WO2008156614A2 - Imidazopyrazines as protein kinase inhibitors - Google Patents

Imidazopyrazines as protein kinase inhibitors Download PDF

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WO2008156614A2
WO2008156614A2 PCT/US2008/007295 US2008007295W WO2008156614A2 WO 2008156614 A2 WO2008156614 A2 WO 2008156614A2 US 2008007295 W US2008007295 W US 2008007295W WO 2008156614 A2 WO2008156614 A2 WO 2008156614A2
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alkyl
compound
heteroaryl
aryl
mmol
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PCT/US2008/007295
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French (fr)
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WO2008156614A3 (en
Inventor
Tao Yu
David B. Belanger
Angela D. Kerekes
Zhaoyang Meng
Jayaram R. Tagat
Sara J. Esposite
Amit K. Mandal
Yushi Xiao
Bheemashankar A. Kulkarni
Yonglian Zhang
Patrick J. Curran
Ronald Doll
M. Arshad Siddiqui
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Schering Corporation
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Application filed by Schering Corporation filed Critical Schering Corporation
Priority to MX2009013729A priority Critical patent/MX2009013729A/en
Priority to CN200880101960A priority patent/CN101772500A/en
Priority to CA2690557A priority patent/CA2690557A1/en
Priority to EP08768351A priority patent/EP2170892A2/en
Priority to JP2010512177A priority patent/JP2010529195A/en
Publication of WO2008156614A2 publication Critical patent/WO2008156614A2/en
Publication of WO2008156614A3 publication Critical patent/WO2008156614A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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
  • Examples of protein kinase inhibitors are described in WO02/22610 A1 and by Y. Mettey et al in J. Med. Chem., (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 5'-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. Also being mentioned are the following: WO2005/047290;
  • imidazopyrazines as protein kinase inhibitors of the following structure:
  • R1 is H, halo, aryl or heteroaryl, wherein each of said aryl and heteroaryl can be unsubstituted or substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, - CH2OR5, -C(O)NR5R6, -C(O)OH, -C(O)NH2, -NR5R6 (wherein the R5 and R6, together with the N of said -NR5R6, form a heterocyclyl ring), -S(O)R5, -S(O2)R5, -CN, -CHO, -SR5,
  • R2 is H, halo, aryl, arylalkyl or heteroaryl, wherein each of said aryl, arylalkyl and heteroaryl can be unsubstituted or optionally independently be substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
  • R3 is H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein:
  • - said alkyl shown above for R3 can be unsubstituted or substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR5, alkoxy, heteroaryl, and -NR5R6;
  • aryl shown above for R3 is unsubstituted, or optionally substituted, or optionally fused, with halo, heteroaryl, heterocyclyl, cycloalkyl or heteroarylalkyl, wherein each of said heteroaryl, heterocyclyl, 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 alkyl, -OR5, -N(R5R6) and -S(O2)R5; and
  • heteroaryl shown above for R3 can be unsubstituted or optionally substituted, or optionally fused, with one or more moieties which can be the same or different with each moiety being independently selected from the group consisting of halo, amino, alkoxycarbonyl, -OR5, alkyl, - CHO, - NR5R6, -S(O2)N(R5R6),
  • R5 is H, alkyl, aminoalkyl, aryl, heteroaryl, heterocyclyl or cycloalkyl
  • R6 is H, alkyl, aryl, arylalkyl, heteroaryl, heterocyclyl or cycloalkyl; further wherein in any -NR5R6 in Formula I, said R5 and R6 can optionally be joined together with the N of said -NR5R6 to form a cyclic ring.
  • Another series of protein kinases are those that play an important role as a checkpoint in cell cycle progression.
  • Checkpoints prevent cell cycle progression at inappropriate times, such as in response to DNA damage, and maintain the metabolic balance of cells while the cell is arrested, and in some instances can induce apoptosis (programmed cell death) when the requirements of the checkpoint have not been met.
  • Checkpoint control can occur in the G1 phase (prior to DNA synthesis) and in G2, prior to entry into mitosis.
  • 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, AbI1 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.
  • Src subfamily of enzymes has been linked to oncogenesis.
  • angiogenesis is the mechanism by which new capillaries are formed from existing vessels.
  • the vascular system has the potential to generate new capillary networks in order to maintain the proper functioning of tissues and organs.
  • 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. Recently, it has been suggested that growth factors such as bFGF may play a critical role in inducing angiogenesis in solid tumors that have reached a certain size. Yoshiji et al., Cancer Research, 57, 3924-3928 (1997).
  • FGF-R is expressed in a number of different cell types throughout the body and may or may not play important roles in other normal physiological processes in the adult. Nonetheless, systemic administration of a small molecule inhibitor of the kinase activity of FGF-R has been reported to block bFGF-induced angiogenesis in mice without apparent toxicity. Mohammad et al., EMBO Journal, 17, 5996-5904 (1998).
  • TEK also known as Tie-2
  • Tie-2 is another receptor tyrosine kinase expressed only on endothelial cells which has been shown to play a role in angiogenesis.
  • the binding of the factor angiopoietin-1 results in autophosphorylation of the kinase domain of TEK and results in a signal transduction process which appears to mediate the interaction of endothelial cells with peri-endothelial support cells, thereby facilitating the maturation of newly formed blood vessels.
  • the factor angiopoietin-2 appears to antagonize the action of angiopoietin-1 on TEK and disrupts angiogenesis. Maisonpierre et al., Science, 277, 55-60 (1997).
  • the kinase, JNK belongs to the mitogen-activated protein kinase (MAPK) superfamily.
  • JNK plays a crucial role in inflammatory responses, stress responses, cell proliferation, apoptosis, and tumorigenesis.
  • JNK kinase activity can be activated by various stimuli, including the proinflammatory cytokines (TNF-alpha and interleukin- 1 ), lymphocyte costimulatory receptors (CD28 and CD40), DNA-damaging chemicals, radiation, and Fas signaling.
  • results from the JNK knockout mice indicate that JNK is involved in apoptosis induction and T helper cell differentiation.
  • Pim-1 is a small serine/threonine kinase.
  • 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 I:
  • R is H, CN, -NR5R6, cycloalkyl, cycloalkenyl, heterocyclenyl, heteroaryl, -C(O)NR5R6, -N(R5)C(O)R6, heterocyclyl, heteroaryl substituted with (CH2)i.3
  • NR5R6 unsubstituted alkyl, or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR5, heterocyclyl,
  • R1 is H, halo, aryl or heteroaryl, wherein each of said aryl and heteroaryl can be unsubstituted or substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, - CH2OR5, -C(O)NR5R6, -C(O)OH, -C(O)NH2, -NR5R6 (wherein the R5 and R6, together with the N of said
  • R2 is H, halo, aryl, arylalkyl or heteroaryl, wherein each of said aryl, arylalkyl and heteroaryl can be unsubstituted or optionally independently be substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
  • R3 is heterocyclyl-(CR7R8)n-X, heterocyclenyl-(CR7R8)n-X, heteroaryl-(CR7R8)n-X or aryl-(CR7R8)n-X wherein each of the heterocyclyl-, heterocyclenyl-, heteroaryl- or aryl- moieties of said R3 can be unsubstituted or substituted with one or more moieties, independently selected from the group consisting Of -CONR5R6,
  • n 1-6
  • X is selected from the group consisting of -NR5R6, -OR5, -SO-R5, -SR5, SO2R5, heteroaryl, heterocyclyl and aryl, wherein said heteroaryl or aryl can be unsubstituted or substituted with one or more moieties, independently selected from the group consisting of -O-alkyl, alkyl, halo, or NR5R6;
  • R7 and R8 are each independently hydrogen, alkyl, heterocyclyl, aryl, heteroaryl or cycloalkyl;
  • R5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxyalkyl,
  • -alkyl-S-alkyl aminoalkyl, aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S- alkylheterocyclyl, heterocyclyl, heterocyclenyl, alkylN(alkyl)2, alkylNH(alkyl), alkylN(alkenyl)2, -alkylN(alkoxyl)2, -alkyl-SH, hydroxyalkyl, trihaloalkyl, dihaloalkyl, monohaloalkyl, wherein each of said alkyl, alkenyl, alkoxyalkyl, -alkyl-S-alkyl, aminoalkyl, aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S-alkylheterocyclyl
  • R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkylSH, alkoxyl, -S- alkyl, hydroxyalkyl, aminoalkyl, -alkyl-OC(O)alkyl, -alkylOC(O)cycloalkyl, -alkylOC(O)aryl, -alkylOC(O)aralkyl, -alkylOC(O)NR5aryl, - alkylOC(O)NR5alkyl, -alkylOC(O)NR5heterocyclyl
  • the compounds of Formula I can be useful as protein kinase inhibitors.
  • the compounds of Formula I can also be useful as Aurora kinase inhibitors.
  • the compounds of Formula I 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 Formula I, or pharmaceutically acceptable salts, solvates, esters or prodrug thereof, wherein the various moieties are as described above.
  • R is H, CN, -NR5R6, cycloalkenyl, heterocyclenyl, -C(O)NR5R6, -N(R5)C(O)R6, or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR5 and - NR5R6;
  • R1 is H, halo, aryl or heteroaryl, wherein each of said aryl and heteroaryl can be unsubstituted or substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, - C(O)NR5R6 and -OR5;
  • R2 is H, halo, or heteroaryl, wherein said 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 and heterocyclyl;
  • R3 is heterocyclyl-(CR7R8)n-X, heterocyclenyl-(CR7R8)n-X, heteroaryl- ⁇ CR7R8)n-X or aryl-(CR7R8)n-X wherein each of the heterocyclyl-, heterocyclenyl-, heteroaryl- or aryl- moieties of said R3 can be unsubstituted or substituted with one or more moieties, independently selected from the group consisting Of -CONR5R6,
  • n 1 ,
  • X is selected from the group consisting of, -NR5R6, -OR5, -SO-R5 and -SR5, R7 and R8 are each independently hydrogen or alkyl; R5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxyalkyl,
  • -alkyl-S-alkyl aminoalkyl, aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S- alkylheterocyclyl, heterocyclyl, heterocyclenyl, alkylN(alkyl)2, alkylNH(alkyl), alkylN(alkenyl)2, -alkylN(alkoxyl)2, -alkyl-SH and hydroxyalkyl, wherein each of said aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S- alkylheterocyclyl, heterocyclyl, heterocyclenyl can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of alkyl, alkyl, alkenyl, aryl,
  • R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkylSH, alkoxyl, -S- alkyl, hydroxyalkyl, and aminoalkyl, wherein each of said aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl can be unsubstituted or substituted with one or
  • R, R1 and R2 are not all H simultaneously.
  • R2 is unsubstituted heteroaryl or heteroaryl substituted with alkyl.
  • R2 is heteroaryl substituted with alkyl. In another embodiment, in Formula I, R2 is pyrazolyl.
  • R2 is pyrazolyl substituted with alkyl. In another embodiment, in Formula I, R2 is 1-methyl-pyrazol-4-yl. In another embodiment, in Formula I, R is H. In another embodiment, in Formula I, R is CN. In another embodiment, in Formula I, R is -C(O)NR5R6.
  • R is -C(O)NH2. In another embodiment, in Formula I, R is heterocyclenyl. In another embodiment, in Formula I, R is tetrahydropyridinyl.
  • R is 1 ,2,3,6-tetrahydropyridinyl.
  • R is alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR1 and -NR5R6.
  • R is alkyl substituted with one or more - NR5R6.
  • R is alkyl substituted with -NH2.
  • R is alkyl substituted with -NH(methyl). In another embodiment, R is unsubstituted alkyl.
  • both R and R1 are not H simultaneously.
