flavopiridol (shown below) is a nonselective CDK inhibitor that is currently undergoing human clinical trials, A. M. Senderowicz et al, J. Clin. Oncol. (1998) 16, 2986-2999.
Figure imgf000003_0001
Other known inhibitors of CDKs include, for example, olomoucine (J. Vesely et al, Eur. J. Biochem., (1994) 224, 771-786) and roscovitine (I. Meijer et al, Eur. J. Biochem., (1997) 243, 527-536). U.S. 6,107,305 describes certain pyrazolo[3,4-b] pyridine compounds as CDK inhibitors. An illustrative compound from the '305 patent is:
Figure imgf000004_0001
K. S. Kim et al, J. Med. Chem. 45 (2002) 3905-3927 and WO 02/10162 disclose certain aminothiazole compounds as CDK inhibitors.
Imidazopyrazines are known. For example, U.S. 6,919,341 (the disclosure of which is incorporated herein by reference) and US2005/0009832 disclose various imidazopyrazines. Also being mentioned are the following: WO2005/047290; US2005/095616; WO2005/039393; WO2005/019220; WO2004/072081 ; WO2005/014599; WO2005/009354; WO2005/005429; WO2005/085252; US2005/009832; US2004/220189; WO2004/074289; WO2004/026877; WO2004/026310; WO2004/022562; WO2003/089434; WO2003/084959; WO2003/051346; US2003/022898; WO2002/060492; WO2002/060386; WO2002/028860; JP (1986)61-057587; J. Burke et al., J. Biological Chem., Vol. 278(3), 1450-1456 (2003); and F. Bondavalli et al, J. Med. Chem., Vol. 45 (22), 4875- 4887 (2002).
Also made reference to are US 2004/0220189 (published November 4, 2004); US 2005/0009832 (published January 13, 2005); US 2006/0084650 (published April 20, 2006) which describe kinase inhibitors, and
US 2006/0106023 (published May 18, 2006) which describe imidazopyrazines as cyclin dependent kinase inhibitors. In addition, US 2007/0117804 (published May 24, 2007), describes imidazopyrazines as protein kinase inhibitors of the following structure:
A compound of the Formula:
Figure imgf000004_0002
or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein: R is H, CN, -NR5R6, cycloalkyl, cycloalkenyl, heterocyclenyl, heteroaryl,
-C(O)NR5R6, -N(R5)C(O)R6, heterocyclyi, heteroaryl substituted with (CH2)^3
NR5R6, unsubstituted alkyl, or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR5, heterocyclyi,
-N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2)i-3-N(R5R6) and -NR5R6; R1 is H, halo, aryl or heteroaryl, wherein each of said aryl and heteroaryl can be unsubstituted or substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyi, -CH2OR5, -C(O)NR5R6, -C(O)OH, -C(O)NH2, -NR5R6 (wherein the R5 and R6, together with the N of said
-NR°Rb, form a heterocyclyi ring), -S(O)R0, -S(O2)R0, -CN, -CHO, -SR0, - C(O)OR5, -C(O)R5 and -OR5;
R2 is H, halo, aryl, arylalkyl or heteroaryl, wherein each of said aryl, arylalkyl and heteroaryl can be unsubstituted or optionally independently be substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
-C(O)OH, -C(O)NH2, -NR5R6 (wherein the R5 and R6, together with the N of said -NR5R6, form a heterocyclyi ring), -CN, arylalkyl,
-CH2OR5, -S(O)R5, -S(O2)R5, -CN, -CHO, -SR5, -C(O)OR5, -C(O)R5, heteroaryl and heterocyclyi; R3 is H, alkyl, cycloalkyl, heterocyclyi, aryl or heteroaryl, wherein:
- said alkyl shown above for R3 can be unsubstituted or substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR5, alkoxy, heteroaryl, and -NR5R6; - said aryl shown above for R3 is unsubstituted, or optionally substituted, or optionally fused, with halo, heteroaryl, heterocyclyi, cycloalkyl or heteroarylalkyl, wherein each of said heteroaryl, heterocyclyi, cycloalkyl and heteroarylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different each moiety being independently selected from alky!, -OR5, -N(R5R6) and
-S(O2)R5; and - said heteroaryl shown above for R3 can be unsubstituted or optionally substituted, or optionally fused, with one or more moieties which can be the same or different with each moiety being independently selected from the group consisting of halo, amino, alkoxycarbonyl, -OR5, alkyl, - CHO, - NR5R6, -S(O2)N(R5R6), -C(O)N(R5R6), -SR5, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclenyl, and heterocyclyl;
R5 is H, alkyl, aminoalkyl, aryl, heteroaryl, heterocyclyl or cycloalkyl; and R6 is H, alkyl, aryl, arylalkyl, heteroaryl, heterocyclyl or cycloalkyl; further wherein in any -NR5R6 in Formula I, said R5 and R6 can optionally be joined together with the N of said -NR5R6 to form a cyclic ring.
Another series of protein kinases are those that play an important role as a checkpoint in cell cycle progression. Checkpoints prevent cell cycle progression at inappropriate times, such as in response to DNA damage, and maintain the metabolic balance of cells while the cell is arrested, and in some instances can induce apoptosis (programmed cell death) when the requirements of the checkpoint have not been met. Checkpoint control can occur in the G1 phase (prior to DNA synthesis) and in G2, prior to entry into mitosis.
One series of checkpoints monitors the integrity of the genome and, upon sensing DNA damage, these "DNA damage checkpoints" block cell cycle progression in Gi & G2 phases, and slow progression through S phase. This action enables DNA repair processes to complete their tasks before replication of the genome and subsequent separation of this genetic material into new daughter cells takes place. Inactivation of CHK1 has been shown to transduce signals from the DNA-damage sensory complex to inhibit activation of the cyclin B/Cdc2 kinase, which promotes mitotic entry, and abrogate G. sub.2 arrest induced by DNA damage inflicted by anticancer agents or endogenous DNA damage, as well as result in preferential killing of the resulting checkpoint defective cells. See, e.g., Peng et al., Science, 277 ', 1501- 1505 (1997); Sanchez et al., Science, 277, 1497-1501 (1997), Nurse, Cell, 91 , 865- 867 (1997); Weinert, Science, 277, 1450-1451 (1997); Walworth et al., Nature, 363, 368-371 (1993); and Al-Khodairy et al., Molec. Biol. Cell., 5, 147-160 (1994).
Selective manipulation of checkpoint control in cancer cells could afford broad utilization in cancer chemotherapeutic and radiotherapy regimens and may, in addition, offer a common hallmark of human cancer "genomic instability" to be exploited as the selective basis for the destruction of cancer cells. A number of factors place CHK1 as a pivotal target in DNA-damage checkpoint control. The elucidation of inhibitors of this and functionally related kinases such as CDS1/CHK2, a kinase recently discovered to cooperate with CHK1 in regulating S phase progression (see Zeng et al., Nature, 395, 507-510 (1998); Matsuoka, Science, 282, 1893-1897 (1998)), could provide valuable new therapeutic entities for the treatment of cancer.
Another group of kinases are the tyrosine kinases. Tyrosine kinases can be of the receptor type (having extracellular, transmembrane and intracellular domains) or the non-receptor type (being wholly intracellular). Receptor-type tyrosine kinases are comprised of a large number of transmembrane receptors with diverse biological activity. In fact, about 20 different subfamilies of receptor-type tyrosine kinases have been identified. One tyrosine kinase subfamily, designated the HER subfamily, is comprised of EGFR (HER1 ), HER2, HER3 and HER4. Ligands of this subfamily of receptors identified so far include epithelial growth factor, TGF-alpha, amphiregulin,
HB-EGF, betacellulin and heregulin. Another subfamily of these receptor-type tyrosine kinases is the insulin subfamily, which includes INS-R, IGF-IR, IR, and IR-R. The PDGF subfamily includes the PDGF-alpha and beta receptors, CSFIR, c-kit and FLK-II. The FLK family is comprised of the kinase insert domain receptor (KDR), fetal liver kinase-1(FLK-1), fetal liver kinase-4 (FLK-4) and the fms-like tyrosine kinase-1 (flt-1 ). For detailed discussion of the receptor-type tyrosine kinases, see Plowman et al., DN&P 7(6): 334-339, 1994.
At least one of the non-receptor protein tyrosine kinases, namely, LCK, is believed to mediate the transduction in T-cells of a signal from the interaction of a cell- surface protein (Cd4) with a cross-linked anti-Cd4 antibody. A more detailed discussion of non-receptor tyrosine kinases is provided in Bolen, Oncogene, 8, 2025- 2031 (1993). The non-receptor type of tyrosine kinases is also comprised of numerous subfamilies, including Src, Frk, Btk, Csk, AbI, Zap70, Fes/Fps, Fak, Jak, Ack, and LIMK. Each of these subfamilies is further sub-divided into varying receptors. For example, the Src subfamily is one of the largest and includes Src, Yes, Fyn, Lyn, Lck, BIk, Hck, Fgr, and Yrk. The Src subfamily of enzymes has been linked to oncogenesis. For a more detailed discussion of the non-receptor type of tyrosine kinases, see Bolen, Oncogene, 8:2025-2031 (1993). In addition to its role in cell-cycle control, protein kinases also play a crucial role in angiogenesis, which is the mechanism by which new capillaries are formed from existing vessels. When required, the vascular system has the potential to generate new capillary networks in order to maintain the proper functioning of tissues and organs. In the adult, however, angiogenesis is fairly limited, occurring only in the process of wound healing and neovascularization of the endometrium during menstruation. On the other hand, unwanted angiogenesis is a hallmark of several diseases, such as retinopathies, psoriasis, rheumatoid arthritis, age-related macular degeneration, and cancer (solid tumors). Protein kinases which have been shown to be involved in the angiogenic process include three members of the growth factor receptor tyrosine kinase family; VEGF-R2 (vascular endothelial growth factor receptor 2, also known as KDR (kinase insert domain receptor) and as FLK 1); FGF-R (fibroblast growth factor receptor); and TEK (also known as Tie-2).
VEGF-R2, which is expressed only on endothelial cells, binds the potent angiogenic growth factor VEGF and mediates the subsequent signal transduction through activation of its intracellular kinase activity. Thus, it is expected that direct inhibition of the kinase activity of VEGF-R2 will result in the reduction of angiogenesis even in the presence of exogenous VEGF (see Strawn et al, Cancer Research, 56, 3540-3545 (1996)), as has been shown with mutants of VEGF-R2 which fail to mediate signal transduction. Millauer et al, Cancer Research, 56, 1615-1620 (1996).
Furthermore, VEGF-R2 appears to have no function in the adult beyond that of mediating the angiogenic activity of VEGF. Therefore, a selective inhibitor of the kinase activity of VEGF-R2 would be expected to exhibit little toxicity.
Similarly, FGFR binds the angiogenic growth factors aFGF and bFGF and mediates subsequent intracellular signal transduction. Recently, it has been suggested that growth factors such as bFGF may play a critical role in inducing angiogenesis in solid tumors that have reached a certain size. Yoshiji et al., Cancer Research, 57, 3924-3928 (1997). Unlike VEGF-R2, however, FGF-R is expressed in a number of different cell types throughout the body and may or may not play important roles in other normal physiological processes in the adult. Nonetheless, systemic administration of a small molecule inhibitor of the kinase activity of FGF-R has been reported to block bFGF-induced angiogenesis in mice without apparent toxicity. Mohammad et al., EMBO Journal, 17, 5996-5904 (1998). TEK (also known as Tie-2) is another receptor tyrosine kinase expressed only on endothelial cells which has been shown to play a role in angiogenesis. The binding of the factor angiopoietin-1 results in autophosphorylation of the kinase domain of
TEK and results in a signal transduction process which appears to mediate the interaction of endothelial cells with peri-endothelial support cells, thereby facilitating the maturation of newly formed blood vessels. The factor angiopoietin-2, on the other hand, appears to antagonize the action of angiopoietin-1 on TEK and disrupts angiogenesis. Maisonpierre et al., Science, 277, 55-60 (1997). The kinase, JNK, belongs to the mitogen-activated protein kinase (MAPK) superfamily. JNK plays a crucial role in inflammatory responses, stress responses, cell proliferation, apoptosis, and tumorigenesis. JNK kinase activity can be activated by various stimuli, including the proinflammatory cytokines (TNF-alpha and interleukin- 1 ), lymphocyte costimulatory receptors (CD28 and CD40), DNA-damaging chemicals, radiation, and Fas signaling. Results from the JNK knockout mice indicate that JNK is involved in apoptosis induction and T helper cell differentiation. Pim-1 is a small serine/threonine kinase. Elevated expression levels of Pim-1 have been detected in lymphoid and myeloid malignancies, and recently Pim-1 was identified as a prognostic marker in prostate cancer. K. Peltola, "Signaling in Cancer: Pim-1 Kinase and its Partners", Annales Universitatis Turkuensis, Sarja - Ser. D Osa
- Tom. 616, (August 30, 2005), http://kiriasto.utu.fi/iulkaisupalvelut/annaalit/2004/D616.html. Pim-1 acts as a cell survival factor and may prevent apoptosis in malignant cells. K. Petersen Shay et al., Molecular Cancer Research 3:170-181 (2005).
