[go: up one dir, main page]

WO2009097233A1 - Imidazopyrazines comme inhibiteurs de protéines kinases - Google Patents

Imidazopyrazines comme inhibiteurs de protéines kinases Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
compound
alkyl
heteroaryl
group
aryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2009/031972
Other languages
English (en)
Other versions
WO2009097233A9 (fr
Inventor
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
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Sharp and Dohme LLC
Curia Global Inc
Original Assignee
Albany Molecular Research Inc
Schering Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Albany Molecular Research Inc, Schering Corp filed Critical Albany Molecular Research Inc
Priority to CA2710929A priority Critical patent/CA2710929A1/fr
Publication of WO2009097233A1 publication Critical patent/WO2009097233A1/fr
Publication of WO2009097233A9 publication Critical patent/WO2009097233A9/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne, dans ses nombreux modes de réalisation, une nouvelle classe de composés d'imidazopyrazine comme inhibiteurs de protéines et/ou Aurora kinases, des procédés de préparation de tels composés, des compositions pharmaceutiques comprenant un ou plusieurs de ces composés, des procédés de préparation de formulations pharmaceutiques comprenant un ou plusieurs de ces composés et des procédés de traitement, de prévention, d'inhibition ou d'amélioration d'une ou de plusieurs maladies associées aux protéines ou Aurora kinases à l'aide de tels composés ou compositions pharmaceutiques.
PCT/US2009/031972 2008-01-28 2009-01-26 Imidazopyrazines comme inhibiteurs de protéines kinases Ceased WO2009097233A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CA2710929A CA2710929A1 (fr) 2008-01-28 2009-01-26 Imidazopyrazines comme inhibiteurs de proteines kinases

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US2401008P 2008-01-28 2008-01-28
US61/024,010 2008-01-28

Publications (2)

Publication Number Publication Date
WO2009097233A1 true WO2009097233A1 (fr) 2009-08-06
WO2009097233A9 WO2009097233A9 (fr) 2009-09-24

Family

ID=40456241

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2009/031972 Ceased WO2009097233A1 (fr) 2008-01-28 2009-01-26 Imidazopyrazines comme inhibiteurs de protéines kinases

Country Status (2)

Country Link
CA (1) CA2710929A1 (fr)
WO (1) WO2009097233A1 (fr)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011113862A1 (fr) 2010-03-18 2011-09-22 Bayer Pharma Aktiengesellschaft Imidazopyrazines
WO2011151259A1 (fr) 2010-06-01 2011-12-08 Bayer Pharma Aktiengesellschaft Imidazopyrazines substituées
CN102363618A (zh) * 2011-07-04 2012-02-29 华东理工大学 一种表皮生长因子受体的新型抑制剂及其应用
WO2013018733A1 (fr) 2011-07-29 2013-02-07 富士フイルム株式会社 Dérivé de 1,5-naphtyridine ou sel de celui-ci
US8716282B2 (en) 2009-10-30 2014-05-06 Janssen Pharmaceutica Nv Imidazo[1,2-b]pyridazine derivatives and their use as PDE10 inhibitors
US8859543B2 (en) 2010-03-09 2014-10-14 Janssen Pharmaceutica Nv Imidazo[1,2-a]pyrazine derivatives and their use for the prevention or treatment of neurological, psychiatric and metabolic disorders and diseases
US8940742B2 (en) 2012-04-10 2015-01-27 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9359365B2 (en) 2013-10-04 2016-06-07 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9550784B2 (en) 2012-07-09 2017-01-24 Beerse Pharmaceutica NV Inhibitors of phosphodiesterase 10 enzyme
US9669035B2 (en) 2012-06-26 2017-06-06 Janssen Pharmaceutica Nv Combinations comprising PDE 2 inhibitors such as 1-aryl-4-methyl-[1,2,4]triazolo-[4,3-A]]quinoxaline compounds and PDE 10 inhibitors for use in the treatment of neurological of metabolic disorders
US9708348B2 (en) 2014-10-03 2017-07-18 Infinity Pharmaceuticals, Inc. Trisubstituted bicyclic heterocyclic compounds with kinase activities and uses thereof
US9751888B2 (en) 2013-10-04 2017-09-05 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9775844B2 (en) 2014-03-19 2017-10-03 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US10160761B2 (en) 2015-09-14 2018-12-25 Infinity Pharmaceuticals, Inc. Solid forms of isoquinolinones, and process of making, composition comprising, and methods of using the same
US10604523B2 (en) 2011-06-27 2020-03-31 Janssen Pharmaceutica Nv 1-aryl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline derivatives
US10759806B2 (en) 2016-03-17 2020-09-01 Infinity Pharmaceuticals, Inc. Isotopologues of isoquinolinone and quinazolinone compounds and uses thereof as PI3K kinase inhibitors
US10919914B2 (en) 2016-06-08 2021-02-16 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060084650A1 (en) * 2004-10-15 2006-04-20 Qing Dong Kinase inhibitors
US20070105864A1 (en) * 2005-11-10 2007-05-10 Schering Corporation Methods for inhibiting protein kinases
WO2007058942A2 (fr) * 2005-11-10 2007-05-24 Schering Corporation Imidazopyrazines inhibant la proteine kinase
WO2007145921A1 (fr) * 2006-06-06 2007-12-21 Schering Corporation Imidazopyrazines utilisées en tant qu'inhibiteur de protéine kinase
WO2009017701A2 (fr) * 2007-07-31 2009-02-05 Schering Corporation Combinaison d'agent antimitotique et d'inhibiteur de l'aurora kinase comme traitement anti-cancer