  • R3 is heteroaryl-CH2-X, wherein X is - OR5, -SOR5, -NR5R6, or -SR5; R5 is hydrogen, -alkylN(alkyl)2, heterocyclylalkyl or heterocyclenylalkyl; or R5 and R6 can optionally be joined together with the N of said - NR5R6 to form a cyclic ring or bridged cyclic ring, wherein said cyclic ring or bridged cyclic ring can be unsubstituted or substituted one or more moities, which can be the same or different, independently selected from the group consisting of hydroxy!, alkyl, alkoxyl, alkoxylalkyl, hydroxyalkyl, arylalkyl, aryl, heterospirocyclyl, heterospirocyclenyl, heterospiroaryl and -CO2alkyl.
  • R3 is heteroaryl-
  • X is -NR5R6, R5 is -alkylN(alkyl)2, alkyl, alkoxyalkyl, hydroxyalkyl, arylalkyl, heterocyclenylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, or -alkylSH, R6 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or -alkylN(alkyl)2; or R5 and R6 can optionally be joined together with the N of said -NR5R6 to form a cyclic ring or bridged cyclic ring, wherein said cyclic ring or bridged cyclic ring can be unsubstituted or substituted one or more moities, which can be the same or different, independently selected from the group consisting of hydroxyl, alkyl, alkoxyl, alkoxylalkyl, hydroxyalkyl, aryl
  • R3 is heteroaryl-CH2-X , wherein the heteroaryl of said heteroaryl-CH2-X is substituted with alkyl or -CONR5R6, wherein X is -NR5R6, R5 is alkyl, R6 is alkyl, or R5 and R6 are optionally joined together with the N of said -NR5R6 to form a cyclic ring.
  • R3 is aryl-CH2-X , wherein the aryl of said aryl-CH2-X is substituted with alkyl, wherein X is heterocyclyl.
  • R5 is s C- ** . or wherein X is selected from the group consisting of, -NR5R6, -OR5 -SO-R5 and -SR5,
  • R5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxyalkyl, -alkyl-S-alkyl, aminoalkyl, aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S- alkylheterocyclyl, heterocyclyl, heterocyclenyl, alkylN(alkyl)2, alkylNH(alkyl), alkylN(alkenyl)2, -alkylN(alkoxyl)2, -alkyl-SH and hydroxyalkyl, wherein each of said aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S- alkylheterocyclyl, heterocyclyl, heterocyclenyl can be unsubstituted or substituted with one or
  • R3 is isothiazole, thiophene or pyrimidine substituted with:
  • R3 is pyrimidinyl substituted with heterocyclylmethyl.
  • R3 is pyrimidinyl substituted with morpholinylmethyll or pyrrolidinylmethyl.
  • R3 is phenyl substituted with heterocyclylalkyl, wherein said heterocyclylalkyl 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 alkyl.
  • R3 is phenyl-CHmethyl-X or phenyl-CH2- X , wherein X is piperazinyl, piperadinyl, pyrrolidinyl, morpholinyl or thiomorpholinyl wherein said piperazinyl, piperadinyl, pyrrolidinyl, morpholinyl or thiomorpholinyl 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 alkyl.
  • R3 is phenyl substituted with heterocyclylmethyl, wherein said phenyl group is further substituted with alkyl.
  • R3 is phenyl substituted with piperidinylmethyl, morpholinylmethyl or thiomorpholinylmethyl, wherein said phenyl group is further substituted with methyl.
  • R3 is x .
  • X is heterocyclyl wherein said heterocyclyl 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 hydroxyl, alkyl, hydroxyalkyl, alkoxyl, -CO2alkyl, arylalkyl, aryl, alkoxyalkyl, and heterocyclyl.
  • R3 is wherein X is heterocyclyl wherein said heterocyclyl 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 alkyl.
  • this invention discloses a compound of the formula:
  • R2 is heteroaryl, wherein said 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, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -C(O)OH, -C(O)NH2, -NR5R6 (where R5 and R6 form a cyclic amine together with the N of said -NR5R6), -CN, arylalkyl, -CH2OR5, -S(O)R5, -S(O2)R5, -CN, -CHO, -SR5, - C(O)OR5, -C(O)R5, heteroaryl and heterocyclyl; R is unsubstituted alkyl or alkyl substituted with one or more moieties which can be the same or different each moiety
  • R1 is H;
  • R3 is heteroaryl-CH2-X or heteroaryl-CHMethyl-X, wherein X is -NR5R6, R5 is - alkylN(alkyl)2, alkyl, alkoxyalkyl, hydroxyalkyl, arylalkyl, heterocyclenylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, or-alkylSH, R6 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or -alkylN(alkyl)2; or R5 and R6 can optionally be joined together with the N of said -NR5R6 to form a cyclic ring or bridged cyclic ring, wherein said cyclic ring or
  • this invention discloses a compound of the formula:
  • R2 is heteroaryl, wherein said 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, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -C(O)OH, -C(O)NH2, -NR5R6 (where R5 and R6 form a cyclic amine together with the N of said -NR5R6), -CN, arylalkyl, -CH2OR5, -S(O)R5, -S(O2)R5, -CN, -CHO, -SR5, - C(O)OR5, -C(O)R5, heteroaryl and heterocyclyl; R is unsubstituted alkyl or alkyl substituted with one or more moieties which can be the same or different each moiety
  • this invention discloses a compound of the formula:
  • R2 is heteroaryl, wherein said 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, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -C(O)OH, -C(O)NH2, -NR5R6 (where R5 and R6 form a cyclic amine together with the N of said -NR5R6), -CN, arylalkyl, -CH2OR5, -S(O)R5, -S(O2)R5, -CN, -CHO, -SR5, - C(O)OR5, -C(O)R5, heteroaryl and heterocyclyl; R is unsubstituted alkyl or alkyl substituted with one or more moieties which can be the same or different each moiety
  • R1 is H
  • R3 is isothiazole, thiophene or pyrimidine substituted with:
  • this invention discloses a compound of the formula:
  • R1 is H;
  • R3 is phenyl-CHmethyl-X or phenyl-CH2-X , wherein said phenyl of each of said phenyl- CHmethyl-X or phenyl-CH2-X can be unsubstituted or substituted with alkyl, further wherein X is piperazinyl, piperadinyl, pyrrolidinyl, morpholinyl or thiomorpholinyl wherein each of said piperazinyl, piperadinyl, pyrrolidinyl, morpholinyl or thiomorpholinyl can be unsubstituted or substituted with alkyl; wherein R5 and R6 are as defined above.
  • this invention discloses a compound of the formula:
  • R3 N-H or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is heteroaryl, wherein said 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, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -C(O)OH, -C(O)NH2, -NR5R6 (where R5 and R6 form a cyclic amine together with the N of said -NR5R6), -CN, arylalkyl, -CH2OR5, -S(O)R5, -S(O2)R5, -CN, -CHO, -SR5, - C(O)OR5, -C(O)R5, heteroaryl and heterocyclyl; R is unsubstituted alkyl or alkyl substituted with one or more moieties which can be the
  • X is selected from the group consisting of, -NR5R6, -OR5 -SO-R5 and -SR5,
  • R5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxyalkyl, -alkyl-S-alkyl, aminoalkyl, aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S- alkylheterocyclyl, heterocyclyl, heterocyclenyl, alkylN(alkyl)2, alkylNH(alkyl), alkylN(alkenyl)2, -alkylN(alkoxyl)2, -alkyl-SH and hydroxyalkyl, wherein each of said aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S- alkylheterocyclyl, heterocyclyl and heterocyclenyl can be unsubstituted or substituted with one or
  • R2 is heteroaryl, wherein said 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, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -C(O)OH, -C(O)NH2, -NR5R6 (where R5 and R6 form a cyclic amine together with the N of said -NR5R6), -CN, arylalkyl, -CH2OR5, -S(O)R5, -S(O2)R5, -CN, -CHO, -SR5, - C(O)OR5, -C(O)R5, heteroaryl and heterocyclyl; R is unsubstituted alkyl or alkyl substituted with one or more moieties which can be the same or different each moiety
  • R5 and R6 are as defined above.
  • this invention discloses a compound of the formula:
  • R1 is H;
  • R3 is heteroaryl-CH2-X or heteroaryl-CHMethyl-X, wherein X is -NR5R6, R5 is - alkylN(alkyl)2, alkyl, alkoxyalkyl, hydroxyalkyl, arylalkyl, heterocyclenylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, or -alkylSH, R6 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or -alkylN(alkyl)2; or R5 and R6 can optionally be joined together with the N of said -NR5R6 to form a cyclic ring or bridged cyclic ring, wherein said cyclic ring
  • this invention discloses a compound of the formula:
  • R2 is pyrazolyl, wherein said pyrazolyl 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, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -C(O)OH, - C(O)NH2, -NR5R6 (where R5 and R6 form a cyclic amine together with the N of said - NR5R6), -CN, arylalkyl, -CH2OR5, -S(O)R5, -S(O2)R5, -CN, -CHO, -SR5, -C(O)OR5, - C(O)R5, heteroaryl and heterocyclyl; R is unsubstituted alkyl or alkyl substituted with one or more moieties which can be the same
  • R2 is pyrazolyl, wherein said pyrazolyl 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, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -C(O)OH, - C(O)NH2, -NR5R6 (where R5 and R6 form a cyclic amine together with the N of said - NR5R6), -CN, arylalkyl, -CH2OR5, -S(O)R5, -S(O2)R5, -CN, -CHO, -SR5, -C(O)OR5, - C(O)R5, heteroaryl and heterocyclyl; R is unsubstituted alkyl or alkyl substituted with one or more moieties which can be the same
  • R1 is H
  • R3 is isothiazole, thiophene or pyrimidine substituted with:
  • R5 and R6 are as defined above.
  • this invention discloses a compound of the formula:
  • R2 is pyrazolyl, wherein said pyrazolyl 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, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -C(O)OH, - C(O)NH2, -NR5R6 (where R5 and R6 form a cyclic amine together with the N of said - NR5R6), -CN, arylalkyl, -CH2OR5, -S(O)R5, -S(O2)R5, -CN, -CHO, -SR5, -C(O)OR5, - C(O)R5, heteroaryl and heterocyclyl; R is unsubstituted alkyl or alkyl substituted with one or more moieties which can be the same
  • R2 is pyrazolyl, wherein said pyrazolyl 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, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -C(O)OH, - C(O)NH2, -NR5R6 (where R5 and R6 form a cyclic amine together with the N of said - NR5R6), -CN, arylalkyl, -CH2OR5, -S(O)R5, -S(O2)R5, -CN, -CHO, -SR5, -C(O)OR5, - C(O)R5, heteroaryl and heterocyclyl; R is unsubstituted alkyl or alkyl substituted with one or more moieties which can be the same
  • R5 and R6 are as defined above.
  • this invention discloses a compound of the formula:
  • R2 is 1-H- pyrazol-4-yl
  • R is unsubstituted alkyl or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR5, heterocyclyl, -N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2)1-3- N(R5R6) and -NR5R6
  • R1 is H
  • R3 is heteroaryl-CH2-X or heteroaryl-CHMethyl-X, wherein X is -NR5R6, R5 is -alkylN(alkyl)2, alkyl, alkoxyalkyl, hydroxyalkyl, arylalkyl, heterocyclenylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, or -alkylSH,
  • this invention discloses a compound of the formula:
  • R2 is 1-A7- pyrazol-4-yl
  • R is unsubstituted alkyl or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR5, heterocyclyl, -N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2)1-3- N(R5R6) and -NR5R6
  • R1 is H
  • R3 is heteroaryl-CH2-X , wherein the heteroaryl of said heteroaryl-CH2-X is substituted with alkyl Or -CONR5R6, wherein X is -NR5R6, R5 is alkyl, R6 is alkyl, or R5 and R6 are optionally joined together with the N of said - NR5R6 to form heterocyclyl.