Yet another group of kinases are Aurora kinases. Aurora kinases (Aurora-A, Aurora-B, Aurora-C) are serine/threonine protein kinases that have been implicated in human cancer, such as colon, breast and other solid tumors. Aurora-A (also sometimes referred to as AIK) is believed to be involved in protein phosphorylation events that regulate the cell cycle. Specifically, Aurora-A may play a role in controlling the accurate segregation of chromosomes during mitosis. Misregulation of the cell cycle can lead to cellular proliferation and other abnormalities. In human colon cancer tissue, Aurora-A, Aurora-B, Aurora-C have been found to be over-expressed (see, Bischoff et al., EMBO J., 17:3052-3065 (1998); Schumacher et al., J. Cell Biol. 143:1635-1646 (1998); Kimura et al., J. Biol. Chem., 272:13766-13771 (1997)). There is a need for effective inhibitors of protein kinases, especially Aurora kinases, in order to treat or prevent disease states associated with abnormal cell proliferation. Moreover, it is desirable to have kinase inhibitors, especially small- molecule compounds that may be readily synthesized.
Summary of the Invention
In its many embodiments, the present invention provides a novel class of imidazo[1 ,2-a]pyrazine compounds, methods of preparing such compounds, pharmaceutical compositions comprising one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition or amelioration of one or more diseases associated with protein kinases using such compounds or pharmaceutical compositions.
In one aspect, the present invention provides compounds represented by Formula Z:
Figure imgf000010_0001
or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof, wherein:
R is H, halo or alkyl; R3 is heteroaryl-X, wherein X is (heterocyclyl)alkyl- wherein said heterocyclyl can be unsubstituted or optionally substituted with 1-4 alkyl moieties;
A is -aryl- , -heteroaryl-, -N(R1)-aryl- or -N(R1)-heteroaryl- , wherein each of said aryl and heteroaryl can be independently unsubstituted or optionally substituted with one or more substituents, which substituents can be the same or different, each substituent being independently selected from the group consisting of alkyi, -NO2, halo, hydroxy, trihaloalkyl, alkoxy, and dialkylamino; ,
RA is -(CH2)i-4-heteroaryl,
Figure imgf000011_0001
wherein said heteroaryl can optionally be fused with an aryl, wherein each of said aryl and heteroaryl can independently be optionally substituted with one or more moieties each moiety being independently selected from the group consisting of trihaloalkyl, -NO2, halo, hydroxyalkyl, alkoxyalkyl and dialkylamino; R1 is H or alkyl;
R2 is H, hydroxyalkyl-, arylalkyl-, heteroaryl, aryl, heteroarylalkyl-, alkyl, dialkylaminoalkyl-, alkylaminoalkyl-, cycloalkylalkyl-, cycloalkyl, heterocyclylalkyl- or heterocyclyl, wherein said aryl and aryl of arylalkyl can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of trihaioalkyi, -NO2, halo, hydroxyalkyl, alkoxyalkyl, dialkylamino and heterocyclylalkyl-, wherein said heterocyclylalkyl can be unsubstituted or substituted with alkyl Or -SO2NH2; said heteroaryl and heteroaryl of heteroarylalkyl can be unsubstituted or substituted with one or more moieties, each moiety being independently selected from the group consisting of hydroxyalkyl, alkoxy, alkyl, halo, hydroxyl, and -NO2; and said cycloalkyl is unsubstituted or substituted with hydroxyl; or R1 and R2 together with the N to which each is attached, form a
heterocyclic group selected from the group consisting of
Figure imgf000011_0002
Figure imgf000011_0003
wherein
Y is alkoxyalkyl, hydroxyalkyl, dialkylaminoalkyl or alkyl, further wherein
Y is hydroxyl.
In another aspect, the present invention provides compounds represented by
Formula 1:
Figure imgf000012_0001
or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof, wherein:
R is halo or alkyl;
R3 is heteroaryl-X, wherein X is heterocyclylalkyl- wherein said heterocyclyl can be unsubstituted or optionally substituted with 1-4 alkyl moieties;
A is heteroaryl, wherein said heteroaryl can be unsubstituted or optionally substituted with one or more substituents, which substituents can be the same or different, each substituent being independently selected from the group consisting of alkyl, -NO2, halo, hydroxy, trihaloalkyl, alkoxy, and dialkyiamino;
RA is -(CH2)i-4-heteroaryl,
Figure imgf000012_0002
wherein said heteroaryl can optionally be fused with an aryl, wherein each of said aryl and heteroaryl can independently be optionally substituted with one or more moieties each moiety being independently selected from the group consisting of trihaloalkyl, -NO2, halo, hydroxyalkyl, alkoxyalkyl and dialkyiamino; R1 is H or alkyl; R2 is H, hydroxyalkyl-, arylalkyl-, heteroaryl, aryl, heteroarylalkyl-, alkyl, dialkylaminoalkyl-, alkylaminoalkyl-, cycloalkylalkyl-, cycloalkyl, heterocyclylalkyl- or heterocyclyl, wherein said aryl and aryl of arylalkyl can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of trihaloalkyl, -NO2, halo, hydroxyalkyl, alkoxyalkyl, dialkyiamino and heterocyclylalkyl-, wherein said heterocyclylalkyl can be unsubstituted or substituted with alkyl or -SO2NH2; said heteroaryl and heteroaryl of heteroarylalkyl can be unsubstituted or substituted with one or more moieties, each moiety being independently selected from the group consisting of hydroxyalkyl, alkoxy, alkyl, halo, hydroxy!, and -NO2; and said cycloalkyl is unsubstituted or substituted with hydroxyl; or R1 and R2 together with the N to which each is attached, form a
heterocyclic group selected from the group consisting of
Figure imgf000013_0001
Figure imgf000013_0002
Y is alkoxyalkyl, hydroxyalkyl, dialkylaminoalkyl or alkyl, further wherein Y is hydroxyl.
The compounds of Formulas I and Z can be useful as protein kinase inhibitors. The compounds of Formulas I and Z can also be useful as Aurora kinase inhibitors. The compounds of Formulas I and Z can be useful in the treatment and prevention of proliferative diseases, for example, cancer, inflammation and arthritis, neurodegenerative diseases such Alzheimer's disease, cardiovascular diseases, viral diseases and fungal diseases.
Detailed Description In an embodiment, the present invention provides imidazopyrazine compounds, especially imidazo[1 ,2-a]pyrazine compounds, which are represented by structural
Formula Z, or pharmaceutically acceptable salts, solvates, esters or prodrug thereof, wherein the various moieties are as described above.
In another embodiment, the present invention provides imidazopyrazine compounds, especially imidazσ[1 ,2-a]pyrazine compounds, which are represented by structural Formula I, or pharmaceutically acceptable salts, solvates, esters or prodrug thereof, wherein the various moieties are as described above.
The following embodiments are intended for, independently, Formula I where applicable, as well as for Formula Z where applicable. The embodiments are independent of one another: In another embodiment, A is aryl, as described above.
In another embodiment, A is heteroaryl, as described above.
In another embodiment, A is -NR1-heteroaryl, as described above.
In another embodiment, A is heteroaryl, as described above.
In another embodiment, A is aryl, as described above. In another embodiment, RA is -(CH2)-ι-4-heteroaryl. In another embodiment, RA
In another embodiment, RA
Figure imgf000014_0001
In another embodiment, R is H.
In another embodiment, R is alkyl. In another embodiment, R is methyl.
In another embodiment, R is halo.
In another embodiment, R1 is H.
In another embodiment, R1 is alkyl.
In another embodiment, R is methyl.
In another embodiment, R is halo.
In another embodiment, R3 is heteroaryl-(unsubstituted heterocyclyl).
In another embodiment, R3 is heteroaryl-(heterocyclyl(methyl)).
In another embodiment, R3 is heteroaryl-(heterocyclyl(methyl)2).
In another embodiment, R3 is thiazolyl substituted with heterocyclyl which is substituted with 1 -3 alkyl.
In another embodiment, R3 is thiazolyl substituted with heterocyclyl which is un substituted.
In another embodiment, R3 is thiazolyl substituted with piperidyl which may be optionally substituted with 1-3 alkyl.
Non-limiting examples of compounds of Formulas I and Z include the various compounds shown in the Tables below, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
As used above, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings, including any possible substitutions of the stated groups or moieties:
"Patient" includes both human and animals. "Mammal" means humans and other mammalian animals. "Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more, lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. "Alkyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, oxime (e.g., =N-OH), - NH(alkyl), -NH(cycloalkyl), -N(alkyl)2, -O-C(O)-aIkyl, -O-C(O)-aryl, -O-C(O)-cycloalkyl, carboxy and -C(O)O-alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.
"Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon- carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about
12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more, lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. "Lower alkenyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. "Alkenyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl. aryl, cycloalkyl, cyano, alkoxy and -S(alkyl). Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut- 2-enyl, n-pentenyl, octenyl and decenyl.
"Alkylene" means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above. Non-limiting examples of alkylene include methylene, ethylene and propylene.
"Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon- carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more, lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3- methylbutynyl. "Alkynyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.
"Aryl" means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. "Bridged cyclic ring" is a hydrocarbon ring such as cycloalkyl, cyclenyl, or aryl or heteroatom containing ring such as, heterocyclyl, heterocyclenyl, or heteroaryl as described herein, that contains a bridge, which is a valence bond or an atom or an unbranched chain of atoms connecting two different parts of the ring. The two tertiary carbon atoms connected through the bridge are termed "bridgeheads". "Heteroaryl" means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl" can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. "Heteroaryl" may also include a heteroaryl as defined above fused to an aryl as defined above. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1 ,2,4- thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1 ,2- ajpyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1 ,2,4-triazinyl, benzothiazolyl and the like. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like. "Aralkyl" or "arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.
"Alkylaryl" means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non-limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl. "Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms.
Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like.
"Cycloalkylalkyl" means a cycloalkyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable cycloalkylalkyls include cyclohexyl methyl, adamantylmethyl and the like. "Cycloalkenyl" means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contain at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. The cycloalkenyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-1 ,3-dienyl, and the like. Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.
"Cycloalkenylalkyl" means a cycloalkenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable cycloalkenylalkyls include cyclopentenylmethyl, cyclohexenylmethyl and the like.
"Halogen" means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine. "Ring system substituent" means a substituent attached to an aromatic or non- aromatic ring system which, for example, replaces an available hydrogen on the ring system. Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, amide, -CHO, -O-C(O)-alkyl, -O-C(O)-aryl, - O-C(O)-cycloalkyl, -C(=N-CN)-NH2, -C(=NH)-NH2, -C(=NH)-NH(alkyl), oxime (e.g. , =N-OH), YiY2N-, YiY2N-alkyl-, YiY2NC(O)-, YiY2NSO2- and -SO2NY1Y2, wherein Yi and Y2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. "Ring system substituent" may also mean a single moiety which simultaneously replaces two available hydrogen on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moiety are methylene dioxy, ethylenedioxy, -C(CH3)2- and the like which form moieties such as, for example:
Figure imgf000018_0001
"Heteroarylalkyl" means a heteroaryl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl and the like.
"Heterocyclyl" means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), -N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention. The heterocyclyl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S, S- dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4- dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like. "Heterocyclyl" may also mean a single moiety (e.g., carbonyl) which simultaneously replaces two available hydrogen on the same carbon atom on a ring system. Example of such moiety is pyrrolidone:
Figure imgf000019_0001
.
"Heterocyclylalkyl" means a heterocyclyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable heterocyclylalkyls include piperidinylmethyl, piperazinylmethyl and the like.
"Heterocyclenyl" means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above. The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non- limiting examples of suitable heterocyclenyl groups include 1 ,2,3,4- tetrahydropyridinyl, 1 ,2-dihydropyridinyl, 1 ,4-dihydropyridinyl, 1 ,2,3,6- tetrahydropyridinyl, 1 ,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2- imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, 7- oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like. "Heterocyclenyl" may also mean a single moiety (e.g., carbonyl) which simultaneously replaces two available hydrogen on the same carbon atom on a ring system. Example of such moiety is pyrrolidinone:
Figure imgf000020_0001
"Heterocyclenylalkyl" means a heterocyclenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
It should be noted that in hetero-atom containing ring systems of this invention, there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom. Thus, for example, in the ring:
Figure imgf000020_0002
there is no -OH attached directly to carbons marked 2 and 5.
It should also be noted that tautomeric forms such as, for example, the moieties:
Figure imgf000020_0003
are considered equivalent in certain embodiments of this invention.
"Alkynylalkyl" means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl.
"Heteroaralkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin-3- ylmethyl. The bond to the parent moiety is through the alkyl.
"Spiro ring systems" have two or more rings linked by one common atom. Preferred spiro ring systems include spiroheteroaryl, spiroheterocyclenyl, spiroheterocyclyl, spirocycloalkyl, spirocyclenyl, and spiroaryl. The spiro ring systems can be optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above. Non-limiting examples of suitable spiro ring
systems include
spiro[4.5]decane
Figure imgf000021_0001
, and
Figure imgf000021_0002
spiro[4.4]nona-2,7-diene.
"Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
"Acyl" means an H-C(O)-, alkyl-C(O)- or cycloalkyl-C(O)-, group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propanoyl.
"Aroyl" means an aryl-C(O)- group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1- naphthoyl.
"Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen. "Aryloxy" means an aryl-O- group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen.
"Aralkyloxy" means an aralkyl-O- group in which the aralkyl group is as previously described. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthaIenemethoxy. The bond to the parent moiety is through the ether oxygen.
"Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The bond to the parent moiety is through the sulfur.
"Arylthio" means an aryl-S- group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The bond to the parent moiety is through the sulfur. "Aralkylthio" means an aralkyl-S- group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur.
"Alkoxycarbonyl" means an alkyl-O-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl.
"Aryloxycarbonyl" means an aryl-O-C(O)- group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.
"Aralkoxycarbonyl" means an aralkyl-O-C(O)- group. Non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl.
"Alkylsulfonyl" means an alkyl-S(O2)- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.
"Arylsulfonyl" means an aryl-S(O2)- group. The bond to the parent moiety is through the sulfonyl.
The term "substituted" means that one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties.
The term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof. Thus, the term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like) , in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences. When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et a/, Protective Groups in organic Synthesis (1991 ), Wiley, New York.
When any variable (e.g., aryl, heterocycle, R2, etc.) occurs more than one time in any constituent or in Formula I, its definition on each occurrence is independent of its definition at every other occurrence.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
Prodrugs and solvates of the compounds of the invention are also contemplated herein. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) |4 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press. The term "prodrug" means a compound (e.g., a drug precursor) that is transformed in vivo to yield a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
For example, if a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (C-i-C8)alkyl, (C2- C-i2)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1- methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4- crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(Ci-C2)alkylamino(C2-C3)alkyl (such as β-dimethylaminoethyl), carbamoyl-(Ci-C2)alkyl, N,N-di (Ci-C2)alkylcarbamoyl-(C1- C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl, and the like.
Similarly, if a compound of Formula (I) contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (CrC-6)alkanoyloxymethyl, 1-((Ci- C6)alkanoyloxy)ethyl, 1-methyl-1-((Ci-C6)alkanoyloxy)ethyl, (Cr C-6)alkoxycarbonyloxymethyl, N-(Ci-C6)alkoxycarbonylaminomethyl, succinoyl, (C1- C-6)alkanoyl, α-amino(Ci-C4)alkanyl, arylacyl and α-aminoacyl, or α-aminoacyl-α- aminoacyl, where each α-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(Ci-C6)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.
If a compound of Formula (I) incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (C-t-Cio)alkyl, (C3-C7) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl or natural α-aminoacyl, — C(OH)C(O)OY1 wherein Y1 is H, (Cr C6)alkyl or benzyl, — C(OY2)Y3 wherein Y2 is (C1-C4) alkyl and Y3 is (CrC6)alkyl, carboxy (CrC6)alkyl, amino(CrC4)alkyl or mono-N — or di-N,N-(Ci-C6)a!kylaminoalkyl, — C(Y4)Y5 wherein Y4 is H or methyl and Y5 is mono-N— or di-N,N-(CrC6)alkylamino morpholino, piperidin-1-yl or pyrrolidin-1-yl, and the like.
One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H2O.
One or more compounds of the invention may optionally be converted to a solvate. Preparation of solvates is generally known. Thus, for example, M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describes the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., 5(1}, article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001 ). A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate). "Effective amount" or "therapeutically effective amount" is meant to describe an amount of compound or a composition of the present invention effective in inhibiting the above-noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect. The compounds of Formulas I and Z can form salts which are also within the scope of this invention. Reference to a compound of Formulas I and Z herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of Formulas I and Z contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful.
Salts of the compounds of the Formulas I and Z may be formed, for example, by reacting a compound of Formulas I and Z with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization. Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts, Properties, Selection and Use. (2002) Zurich: Wiley- VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1 ) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D. C. on their website). These disclosures are incorporated herein by reference thereto.
Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others. All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention. Pharmaceutically acceptable esters of the present compounds include the following groups: (1 ) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n- propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, Ci^alkyl, or C^alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a Ci-2O alcohol or reactive derivative thereof, or by a 2,3-di (C6-24)acyl glycerol.
Compounds of Formula I, and salts, solvates, esters and prodrugs thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.
The compounds of Formula (I) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula (I) as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column.
It is also possible that the compounds of Formula (I) may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.
All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.) Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate", "ester", "prodrug" and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 170, 31P, 32P, 35S, 18F, and 36CI, respectively. Certain isotopically-labelled compounds of Formula (I) (e.g., those labeled with
3H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such „ as deuterium (i.e., H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances, lsotopically labeled compounds of Formula (I) can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an appropriate isotopically labeled reagent for a non-isotopically labeled reagent.
Polymorphic forms of the compounds of Formula I, and of the salts, solvates, esters and prodrugs of the compounds of Formula I, are intended to be included in the present invention. The compounds according to the invention have pharmacological properties; in particular, the compounds of Formulas I and Z can be inhibitors, regulators or modulators of protein kinases. Non-limiting examples of protein kinases that can be inhibited, regulated or modulated include cyclin-dependent kinases (CDKs), such as, CDK1 , CDK2, CDK3, CDK4, CDK5, CDK6 and CDK7, CDK8, mitogen activated protein kinase (MAPK/ERK), glycogen synthase kinase 3 (GSK3beta), Pim-1 kinases,
Chk kinases (such as Chk1 and Chk2), tyrosine kinases, such as the HER subfamily
(including, for example, EGFR (HER1), HER2, HER3 and HER4), the insulin subfamily (including, for example, INS-R, IGF-IR, IR, and IR-R), the PDGF subfamily (including, for example, PDGF-alpha and beta receptors, CSFIR, c-kit and FLK-II), the FLK family (including, for example, kinase insert domain receptor (KDR), fetal liver kinase-1(FLK-1 ), fetal liver kinase-4 (FLK-4) and the fms-like tyrosine kinase-1 (flt-1)), non-receptor protein tyrosine kinases, for example LCK, Src, Frk, Btk, Csk, AbI, Zap70, Fes/Fps, Fak, Jak, Ack, and LIMK, growth factor receptor tyrosine kinases such as VEGF-R2, FGF-R, TEK, Akt kinases, Aurora kinases (Aurora A, Aurora B, Aurora C) and the like.
The compounds of Formulas I and Z can be inhibitors of protein kinases such as, for example, the inhibitors of the checkpoint kinases such as Chk1 , Chk2 and the like. Preferred compounds can exhibit IC5O values of less than about 5//m, preferably about 0.001 to about 1.0 μm, and more preferably about 0.001 to about 0.1 μm. The assay methods are described in the Examples set forth below.
The compounds of Formulas I and Z can be useful in the therapy of proliferative diseases such as cancer, autoimmune diseases, viral diseases, fungal diseases, neurological/neurodegenerative disorders, arthritis, inflammation, antiproliferative (e.g., ocular retinopathy), neuronal, alopecia and cardiovascular disease. Many of these diseases and disorders are listed in U.S. 6,413,974 cited earlier, incorporated by reference herein.
More specifically, the compounds of Formulas I and Z can be useful in the treatment of a variety of cancers, including (but not limited to) the following: tumor of the bladder, breast (including BRCA-mutated breast cancer, colorectal, colon, kidney, liver, lung, small cell lung cancer, non-small cell lung cancer, head and neck, esophagus, bladder, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T- cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma and Burkett's lymphoma; chronic lymphocytic leukemia ("CLL"), acute and chronic myelogenous leukemia, myelodysplastic syndrome and promyelocytic leukemia; fibrosarcoma, rhabdomyosarcoma; head and neck, mantle cell lymphoma, myeloma; astrocytoma, neuroblastoma, glioma, glioblastoma, malignant glial tumors, astrocytoma, hepatocellular carcinoma, gastrointestinal stromal tumors ("GIST") and schwannomas; melanoma, multiple myeloma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma. Due to the key role of kinases in the regulation of cellular proliferation in general, inhibitors could act as reversible cytostatic agents which may be useful in the treatment of any disease process which features abnormal cellular proliferation, e.g., benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, endotoxic shock, and fungal infections. Compounds of Formulas I and Z may also be useful in the treatment of Alzheimer's disease, as suggested by the recent finding that CDK5 is involved in the phosphorylation of tau protein (J. Biochem, (1995) 117, 741-749).
Compounds of Formulas I and Z may induce or inhibit apoptosis. The apoptotic response is aberrant in a variety of human diseases. Compounds of Formula I, as modulators of apoptosis, will be useful in the treatment of cancer (including but not limited to those types mentioned hereinabove), viral infections
(including but not limited to herpevirus, poxvirus, Epstein- Barr virus, Sindbis virus and adenovirus), prevention of AIDS development in HIV-infected individuals, autoimmune diseases (including but not limited to systemic lupus, erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes mellitus), neurodegenerative disorders (including but not limited to Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration), myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol related liver diseases, hematological diseases (including but not limited to chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including but not limited to osteoporosis and arthritis) aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain.
Compounds of Formula I, as inhibitors of kinases, can modulate the level of cellular RNA and DNA synthesis. These agents would therefore be useful in the treatment of viral infections (including but not limited to HIV, human papilloma virus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus). Compounds of Formulas I and Z may also be useful in the chemoprevention of cancer. Chemoprevention is defined as inhibiting the development of invasive cancer by either blocking the initiating mutagenic event or by blocking the progression of pre- malignant cells that have already suffered an insult or inhibiting tumor relapse. Compounds of Formulas I and Z may also be useful in inhibiting tumor angiogenesis and metastasis.
Compounds of Formulas I and Z may also act as inhibitors of cyclin dependent kinases and other protein kinases, e.g., protein kinase C, her2, raf 1 , MEK1 , MAP kinase, EGF receptor, PDGF receptor, IGF receptor, PI3 kinase, weel kinase, Src, AbI and thus be effective in the treatment of diseases associated with other protein kinases.
Another aspect of this invention is a method of treating a mammal (e.g., human) having a disease or condition associated with kinases (e.g., CDKs, CHK and Aurora kinases) by administering a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound to the mammal.
A preferred dosage is about 0.001 to 1000 mg/kg of body weight/day of the compound of Formula I. An especially preferred dosage is about 0.01 to 25 mg/kg of body weight/day of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound.
The compounds of this invention may also be useful in combination (administered together or sequentially) with one or more of anti-cancer treatments such as radiation therapy, and/or one or more anti-cancer agents different from the compound of
Formula I. The compounds of the present invention can be present in the same dosage unit as the anti-cancer agent or in separate dosage units.
Another aspect of the present invention is a method of treating one or more diseases associated with a kinase (such as CDK, CHK and Aurora), comprising administering to a mammal in need of such treatment: an amount of a first compound, which is a compound of Formula 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; and an amount of at least one second compound, the second compound being an anti-cancer agent different from the compound of Formula 1 , wherein the amounts of the first compound and the second compound result in a therapeutic effect. Non-limiting examples of suitable anti-cancer agent is selected from the group consisting of a cytostatic agent, cisplatin, doxorubicin, liposomal doxorubicin (e.g., Caelyx®, Myocet®, Doxil®), taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, R115777®, L778,123®, BMS 214662®, Iressa®, Tarceva®, antibodies to EGFR1 antibodies to IGFR (including, for example, those published in US 2005/0136063 published June 23, 2005), KSP inhibitors (such as, for example, those published in WO 2006/098962 and WO 2006/098961 ; ispinesib, SB-743921 from Cytokinetics), centrosome associated protein E ("CENP- E") inhibitors (e.g., GSK-923295), Gleevec®, intron, ara-C, adriamycin, Cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN™, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone,
Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole,
Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, Avastin, herceptin, Bexxar, bortezomib ("Velcade"), Zevalin, Trisenox, Xeloda, Vinorelbine,
Porfimer, Erbitux, Liposomal, Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane, Fulvestrant, Ifosfomide, Rituximab, C225®, satriplatin, mylotarg, Avastin, Rituxan, panitubimab, Sutent, sorafinib, Sprycel (dastinib), nilotinib, Tykerb (lapatinib) and Campath. If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent or treatment within its dosage range. For example, the CDC2 inhibitor olomucine has been found to act synergistically with known cytotoxic agents in inducing apoptosis (J, Cell ScL, (1995) 108, 2897. Compounds of Formulas I and Z may also be administered sequentially with known anticancer or cytotoxic agents when a combination formulation is inappropriate. The invention is not limited in the sequence of administration; compounds of Formulas I and Z may be administered either prior to or after administration of the known anticancer or cytotoxic agent. For example, the cytotoxic activity of the cyclin-dependent kinase inhibitor flavopiridol is affected by the sequence of administration with anticancer agents. Cancer Research, (1997) 57, 3375. Such techniques are within the skills of persons skilled in the art as well as attending physicians. Accordingly, in an aspect, this invention includes combinations comprising an amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an amount of one or more anti-cancer treatments and anti-cancer agents listed above wherein the amounts of the compounds/ treatments result in desired therapeutic effect.