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060084650A1 (en) * 2004-10-15 2006-04-20 Qing Dong Kinase inhibitors
US20070105864A1 (en) * 2005-11-10 2007-05-10 Schering Corporation Methods for inhibiting protein kinases
WO2007058942A2 (fr) * 2005-11-10 2007-05-24 Schering Corporation Imidazopyrazines inhibant la proteine kinase
WO2007145921A1 (fr) * 2006-06-06 2007-12-21 Schering Corporation Imidazopyrazines utilisées en tant qu'inhibiteur de protéine kinase
WO2009017701A2 (fr) * 2007-07-31 2009-02-05 Schering Corporation Combinaison d'agent antimitotique et d'inhibiteur de l'aurora kinase comme traitement anti-cancer

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8716282B2 (en) 2009-10-30 2014-05-06 Janssen Pharmaceutica Nv Imidazo[1,2-b]pyridazine derivatives and their use as PDE10 inhibitors
US8859543B2 (en) 2010-03-09 2014-10-14 Janssen Pharmaceutica Nv Imidazo[1,2-a]pyrazine derivatives and their use for the prevention or treatment of neurological, psychiatric and metabolic disorders and diseases
WO2011113862A1 (fr) 2010-03-18 2011-09-22 Bayer Pharma Aktiengesellschaft Imidazopyrazines
US9468642B2 (en) 2010-03-18 2016-10-18 Bayer Intellectual Property Gmbh Imidazopyrazines
WO2011151259A1 (fr) 2010-06-01 2011-12-08 Bayer Pharma Aktiengesellschaft Imidazopyrazines substituées
US10604523B2 (en) 2011-06-27 2020-03-31 Janssen Pharmaceutica Nv 1-aryl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline derivatives
CN102363618A (zh) * 2011-07-04 2012-02-29 华东理工大学 一种表皮生长因子受体的新型抑制剂及其应用
WO2013018733A1 (fr) 2011-07-29 2013-02-07 富士フイルム株式会社 Dérivé de 1,5-naphtyridine ou sel de celui-ci
US8940742B2 (en) 2012-04-10 2015-01-27 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9255108B2 (en) 2012-04-10 2016-02-09 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9669035B2 (en) 2012-06-26 2017-06-06 Janssen Pharmaceutica Nv Combinations comprising PDE 2 inhibitors such as 1-aryl-4-methyl-[1,2,4]triazolo-[4,3-A]]quinoxaline compounds and PDE 10 inhibitors for use in the treatment of neurological of metabolic disorders
US9550784B2 (en) 2012-07-09 2017-01-24 Beerse Pharmaceutica NV Inhibitors of phosphodiesterase 10 enzyme
US9359365B2 (en) 2013-10-04 2016-06-07 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9751888B2 (en) 2013-10-04 2017-09-05 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US12152032B2 (en) 2013-10-04 2024-11-26 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9828377B2 (en) 2013-10-04 2017-11-28 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US10329299B2 (en) 2013-10-04 2019-06-25 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9775844B2 (en) 2014-03-19 2017-10-03 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US10675286B2 (en) 2014-03-19 2020-06-09 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US11541059B2 (en) 2014-03-19 2023-01-03 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US10253047B2 (en) 2014-10-03 2019-04-09 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US10941162B2 (en) 2014-10-03 2021-03-09 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9708348B2 (en) 2014-10-03 2017-07-18 Infinity Pharmaceuticals, Inc. Trisubstituted bicyclic heterocyclic compounds with kinase activities and uses thereof