  • R5 and R6 are as defined above.
  • R2 is 1- H-pyrazol-4-yl
  • R is unsubstituted alkyl or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR5, heterocyclyl, -N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2)1-3- N(R5R6) and -NR5R6
  • R1 is H
  • R3 is isothiazole, thiophene or pyrimidine substituted with:
  • this invention discloses a compound of the formula:
  • R2 is 1- H-pyrazol-4-yl
  • R is unsubstituted alkyl or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR5, heterocyclyl, -N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2)1-3- N(R5R6) and -NR5R6
  • R1 is H
  • R3 is phenyl-CHmethyl-X or phenyl-CH2-X , wherein said phenyl of each of said phenyl-CHmethyl-X or phenyl-CH2-X can be unsubstituted or substituted with alkyl, further wherein X is piperazinyl, piperadinyl, pyrrolidinyl, morpholinyl or thiomorpholinyl wherein each of said piperazin
  • this invention discloses a compound of the formula:
  • R2 is 1-H- pyrazol-4-yl
  • R is unsubstituted alkyl or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR5, heterocyclyl, -N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2)1-3-
  • this invention discloses a compound of the formula:
  • R2 is 1-H- pyrazol-4-yl; R is unsubstituted alkyl; R1 is H; R3 is heteroaryl-CH2-X or heteroaryl- CHMethyl-X, wherein X is -NR5R6, R5 is -alkylN(alkyl)2) alkyl, alkoxyalkyl, hydroxyalkyl, arylalkyl, heterocyclenylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, or -alkylSH, R6 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or -alkylN(alkyl)2; or R5 and R6 can optionally be joined together with the N of said -NR5R6 to form a cyclic ring or bridged cyclic ring, wherein said cyclic ring or bridged cyclic
  • this invention discloses a compound of the formula:
  • R2 is 1-H- pyrazol-4-yl; R is unsubstituted alkyl; R1 is H; R3 is heteroaryl-CH2-X , wherein the heteroaryl of said heteroaryl-CH2-X is substituted with alkyl or -CONR5R6, wherein X is -NR5R6, R5 is alkyl, R6 is alkyl, or R5 and R6 are optionally joined together with the N of said -NR5R6 to form heterocyclyl; wherein R5 and R6 are as defined above.
  • this invention discloses a compound of the formula:
  • R2 is 1- H-pyrazol-4-yl; R is unsubstituted alkyl; R1 is H; R3 is isothiazole, thiophene or pyrimidine substituted with:
  • R5 and R6 are as defined above.
  • this invention discloses a compound of the formula:
  • R2 is 1- H-pyrazol-4-yl; R is unsubstituted alkyl; R1 is H; R3 is phenyl-CHmethyl-X or phenyl- CH2-X , wherein said phenyl of each of said phenyl-CHmethyl-X or phenyl-CH2-X can be unsubstituted or substituted with alkyl, further wherein X is piperazinyl, piperadinyl, pyrrolidinyl, morpholinyl or thiomorpholinyl wherein each of said piperazinyl, piperadinyl, pyrrolidinyl, morpholinyl or thiomorpholinyl can be unsubstituted or substituted with alkyl; wherein R5 and R6 are as defined above.
  • this invention discloses a compound of the formula:
  • R is unsubstituted alkyl
  • R1 is H
  • R3 is, , ,
  • this invention discloses a compound of the formula:
  • R2 is 1-H- pyrazol-4-yl; R is methyl, R1 is H; R3 is heteroaryl-CH2-X or heteroaryl-CHMethyl-X, wherein X is -NR5R6, R5 is -alkylN(alkyl)2, alkyl, alkoxyalkyl, hydroxyalkyl, arylalkyl, heterocyclenylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, or -alkylSH, R6 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or -alkylN(alkyl)2; or R5 and R6 can optionally be joined together with the N of said -NR5R6 to form a cyclic ring or bridged cyclic ring, wherein said cyclic ring or bridged cyclic ring can be unsubsti
  • this invention discloses a compound of the formula:
  • R2 is 1-H- pyrazol-4-yl
  • R is methyl, R1 is H
  • R3 is heteroaryl-CH2-X , wherein the heteroaryl of said heteroaryl-CH2-X is substituted with alkyl or -CONR5R6, wherein X is -NR5R6, R5 is alkyl, R6 is alkyl, or R5 and R6 are optionally joined together with the N of said - NR5R6 to form heterocyclyl; wherein R5 and R6 are as defined above.
  • this invention discloses a compound of the formula:
  • R2 is 1- H-pyrazol-4-yl; R is methyl, R1 is H; R3 is isothiazole, thiophene or pyrimidine substituted with:
  • this invention discloses a compound of the formula:
  • R is methyl, R1 is H; R3 is phenyl-CHmethyl-X or phenyl-CH2-X , wherein said phenyl of each of said phenyl-CHmethyl-X or phenyl-CH2-X can be unsubstituted or substituted with alkyl, further wherein X is piperazinyl, piperadinyl, pyrrolidinyl, morpholinyl or thiomorpholinyl wherein each of said piperazinyl, piperadinyl, pyrrolidinyl, morpholinyl or thiomorpholinyl can be unsubstituted or substituted with alkyl.
  • this invention discloses a compound of the formula:
  • this invention discloses a compound of the formula:
  • R5 is alkyl
  • R6 is selected from the group consisting of alkoxyalkyl, hydroxyalkyl, cycloalkyl, wherein said cycloalkyl is substituted by hydroxyalkyl; or R5 and R6 together with the N of said -NR5R6 to form a cyclic ring, wherein said cyclic ring is substituted by one or more moieties independently selected from the group consisting of alkoxyalkyl, hydroxyalkyl, and alkyl.
  • this invention discloses a compound of the formula:
  • R5 is methyl, ethyl, or propyl
  • R6 is selected from the group consisting of ethoxyethyl, 1 ,1- dimethylhydroxyethyl, cyclopentyl, cyclohexyl, wherein each of said cyclopentyl and cyclohexyl is substituted by hydroxymethyl
  • R5 and R6 together with the N of said - NR5R6 to form a cyclic ring, wherein said cyclic ring is substituted by one or more moieties independently selected from the group consisting of ethoxymethyl, methoxymethyl, hydroxymethyl, and methyl.
  • Non-limiting examples of compounds of Formula I include:
  • 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 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more, lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. "Lower alkenyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
  • alkenyl may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl. aryl, cycloalkyl, cyano, alkoxy and -S(alkyl).
  • 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 are termed "bridgeheads".
  • Heteroaryl means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms.
  • the "heteroaryl” can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • the prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom.
  • 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- a]pyridinyl, imidazo[2,1-b]thiazolyl,
  • 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, norbomyl, 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 cyclohexylmethyl, 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, hetero
  • Ring system substituent may also mean a single moiety which simultaneously replaces two available hydrogen on two adjacent carbon atoms (one H on each carbon) on a ring system.
  • Examples of such moiety are methylene dioxy, ethylenedioxy, -C(CH3)2- and the like which form moieties such as, for example:
  • 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-naphthalenemethoxy.
  • 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.
  • Alkylthio means an aralkyl-S- group in which the aralkyl group is as previously described.
  • Non-limiting example of a suitable aralkylthio group is benzylthio.
  • the bond to the parent moiety is through the sulfur.
  • Alkoxycarbonyl means an alkyl-O-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl.
  • Aryloxycarbonyl means an aryl-O-C(O)- group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.
  • 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(O2)- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.
  • Arylsulfonyl means an aryl-S(O2)- group. The bond to the parent moiety is through the sulfonyl.
  • 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.
  • 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.
  • protecting groups When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in organic Synthesis (1991 ), Wiley, New York.
  • 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) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press.
  • the term "prodrug” means a compound (e.g., a drug precursor) that is transformed in vivo to yield a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood.
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (C1-C ⁇ JalkyI, (C2- C12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1- methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)a group such as, for example, (C1-C ⁇ JalkyI, (C2- C12)alkanoyloxymethyl, 1-(alkanoyl
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C1-C6)alkanoyloxymethyl, 1-((Cr C6)alkanoyloxy)ethyl, 1 -methyl-1 -((C1-C6)alkanoyloxy)ethyl, (Cr C6)alkoxycarbonyloxymethyl, N-(C1-C6)alkoxycarbonylaminomethyl, succinoyl, (C1- C-6)alkanoyl, ⁇ -amino(C1-C4)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, -P(O)(O(C1-C6)alky
  • 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 (C1-C- ⁇ O)alkyl, (C3-C7) cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ -aminoacyl or natural ⁇ -aminoacyl, — C(OH)C(O)OY1 wherein Y1 is H, (C1- C6)alkyl or benzyl, — C(OY2)Y3 wherein Y2 is (CrC4) alkyl and Y3 is (C1-C ⁇ )alkyl, carboxy (C1-C6)alkyl, amino(C1-C4)alkyl or mono-N — or di-N,N-(C1-C6)alkyla
  • One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.
  • “Hydrate” is a solvate wherein the solvent molecule is H2O.
  • One or more compounds of the invention may optionally be converted to a solvate.
  • Preparation of solvates is generally known.
  • M. Caira et al, J. Pharmaceutical Sd., 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£ ⁇ , 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 Formula I can form salts which are also within the scope of this invention. Reference to a compound of Formula I herein is understood to include reference to salts thereof, unless otherwise indicated.
  • salts when a compound of Formula I 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 Formula I may be formed, for example, by reacting a compound of Formula I 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, C-i ⁇ alkyl, or C-i ⁇ 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);
  • 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 Moshei ⁇ 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 Moshei ⁇ s acid chloride
  • the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column. It is also possible that the compounds of Formula (I) may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.
  • All stereoisomers for example, geometric isomers, optical isomers and the like
  • of the present compounds including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs
  • 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).
  • the use of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
  • the present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 180, 170, 31P, 32P, 35S, 18F, and 36CI, respectively.
  • Certain isotopically-labelled compounds of Formula (I) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability.
  • 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.
  • the compounds according to the invention have pharmacological properties; in particular, the compounds of Formula I can be inhibitors, regulators or modulators of protein kinases.
  • protein kinases that can be inhibited, regulated or modulated include cyclin-dependent kinases (CDKs), such as, CDK1 , CDK2, CDK3, CDK4, CDK5, CDK6 and CDK7, CDK8, mitogen activated protein kinase (MAPK/ERK), glycogen synthase kinase 3 (GSK3beta), Pim-1 kinases, Chk kinases (such as Chk1 and Chk2), tyrosine kinases, such as the HER subfamily (including, for example, EGFR (HER1 ), HER2, HER3 and HER4), the insulin subfamily (including, for example, INS-R, IGF-IR, IR, and IR-R), the PDGF subfamily (including, for example, PDGF-
  • the compounds of Formula I can be inhibitors of protein kinases such as, for example, the inhibitors of the checkpoint kinases such as Chk1 , Chk2 and the like.
  • Preferred compounds can exhibit IC5O values of less than about 5 ⁇ m, preferably about 0.001 to about 1.0 ⁇ 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 Formula I can be useful in the therapy of proliferative diseases such as cancer, autoimmune diseases, viral diseases, fungal diseases, neurological/neurodegenerative disorders, arthritis, inflammation, anti-proliferative (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, anti-proliferative (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, anti-proliferative (e.g., ocular retinopathy), neuronal, alopecia and cardiovascular disease.
  • the compounds of Formula I can be useful in the treatment of a variety of cancers, including (but not limited to) the following: tumor of the bladder, breast (including BRCA-mutated breast cancer, colorectal, colon, kidney, liver, lung, small cell lung cancer, non-small cell lung cancer, head and neck, esophagus, bladder, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T- cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma and Burkett's lymphoma; chronic lymphocytic leukemia ("CLL”), acute and chronic myelogenous leukemia, myelodysplastic syndrome and promyelocytic leuk
  • 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 Formula I 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 Formula I may induce or inhibit apoptosis.