Another aspect of the present invention is a method of inhibiting one or more
Aurora kinases in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of at least one compound of Formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
Another aspect of the present invention is a method of treating, or slowing the progression of, a disease associated with one or more Aurora kinases in a patient in need thereof, comprising administering a therapeutically effective amount of at least one compound of Formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
Yet another aspect of the present invention is a method of treating one or more diseases associated with Aurora kinase, comprising administering to a mammal in need of such treatment an amount of a first compound, which is a compound of Formula 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; and an amount of at least one second compound, the second compound being an anti-cancer agent, wherein the amounts of the first compound and the second compound result in a therapeutic effect.
Another aspect of the present invention is a method of treating, or slowing the progression of, a disease associated with one or more Aurora kinases in a patient in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising in combination at least one pharmaceutically acceptable carrier and at least one compound according to Formula 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
In the above methods, the Aurora kinase to be inhibited can be Aurora A, Aurora B and/or Aurora C.
Another aspect of the present invention is a method of inhibiting one or more Checkpoint kinases in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. Another aspect of the present invention is a method of treating, or slowing the progression of, a disease associated with one or more Checkpoint kinases in a patient in need thereof, comprising administering a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
Yet another aspect of the present invention is a method of treating one or more diseases associated with Checkpoint kinase, comprising administering to a mammal in need of such treatment an amount of a first compound, which is a compound of formula 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; and an amount of at least one second compound, the second compound being an anti- cancer agent, wherein the amounts of the first compound and the second compound result in a therapeutic effect.
Another aspect of the present invention is a method of treating, or slowing the progression of, a disease associated with one or more Checkpoint kinases in a patient in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising in combination at least one pharmaceutically acceptable carrier and at least one compound according to formula 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
In the above methods, the checkpoint kinase to be inhibited can be Chk1 and/or Chk2. Another aspect of the present invention is a method of inhibiting one or more cyclin dependent kinases in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. Another aspect of the present invention is a method of treating, or slowing the progression of, a disease associated with one or more cyclin dependent kinases in a patient in need thereof, comprising administering a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
Yet another aspect of the present invention is a method of treating one or more diseases associated with cyclin dependent kinase, comprising administering to a mammal in need of such treatment an amount of a first compound, which is a compound of formula 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; and an amount of at least one second compound, the second compound being an anti-cancer agent, wherein the amounts of the first compound and the second compound result in a therapeutic effect.
Another aspect of the present invention is a method of treating, or slowing the progression of, a disease associated with one or more cyclin dependent kinases in a patient in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising in combination at least one pharmaceutically acceptable carrier and at least one compound according to formula 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
In the above methods, the checkpoint kinase to be inhibited can be CDK1 and/or CDK2.
Another aspect of the present invention is a method of inhibiting one or more tyrosine kinases in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of at least one compound of Formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
Yet another aspect of the present invention is a method of treating, or slowing the progression of, a disease associated with one or more tyrosine kinases in a patient in need thereof, comprising administering a therapeutically effective amount of at least one compound of Formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. Another aspect of the present invention is a method of treating one or more diseases associated with tyrosine kinase, comprising administering to a mammal in need of such treatment an amount of a first compound, which is a compound of Formula 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; and an amount of at least one second compound, the second compound being an anti-cancer agent, wherein the amounts of the first compound and the second compound result in a therapeutic effect. Another aspect of the present invention is a method of treating, or slowing the progression of, a disease associated with one or more tyrosine kinases in a patient in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising in combination at least one pharmaceutically acceptable carrier and at least one compound according to Formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. In the above methods, the tyrosine kinase can be VEGFR (VEGF-R2), EGFR,
HER2, SRC, JAK and/or TEK.
Another aspect of the present invention is a method of inhibiting one or more Pim-1 kinases in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of at least one compound of Formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
Yet another aspect of the present invention is a method of treating, or slowing the progression of, a disease associated with one or more Pim-1 kinases in a patient in need thereof, comprising administering a therapeutically effective amount of at least one compound of Formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
Another aspect of the present invention is a method of treating one or more diseases associated with Pim-1 kinase, comprising administering to a mammal in need of such treatment an amount of a first compound, which is a compound of
Formula 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; and an amount of at least one second compound, the second compound being an anti-cancer agent, wherein the amounts of the first compound and the second compound result in a therapeutic effect.
Another aspect of the present invention is a method of treating, or slowing the progression of, a disease associated with one or more Pim-1 kinases in a patient in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising in combination at least one pharmaceutically acceptable carrier and at least one compound according to Formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. The pharmacological properties of the compounds of this invention may be confirmed by a number of pharmacological assays. The exemplified pharmacological assays which are described herein below have been carried out with compounds according to the invention and their salts, solvates, esters or prodrugs.
This invention is also directed to pharmaceutical compositions which comprise at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound and at least one pharmaceutically acceptable carrier.
For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania.
Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration. Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.
Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
The compounds of this invention may also be delivered subcutaneously.
Preferably the compound is administered orally or intravenously.
Also contemplated are delivery methods that are combinations of the above- noted delivery methods, Such methods are typically decided by those skilled in the art.
Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg, according to the particular application. The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two to four divided doses.
Another aspect of this invention is a kit comprising a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound and a pharmaceutically acceptable carrier, vehicle or diluent.
Yet another aspect of this invention is a kit comprising an amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound and an amount of at least one anticancer therapy and/or anti-cancer agent listed above, wherein the amounts of the two or more ingredients result in desired therapeutic effect.
The invention disclosed herein is exemplified by the following preparations and examples which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures will be apparent to those skilled in the art.
Where NMR data are presented, 1 H spectra were obtained on either a Varian
VXR-200 (200 MHz, 1 H), Varian Gemini-300 (300 MHz) or XL-400 (400 MHz) and are reported as ppm down field from Me4Si with number of protons, multiplicities, and coupling constants in Hertz indicated parenthetically. Where LC/MS data are presented, analyses was performed using an Applied Biosystems API-100 mass spectrometer and Shimadzu SCL-10A LC column: Altech platinum C18, 3 micron,
33mm x 7mm ID; gradient flow: 0 min - 10% CH3CN, 5 min - 95% CH3CN, 7 min -
95% CH3CN, 7.5 min - 10% CH3CN, 9 min - stop. The retention time and observed parent ion are given.
The following solvents and reagents may be referred to by their abbreviations in parenthesis:
Thin layer chromatography: TLC dichloromethane: CH2CI2 dimethylformamide: DMF
1 ,1'-Bis(diphenylphosphino)ferocene : dppf dithiothreitol: DTT ethyl acetate: AcOEt or EtOAc methanol: MeOH N-iodosuccinimide : NIS trifluoroacetate: TFA triethylamine: Et3N or TEA butoxycarbonyl: n-Boc or Boc nuclear magnetic resonance spectroscopy: NMR liquid chromatography mass spectrometry: LCMS high resolution mass spectrometry: HRMS milliliters: mL millimoles: mmol microliters: μl grams: g milligrams: mg room temperature or rt (ambient): about 250C. dimethoxyethane: DME
The synthesis of the inventive compounds is illustrated below. Also, it should be noted that the disclosure of commonly-owned U.S. 6,919,341 and U.S. Appl. No. 11/598186 is incorporated herein by reference. EXAMPLE 1
Figure imgf000041_0001
Part A: The title compound was prepared according to US20060106023 (A1 ). Part B: To a solution of compound from Example 1 , Part A (2.00 g, 8.19 mmol) in DMF (50 ml_) was added N-iodosuccinimide (1.84 g, 8.19 mmol). The reaction mixture was stirred at 6OC for 16 hours. The mixture was cooled to 25C and concentrated. The residue was dissolved in DCM with a small amount of methanol and then loaded on the column. Purification by column chromatography (SiO2, 40% ethyl acetate/hexanes) afforded compound as a white solid 2.30 g (76%). 1H-NMR (400
MHz, DMSO-de ) δ 8.3 (s, 1 H), 7.8 (s, 1 H), 2.6 (s, 3H). HPLC-MS tR = 1.87 Min (UV
254πm)- Mass calculated for formula C7H5BrlN3S 370.01 , observed LC/MS m/z 370.9
(M+H).
Part C: A suspension of bromide from Part A (45.6 g), Pd(PPh3)4 (10.8 g), potassium carbonate (77.4 g), trimethylboroxine (46.9 g) and potassium carbonate (77.4 g) in DMF (410 (T)L) was heated overnight under nitrogen at 105C. After cooling, the mixture was diluted with ethyl acetate (1 L), washed with brine (2 x 500 mL), dried (magnesium sulfate), filtered, concentrated and purified by chromatography on silica gel. The title compound was obtained as a pale yellow solid (21.4 g, 64%). Part D: To a DMF (400 mL) solution of compound from Example 1 , Part C (21.8 g) was added N-iodosuccinimide (26.9 g) and the resulting mixture was heated overnight at 6OC. The mixture was concentrated and water (400 mL) was added. After stirring 1 hr at rt, saturated sodium carbonate was added (250 mL) and subsequently stirred an additional 30 min at rt. The mixture was filtered, washed with water, methanol (100 mL) and the filter cake was dried overnight under vacuum. A brown solid was obtained (31.4 g, 87%). EXAMPLE 2
Figure imgf000042_0001
A solution of terf-butyl 2-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1H- pyrazol-1-yl)acetate (318 mg, 1.03 mmol) in 1 ,4-dioxane (3 mL) and water (0.30 mL) was added to an argon degassed mixture of compound from Example 1 , Part B (292 mg, 0.79 mmol), Pd(dppf)CI2 (58 mg, 0.079 mmol) and potassium phosphate (503 mg, 2.37 mmol). The reaction was heated to 40 0C and allowed to stir for 12 hours. The reaction was cooled to room temperature, filtered through Celite eluting with ethyl acetate then concentrated to dryness. Purification of the crude residue by flash chromatography (SiO2, 12 g; 5% to 40% ethyl acetate in hexanes) afforded the title compound as a light brown solid 244 mg (73%). 1H NMR (300 MHz, CDCI3) δ 7.94 (s, 1 H), 7.81 (s, 1 H), 7.80 (s, 1 H), 7.65 (s, 1 H), 4.94 (s, 2H), 2.68 (s, 3H), 1.51 (s, 9H). EXAMPLE 3
Figure imgf000043_0001
3-Chloroperoxybenzoic acid (204 mg, 1.18 mmol) was added to a room temperature solution of ester from Example 2 (244 mg, 0.58 mmol) in methylene chloride (3 mL). The reaction was allowed to stir for 1 hour. Upon completion, the reaction was concentrated to dryness then taken up into ethyl acetate (50 mL). The solution was washed with saturated aqueous sodium bicarbonate solution (50 mL) and brine (2 * 50 mL) then dried (sodium sulfate), filtered and concentrated to dryness to give 220 mg of crude sulfoxide. The crude sulfoxide (220 mg, 0.48 mmol) in dimethylsulfoxide (2.5 mL) was added to a premixed solution of sodium hydride (106 mg, 1.45 mmol) and 2-amino-4-methylisothiazole (78 mg, 0.68 mmol) in dimethylsulfoxide (2.5 mL). The reaction was stirred for 20 minutes then quenched with saturated aqueous ammonium chloride (50 mL). The aqueous layer was extracted with diethyl ether (2 * 50 mL) and ethyl acetate (2 * 50 mL). The combined organic layers were washed with brine (2 χ 50 mL), dried (sodium sulfate), filtered and concentrated to dryness. Purification of the resultant residue by flash chromatography (SiO2, 12 g; 5% to 40 % ethyl acetate in methylene chloride) and then on prep-HPLC afforded the title compound as a yellow solid 2 mg (0.8%). 1H NMR (300 MHz, CDCI3) δ 8.35 (s, 1H), 8.32 (s, 1 H), 8.02 (s, 1H), 7.93 (s, 1 H), 7.17 (s, 1H), 6.90 (s, 1H), 5.37 (s, 2H), 2.63 (s, 3H), 2.46 (s, 3H). HPLC tR = 4.62 min (UV 254nm). Mass calculated for formula Ci9Hi6BrN9OS2 529.01; observed MH+ (APCI MS) 531.1 (m/z). EXAMPLE 4
Figure imgf000044_0001
A solution of ferf-butyl 2-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- pyrazol-1-yl)acetate (135 mg, 0.44 mmol) in 1 ,4-dioxane (3 ml_) and water (0.30 mL) was added to a nitrogen flushed mixture of iodide (200 mg, 0.34 mmol), Pd(dppf)CI2 (25 mg, 0.034 mmol) and potassium phosphate (216 mg, 1.02 mmol). The reaction mixture was heated to 90 0C and allowed to stir for 12 hours. Upon completion, the reaction was allowed to cool to room temperature and then was concentrated to dryness. Purification of the resultant residue by flash chromatography (SiO2; 12 g; 10% to 80% ethyl acetate in methylene chloride) afforded the desired coupled intermediate. Trifluoroacetic acid (1 mL) was added to a room temperature solution of the desired coupled ester (80 mg, 0.125 mmol) in methylene chloride (3 mL). The reaction was stirred for 12 hours then concentrated to dryness. Purification of the resultant residue by prep-HPLC afforded the title compound as a yellow solid 40 mg (45%). 1H NMR (300 MHz, CD3OD) δ 8.34 (s, 1 H), 8.26 (s, 1 H), 8.08 (s, 1 H), 8.01 (s, 1 H), 7.36 (s, 1 H), 5.15 (s, 2H), 4.43 (s, 2H), 3.17-2.99 (m, 2H), 2.71-2.55 (m, 2H), 2.64 (s, 3H), 2.06-1.71 (m, 5H), 1.65-1.46 (m, 1 H). HPLC tR = 3.82 min (UV 254nm). Mass calculated for formula C2IH24N8O2S 452.17; observed MH+ (ESI MS) 453.1 (m/z). EXAMPLE 5
Figure imgf000045_0001
Example 5 was prepared in a similar manner to Example 4. 1H NMR (300 MHz, CD3OD) δ 8.34 (s, 1 H), 8.26 (s, 1 H), 8.08 (s, 1 H), 8.01 (s, 1 H), 7.36 (s, 1 H), 5.15 (s, 2H), 4.43 (s, 2H), 3.17-2.99 (m, 2H), 2.71-2.55 (m, 2H), 2.64 (s, 3H), 2.06- 1.71 (m, 5H), 1.65-1.46 (m, 1 H). HPLC tR = 3.82 min (UV 254nm)- Mass calculated for formula C2IH24N8O2S 452.17; observed MH+ (ESI MS) 453.1 (m/z). EXAMPLE 6
The compounds shown in column 2 of Table 1 were prepared as follows:
Figure imgf000045_0002
A mixture of acid (1 equivalent), the respective amine (1.5 equivalents), HATU (1.5 equivalents), and diisopropylethylamine (3 equivalents) in anhydrous DMF (500 μL) was stirred at room temperature for 2 hours. The reaction was then concentrated under reduced pressure, purified by preparative HPLC and conversion to the hydrochloride salt afforded compounds shown in Column 2 of Table 1.