US10160761B2 (en) 2015-09-14 2018-12-25 Infinity Pharmaceuticals, Inc. Solid forms of isoquinolinones, and process of making, composition comprising, and methods of using the same
US11247995B2 (en) 2015-09-14 2022-02-15 Infinity Pharmaceuticals, Inc. Solid forms of isoquinolinones, and process of making, composition comprising, and methods of using the same
US11939333B2 (en) 2015-09-14 2024-03-26 Infinity Pharmaceuticals, Inc. Solid forms of isoquinolinones, and process of making, composition comprising, and methods of using the same
US12384792B2 (en) 2015-09-14 2025-08-12 Twelve Therapeutics, Inc. Solid forms of isoquinolinones, and process of making, composition comprising, and methods of using the same
US10759806B2 (en) 2016-03-17 2020-09-01 Infinity Pharmaceuticals, Inc. Isotopologues of isoquinolinone and quinazolinone compounds and uses thereof as PI3K kinase inhibitors
US10919914B2 (en) 2016-06-08 2021-02-16 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof

Also Published As

Publication number Publication date
CA2710929A1 (fr) 2009-08-06
WO2009097233A9 (fr) 2009-09-24

Similar Documents

Publication Publication Date Title
US7511040B2 (en) Imidazopyrazines as protein kinase inhibitors
US7645762B2 (en) Substituted pyrazolo[1,5-a] pyrimidines as protein kinase inhibitors
EP1931676B1 (fr) Pyrazolopyrimidines en tant qu'inhibiteurs de protéines kinases
US7557104B2 (en) Imidazopyrazines as protein kinase inhibitors
WO2009097233A1 (fr) Imidazopyrazines comme inhibiteurs de protéines kinases
US7642266B2 (en) Substituted pyrazolo[1,5-a]pyrimidines as protein kinase inhibitors
US20090175852A1 (en) Imidazopyrazines as protein kinase inhibitors
WO2008156614A2 (fr) Imidazopyrazines comme inhibiteurs de la protéine kinase
WO2007058942A2 (fr) Imidazopyrazines inhibant la proteine kinase
EP1942900A2 (fr) Utilisation de derives de pyrazolo [1,5-a] pyrimidine comme inhibiteurs de proteines kinases procedes d'inhibition de proteines kinases
NZ582708A (en) Heterocyclic amide compounds as protein kinase inhibitors
EP2027127A1 (fr) Pyrazolo [1, 5-a]pyrimidines en tant qu'inhibiteurs de cdk
EP1945216A1 (fr) Méthodes d'inhibition de protéine kinases
AU2006302435B2 (en) Use of pyrazolo [1 , 5 -a] pyrimidine derivatives for inhibiting protein kinases methods for inhibiting protein kinases

Legal Events

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

Ref document number: 09705810

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2710929

Country of ref document: CA

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09705810

Country of ref document: EP

Kind code of ref document: A1