  • the apoptotic response is aberrant in a variety of human diseases.
  • Compounds of Formula I, as modulators of apoptosis, will be useful in the treatment of cancer (including but not limited to those types mentioned hereinabove), viral infections (including but not limited to herpevirus, poxvirus, Epstein- Barr virus, Sindbis virus and adenovirus), prevention of AIDS development in HIV-infected individuals, autoimmune diseases (including but not limited to systemic lupus, erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes mellitus), neurodegenerative disorders (including but not limited to Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration), mye
  • 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).
  • viral infections including but not limited to HIV, human papilloma virus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus.
  • 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 Formula I may also be useful in inhibiting tumor angiogenesis and metastasis.
  • Compounds of Formula I 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 Formula I.
  • the compounds of the present invention can be present in the same dosage unit as the anti-cancer agent or in separate dosage units.
  • Another aspect of the present invention is a method of treating one or more diseases associated with a kinase (such as CDK, CHK and Aurora), comprising administering to a mammal in need of such treatment: an amount of a first compound, which is a compound of Formula 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; and an amount of at least one second compound, the second compound being an anti-cancer agent different from the compound of Formula 1 , wherein the amounts of the first compound and the second compound result in a therapeutic effect.
  • 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, antibodies to IGFR (including, for example, those published in US 2005/0136063 published June 23, 2005), KSP inhibitors (such as, for example, those published in WO 2006/098962 and WO 2006/098961 ;
  • such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent or treatment within its dosage range.
  • the CDC2 inhibitor olomucine has been found to act synergistically with known cytotoxic agents in inducing apoptosis (J. Cell Sci., (1995) 108, 2897.
  • Compounds of Formula I 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 Formula I may be administered either prior to or after administration of the known anticancer or cytotoxic agent.
  • cytotoxic activity of the cyclin-dependent kinase inhibitor flavopiridol is affected by the sequence of administration with anticancer agents. Cancer Research, (1997) 57, 3375. Such techniques are within the skills of persons skilled in the art as well as attending physicians.
  • 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
  • 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.
  • 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.
  • 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 Pim-1 kinases in a patient in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising in combination at least one pharmaceutically acceptable carrier and at least one compound according to Formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
  • the pharmacological properties of the compounds of this invention may be confirmed by a number of pharmacological assays.
  • the exemplified pharmacological assays which are described herein below have been carried out with compounds according to the invention and their salts, solvates, esters or prodrugs.
  • 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.
  • 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. The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated.
  • a typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two to four divided doses.
  • 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, 1H), 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, 33mm x 7mm ID; gradient flow: 0 min - 10% CH3CN, 5 min - 95% CH3CN, 7 min - 95% CH3CN, 7.5 min - 10% CH3CN, 9 min - stop. The retention time and observed parent ion are given.
  • Part A 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 (Si ⁇ 2, 40% ethyl acetate/hexanes) afforded compound 4 as a white solid 2.30 g (76%).
  • Part C A suspension of bromide from Part B (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 mL) was heated overnight under nitrogen at 105C. After cooling, the mixture was diluted with ethyl acetate (1 L), washed with brine (2 x 500 mL), dried (magnesium sulfate), filtered, concentrated and purified by chromatography on silica gel. The title compound was obtained as a pale yellow solid (21.4 g, 64%).
  • Part D To a DMF (400 mL) solution of compound from Example 1 , Part C (21.8 g) was added N-iodosuccinimide (26.9 g) and the resulting mixture was heated overnight at 6OC. The mixture was concentrated and water (400 mL) was added. After stirring 1 hr at rt, saturated sodium carbonate was added (250 mL) and subsequently stirred an additional 30 min at rt. The mixture was filtered, washed with water, methanol (100 mL) and the filter cake was dried overnight under vacuum. A brown solid was obtained (31.4 g, 87%).
  • Part E A flask was charged with iodide from Part D (1.00 equiv), Bpin-compound 5a (1.3 equiv), PdCI2(dppf) (0.1 equiv) and potassium phosphate monohydrate (3.0 equiv). After purging the flask with argon, 1 ,4-dioxane (50 mL) and water (5) were added and the resulting mixture was heated at 8OC overnight (23 h). The reaction was cooled to room temperature. EtOAc was added to the reaction mixture and filtered through Celite. After concentration the residue was purified by column chromatography (silica gel, 25% EtOAc/hexane) to give the title compound.
  • Part F To a solution of compound from Example 1 , Part E (1.0 equiv) in DCM (10 mL) was added m-CPBA (2.05 equiv) in one portion. The resulting mixture was stirred at room temperature for 30 min. The mixture was concentrated and then partitioned between EtOAc and water. The organic layer was washed with NaHCO3 (sat. aq., twice), brine and dried (Na2SO4). After concentration, the title compound was obtained and used in the next step directly without further purification.
  • Step A To a solution of 4 (76 mg, 0.14 mmol) in 6 mL of THF was added Pd(PPh3J4 (16 mg, 0.014 mmol) and 0.35 mL of MeZnCI (2 M solution in THF, 0.69 mmol). The reaction was stirred at 80 °C for 20 min. It was cooled to room temperature and quenched by adding 0.5 mL of MeOH. It was diluted with 30 mL of CH2CI2 and washed with 20 mL of 0.5 N aqueous HCI solution. The solvent was removed under vacuum.
  • Step B The above crude material was dissolved in 5 mL of THF. To the solution was added 0.5 mL of LiBHEt3 (1 M solution in THF). The reaction was stirred at room temperature for 30 min.
  • Step A Mixture of compound 6 (17 mg, 0.032 mmol) and sodium azide (15 mg, 0.23 mmol) in 1 mL of DMF was heated at 70 °C for 3 h. It was cooled to room temperature and added 10 mL of water. The resulting solid was collected by filtration and purified by flash chromatography eluting with 5% MeOHZCH2CI2 to give 12 mg of (3- azidomethyl-isothiazol-5-yl)- ⁇ 6-methyl-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1 H- pyrazol-4-yl]-imidazo[1 ,2-a]pyrazin-8-yl ⁇ -amine.
  • Step B The above material was dissolved in 3 mL of MeOH. To the solution was added 15 mg of 10% wt. Pd/C. The mixture was stirred under H2 (1 atm) for 1 h. It was filtered through celite. The filtrate was concentrated under vacuum to give 12 mg of compound 7.
  • NMR (400 MHz, CDCI3) ⁇ 7.88 (s, 1 H), 7.80 (s, 1 H), 7.60 (s, 1 H), 7.47 (s, 1 H), 6.86 (s, 1 H), 5.55 (s, 2H), 4.00 (brs, 2H), 3.65 (t, 2H), 2.50 (s, 3H), 1.00 (t, 2H), 0.00 (s, 9H).
  • Step A To a solution of compound 7 (9 mg, 0.02 mmol) in 1 mL of MeOH/CH2Cl2 (1 :1 ), was added formaldehyde (40% wt. in water, 6 mg, 0.2 mmol). It was stirred at room temperature for 15 min when NaBH4 (16 mg, 0.4 mmol) was added in two portions.
  • Step B The above material was then dissolved in 2 mL of THF. The resulting solution was heated at 70 °C when 0.5 mL of 4 N HCI in dioxane was added. To the resulting mixture was added 1 mL of MeOH. The reaction was stirred at 70 °C for 1 h and then cooled to room temperature. Most of the solvent was removed under vacuum. To the residue was added 5 mL of ether. The solid was collected by filtration and washed with ether to give 5 mg of compound 9 as its HCI salt form.
  • Step A A solution of compound 10 (100 mg, 0.220 mmol) and pyrrolidine (156 mg, 2.20 mmol) in 14 mL of CH2CI2 was stirred at room temperature for 20 min. To the solution was added two drops of acetic acid, followed by NaBH4 (67 mg, 1.8 mmol). The resulting mixture was stirred at room temperature for 5 min when 3 mL of MeOH was added. The stirring was continued for additional 20 min. The reaction was quenched by adding 15 mL of saturated aqueous NaHCO3 solution. After diluted with 20 mL of CH2Ck, the organic was isolated. The solvent was removed under vacuum.
  • Step B To a solution of ⁇ 6-methyl-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1 H-pyrazol-4- yl]-imidazo[1 ,2-a]pyrazin-8-yl ⁇ -(3-pyrrolidin-1-ylmethyl-isothiazol-5-yl)-amine (98 mg, 0.19 mmol) in 8 mL of THF heated at 70 °C, was added 2 mL of 4 N HCI in dioxane. To the resulting mixture was added MeOH until it became homogeneous. The reaction was stirred at 70 °C for 1 h and then cooled to room temperature. To the mixture was added 3 mL of ether.
  • Part C A solution of alcohol from Part B (0.52 g, 0.88 mmol, 1 equivalent) in DCM (15 mL) was treated with triethylamine (1.5 equivalents) for 15 min at OC (ice-bath), at which time, methanesulfonyl chloride (1.2 equivalents) was added to the reaction at OC. The resulting solution was allowed to slowly warm to rt and continued to stir at rt for a further 3h. LC-MS analysis indicated the reaction was complete. The reaction mixture was diluted with ethyl acetate (10OmL) and washed with water, brine, dried (anh.
  • Part D A solution of the respective alcohol (3 equivalents) in THF (1.5 mL) was treated with NaH (60% dispersion in oil, 2 equivalents) for 15 min at rt, at which time, mesylate from Part C (40 mg, 0.06 mmol, 1 equivalent) was added to the reaction mixture. After stirring at rt for 1h, LC-MS analysis indicated the reaction was complete. The reaction was quenched with sat. aq. ammonium chloride and then extracted with ethyl acetate (twice). The combined organic layer was dried (sodium sulfate) and concentrated to afford crude ether, which was used without further purification.
  • Part E A solution of compound from Part D in 1 ,4-dioxane (1 mL) was treated with 4N HCI in 1 ,4-dioxane solution (1 mL) at 6OC for 10 min at which time HPLC-MS indicated that the reaction was complete. The solvent was removed and the residue was purified by Prep-LC. Conversion to a hydrochloric salt afforded compounds listed in Table 3.
  • Example 19 was prepared in similar manner to Example 4. 1H NMR (300 MHz, DMSO-de) ⁇ 12.4 (bs, 1 H), 7.81 (s, 1 H), 7.75 (s, 1 H), 7.59 (s, 1 H), 3.85 (s, 3H), 2.49 (s, 3H).
  • Example 20 was prepared in similar manner to Example 17, Part A.
  • Example 23 was prepared in a similar manner to example 22 with the substitution of 3-methylpiperidine for piperidine.
  • Example 24 was prepared in a similar manner to example 23 with the substitution of pyrrolidine for piperidine.
  • Example 26 was prepared in a similar manner to example 25.
  • 1H NMR 300 MHz, CD3OD
  • a flask containing the prepared aryl iodide scaffolds (compound from Example 22, 23, or 24, 1 equivalent), commercially available or readily prepared in 1 to 3 steps aryl/heteroaryl/alkyl boronic acid/ester/boroxine or aryl/heteroaryl/alkyl magnesium bromide or aryl/heteroaryl/alkyl zinc chloride (1.5 - 3 equivalents), potassium phosphate or potassium carbonate (2- 3 equivalents) and Pd(PPh3J4 or PdCI2dppf (0.05 - 0.10 equivalents) was evacuated, backfilled with nitrogen and repeated.
  • Example 30 was prepared in a similar manner as Example 29.