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
EXAMPLE 7
Figure imgf000074_0001
Part A: To a solution of 4-(4,4,5,5-Tetramethyl-1 ,3)2-dioxaborolan-2-yl)-1 H-pyrazole (2.2 g, 11.32) and bromide (2.83 g, 11.32 mmol) in DMA (5 ml_) was added potassium carbonate (1.9 g, 13.6 mmol). The mixture was heated at 6OC for 20 hr. To the reaction mixture was added half sat'd ammonium chloride and ethyl acetate. The organic phase was washed with water (2x), brine and dried (sodium sulfate). Concentration and purification by chromatography (50% ethyl acetate in hexanes) afforded the title compound as a pale yellow solid. (2.1 g, 51%). 1H NMR (300 MHz, DMSO-d6) δ 10.3 (1 H, br s), 7.95 (1 H, s), 7.7-7.6 (1H, app t), 7.59 (1 H, s), 7.1-7.2 (1 H, m), 5.12 (s, 2H), 1.23 (s, 12H).
Part B: A mixture of Example 1 , Part D (1.49 g), boronate from Example 7, Part A (2.13 g), PdCI2(dppf) (0.398 g), potassium phosphate (2.07 g), in DME (45 ml_) and water (5 ml_) was heated at 95C overnight. The reaction was allowed to cool, diluted with ethyl acetate and filtered through Celite. The filtrate was washed with water, brine and dried (sodium sulfate). Chromatography afforded the title compound. Part C: A solution of the compound from Example 7, Part B (260 mg) in THF (25 ml_) at rt was added MCPBA (288 mg) in one portion. After 1 hr at rt, ethyl acetate was added and was washed with sat. sodium bicarbonate (2x), brine and dried (sodium sulfate). Concentration afforded the title compound that was used without further purification.
Part D: A solution of the compound from Example 7, Part C (1 equiv), amine (5 equiv), DIEA (5 equiv) in NMP was heated at 5OC overnight. The reaction mixture was concentrated and purified by Prep-LC. Using this general procedure compounds listed in Table 2 were prepared.
Table 2
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
EXAMPLE 8
Figure imgf000081_0001
To a stirring suspension of carboxylic acid (1 equiv) in dichloromethane at 0 0C was added 1-chIoro-N,N-2-trimethyl-1-propenylamine (5 equiv). After stirring for 1 hour the amine was added as a solution in dichloromethane or pyridine. When the reaction was deemed complete by HPLC analysis the mixture was concentrated under reduced pressure. Purification by prep-HPLC and conversion to the hydrochloride salt provided the compounds listed in Table 3.
Table 3
Figure imgf000081_0002
Figure imgf000082_0001
Figure imgf000083_0002
EXAMPLE 9
Figure imgf000083_0001
Lithium aluminum hydride (2 mg, 2.2 equiv) was added to a stirring suspension of amide (14 mg, 1 equiv) in THF (1 mL) at room temperature. HPLC analysis after 15 minutes showed no starting material so reaction was quenched with methanol, concentrated under reduced pressure, purified by prep-HPLC, and conversion to the hydrochloride salt afforded the title compound as a white solid 6.5 mg (47%)). 1H NMR (300 MHz, DMSO-d6) δ 12.3 (s, 1H), 10.1 (bs, 1H), 8.41 (s, 1H), 8.03 (s, 1H)1 7.89 (m, 2H), 7.30 (s, 1H), 6.97 (m, 1H), 6.55 (m, 2H), 4.39 (m, 4H), 3.67 (m, 2H), 3.39 (m, 2H), 2.80 (m, 2H), 2.48 (s, 3H), 1.79 (m, 4H), 1.05 (m, 1H), 0.89 (m, 3H). HPLC tR = 5.58 min (UV 254nm). Mass calculated for formula C28H3IF2N9S 563.24; observed MH+ (ESI MS) 564.8 (m/z). EXAMPLE 10
Figure imgf000084_0001
Part A: Potassium hydroxide (1.45 g, 10.0 equiv) was added to a stirring solution of A- (4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1H-pyrazole (500 mg, 1.00 equiv) in DMSO (5 ml_) at room temperature. After stirring for 1 hour, 1 ,2-dibromoethane (9.69 g, 20.0 equiv) was added. The reaction was stirred for 16 hours at which time TLC indicated no starting material remained so the reaction was quenched with water (10 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organics were washed with brine (20 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purification by silica gel chromatography (12g SiO2, dichloromethane to 5% methanol in dichloromethane) afforded the desired boronate as a yellow oil 350 mg (45%).
Part B: A mixture of the boronate from example 10 part A (250 mg, 1.00 equiv), sodium azide (108 mg, 2.00 equiv), and sodium iodide (124 mg, 1.00 equiv) in DMSO (2 mL) was stirred at 50 0C for 2 hours at which time TLC indicated no starting material remained. The reaction was allowed to cool to room temperature, then quenched with water (8 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organics were washed with brine (15 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purification by silica gel chromatography (12g SiO2, dichloromethane to 5% methanol in dichloromethane) afforded the desired boronate as a yellow solid 170 mg (78%). Part C: To a mixture of aryl iodide from Part B (315 mg, 1.00 equiv), PdCI2(dppf) (39 mg, 0.10 equiv), and potassium phosphate (228 mg, 2.00 equiv) under nitrogen was added a solution of the boronate from Part B (170 mg, 1.20 equiv) in 1 ,4-dioxane (1.5 mL), followed by water (0.15 mL). The mixture was stirred at 90 0C for 17 hours at which time TLC indicated no starting material remained. The reaction was allowed to cool to room then diluted with ethyl acetate (8 mL) and washed with brine (10 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purification by silica gel chromatography (12g SiO2, dichloromethane to 5% methanol in dichloromethane) afforded the desired azide as a brown solid 125 mg (39%). Part D: To a stirring solution of azide from Part C (125 mg, 1.00 equiv) in 1 ,4-dioxane (2 mL) and water (0.2 mL) was added poly-styrene bound triphenylphosphine (84 mg, 1.20 equiv). The reaction was stirred at room temperature for 3 days at which time
0 TLC indicated no starting material remained. The mixture was filtered, the mother liquor concentrated under reduced pressure, and the resulting residue purified by silica gel chromatography (12 g S1O2, dichloromethane to 10% methanol in dichloromethane) affording the desired amine as a brown oil 77 mg (64%).
EXAMPLE 11
Figure imgf000085_0001
N-Methyl morpholine (14 mg, 2.00 equiv) was added to a stirring mixture of carboxylic acid (14 mg, 1.50 equiv) and HATU (39 mg, 1.50 equiv) in DMF (0.5 mL). After 30 minutes, the amine from example 10 (38.5 mg, 1.00 equiv) was added as a
,0 solution in DMF (0.5 mL). The mixture was stirred for 5 hours at which time HPLC indicated no starting material remained. The mixture was concentrated and the residue dissolved in 1 ,4-dioxane (1 mL). A solution on HCI in dioxane (1 mL, 4M in dioxane) was added and the mixture was sonicated for 1.5 hours at which time HPLC indicated no starting material remained. The mixture was concentrated under reduced 5 pressure, purified by prep-HPLC, and conversion to the HCI salt afforded the desired compound as a yellow solid 6 mg (14%). 1H NMR (300 MHz, CD3OD) δ 8.90 (m, 1 H), 8.72 (m, 1H), 8,36 (s, 1H), 8.24 (s, 1 H), 8.01(m, 3H), 7.32 (s, 1H), 4.58 (m, 2H), 4.42 (s, 2H), 3.94 (m, 2H), 3.60 (m, 2H), 3.09 (m, 2H), 2.61 (s, 3H), 1.81 (m, 6H), 1.55 (m, 2H). HPLC tR = 3.97 min (UV 254nm). Mass calculated for formula C2TH29FN10OS 560.22; observed MH+ (ESI MS) 561.3 (m/z).
EXAMPLE 12
Figure imgf000086_0001
To a stirring solution of amine from example 10 (38.5 mg, 1.00 equiv) and triethylamine (14 mg, 2.00 equiv) in dichloromethane (0.75 mL) was added 2,3- difluorobenzoylchloride (13 mg, 1.10 equiv) dropwise. HPLC analysis after 4 hours showed no starting material so reaction was quenched with saturated aqueous sodium bicarbonate (2 mL) and then extracted with dichloromethane (3 x 1 mL). The combined organics were concentrated and the resulting residue was dissolved in 1 ,4- dioxane (1 mL) and a solution on HCI in dioxane (1 mL, 4M in dioxane) was added and the mixture was sonicated for 1.5 hours at which time HPLC indicated no starting material remained. The mixture was concentrated under reduced pressure, purified by prep-HPLC, and conversion to the HCI salt afforded the desired compound as a yellow solid 5 mg (11%). 1H NMR (300 MHz, CD3OD) δ 8.34 (s, 1H), 8.21 (s, 1H), 8.06 (s, 1H), 7.92 (s, 1H), 7.44 (m, 2H), 7.36 (2, 1 H), 7.20 (m, 1H), 4.56 (m, 2H), 4.41 (s, 2H), 3.92 (m, 2H), 3.59 (m, 2H), 3.08 (m, 2H), 2.59 (s, 3H), 1.78 (m, 6H). HPLC tR = 4.61 min (UV 254nm)- ass calculated for formula C2SH2SF2NgOS 577.22; observed MH+ (ESI MS) 578.8 (m/z). EXAMPLE 13
Figure imgf000087_0001
Sodium triacetoxyboro hydride (1.50 equiv) was added to a stirring mixture of aldehyde (1.00 equiv), amine (1.20 equiv), and acetic acid (1.00 equiv) in 1 ,2-dichloroethane at room temperature. The mixture was stirred until no starting material remained as judged by TLC. The reaction was then quenched with 1 N NaOH and extracted three times with chloroform. The combined organics were dried over sodium sulfate, filtered, and concentrated. The residue was then added as a solution in dioxane (1 equiv) to a mixture of boronate (1.50 equiv), PdCI2(dppf) (0.10 equiv), and potassium phosphate (2.00 equiv) under nitrogen. Water was added and the mixture was stirred at 90 0C for 17 hours at which time HPLC indicated no starting material remained. The reaction was allowed to cool to room temperature the diluted with ethyl acetate, washed with water, dried over sodium sulfate, filtered, concentrated under reduced pressure, and purification by silica gel chromatography afforded the coupled product. This material was dissolved in 1 ,4-dioxane, HCI (4N in dioxane) was added and the mixture was sonicated until such time that HPLC indicated no starting material remained. The mixture was concentrated under reduced pressure, purified by prep- HPLC, and conversion to the hydrochloride salt afforded the title compounds as white solids in Table 4.
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0002
EXAMPLE 14
Figure imgf000090_0001
Part A: Chloroacetic acid (5.11 g, 1.3 equiv) was added to a stirring solution of 2- amino-3,4-difluoroaniline (6.00 g, 1 equiv) in 6 N hydrochloric acid (28 ml_). After stirring for 18 hours at 95 0C the reaction was cooled to room temperature, made basic with 10% aqueous potassium carbonate and extracted with ethyl acetate (850 ml_). The organic layer was separated, dried over sodium sulfate, filtered, concentrated under reduced pressure, and purification by silica gel chromatography (120 g SiO2, hexanes to 60% ethyl acetate in hexanes) afforded the desired benzimidazole as a pink solid 6.24 g (74%).