  • 1H NMR 300 MHz, CD3OD
  • ⁇ 7.77 (s, 1 H), 7.68 (s, 1 H), 7.20 (s, 1 H), 4.39 (s, 2H), 3.47-3.67 (m, 2H), 2.97 (m, 1 H), 2.71 (m, 1 H), 2.55 (s, 3H)1 1.77-2.01 (m, 4H), 1.20 (m, 1 H), 1.00 (d, J 6.4 Hz, 3H).
  • HPLC tR 4.98 min. Mass calculated for formula C17H2iCIN6S 376.12; observed MH+ 377.6 (m/z).
  • Example 31 was prepared in a similar manner to compound 29 with the substitution of tetrachlorodibromoethane for hexachloroethane.
  • 1H NMR 300 MHz, CD3OD
  • HPLC tR 5.19 min. Mass calculated for formula C16Hi9BrN6S 406.06; observed MH+ 407.4 (m/z).
  • Example 36 was prepared in a similar manner to Example 31.
  • 1H NMR 300 MHz, CD3OD
  • HPLC tR 5.00 min (UV 254nm)- Mass calculated for formula C16H19IN6S 454.04; observed MH+ (ESI MS) 455.0 (m/z).
  • Part B To a stirred solution of (2-Bromo-thiazol-5-yl)-carbamic acid tert-butyl ester (2.5 g, 8.9928 mmol) in 1 ,4-dioxane (20.0 mL) were added tributy(vinyl)tin (2.9 mL, 9.892 mmol), 2,6-di-tert-butyl-4-methylphenol (cat. amt) and tetrakis(triphenyl phosphine) palladium(O) (506.0 mg, 0.4496 mmol). The reaction mixture was heated to 100 °C and stirred for 12 hrs, LCMS showed the complete disappearance of the starting material.
  • Part D To a stirred solution of (2-Formyl-thiazol-5-yl)-carbamic acid tert-butyl ester (0.76 g, 2.857 mmol) in 1 ,2-dichloroethane(10 mL) were added Morpholine (250 mg, 1.1135 mmol) triacetoxysodium borohydride (472 mg, 2.227 mmol) and Cat amount acetic acid (three drops) and stirred for two hrs at room temp. To the reaction mixture was added sodium borohydride (126 mg, 3.3405 mmol) and stirred for one hrs. LCMS showed the disappearance of the starting material.
  • Part E To a stirred solution of (2-M ⁇ rpholin-4-ylmethyl-thiazol-5-yl)-carbamic acid tert- butyl ester (80.0 mg, 0.268 mmol) in dichloromethane(5 mL) was added iodotirmethylsilane ( 44 ⁇ l_, 0.321 mmol) and stirred for 10 min. LCMS showed the disappearance of the starting material.
  • Part F To a stirred solution of 2-Morpholin-4-ylmethyl-thiazol-5-ylamine (30.0 mg, 0.151 mmol) in DMSO (2.5 mL) was added 8-Methanesulfonyl-6-methyl-3-(1 H- pyrazol-4-yl)-imidazo[1 ,2-a]pyrazine ( 25.0 mg, 0.09045 mmol) followed by NaH 60% in mineral oil (48 mg, 1.206 mmol) and stirred for 30 min. LCMS showed the disappearance of the starting material.
  • Et3N (1261.6 uL, 9.05 mmol) was added at O°C to a mixture of 5-tert- Butoxycarbonylamino- thiophene-2-carboxylic acid (550 mg, 2.26mmol), EDCI (1086 mg, 5.65 mmol) , and piperidine (447 uL, 4.52 mmol) in DMF (6ml). The reaction mixture was warmed up to room temperature and stirred at this temperature overnight.
  • THF was treated with HCI in dioxane (4M; 0.5 mL) and placed in an oil bath at 70°C After heating for 30 min, a precipitate formed which dissolved upon adding 0.5 mL of methanol.
  • the reaction mixture was heated at a bath temperature of 7O°C for an additional 1 hr.
  • the contents of the reaction were cooled to RT and all the volatiles were removed on a rotary evaporator.
  • the residue was suspended in THF and triturated with ether.
  • the precipitate was collected by filtration, washed with ⁇ 10 mL of ether and dried in air (0.5 hr) and in vacuo (16 hr) to furnish 10 mg (93%) of the title compound as a yellow solid.
  • Part A Lithium hexamethyldisilazide (1 M in THF; 0.18 mL) was added to an amber solution of 4-morpholin-4-ylmethyl phenylamine (0.013g; 0.068 mmol) and 8- methanesulfonyl-6-methyl-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1/-/-pyrazol-4-yl]- imidazo[1 , 2-a]pyrazine (0.025g; 0.061 mmol) in 2 mL of THF at RT resulting in a burgundy solution. After stirring at RT for 20 minutes, the reaction mixture was quenched with saturated aqueous NH4CI solution.
  • the contents were diluted with ethyl acetate and washed with water and brine.
  • the crude material from the organic extract was purified by prep TLC (5% methanol-CH2CI2) to obtain the title compound as pale yellow oil (0.025 g; 80%).
  • Part B The compound from Part A (0.025g; 0.048 mmol) was suspended in dry THF and treated with HCI in dioxane (4M; 1 mL) and heated in an oil bath set to 7O°C for 15 minutes when a white precipitate was formed. Methanol was added to dissolve some of the solid and the reaction mixture was continued to be heated for 45 minutes more. After cooling to RT, the volatiles were removed on the rotary evaporator. The residue was suspended in THF and the precipitated solid was collected by filtration, washed with ether and dried in vacuo overnight. The title compound was isolated as a beige solid (14 mg; 78%). All the analogues in Table 12 were similarly prepared. TABLE 12
  • Part A A solution of 4-Amino-2-methyl-benzoic acid methyl ester (0.33 g; 2 mmol; prepared from commercially available 4-nitro-2-methyl-benzoic acid) and 8- methanesulfonyl-6-bromo-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1/-/-pyrazol-4-yl]- imidazo[1 , 2-a]pyrazine (0.472 g; 1.0 mmol) was treated with LiHMDS (1 M in THF; 2 mL) at RT. The resulting burgundy solution was stirred at RT for 20 minutes and then quenched with saturated aqueous NH4CI solution. Standard work up as described for Example 65 and flash silicagel chromatography (25% EtOAc in CH2CI2) provided the title compound as pale yellow foam (0.48 g; 86%).
  • Part B A solution of compound from Part A (0.48 g; 0.86 mmol) in 2 mL of dry THF was treated with a solution of dimethyl zinc (2M; 4 mL) dropwise. After the effervescence ceased, solid Pd(PPh3)4 was added and the reaction was flushed with nitrogen, fitted with a reflux condenser and heated in an oil bath at 65-70°C After 0.5 hr, the reaction mixture had turned from yellow orange to deep red and after 4 more hours, it had become an opaque black. TLC (25% EtOAc- CH2CI2) indicated the formation of a slightly more polar spot. The reaction was cooled to RT, quenched with saturated aqueous NH4CI solution and extracted with EtOAc.
  • the substrate (1 g, 5.07 mmol) was dissolved in THF:H2O (12 mL, 1 :1 , v/v) and treated with K2CO3 (1.4 g, 10.15 mmol) at room temperature. Then benzyl chloroformate (0.79 ml, 5.58 mmol) in THF (2 mL) was slowly added. The mixture was stirred for 16 h. It was diluted with ethyl acetate (25 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (2 * 25 mL).
  • the crude product was hydrogenated in ethyl acetate using 10% Pd/C at 1 atmosphere hydrogen pressure.
  • the catalyst was filtered off, and solvent was evaporated under reduce pressure to give the crude product.
  • Part A The substrate (1 eq.), amine (4 eq.), catalytic AcOH, NaB(OAc)3H in 1 ,2- dichloroethane was stirred at room temperature for 2 h. Then sodium borohydride (3 eq.) was added and the mixture was stirred for 30 min at which point LC-MS analysis indicate complete consumption of starting material to product. Then the reaction was quenched with 2N aqueous NaOH, and the mixture was stirred vigorously until two clear layer separated. The organic layer was washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure to give the product.
  • Part B The crude product was hydrogenated in ethyl acetate using 10% Pd/C at 1 atmosphere hydrogen pressure. The catalyst was filtered off, and solvent was evaporated under reduce pressure to give the crude product.
  • Part A The substrate (1 eq.), amine (4 eq.), catalytic AcOH, NaB(OAc)3H in 1 ,2- dichloroethane was stirred at room temperature for 2 h. Then sodium borohydride (3 eq.) was added and the mixture was stirred for 30 min at which point LC-MS analysis indicate complete consumption of starting material to product. Then the reaction was quenched with 2N aqueous NaOH, and the mixture was stirred vigorously until two clear layer separated. The organic layer was washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure to give the product.
  • Part B The crude product was hydrogenated in ethyl acetate using 10% Pd/C at 1 atmosphere hydrogen pressure. The catalyst was filtered off, and solvent was evaporated under reduce pressure to give the crude product.
  • Part A The substrate (1 eq.) and amine (1.5-2 eq.) was dissolved in DMSO under argon, and treated with NaH (5 eq., 60% dispersion in oil). After 30 min, LC-MS analysis indicated complete consumption of starting material. The reaction was quenched by addition of saturated aqueous NH4CI-acetonitrile (1 :1 , v/v). The two layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to give the crude product. Part B: The substrate was dissolved in 4N HCI in dioxane, and stirred at room temperature for 30 min. The solvent was then evaporated, and the residue was purified by Prep-LC. Conversion to hydrochloride salt afforded the product as solid.
  • Part C To a solution of compound from Part B (30 mg, 0.105 mmol, 1 equivalent), 3- methylpiperidine (10 equivalents) in dichloromethane:methanol (5:1 ) (3 ml) was added acetic acid (1 drop). The resulting solution was stirred at rt for 30 minutes, and then sodium borohydride (8 equivalents) added to the reaction. The reaction mixture was stirred at rt for 1 hour at which time LC-MS analysis indicated the reaction was complete. The reaction was quenched with sat. aq. sodium bicarbonate and then extracted with dichloromethane (x2). The combined organic layer was dried (sodium sulfate) and concentrated.
  • Step A Sodium hydride (60% dispersion in mineral oil, 6.68 g, 3.40 equiv) was slowly added in one portion to a stirring mixture of compound sulfone (20.0 g, 1.00 equiv) and aminoisothiazole (11.5 g, 1.20 equiv, as HCI salt) in DMF (490 mL) at room temperature (with aid of a room temperature water bath). Reaction was allowed to stir for 1 hour at which time HPLC analysis indicated the reaction was complete. The reaction was carefully quenched with saturated aqueous sodium bicarbonate (200 mL) and then diluted with water (1 L).
  • Step B A mixture of compound from Step A (4.27g, 3.73 mmol) was dissolved in 180 mL of THF. The resulting solution was cooled to 0 °C and LiAIH4 powder (2.6 g, 68.5 mmol) was carefully added. The cooling bath was removed and the reaction was stirred at RT under a N2 atmosphere for 1.5 hr. The reaction was cooled to 0 °C and carefully quenched by the sequential addition of 2.6 mL of H2O; 2.6 mL of 15 % NaOH (aq); 7.8 mL H2O. After stirring for 10 min, the reaction was filtered through a very thin pad of Celite (rinsing with THF, EtOAc and DCM).
  • Step B (Alternative procedure; e.g. Example 76-39): A solution of 4,4- difluoropiperidine hydrochloride (25.1 mg, 0.16 mmol) in THF (2.0 mL) was added NaH (60% dispersion in mineral oil, 12 mg, 0.30 mmol). The mixture was stirred under a N2 atmosphere at room temperature for 10 min, then mesylate (31.4 mg, 0.06 mmol) and NaI (4 mg, 0.03 mmol) were added to the reaction flask.
  • the reaction was heated at 80 °C under a N2 atmosphere for 8 hr.
  • the reaction was cooled to room temperature and 15 mL of saturated NH4CI (aq) solution was added.
  • the reaction was diluted with dichloromethane (20 mL) and the layers were separated.
  • the aqueous layer was extracted with dichloromethane (2 x 20 mL).
  • the organic phase was washed with 15 mL of saturated NaHCO3 (aq), then brine (15 mL).
  • the organic phase was dried over NaSO4 and concentrated in vacuo. Purification via preparative TLC (10% MeOH/CH2CI2) gave 19.7 mg (60% yield) of the title compound.
  • Step C A mixture of compound from Step B (2.40 g, 4.49 mmol), amine (1.57 g, 13.46 mmol), and NaI (63.0 mg, 0.449 mmol) in 45 mL of THF was heated at 80 °C for 12 h. It was diluted with 200 mL of CH2CI2, and washed with 100 mL of saturated aqueous NaHCO3 solution, then with brine (100 mL). The solvent was removed under vacuum. The residue was purified by flash chromatography eluting with 5% to 10% MeOH/CH2CI2 to give 1.68 g of the title compound.
  • Example 76 Using essentially the same procedures as described for Example 76, the following compounds were prepared.
  • Example 76-3 1H NMR (400 MHz, CD3OD) ⁇ 8.16 (s, 2H), 8.13 (s, 1 H), 7.99 (s, 1 H),
  • Example 76-7 1H-NMR (400 MHz, CD3OD ) ⁇ 8.33 m (3H), 8.15 s (1H), 7.41 s (1H), 4.80 (d, 2H), 4.15 (d, 2H), 4.06 (d, 2H), 3.62 (d, 2H), 3.58 (m, 1H), 2.68 (d, 3H), 2.21 (m, 1H), 1.81 (m , 6H) and 1.45 (s, 3H).
  • HPLC-MS tR 1.80Min (UV 254nm). Mass calculated for formula C21H26N8OS 438.55, observed LC/MS m/z 439.1 (M+H).
  • Example 76-8 1H-NMR (400 MHz, DMSO-d6 ) ⁇ 12.73 bs (1H), 9.2 bs (1H), 8.28 s (2H), 8.09 s (1H), 8.08 s (1H), 7.36 s (1H), 4.71 m (1H), 4.05 m (1H), 3.82 m (1H), 3.63 m (1 H), 3.25 m (2H), 1.97 m (1 H), 1.65 m (6H) and 1.30 s (3H).
  • Example 76-9 1H-NMR (400 MHz, DMSO-d6 ) ⁇ 8.28 (1H), 8.25 (2H), 8.08 (1 H), 7.32 (1 H), 4.71 (1 H), 4.08 (1 H), 3.84 (1 H), 3.52 (3 H), 3.46 (1 H), 2.63 (3 H), 2.17 (2 H), 1.87-1.73(6H), 1.45(3H).
  • Example 76-10 1H-NMR (400 MHz, DMSO-d6 ) ⁇ 8.28 (1H), 8.25 (2H), 8.08 (1 H), 7.32 (1 H), 4.71 (1 H), 4.08 (1 H), 3.84 (1 H), 3.52 (3 H), 3.46 (1 H), 2.63 (3 H), 2.17 (2 H), 1.87-1.73(6H), 1.45(3H).
  • Example 76-11 1HNMR (400 MHz, CD3OD) ⁇ 8.20 (s, 2H), 8.14 (s, 1H), 8.03 (s, 1H), 7.25 (s, 1H), 4.48 (d, 1H), 4.37 (d, 1H), 3.46 (s, 3H), 2.91-3.60 (m, 6H), 2.62 (s, 3H),
  • Example 76-12 1HNMR (400 MHz, CD3OD) ⁇ 8.20 (s, 2H), 8.14 (s, 1 H)1 8.03 (s, 1 H), 7.25 (s, 1 H)1 4.48 (d, 1 H), 4.37 (d, 1 H)1 3.46 (s, 3H)1 2.91-3.60 (m, 6H)1 2.62 (s, 3H), 1.40 - 1.89 (m, 4H), 0.92 (s, 3H).
  • Example 76-40 1H NMR (400 MHz1 CD3OD) ⁇ 8.28 (s, 1 H), 8.25 (s, 2H), 8.10 (s, 1 H), 7.38 (s, 1 H), 4.59 (s, 2H)1 3.3-3.9 (m, 4H), 2.64 (s, 3H), 2.3-2.5 (m, 4H).
  • Example 76-42 1H NMR (400 MHz1 CD3OD) ⁇ 8.13 (broad s, 2H), 7.85 (s, 1 H)1 7.78 (s, 1 H)1 7.15 (s, 1 H), 4.10 (d, J ⁇ 14 Hz, 1 H), 3.96 (d, J -14 Hz1 1 H)1 3.54-3.66 (m, 1 H), 3.07-3.17 (m, 1 H), 2.62-2.72 (m, 1 H), 2.53 (s, 3H), 1.82-2.21 (m, 4H).
  • Step A The substrate (10 g) was suspended in THF (200 mL). Then lithium aluminum hydride solution (110 mL, 2M in THF) was slowly added. The mixture was stirred at room temperature for 12 h. The solution was cooled to 0 °C, and saturated aqueous Na2SO4 (200 mL) was slowly added. The mixture was filtered through Celite, and filtercake was washed with ethyl acetate (400 mL). The organic layer was washed with water (200 mL) and brine (200 mL). The organic layer was dried (anhydrous Na2SO4), filtered and evaporated to give the amino alcohol (6.9g).
  • Step B The alcohol from Step A (1.936 g) was dissolved in dichloromethane (80 mL), and treated with proton sponge (8.32 g) at room temperature. Then trimethyloxonium tetrafluoroborate (5.69 g) was added. The mixture was stirred for 1 h. The reaction was quenched with saturated aqueous ammonium chloride solution (100 mL). The two layers were separated, and the aqueous layer was extracted with dichloromethane (2 x 100 mL).
  • Step C The enantiomerically pure methyl ether from Step B in EtOH was treated with Pd(OH)2 on carbon (20% wt) and stirred in hydrogen atmosphere at atmospheric pressure at room temperature for 2 h. The mixture was filtered off, and the filtrate was evaporated under reduced pressure to give the amine.
  • Step D The enatiomerically pure isomers from Step C were dissolved in (1 mmol, 277 mg) in EtOH (6 ml) was mixed with 20% Pd(OH)2 (51 mg) and stirred under H2 balloon at room temperature for 2h. Filtration through celite and concentration afforded the title compound, which was used for next step without further purification.
  • LCMS tR 0.26 Min. Mass calculated for, M+ 143.1 , observed LC/MS m/z 144.1 (M+H).
  • Step A The parent compounds were prepared from Example 76-2 using acid chlorides, acids, ureas and isocyanates using standard reaction conditions.
  • Step B Sem-protected material from Step A was dissolved in 1 ,4-dioxane (1 mL) and treated with 4 N HCI in 1 ,4-dioxane (1 mL). then heated at 6OC for 1 hr.. The mixture was concentrated under reduced pressure and the resulting residue was purified by prep-HPLC and conversion to the hydrochloride salt afforded the title compound as a colorless solid.
  • Step A The starting sulfone was prepared by essentially the same procedure described in Example 6 except that ethylboronic acid or cyclopropylboronic acid was used. Final products listed in Table 17 were obtained by using the procedures described for Example 76.
  • Step A The title compound was prepared using as described for Example 7 except that f-butylamine was used.
  • Step B To a solution of the product of Step A (1 equivalent) in THF (3 mL) was added DIEA (3 equivalents), and the respective trifilate (1.2 equivalents) at room temperature. The reaction was heated at reflux until consumption of starting material was observed by LC-MS analysis. The solution was cooled to room temperature and concentrated under reduced pressure. Purification by column chromatography (Si ⁇ 2, 30% ethyl acetate/dichloromethane) afforded the desired coupled intermediate. 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 18.
  • Step A Sodium thiomethoxide (39 mg, 3.00 equiv) was added to a stirring mixture of mesylate prepared in example 7 (100 mg, 1.00 equiv) and sodium iodide (14 mg, 0.50 equiv) in DMF (6 ml.) at room temperature. The resulting mixture was allowed to stir for 2.5 hours at which time LC-MS analysis indicated the reaction was complete. The reaction was quenched with saturated aqueous sodium bicarbonate (30 mL) and then extracted with dichloromethane (2 * 70 mL). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound as a yellow solid, 100 mg (>99%).
  • Step B m-Chloroperbenzoic acid (66 mg, 2.05 equiv) was added to a stirring solution of compound from Step A (91 mg, 1.00 equiv) in dichloromethane (3 mL) at room temperature. The mixture was allowed to stir for 2 hours at which time thin layer chromatography indicated the reaction was complete. The mixture was diluted with ethyl acetate (40 mL) and then washed with saturated aqueous sodium bicarbonate (15 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Step C To a solution of nitroamide (435.6 mg, 1.69 mmol) in HOAc (20 mL) was added iron powder (471.5 mg, 8.44 mmol). The reaction mixture was heated at 7O°C for 30 min. The mixture was cooled to room temperature and concentrated to dryness. To the residue was added 3OmL of 20% MeOH/CH2CI2 followed by 20 mL of saturated aqueous NaHCO3. The mixture was stirred until it stoped bobbling. The mixture was extracted by EtOAc (x 2), dried over Na2SO4, and then concentrated. The crude amine was used for displacement reaction without further purification.
  • Step A To a solution of nitroester (2285 mg, 12.22 mmol) in HOAc (55 mL) was added iron powder (6825 mg, 122.20 mmol). The reaction mixture was heated at 75°C for 10 min. The mixture was cooled to room temperature and then added 200 mL of MeOH. The resulting mixture was filtered through celite (the celite was rinsed with additional amount MeOH). The filtrate was concentrated to remove most of AcOH. To the residue was added 50 mL of 20% MeOH/CH2CI2 followed by saturated aqueous NaHC ⁇ 3 until it stoped bubbling. The mixture was extracted by EtOAc (x 2), dried over Na2SO4, and then concentrated. The crude amine was used without further purification.
  • Step C To a solution of the product of Step B (206 mg, 0.4271 mmol) in THF (8 mL) was treated with DIBAL (1.0 M in CH2CI2, 2.56 mL) at -78°C dropwise. After stirring at -78°C for 4.5h, LCMS indicated the existence of small amount of starting material.. Two more equivalents DIBAL (0.85 mL) were added. After stirring at -78°C for another 0.5 h, brine (6 mL) was added portionwise at -78°C to quench the excess reagents. The reaction mixture was extracted with CH2CI2 (3X).
  • Step D To a solution of alcohol from Step C (537 mg, 1.17 mmol) in THF (26 mL), was added H2O (0.078 mL) followed by Dess-Martin periodinane (599 mg, 1.41 mmol) at 0°C The reaction was stirred at room temperature until LCMS indicated the reaction was complete.
  • Step A To a solution of mesylate (1.1 g, 1.65 mmol) in DMSO (20 mL) at room temperature was added NaI (280 mg, 1.88 mmol) and NaCN (300 mg, 6.12 mmol). The mixture was stirred at 60 °C for 1 h. It was diluted with 200 mL of EtOAc and washed with water (200 mL X 2). The solvent was removed under vacuum. The residue was purified by column chromatography (Si ⁇ 2, 60% EtOAc/hexanes) to afford 980 mg of the title compound.
  • Step B A solution of compound from Step A (530 mg, 0.889 mmol) in 30 mL of CH2Cb was cooled to 0 °C.