Part B: A mixture of the benzimidazole from example 14 part A (4.18 g, 1.00 equiv), potassium carbonate (8.53 g, 3.00 equiv) in DMF (50 mL) was stirred at room temperature for 5 minutes at which time 2-(trimethylsilyl)ethoxymethyl chloride (4.0 mL, 1.1 equiv) was added. After stirring at room temperature for 18 hours the reaction was quenched with a saturated aqueous solution of sodium bicarbonate (40 mL) and concentrated under reduced pressure to a residue. The residue was diluted with ethyl acetate (500 mL) and washed with water (150 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purification by silica gel chromatography (120 g Siθ2, hexanes to 50% of ethyl acetate in hexanes) afforded the desired benzimidazole as a brown oil 3.11 g (45%).
Part C: To a solution of 4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (1.65 g, 1 equiv), benzimidazole from Example 14 part B (3.11 g, 1.1 equiv) in DMA (57 mL) was added potassium carbonate (3.51 g, 3 equiv). The mixture was heated at 50 0C for 18 hours. The reaction mixture was poured into water (250 mL), extracted with ethyl acetate (500 mL), the organic layer washed with brine (250 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purification by silica gel chromatography (80 g SiO2, hexanes to 50% of ethyl acetate in hexanes) afforded the desired boronate as a off-white solid 2.67 g (64%).
EXAMPLE 15
Figure imgf000091_0001
To a mixture of aryl iodide (100 mg, 1.00 equiv), PdCI2(dppf) (12 mg, 0.10 equiv), and potassium phosphate (71 mg, 2.00 equiv) under nitrogen was added a solution of the boronate from Example 14 part C (123 mg, 1.20 equiv) in 1 ,4-dioxane (2.0 mL), followed by water (0.2 mL). The mixture was stirred at 90 0C for 18 hours at which time TLC indicated no starting material remained. The reaction was allowed to cool to room temperature, then diluted with ethyl acetate (100 mL) and washed with water (3OmL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purification by silica gel chromatography (12 g Siθ2, dichloromethane to 10% methanol in dichloromethane) afforded the desired coupled product. This material was dissolved in 1 ,4-dioxane, HCI (4N in dioxane) was added and the mixture was sonicated until such time that HPLC indicated no starting material remained. The mixture was concentrated under reduced pressure, purified by prep-HPLC, and conversion to the hydrochloride salt afforded the title compounds as off-white solids in Table 5.
Table 5
Figure imgf000092_0002
EXAMPLE 16
Figure imgf000092_0001
To a mixture of aryl iodide (2.15 g, 1.00 equiv), PdCl2(dppf) (288 mg, 0.10 equiv), and potassium phosphate (1.67 mg, 2.00 equiv) under nitrogen was added a solution of the boronate from Example 14 part C (2.51 g, 1.20 equiv) in 1 ,4-dioxane (47 rnL), followed by water (4.7ml_). The mixture was stirred at 90 0C for 3 hours at which time TLC indicated no starting material remained. The reaction was allowed to cool to room then diluted with ethyl acetate (700 mt_) and washed with water (250 ml_), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purification by silica gel chromatography (120 g SiO2, hexanes to 100% ethyl acetate) afforded the desired coupled product as a brown foam 2.04 g (66%).
EXAMPLE 17
Figure imgf000093_0001
Part A: To a stirring solution of the coupled product from Example 16 (2.04 g, 1 equiv) in tetrahydrofuran (63 mL) at -78 0C was added DIBAL-H (1 M in dichloromethane, 6.5 mL, 2.5 equiv) dropwise. The mixture was stirred at -78 0C for 5 hours at which time thin layer chromatography (30% ethyl acetate/hexanes) indicated the reaction was complete. The mixture was quickly poured into stirring saturated aqueous sodium potassium tartrate and stirred at room temperature for 14 hours. The mixture was extracted with ethyl acetate (500 ml_), the organic layer separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure affording the aldehyde as a brown foam 1.96 g (100%).
Part B: Sodium triacetoxyborohydride (1.50 equiv) was added to a stirring mixture of aldehyde (1.00 equiv), amine (1.20 equiv), and acetic acid (1.00 equiv) in 1 ,2- dichloroethane at room temperature. The mixture was stirred until no starting material remained as judged by TLC. The reaction was then quenched with 1 N NaOH and extracted three times with chloroform. The combined organics were dried over sodium sulfate, filtered, and concentrated. This material was dissolved in 1 ,4- dioxane, HCI (4N in dioxane) was added and the mixture was sonicated until such time that HPLC indicated no starting material remained. The mixture was concentrated under reduced pressure, purified by prep-HPLC, and conversion to the hydrochloride salt afforded the title compounds as off-white solids in Table 6.
Table 6
Figure imgf000094_0001
Figure imgf000095_0001
EXAMPLE 18
Figure imgf000096_0001
Part A: Sodium borohydride (2.0 equiv) was added to a stirring mixture of aldehyde from Example 17 part A (1.00 equiv) in acetic acid (5.7 ml_) in 1 ,2-dichloromethane (17 ml_) at room temperature. The mixture was stirred until no starting material remained as judged by TLC. The reaction was then quenched with 2N NaOH (11 mL) and a saturated solution of aqueous sodium bicarbonate (35 mL). After stirring at room temperature for 15 minutes, the phases were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the alcohol as a brown foam 1.01 g (100%).
Part B: Methane sulfonyl chloride (2 equiv) was added to a stirring solution of alcohol from Example 18 part A (1 equiv) and triethylamine (4 equiv) in THF (40 mL). After stirring at room temperature for 30 minutes the reaction was quenched with a saturated aqueous solution of ammonium chloride (14 mL) and water (14 mL), extracted with dichloromethane (2*80 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure affording the mesylate as a brown foam 1.04 g (90%).
Part C: To a stirring solution of mesylate from Example 18 part B (1 equiv), amine (3 equiv), sodium iodide (0.5 equiv) in THF (1.0 mL) was added diisopropylethylamine (3 equiv) and the reaction heated at 60 0C for 18 hours. The reaction was cooled to room temperature, diluted with dichloromethane (50 mL) and the organic layer washed with water (30 ml_), brine (30 ml_), dried over sodium sulfate, filtered and concentrated under reduced pressure. This materia! was dissolved in 1 ,4-dioxane, HCI (4N in dioxane) was added and the mixture was sonicated until such time that HPLC indicated no starting material remained. The mixture was concentrated under reduced pressure, purified by prep-HPLC, and conversion to the hydrochloride salt afforded the title compounds as off-white solids in Table 7.
Table 7
Figure imgf000097_0001
Figure imgf000098_0001
EXAMPLE 19
The following compounds (Table 8) can be prepared by a method similar to the method described in Example 18.
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
EXAMPLE 21
Figure imgf000107_0001
Sodium azide (116 mg, 1.79 mmol) was added to a solution of bromide (408 mg, 1.63 mmol) in dimethylformamide (30 ml_). The reaction mixture was then heated to 60 0C and stirred for 12 hours. Upon completion, the reaction was cooled to room temperature and the solvent was removed in vacuo. The resultant residue was taken into ethyl acetate (75 ml_) then washed with sodium bicarbonate (50 mL), water (50 mL) and brine (50 mL). The organic layer was then dried (sodium sulfate), filtered, and concentrated to dryness. The resultant solid was placed onto a flash column (SiO2; 12 g; 10% to 50% ethyl acetate in hexanes) to give the title compound as a white solid 240 mg (69%). 1H NMR (300 MHz, CDCI3) δ 8.28 (br s, 1 H), 8.12-7.96 (m, 1 H), 7.16-7.02 (m, 1 H), 7.01-6.87 (m, 1 H), 4.20 (s, 2H).
EXAMPLE 22
Figure imgf000107_0002
Copper powder (5 mg, 0.08 mmol) was added to a solution of alkyne (19 mg, 0.04 mmol) from Example 21 and azide (16 mg, 0.08 mmol) from Example 22 in f-butyl alcohol (0.3 mL) and water (0.6 mL). The reaction was stirred at room temperature for 72 hours then diluted with ethyl acetate (100 mL). The organic layer was washed with water (100 mL) and brine (100 mL) then dried (sodium sulfate), filtered and concentrated. The resultant residue was placed onto a flash column (SiO2; 4 g; 0% to 10% methanol in methylene chloride) to afford the coupled intermediate. The desired intermediate was then dissolved in dioxane (2 mL) and treated with 4 N HCI in dioxane (2 mL). The reaction was sonicated at room temperature for 1 hour. The solvent was removed and the residue was purified by prep-HPLC (95:5 to 5:95 water/acetonitrile with 0.1% trifluoroacetic acid). The fractions were collected and dried and the residue treated with 0.2 N HCI and freeze-dried to afford the title compound as a white solid 6.9 mg (28%). 1H NMR (300 MHz, CD3OD) δ 8.65 (s, 1H), 8.58 (s, 1H), 8.13 (s, 1H), 7.77-7.70 (m, 1H), 7.21 (s, 1 H), 7.17-7.04 (m, 2H), 5.59 (s, 2H), 4.38 (s, 2H), 3.71-3.46 (m, 2H), 3.13-3.09 (m, 1 H), 2.79-2.63 (m, 1 H), 2.58 (s, 3H), 2.06-1.74 (m, 4H), 1.32-1.11 (m, 1 H), 1.00 (d, J = 6.4 Hz, 3H). HPLC tR = 5.45 min (UV 254nm)- Mass calculated for formula C27H28F2N10OS 578.2; observed MH+ (ESI MS) 579.8 (m/z).
EXAMPLE 23
Figure imgf000108_0001
Example 24 was prepared in a similar manner to Example 15. 1H NMR (300 MHz, CD3OD) δ 8.30 (s, 1 H), 8.21 (s, 1 H), 8.03 (s, 1 H), 8.00 (s, 1 H), 7.35 (s, 1 H), 5.31-5.22 (m, 1 H), 4.49-4.37 (m, 4H), 3.91 (s, 4H), 3.69-3.46 (m, 2H), 3.10-2.91 (m, 1 H), 2.80- 2.66 (m, 1H), 2.63 (s, 3H), 2.07-1.74 (m. 4H), 1.39-1.12 (m, 1H), 1.00 (d, J = 6.5 Hz, 3H). HPLC tR = 7.36 min (UV 254nm)- Mass calculated for formula C24H30N8O2S 494.2; observed MH+ (ESI MS) 495.8 (m/z). EXAMPLE 24
Figure imgf000109_0001
Example 25 was prepared in a similar manner to Example 6. 1H NMR (300 MHz, CD3OD) δ 8.20 (s, 1 H), 7.94 (s, 1 H), 7.85 (s, 1 H), 7.77 (s, 1 H), 7.18 (s, 1 H), 4.98 (s, 2H), 4.37 (br s, 2H), 4.17-3.81 (m, 2H), 3.71-3.40 (m, 2H), 3.20-3.05 (m, 1H), 3.03- 2.84 (m, 2H), 2.79-2.62 (m, 1 H), 2.52 (s, 3H), 2.06-1.97 (m, 4H), 1.97-1.69 (m, 5H), 1.46 (s, 9H), 1.32-1.14 (m, 1H), 1.00 (d, J = 6.4 Hz, 3H).
EXAMPLE 25
Figure imgf000109_0002
Trifluoroacetic acid (2 mL) was added to a solution of amide (20 mg, 0.02 mmol) in methylene chloride (2 mL). The reaction was allowed to stir at room temperature for 2 hours. The solvent was removed and the resultant residue placed onto a prep-HPLC (95:5 to 40:60 water/acetonitrile with 0.1% trifluoroacetic acid). The collected fractions were concentrated then treated with 0.2 N HCI and freeze-dried to afford the title compound as a white solid 3.2 mg (23%). 1H NMR (300 MHz, CD3OD) δ 8.23 (s, 1H), 7.96 (s, 1 H), 7.91 (s, 1 H), 7.85 (s, 1 H), 7.21 (s, 1 H), 5.00 (s, 2H), 4.39 (br s, 2H), 4.09- 3.93 (m, 1 H), 3.68-3.39 (m, 4H), 3.20-3.04 (m, 2H)1 3.04-2.89 (m, 1 H), 2.79-2.63 (m, 1 H), 2.51 (s, 3H), 2.24-2.09 (m, 2H), 2.05-1.67 (m, 6H), 1.32-1.12 (m, 1 H), 1.01 (d, J 6.4 Hz, 3H). HPLC tR = 3.47 min (UV 254nm)- Mass calculated for formula C27H36N10OS 548.3; observed MH+ (ESl MS) 549.9 (m/z).
EXAMPLE 26
Figure imgf000110_0001
Figure imgf000110_0002
Part A: To a solution of iodide (390 mg, 0.757 mmol) in 10 mL of CH2CI2 was added 8 mL of AcOH. NaBH4 (57 mg, 1.51 mmol) was then added in one portion. The reaction was stirred at room temperature for 15 min. It was diluted with 100 mL of CH2CI2, and neutralized by 5 N NaOH (aq.). To the mixture was added 100 ml of saturated aqueous NaHCO3. The resulting mixture was stirred at room temperature for 30 min. The organic layer was isolated. It was dried over anhydrous Na2SO4, and then concentrated. The residue was purified by flash chromatography eluting with 60% EtOAc/ CH2CI2 to give 390 mg of the title compound. 1H NMR (400 MHz, CDCI3) δ 7.72 (s, 1 H), 7.60 (s, 1 H), 7.13 (s, 1 H), 6.58 (brs, 2H), 4.78 (s, 2H), 3.72 (t, 2H), 2.60 (s, 3H), 0.95 (t, 2H), -0.10 (s, 9H). Part B: To a mixture of alcohol from Part A (80 mg, 0.15 mmol), boronate from Example 7, Part A (84 mg, 0.23 mmol) and Pd(PPh3)4 (17.8 mg, 0.015 mmol) was added 2 mL of DMF followed by 3 M aqueous K3PO4 solution (0.21 mL, 0.63 mmol). The reaction mixture was heated at 65 0C for 18 h. It was diluted with 30 ml_ of EtOAc and washed with 1 N aqueous NH4CI solution (20 mL x 2). The organic layer was concentrated under vacuum. The residue was purified by flash chromatography eluting with 4% MeOH/CH2CI2 to give 68 m g of 5. 1H NMR (400 MHz, CDCI3) δ 8.90 (brs, 1 H), 8.02-8.12 (m, 1 H), 8.00 (s, 1 H), 7.87 (s, 1 H), 7.68 (s, 1 H), 7.57 (s, 1H), 7.15 (s, 1 H), 6.90-7.13 (m, 2H), 6.65 (brs, 2H), 5.09 (s, 2H), 4.75-4.81 (m, 2H), 3.77 (t, 2H), 2.80 (brs, 1 H), 2.60 (s, 3H), 0.95 (t, 2H), -0.10 (s, 9H).
Part C: To a solution of alcohol from Part B (31 mg, 0.049 mmol) in 1.5 mL of THF, was added 3 CL of water followed by Dess-Martin periodinane (64 mg, 0.15 mmol). The reaction mixture was stirred at room temperature for 30 min. It was diluted with 5 mL of THF. The mixture was filtered. The filtrate was diluted with 20 mL of CH2CI2 and washed with 10 mL of saturated aqueous NaHCO3 solution. It was dried over anhydrous Na2SO4 and then concentrated to give 30 mg of the title compound which was used in the subsequent reactions without further purification. Part D: A solution of aldehyde (12 mg, 0.019 mmol), 3,3-dimethylpiperidine (22 mg,
0.19 mmol) in 1 mL of CH2CI2 was stirred at room temperature for 30 min. To the solution was added NaBH4 (3.6 mg, 0.096 mmol) followed by 0.3 mL of MeOH. The reaction was stirred at room temperature for 1 h. It was diluted with 10 mL of CH2CI2 and 10 mL of saturated aqueous NaHCO3 solution. The resulting mixture was stirred for 1 h. The organic was separated and concentrated under vacuum. The residue was purified by flash chromatography eluting with NH4OH (aq.)/MeOH/ CH2CI2 (1 :10:190) to give 10 mg of the SEM-protected title compound. To a solution of SEM- protected material (10 mg, 0.014 mmol) in 2 mL of THF heated at 80 0C was added 0.2 mL of 4 N HCI in dioxane. The reaction was stirred at 80 0C for 1.5 h. It was cooled to room temperature and then added 8 mL of ether. The solid was collected by filtration and washed with ether to give 8.7 mg of the title compound. 1H NMR (400 MHz, CD3OD) δ 8.38 (s, 1 H), 8.15 (s, 1 H), 8.08 (s, 1 H), 8.02 (s, 1 H), 7.72-7.81 (m, 1 H), 7.27 (s, 1 H), 7.03-7.20 (m, 2H), 5.30 (s, 2H), 4.35-4.60 (m, 2H), 3.55-3.65 (d, 1 H), 3.00-3.10 (m, 1 H), 2.80-2.90 (d, 1 H), 2.60 (s, 3H), 1.81-2.10 (m, 2H), 1.40-1.69 (m, 2H), 1.20 (s, 3H), 1.00 (s, 3H). HPLC-MS tR = 2.96 min (UV 254nm). Mass calculated for formula C29H31F2N9OS 591.2; observed MH+ (LCMS) 592.3 (m/z). EXAMPLE 27
By essentially the same procedure set forth in Example 26, only replacing 3,3- dimethylpiperidine with other respective amines in Part A, compounds shown in column 2 of Table 9 were prepared.
Figure imgf000112_0001
EXAMPLE 28
Figure imgf000113_0001
Part A: To a solution of alcohol from Example 26, Part B (30 mg, 0.047 mmol) in 1.5 mL of THF, was added triethylamine (9.5 mg, 0.094 mmol) followed by methanesulfonylchloride (7.3 μl_, 0.094 mmol). The reaction was stirred at room temperature for 20 min. It was diluted with 10 mL of CH2CI2, washed with 5 mL of 1 N aqueous HCI. The organic was dried over anhydrous Na2SO4. The solvent was removed to give 31 mg of the title compound as a crude material which was used in the subsequent reaction without further purification.
Part B: A mixture of mesylate from Part A (9.6 mg, 0.014 mmol), N, N- diethylisopropylamine (6.0 mg, 0.068 mmol) and NaI (4.1 mg, 0.027 mmol) in 1 mL of THF was stirred at 60 0C for 3 h. It was diluted with 10 mL of CH2CI2 and washed with water. The organic was concentrated under vacuum. The residue was purified by flash chromatography eluting with NH4OH (aq.)/MeOH/CH2CI2 (1 :10:190) to give 8 mg of A/-(2,3-difluoro-phenyl)-2-(4-{8-[{3-[(ethyl-isopropyl-amino)-methyl]-isothiazol-5-yl}- (2-trimethylsilanyl-ethoxymethyl)-amino]-6-methyl-imidazo[1 ,2-a]pyrazin-3-yl}-pyrazol- 1-yl)-acetamide. To a solution of /V-(2,3-difluoro-phenyl)-2-(4-{8-[{3-[(ethyl-isopropyl- amino)-methyl]-isothiazol-5-yl}-(2-trimethylsilanyl-ethoxymethyl)-amino]-6-methyl- imidazo[1 ,2-a]pyrazin-3-yl}-pyrazol-1-yl)-acetamide (8.0 mg, 0.011 mmol) in 2 mL of THF heated at 800C was added 0.2 mL of 4 N HCI in dioxane. The reaction was stirred at 80 0C for 1.5 h. It was cooled to room temperature and then added 8 mL of ether. The solid was collected by filtration and washed with ether to give 5.8 mg of the title compound. 1H NMR (400 MHz, CD3OD) δ 8.35 (s, 1 H), 7.95-8.10 (m, 3H), 7.70- 7.82 (m, 1 H), 7.25 (s, 1 H), 7.00-7.20 (m, 2H), 5.30 (s, 2H), 4.30-4.60 (m, 2H), 3.75- 3.85 (m, 1 H), 2.60 (s, 3H), 1.30-1.50 (m, 9H). HPLC-MS tR = 2.80 min (UV 254nm). Mass calculated for formula C27H29F2N9OS 565.2; observed MH+ (LCMS) 566.3 (m/z). EXAMPLE 29
Figure imgf000114_0001
Part A: To a solution of 4-amino-3-fluoro pyridine (560 mg, 5.0 mmol) and Et3N (760 mg, 7.5 mmol) in 20 ml_ of THF, was added chloroacetyl chloride (622 mg, 5.5 mmol). The reaction was stirred at room temperature and monitored by thin layer chromatography. More chloroacetyl chloride was added until 4-amino-3-fluoro pyridine was consumed. It was quenched by adding 20 ml_ of saturated aqueous NaHCθ3. The mixture was diluted with 150 ml_ of CH2CI2. The organic layer was concentrated and purified by flash chromatography eluting with 35% EtOAc/CH2CI2 to give 850 mg of the title compound. NMR (400 MHz, CDCI3) δ 8.62 (brs, 1 H), 8.41 (d, 1 H), 8.33 (d, 1 H), 8.26 (t, 1 H), 4.20 (s, 2H).
Part B: A mixture of amide from Part A (106 mg, 0.55 mmol) and Cs2CO3 (326 mg, 1.0 mmol) in 2 rnL of DMSO was heated at 100 0C for 5 min. To the mixture was added 4- pyrazoleboronic acid pinacol ester (94 mg, 0.50 mmol). The reaction was stirred at 100 0C for 20 min. It was cooled to room temperature and diluted with 30 ml_ of CH2Cl2. The mixture was washed with water. The organic was concentrated and purified by running a quick column eluting with 2% MeOH/EtOAc to give 52 mg of the title compound. NMR (400 MHz, CDCI3) δ 9.30 (brs, 1 H), 8.33 (d, 1 H), 8.20-8.30 (m, 2H), 7.93 (s, 1 H), 7.75 (s, 1 H), 4.90 (s, 2H), 1.24 (s, 12H).
EXAMPLE 30
Figure imgf000115_0001
Part A: To a mixture of iodide (43 mg, 0.083 mmol), boronate from Example 29, Part B (43 mg, 0.124 mmol) and Pd(PPh3)4 (14 mg, 0.012 mmol) in a vial, was added 1.1 mL of DMF, followed by adding 0.11 mL of 3 M aqueous KsPO4 solution (0.33 mmol). The vial was sealed and stirred at 65 0C overnight. It was diluted with 30 mL of EtOAc and washed with water. It was concentrated and purified by flash chromatography eluting with 7% MeOH/DCM to give 24 mg of the title compound. NMR (400 MHz, CDCI3) δ 9.25 (brs, 1H), 8.25-8.43 (m, 3H), 7.95 (s, 1 H), 7.80 (s, 1H), 7.61 (s, 1 H), 7.50 (s, 1 H), 7.09 (s, 1 H), 6.60 (s, 2H), 5.05 (s, 2H), 4.72 (s, 2H), 3.70 (t, 2H), 2.75 (brs, 1H), 2.48 (S, 3H), 0.90 (t, 2H), -0.14 (s, 9H).
Part B: To a solution of alcohol from Part A (102 mg, 0.17 mmol) in 5 mL of THF, was added NEt3 (0.094 mL, 0.67 mmol), followed by methanesulfonylchloride (0.029 mL, 0.37 mmol). The reaction was stirred at room temperature for 15 min. It was monitored by thin layer chromatography and found starting alcohol was not totally consumed. Additional methanesulfonylchloride (0.0035 mL, 0.039 mmol) was added. The stirring was continued for 5 min. It was quenched by adding 2 mL of saturated NH4Cl (aq.) and 2 mL of water. The organic layer was collected. The aqueous layer was extracted with CH2CI2 (10 mL X 3) until no desired product remains in aqueous layer. The combined organics were further purified by flash chromatography eluting with MeOH/CH2Cl2 (1 :10) to give 63.3 mg of the title compound as a light yellow solid. 1H NMR (400 MHz, DMSO-Cf6) δ 10.75 (s, 1H), 8.60 (d, 1 H), 8.51 (s, 1 H), 8.36 (d, 1 H), 8.20 (t, 1H), 8.10 (s, 2H), 7.96 (s, 1 H), 7.38 (s, 1 H), 6.70 (brs, 2H), 5.34 (s, 2H), 5.28 (s, 2H), 3.68 (t, 2H), 3.28 (s, 3H), 2.54 (s, 3H), 0.85 (t, 2H), -0.10 (s, 9H). Part C: A mixture of mesylate from Part B (24.7 mg, 0.036 mmol), N, N- diethylisopropylamine (7.8 mg, 0.089 mmol) and NaI (1 mg, 0.007 mmol) in 1.5 ml_ of THF was stirred at 80 0C for 4 h. It was diluted with 10 ml_ of CH2CI2 and washed with water and brine. It was dried over anhydrous Na2SO4. The organic was concentrated under vacuum. The residue was purified by flash chromatography eluting with 7N NH3 in MeOH /CH2CI2 (1 :30) to give 11.5 mg of 2-(4-{8-[{3-[(ethyl-isopropyl-amino)- methyl]-isothiazol-5-yl}-(2-trimethylsilanyl-ethoxymethyl)-amino]-6-methyl-imidazo[1 ,2- a]pyrazin-3-yl}-pyrazol-1-yl)-A/-(3-fluoro-pyridin-4-yl)-acetamide. NMR (400 MHz, CDCI3) δ 9.36 (brs, 1 H), 8.30-8.48 (m, 3H), 8.02 (s, 1 H), 7.85 (s, 1 H), 7.66 (s, 1 H), 7.55 (s, 1H), 7.30 (s, 1H), 6.62 (s, 2H), 3.60-3.85 (m, 4H), 2.96-3.15 (brs, 3H), 2.40- 2.68 (m, 5H), 0.90-1.20 (m, 12H), 0.00 (s, 9H)._To a solution of 2-(4-{8-[{3-[(ethyl- isopropyl-amino)-methyl]-isothiazol-5-yl}-(2-trimethylsilanyl-ethoxymethyl)-amino]-6- methyl-imidazo[1 ,2-a]pyrazin-3-yl}-pyrazol-1-yl)-A/-(3-fluoro-pyridin-4-yl)-acetamide (11.5 mg, 0.0169 mmol) in 0.4 mL of THF heated at 80 0C was added 0.4 mL of 4 N HCI in dioxane. The reaction was stirred at 80 0C for 1 h. It was cooled to room temperature and then added 8 mL of ether. The solid was collected by filtration and washed with ether to give 10 mg of the title compound. HPLC-MS tR = 2.18 min (UV 254nm). Mass calculated for formula C26H2gFNioOS 548.2; observed MH+ (LCMS) 549.3 (m/z).