  • Step C A solution of compound from Step B (400 mg, 0.667 mmol) and NaOAc (400 mg, 4.88 mmol) in 20 mL of AcOH was stirred at 60 °C. To this was slowly added t- butyl nitrite (1.40 mL, 11.8 mmol). The reaction was stirred at 60 °C for 20 min. It was cooled to room temperature and added 20 mL of CH2CI2. The solid was filtered off, and the solvent in the filtrate was removed under vacuum. The residue was diluted with 100 mL of CH2CI2 and washed with 50 mL of saturated NaHCO3 aqueous solution. The organic portion was concentrated. The residuw was dissolved in 10 mL of MeOH.
  • Step A To a solution of Example 90 (200 mg, 0.333 mol) in 10 mL of THF, was added NEt3 (84 mg, 0.830 mmol) followed by methanesulfonyl chloride (76.4 mg, 0.667 mmol). The reaction was stirred at room temperature for 20 min. It was quenched by adding 10 mL of water and diluted with 50 mL of CH2CI2. The mixture was washed with 20 mL of 0.5 N aqueous HCI solution. The organic was dried over anhydrous Na2SO4. The solvent was removed under vacuum. The residue was purified by column chromatography (SiO2, 70% EtOAc/hexanes) to give 180 mg of the title compound.
  • Step B A mixture of mesylate from Step A (42 mg, 0.062 mmol), thiomorpholine (16 mg, 0.16 mmol), K2CO3 (8.5 mg, 0.062 mmol) and a trace amount of NaI in 1.5 mL of THF was stirred at 80 °C for 24 h. It was cooled to room temperature. The solvent was removed under vacuum. The residue was purified by column chromatography (SiO2, 5% 7 N NH3 in MeOH/CH2CI2) to give 37 mg of the title compound.
  • Step C To a solution of product from Step B (37 mg, 0.054 mmol) in 2 mL of THF/MeOH (1 :1 ) stirred at 80 °C, was added 0.5 mL of 4 N HCI in dioxane solution. The reaction was stirred at 80 °C for 30 min. It was cooled to room temperature and diluted with 2 mL of THF and 1 mL of ether. The solid was collected by filtration and washed with ether to give 26 mg of the title compound as its HCI salt form.
  • HPLC-MS tR 2.21 min (UV 254nm)- Mass calculated for formula C19H2ONsOS 426.1 ; observed MH+ (LCMS) 427.2 (m/z).
  • Step A To a solution of carbon tetrabromide (170 mg, 0.512 mmol) in 4 mL of CH2CI2 stirred at 0 °C, was added PPh3 (267 mg, 1.02 mmol). The reaction was stirred at 0 °C for 15 min when the aldehyde (200 mg, 0.341 mmol) was added. The resulting solution was further stirred at 0 °C for 15 min. It was quenched with 10 mL of saturated NaHCO3 aqueous solution. The mixture was extracted by 20 mL of CH2CI2. The aqueous phase was further extracted by CH2CI2 (10 mL X 2). The combined organics were concentrated and further purified by column chromatography (SiO2, 50% EtOAc/hexanes) to give 150 mg of the title compound.
  • Step B A stirred solution of compound from Step A (40 mg, 0.054 mmol) and pyrrolidine (30 mg, 0.43 mmol) in 0.6 mL of DMSO and 0.15 mL of water was stirred at 100 °C for 3 h. It was cooled to room temperature and diluted with 15 mL of CH2CI2. The content was washed with water, saturated aqueous NaHCO3 and brine sequentially. The organic was concentrated and purified by column chromatography (SiO2, 3.5% 7 N NH3 in MeOH/ CH2CI2) to give 20 mg of the title compound.
  • Step A To a solution of mesylate (560 mg, 0.841 mmol) in 16 mL of acetone was added LiBr (730 mg, 8.41 mmol). The mixture was stirred at room temperature for 1.5 h. It was diluted with 100 mL of CH2Ck and washed with brine (100 mL). The solvent was removed under vacuum.
  • Step B To a solution of compound from Step A (40 mg, 0.061 mmol) in 1.5 mL of THF, was added 2-tri-n-butylstannylpyridine (45 mg, 0.12 mmol), and Pd(PPh3J4 (17 mg, 0.015 mmol). The reaction was stirred at 80 °C in a sealed vial for 16 h. The solvent was removed under vacuum. The residue was purified by column chromatography (SiO2, 3% 7 N NH3 in MeOH/ CH2CI2) to give 32 mg of crude title compound contaminated by triphenylphosphine oxide. This material was used in Step C without further purification.
  • Step C The product of Step B was dissolved in 2 mL of MeOH/THF (1 :1 ) at 80 °C. To this solution was added 0.5 mL of 4 N HCI in dioxane. The reaction was stirred at 80 °C for 30 min. It was cooled to room temperature and diluted with 1 mL of THF. The solid was collected by filtration and washed with THF and ether to give 15 mg of the title compound as its HCI salt form, ⁇ 8.8(d, 1 H), 8.86 (t, 1 H), 8.10 (s, 3H), 7.92-8.08 (m, 3H), 7.22 (s, 1 H)1 4.60 (s, 2H), 2.58 (s, 3H).
  • Step A To a mixture of 10 mL of THF/DMF (1 :1) was added NaH (39.3 mg, 1.64 mmol). It was cooled to -10 °C and a solution of trimethylsulfonium iodide (334 mg, 1.64 mmol) in 5 mL of DMSO was then slowly added. To the resulting mixture was added aldehyde. The reaction was stirred at room temperature for 40 min. It was quenched with ice water, and diluted with 50 mL of CH2Cb. The mixture was washed with water and brine. The solvent was removed under vacuum.
  • Step B A solution of compound from Step A (270 mg, 0.450 mmol) in 4 mL of DMF was treated with sodium methanethiolate (100 mg, 1.43 mmol). The reaction was stirred at room temperature for 30 min. It was diluted with 15 mL of water. The mixture was extracted with EtOAc (20 mL x 3). The combined organics were washed with brine (20 mL) and then concentrated.
  • Step C To a solution of compound from Step B (30 mg, 0.046 mol) in 1 mL of THF, was added NEt3 (14 mg, 0.14 mmol) followed by methanesulfonyl chloride (16 mg, 0.14 mmol). The reaction was stirred at room temperature for 15 min. It was quenched by adding 2 mL of water and diluted with 15 mL of CH2CI2. The mixture was washed with 10 mL of 0.2 N aqueous HCI solution. The organic was dried over anhydrous Na2SO4 and then concentrated. The residue was treated with NaI (10 mg, 0.071 mmol) and piperidine (13 mg, 0.15 mmol) in 1 mL of THF.
  • Step D To a solution of compound from Step C (12 mg, 0.017 mmol) in 1 mL of THF/MeOH (1 :1 ), was added 0.5 mL of 4 N HCI in dioxane. The reaction was stirred at 80 °C for 1 h. It was cooled to room temperature and diluted with 10 mL of ether. The solid was collected by filtration and washed with ether to give 8 mg of the title compound as its HCI salt form.
  • HPLC-MS tR 2.88 min (UV 254nm)- Mass calculated for formula C21H26N8S2 454.2; observed MH+ (LCMS) 455.3 (m/z).
  • Step A To a stirred solution of compound alcohol (1.00 g, 1.70 mmol) in 20 mL of THF, was added Dess-Martin periodinane (1.84 g, 4.26 mmol) and a trace amount of water. The reaction was stirred at room temperature for 40 min. It was diluted with 200 mL of CH2CI2, and washed with water and brine. The organic was dried over anhydrous Na2SO4. The solvent was removed under vacuum. The residue was purified by column chromatography (SiO2, 40% EtOAc/hexanes) to give 250 mg of the title compound.
  • Step B To a solution of compound from Step A (0.05 mmol) in 1 mL of CH2CI2/MeOH (1 :1 ) was added the respective amine (5 equivalent) and a trace amount of trifluoroacetic acid. The mixture was stirred at room temperature for 30 min when NaBH4 (10 equivalent) was added. The stirring was continued for additional 10 min. The reaction was quenched with saturated aqueous NH4CI solution. The mixture was extracted with CH2CI2. The organic was concentrated and the residue was purified by column chromatography (SiO2, 5% 7 N NH3 in MeOH/ CH2CI2) to give title compound.
  • Step C To a solution of compound from Step B(0.05 mmol) in 1 mL of THF/MeOH (1 :1), was added 1 mL of 4 N HCI in dioxane. The reaction was stirred at 80 °C for 30 min. It was cooled to room temperature and diluted with 10 mL of ether. The solid was collected by filtration to afford compound 97-1 and 97-2, respectively. TABLE 26
  • Part A To a solution of the isothiazole-aldehyde (534 mg; 0.9 mmol) in anhydrous THF (9 mL) was added methyl magnesium bromide (3M; 1.8 mL) at room temperature. After stirring for 20 min, the reaction mixture was quenched with 5 mL of saturated aqueous NH4CI solution and diluted with CH2Ck. The organic layer was washed with water and brine. The aqueous layer was back extracted with CH2CI2. The combined organic layers were dried over sodium sulfate and concentrated to obtain the crude product.
  • methyl magnesium bromide 3M
  • Part C A solution of the mesylate (40 mg; 0.06 mmol) in 2 mL of anhydrous THF was treated with hexamethyleneimine (15 mg; 0.15 mmol) plus a catalytic amount of NaI and the mixture was heated at reflux in an oil bath (8O°C; 20 h). The reaction mixture was cooled to room temperature and diluted with water and CH2CI2. The organic layer was washed with water, brine and dried over Na2SO4. Concentration in vacuo gave the crude product. Purification was carried out on flash silica gel column, eluting the product with CH2CI2 containing 2-4% of 7N-Ammonia in methanol.
  • Part D To a solution of the above di-SEM protected amine from Part C (31 mg; 0.045 mmol) in 0.2 mL of THF and 0.2 mL of CH3OH was added 4N-HCI in dioxane (0.2 mL). The resulting mixture was heated at 8O°C in an oil bath for 30 min and then allowed to cool to room temperature. THF (2 mL) was added to the reaction mixture and the precipitated product was collected by filtration. The filer cake was washed with THF and ether and dried under vacuum to obtain the title product as white solid (23 mg). By using appropriate Grignard reagents in the first step and appropriate amine in the third step in the procedures described above, all the target compounds listed in Table 1 were prepared and characterized. TABLE 27
  • the substrate 500 mg was suspended in f-BuOH (30 mL), and Et3N (0.45 mL) and DPPA (0.73 mL) was added sequentially at room temperature. Then the mixture was heated at 85 °C overnight. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was taken up in ethyl acetate (50 mL) and water (50 mL) was added. The biphasic mixture was stirred for 15 min. Then two layers were separated, and the aqueous layer was extracted with ethyl acetate (2 * 50 mL).
  • Diacid (3 g) was suspended in CH2CI2 (50 mL), and N1O- dimethylhydroxylamine hydrochloride (1.69 g), HATU (6.6 g) and diisopropylethylamine (12.12 mL) was added sequentially at room temperature. The reaction mixture was stirred overnight, and quenched by addition of water (100 mL).
  • the two layers were separated.
  • the aqueous layer was acidified to pH 4.0, and extracted with CHCb (5 * 100 mL).
  • the organic layers were combined, and dried
  • Part B The substrate from Part A (3.2 g) was suspended in f-BuOH (100 mL), and Et ⁇ N (2.27 mL) and DPPA (3.64 mL) was added sequentially at room temperature. Then the mixture was heated at 85 CC overnight. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was taken up in ethyl acetate (100 mL) and water (100 mL) was added. The biphasic mixture was stirred for 15 min. Then two layers were separated, and the aqueous layer was extracted with ethyl acetate (2 x 100 mL).
  • Part C The substrate from Part B (191 mg) was dissolved in THF/Et2O (3mL/6mL) and cooled to 0 °C. Then methylmagnesium bromide (0.83 mL, 2.0 M solution) was added dropwise. The reaction mixture was warmed to room temperature, and stirred for 12 h and quenched by addition of saturated ammonium chloride (10 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layer was washed with brine (30 mL), dried (Na2SO4), filtered and evaporated under reduced pressure to give the crude product which was purified by column chromatography (SiO2).