EXAMPLE 31
By essentially the same procedure set forth in Example 30, only replacing ethylisopropylamine with other respective amines in Part C, compounds shown in column 2 of Table 10 were prepared.
Figure imgf000117_0001
Figure imgf000118_0001
ASSAYS:
Aurora Enzyme Assay
An in vitro assay was developed that utilizes recombinant Aurora A or Aurora B as an enzyme source and a peptide based on PKA as the substrate. Aurora A Assay:
Aurora A kinase assays were performed in low protein binding 384-well plates (Corning Inc). All reagents were thawed on ice. Compounds were diluted in 100% DMSO to desirable concentrations. Each reaction consisted of 8 nM enzyme (Aurora A, Upstate cat#14-511), 100 nM Tamra-PKAtide (Molecular Devices, 5TAMRA- GRTGRRNSICOOH ), 25 μM ATP (Roche), 1 mM DTT (Pierce), and kinase buffer (10 mM Tris, 10 mM MgCI2, 0.01% Tween 20). For each reaction, 14 μl containing TAMRA-PKAtide, ATP, DTT and kinase buffer were combined with 1 μl diluted compound. The kinase reaction was started by the addition of 5 μl diluted enzyme. The reaction was allowed to run for 2 hours at room temperature. The reaction was stopped by adding 60 μl IMAP beads (1 :400 beads in progressive (94.7% buffer A: 5.3% buffer B) 1X buffer, 24 mM NaCI). After an additional 2 hours, fluorescent polarization was measured using an Analyst AD (Molecular devices). Aurora B Assay.
Aurora B kinase assays were performed in low protein binding 384-well plates
(Corning Inc). All reagents were thawed on ice. Compounds were diluted in 100%
DMSO to desirable concentrations. Each reaction consisted of 26 nM enzyme (Aurora B, Invitrogen cat#pv3970), 100 nM Tamra-PKAtide (Molecular Devices, 5TAMRA-GRTGRRNSICOOH ), 50 μM ATP (Roche), 1 mM DTT (Pierce), and kinase buffer (10 mM Tris, 10 mM MgCI2, 0.01% Tween 20). For each reaction, 14 μl containing TAMRA-PKAtide, ATP, DTT and kinase buffer were combined with 1 μl diluted compound. The kinase reaction was started by the addition of 5 μl diluted enzyme. The reaction was allowed to run for 2 hours at room temperature. The reaction was stopped by adding 60 μl IMAP beads (1 :400 beads in progressive (94.7% buffer A: 5.3% buffer B) 1X buffer, 24 mM NaCI). After an additional 2 hours, fluorescent polarization was measured using an Analyst AD (Molecular devices). ICgo Determinations:
Dose-response curves were plotted from inhibition data generated each in duplicate, from 8 point serial dilutions of inhibitory compounds. Concentration of compound was plotted against kinase activity, calculated by degree of fluorescent polarization. To generate IC50 values, the dose-response curves were then fitted to a standard sigmoidal curve and IC50 values were derived by nonlinear regression analysis.
Several compounds of the present invention exhibit Aurora A IC50 values of about 0.0001 nm to about 4 nm, Aurora B IC50 values of about 0.0001 nm to about 13 nM, and p-HH3 IC50 values of about 1 nM to about 10,000 nM. Additional compounds exhibit Aurora A IC50 values of about 0.0001 nm to about 3000 nm, Aurora B IC50 values of about 0.0001 nm to about 3000 nM, and p-HH3 IC50 values of about 1 nM to about 10,00O nM.
While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and other variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

Claims

CLAIMSWhat is claimed is:
1. A compound of Formula I:
Figure imgf000121_0001
or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof, wherein:
R is H, halo or alkyl; i R is heteroaryl-X, wherein X is heterocyclylalkyl- wherein said heterocyclyl can be unsubstituted or optionally substituted with 1-4 alkyl moieties;
A is -aryl- , -heteroaryl-, -N(R1)-aryl- or -N(R1)-heteroaryl- , wherein each of said aryl and heteroaryl can independently be unsubstituted or is optionally substituted with one or more substituents, which substituents can be the same or different, each substituent being independently selected from the group consisting of alkyl, -NO2, halo, hydroxy, trihaloalkyl, alkoxy, and dialkylamino;
RA is -(CH2)i-4-heteroaryl,
Figure imgf000121_0002
wherein said heteroaryl can optionally be fused with an aryl, wherein each of said aryl and heteroaryl can independently be optionally substituted with one or more moieties each moiety being independently selected from the group consisting of trihaloalkyl, -NO2, halo, hydroxyalkyl, alkoxyalkyl and dialkylamino; R1 is H or alkyl;
R2 is H, hydroxyalkyl-, arylalkyl-, heteroaryl, aryl, heteroarylalkyl-, alkyl, dialkylaminoalkyl-, alkylaminoalkyl-, cycloalkylalkyl-, cycloalkyl, heterocyclylalkyl- or heterocyclyl, wherein said aryl and aryl of arylalkyl can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of trihaloalkyl, -NO2, halo, hydroxyalkyl, alkoxyalkyl, dialkylamino and heterocyclylalkyl-, wherein said heterocyclylalkyl can be unsubstituted or substituted with alkyl or -SO2NH2; said heteroaryl and heteroaryl of heteroarylalkyl can be unsubstituted or substituted with one or more moieties, each moiety being independently selected from the group consisting of hydroxyalkyl, alkoxy, alkyl, halo, hydroxyl, and -NO2; and said cycloalkyl is unsubstituted or substituted with hydroxyl; or
R1 and R2 together with the N to which each is attached, form a
heterocyclic group selected from the group consisting of
Figure imgf000122_0001
Figure imgf000122_0002
, wherein
Y is alkoxyalkyl, hydroxyalkyl, dialkylaminoalkyl or alkyl, further wherein
Y is hydroxyl.
2. A compound of the following Formula:
Figure imgf000122_0003
or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof, wherein:
R is Br or methyl;
R3 is
Figure imgf000122_0004
, wherein X is which can be unsubstituted or substituted with methyl;
Figure imgf000122_0005
R is
Figure imgf000122_0006
wherein either (i) R1 is H or methyl; and R >2 : is hydrogen,
Figure imgf000123_0004
, phenyl methyl,
Figure imgf000123_0001
Figure imgf000123_0002
, wherein said phenyl methyl can be unsubstituted or substituted with one or more moieties each independently selected from the group consisting Of -NO2, -F, -Cl, hydroxy,-CF3, -OCH3, and -N(CH3)2, further wherein
Figure imgf000123_0003
independently unsubstituted or substituted with one or more moieties independently selected from the group consisting of hydroxyalkyl, alkyl, halo, hydroxyl, and -NO2; or (ii) R1 and R2 together with the N to which each is attached, form a
heterocyclic group selected from the group consisting of
Figure imgf000124_0001
Figure imgf000124_0002
methyl, and
Y is hydroxyl.
3. The compound of claim 1 , wherein A is aryl.
4. The compound of claim 1 , wherein A is heteroaryl.
5. The compound of claim 1 , wherein A is -N(R1)-heteroaryl.
6. The compound of claim 1 , wherein A is - N(R1)-aryl.
7. The compound of claim 1 , wherein A is -N(H)-heteroaryl.
8. The compound of claim 1 , wherein A is -N(H)-aryl.
9. The compound of claim 1 , wherein R is H.
10. The compound of claim 1 , wherein R is alkyl.
11. The compound of claim 1 , wherein R is methyl.
12. The compound of claim 1 , wherein R is halo.
13. The compound of claim 1 , wherein R1 is H.
14. The compound of claim 1 , wherein R1 is alkyl.
15. The compound of claim 1 , wherein R is methyl.
16. The compound of claim 1 , wherein R is halo.
17. The compound of claim 1 , wherein R3 is heteroaryl-(unsubstituted heterocyclyl).
18. The compound of claim 1 , wherein R3 is heteroaryl-(heterocyclyl(methyl)).
19. The compound of claim 1 , wherein R3 is heteroaryl-(heterocyclyl(methyl)2).
20. The compound of claim 1 , wherein R3 is thiazolyl substituted with heterocyclyl which is substituted with 1-3 alkyl.
21. The compound of claim 1 , wherein R3 is thiazolyl substituted with heterocyclyl which is unsubstituted.
22. The compound of claim 1 , wherein R3 is thiazolyl substituted with piperidyl which may be optionally substituted with 1-3 alkyl.
23. a compound according to claim 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, in purified form.
24. A compound according to claim 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, in isolated form.
25. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, in combination with at least one pharmaceutically acceptable carrier.
26. The pharmaceutical composition according to claim 25, further comprising one or more anti-cancer agents different from the compound of claim 1.
27. The pharmaceutical composition according to claim 26, wherein the one or more anti-cancer agents are selected from the group consisting of a cytostatic agent, cisplatin, doxorubicin, liposomal doxorubicin, Caelyx®, Myocet®, Doxil®, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH
66336, R115777®, L778.123®, BMS 214662®, Iressa®, Tarceva®, antibodies to EGFR, antibodies to IGFR, KSP inhibitors, ispinesib, SB-743921 , centrosome associated protein E ("CENP-E") inhibitors, GSK-923295, Gleevec®, intron, ara-C, adriamycin, Cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan,
Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN™, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin,
Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin,
Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17α-Ethinylestradiol,
Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, Avastin, herceptin, Bexxar, bortezomib ("Velcade"), Zevalin, Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane, Fulvestrant, Ifosfomide, Rituximab, C225®, satriplatin, mylotarg, Avastin, Rituxan, panitubimab, Sutent, sorafinib, Sprycel (dastinib), nilotinib, Tykerb (lapatinib) and Campath.
28. A method of inhibiting one or more Aurora kinases, comprising administering a therapeutically effective amount of at least one compound of claim 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, to a patient.
29. A method of treating one or more diseases by inhibiting an Aurora kinase, comprising administering a therapeutically effective amount of at least one compound of claim 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, to a patient.
30. A method of treating one or more diseases by inhibiting an Aurora kinase, comprising administering to a mammal in need of such treatment an amount of a first compound, which is a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; and an amount of at least one second compound, the second compound being an anti-cancer agent different from the compound of claim 1 ; wherein the amounts of the first compound and the second compound result in a therapeutic effect.
31. The method according to any of claims 28, 29, or 30, wherein the Aurora kinase is Aurora A.
32. The method according to any of claims 28, 29, or 30, wherein the Aurora kinase is Aurora B.
33. The method according to any of claims 29 or 30, wherein the disease is selected from the group consisting of: tumor of the bladder, breast (including BRCA-mutated breast cancer, colorectal, colon, kidney, liver, lung, small cell lung cancer, non-small cell lung cancer, head and neck, esophagus, bladder, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T- cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma and Burkett's lymphoma; chronic lymphocytic leukemia ("CLL"), acute and chronic myelogenous leukemia, myelodysplastic syndrome and promyelocyte leukemia; fibrosarcoma, rhabdomyosarcoma; head and neck, mantle cell lymphoma, myeloma; astrocytoma, neuroblastoma, glioma, glioblastoma, malignant glial tumors, astrocytoma, hepatocellular carcinoma, gastrointestinal stromal tumors ("GIST") and schwannomas; melanoma, multiple myeloma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.
34. The method according to any of claims 28, 29 or 30, further comprising radiation therapy.
35. The method according to claim 30, wherein the anti-cancer agent is selected from the group consisting of a cytostatic agent, cisplatin, doxorubicin, liposomal doxorubicin, Caelyx®, Myocet®, Doxil®, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, R115777®, L778.123®, BMS 214662®, Iressa®, Tarceva®, antibodies to EGFR, antibodies to IGFR, KSP inhibitors, ispinesib, SB-743921 , centrosome associated protein E ("CENP-E") inhibitors, GSK-923295, Gleevec®, intron, ara-C, adriamycin, Cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan,
Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin,
ELOXATIN™, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine,
Figure imgf000128_0001
acceptable salt, solvate, ester or prodrug thereof.
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US10759806B2 (en) 2016-03-17 2020-09-01 Infinity Pharmaceuticals, Inc. Isotopologues of isoquinolinone and quinazolinone compounds and uses thereof as PI3K kinase inhibitors
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