  • Part D The substrate from Part C (10 mg) was dissolved in 30% TFA in CH2CI2 (2 mL), and the mixture was stirred for 30 min. Then the solvent was evaporated under reduced pressure and the residue was dried in vacuum. The crude product was used in the next step without further purification.
  • Part E The sulfone (574.19 mg) and amine trifluoroacetic acid salt (514 mg) was dissolved in DMF (15 mL) under argon and treated with NaH (432 mg, 60% dispersion in oil). After LCMS indicated complete conversion of starting material to product, the reaction mixture was quenched with saturated ammonium chloride solution (15 mL). Then ethyl acetate (25 mL) was added. The two layers were separated, and the aqueous layer was extracted with ethyl acetate (25 mL).
  • Step A To a solution of 2-ethoxyethylamine (2.0 g, 22.4 mmol) in diethyl ether (40 mL) at 0 °C was added trifluoroacetic anhydride (4.7 g, 22.4 mmol) dropwise. The reaction was stirred at room temperature for 1 hr. Potassium carbonate (10 g) was added to the reaction solution. The reaction was stirred at room temperature for 1 hr. The mixture was filtered through Celite and the organic filtrate was concentrated to give 1.5 g (36% yield) of the title compound.
  • Step B A solution of the (trifluoromethyl)acetamide from Step A (1.5 g, 8.1 mmol) in Et2 ⁇ (20 mL) was added to a flask charged with lithium aluminum hydride (0.92 g, 24.3 mmol) in Et2 ⁇ (20 mL). The reaction was stirred at room temperature for 30 min, then at reflux for 12 hr. The reaction was cooled to room temperature and quenched with MeOH until the bubbling ceased. The reaction was diluted with Et2 ⁇ (30 mL) and filtered through a pad of Celite. The filtrate was concentrated by distillation to give 0.5 g (36% yield) of title compound as a colorless liquid. The amine was used without further purification.
  • Step A To a solution of 2-ethoxyethylamine (1.0 g, 11.2 mmol) in dichloromethane (50 mL) at 0 °C was added pyridine (2.2 g, 28.1 mmol). Difluoroacetic anhydride (2.3 g, 13.5 mmol) was then slowly added to the reaction solution. The reaction was further stirred at 0 °C for 15 min, then at room temperature for 2.5 hr. The reaction was diluted with dichloromethane (50 mL) and H2O (20 mL). The reaction was sequentially washed with 1 N HCI (aq); saturated NaHCO3 (aq); brine. The organic phase was dried over NaSCU and concentrated in vacuo to give 1.03 g (55% yield) of the (difluoromethyl)acetamide as a colorless liquid.
  • Step B A solution of the (difluoromethyl)acetamide from Step A (1.04 g, 6.20 mmol) in Et2O (21 mL) was added to a flask charged with lithium aluminum hydride (0.47 g, 12.39 mmol) in Et2O (25 mL) at 0 °C while under a N2 atmosphere. The reaction was stirred under a N2 atmosphere at room temperature for 2 hr. The reaction was quenched by the sequential addition of 0.47 mL of H2O; 0.47 mL of 15 % NaOH (aq) solution; 1.4 mL H2O. The reaction was stirred at room temperature for 15 min then filtered through a pad of Celite. The filtrate was concentrated by distillation to give 0.79 g (83% yield) of the title compound as a colorless liquid. The amine was used without further purification.
  • Step A To a solution of 1-amino-1-cyclopentane methanol (1.0 g, 8.68 mmol) in dichloromethane (35 mL) at 0 °C was added pyridine (2.4 g, 30.4 mmol). Trifluoroacetic anhydride (4.6 g, 21.7 mmol) was then slowly added to the reaction solution. The reaction was further stirred at 0 °C for 15 min, then at room temperature for 16 hr. The reaction was sequentially washed with 1 N HCI (aq); saturated NaHCO3 (aq); brine. The organic phase was dried over NaSO4 and concentrated in vacuo to give 1.07 g (60% yield) of the title compound as a light brown liquid.
  • Step B A solution of the (trifluoromethyl)acetamide from Step A (0.64 g, 3.06 mmol) in Et2O (10 mL) was added to a flask charged with lithium aluminum hydride (0.35 g, 9.1 mmol) in Et2O (30 mL) at 0 °C while under a N2 atmosphere. The reaction was stirred under a N2 atmosphere at 0 °C for 30 min, then at room temperature for 19 hr. The reaction was cooled to room temperature and stirred for 3 days.
  • the reaction was then cooled to 0 °C and quenched by the sequential addition of 0.35 mL of H2O; 0.35 mL of 15 % NaOH (aq) solution; 1.05 mL H2O.
  • the reaction was stirred at room temperature for 20 min then filtered through a pad of Celite. The filtercake was washed with Et2O and concentrated in vacuo to give 0.39 g (65% yield) of the title compound as a white solid.
  • the amine was used without further purification.
  • Step A To a solution of 2-amino-2-methyl-1-propanol (1.0 g, 11.2 mmol) in dichloromethane (100 mL) at 0 °C was added pyridine (3.1 g, 39.6 mmol). Trifluoroacetic anhydride (5.9 g, 28.1 mmol) was then slowly added to the reaction solution. The reaction was further stirred at 0 °C for 15 min, then at room temperature for 16 hr. The reaction was sequentially washed with 1 N HCI (aq); saturated NaHCO3 (aq); brine. The organic phase was dried over NaSO4 and concentrated in vacuo to give 0.79 g (38% yield) of the title compound as a white solid.
  • Step B A solution of the (trifluoromethyl)acetamide from Step A (0.79 g, 4.29 mmol) in Et2O (43 mL) was added to a flask charged with lithium aluminum hydride (0.49 g, 12.91 mmol) in Et2O (13 mL) at 0 °C while under a N2 atmosphere. The reaction was stirred under a N2 atmosphere at 0 °C for 30 min, then at reflux for 4 hr. The reaction was cooled to room temperature and stirred for 3 days.
  • the reaction was then cooled to 0 °C and quenched by the sequential addition of 0.49 mL of H2O; 0.49 mL of 15 % NaOH (aq) solution; 1.47 mL H2O.
  • the reaction was stirred at room temperature for 20 min, then filtered through a pad of Celite. The filtercake was washed with Et2O and concentrated in vacuo to give 0.67 g (92% yield) of the title compound as a white solid.
  • the amine was used without further purification.
  • Step A To a solution of 2-amino-2-methyl-1-propanol (1.0 g, 11.2 mmol) in dichloromethane (50 mL) at 0 °C was added pyridine (2.7 g, 33.7 mmol). Difluoroacetic anhydride (3.9 g, 22.4 mmol) was then slowly added to the reaction solution. The reaction was further stirred at 0 °C for 15 min, then at room temperature for 2 hr. The reaction was diluted with dichloromethane (50 mL) and H2O (20 mL). The reaction was sequentially washed with 1 N HCI (aq); saturated NaHCO3 (aq); brine. The organic phase was dried over NaSO4 and concentrated in vacuo to give 2.04 g (74% yield) of the title compound as a colorless liquid.
  • Step B A solution of the (difluoromethyl)acetamide from Step A (2.04 g, 8.31 mmol) in Et2O (17 mL) was added to a flask charged with lithium aluminum hydride (0.95 g, 24.92 mmol) in Et2O (50 mL) at 0 °C while under a N2 atmosphere. The reaction was stirred under a N2 atmosphere at room temperature for 2 hr. The reaction was quenched by the sequential addition of 0.95 mL of H2O; 0.95 mL of 15 % NaOH (aq) solution; 2.85 mL H2O. The reaction was stirred at room temperature for 15 min then filtered through a pad of Celite. The filtercake was washed with Et2O and concentrated in vacuo to give 1.23 g (97% yield) of the title compound as white needles. The amine was used without further purification.
  • Step A Dess-Martin periodinane reagent (1.3 g; 3.1 mmol) was added to a solution of the isothiazole-alcohol (450 mg; 1 mmol) in 30 mL of THF containing 0.06 mL of water and the reaction mixture was stirred at room temperature for 45 min. The reaction was diluted with ether and filtered and washed with more ether. The filtrate was washed with saturated NaHCO3 solution, brine and dried. Concentration in vacuo gave the isothiazole aldehyde (418 mg; 93%).
  • Step B To a solution of sodium hydride (60% in mineral oil; 169 mg; 4.2 mmol) in a mixture of 3.6 mL of DMSO and 3.6 mL of THF cooled to -1O°C, was added a solution of trimethyl sulfonium iodide (863 mg; 4.2 mmol) in 3.6 mL of DMSO drop wise. This was followed by the addition of a solution of the aldyhyde (363 mg; 0.84 mmol) in 5.6 mL of anhydrous THF, added in one portion. After stirring at room temperature for one hour, the reaction mixture was quenched with ice water. The organic products were extracted with EtOAc.
  • Step C A solution of sodium methoxide in methanol (25% by wt; 4.5 mmol; 1 mL) was added to a solution of the epoxide (201 mg; 0.45 mmol) in a 1 :1 mixture of DMF- methanol (4 mL). The resulting solution was heated at 6O°C for 3.5 hr, then cooled to room temperature and quenched with water. Extracted the organic product with EtOAc, washed the organic extract with water and brine and dried over Na2SO4. Concentration gave the crude product. Purification by flash silica gel chromatography using 1 :1 mixture of CH2CI2 and EtOAc provided the desired methoxymethyl carbinol (180 mg; 84%) as colorless oil.
  • Step D-F This sequence of steps was carried out as described for Example 76 in 64% overall yield for the 3 step sequence.
  • 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 (Corning Inc). All reagents were thawed on ice. Compounds were diluted in 100% DMSO to desirable concentrations. Each reaction consisted of 26 nM enzyme (Aurora B, Invitrogen cat#pv3970), 100 nM Tamra-PKAtide (Molecular Devices, 5TAMRA-GRTGRRNSICOOH ), 50 ⁇ M ATP (Roche), 1 mM DTT (Pierce), and kinase buffer (10 mM Tris, 10 mM MgCI2, 0.01 % Tween 20).
  • Dose-response curves were plotted from inhibition data generated each in duplicate, from 8 point serial dilutions of inhibitory compounds. Concentration of compound was plotted against kinase activity, calculated by degree of fluorescent polarization. To generate IC50 values, the dose-response curves were then fitted to a standard sigmoidal curve and IC50 values were derived by nonlinear regression analysis.
  • Compounds of the present invention exhibit Aurora A IC50 values of about 4 nm to about 3000 nM, Aurora B IC50 values of about 13 nM to about 3000 nM, and p-HH3 IC50 values of about 1 nM to about 10,000 nM.

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Abstract

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

Description

IMIDAZOPYRAZINES AS PROTEIN KINASE INHIBITORS
Field of the Invention
The present invention relates to imidazo[1 ,2-a]pyrazine compounds useful as protein kinase inhibitors, regulators or modulators, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds and compositions to treat diseases such as, for example, cancer, inflammation, arthritis, viral diseases, neurodegenerative diseases such as Alzheimer's disease, cardiovascular diseases, and fungal diseases. The present compounds are especially useful as Aurora kinase inhibitors.
Background of the Invention
Protein kinases are a family of enzymes that catalyze phosphorylation of proteins, in particular the hydroxyl group of specific tyrosine, serine, or threonine residues in proteins. Protein kinases are pivotal in the regulation of a wide variety of cellular processes, including metabolism, cell proliferation, cell differentiation, and cell survival. Uncontrolled proliferation is a hallmark of cancer cells, and can be manifested by a deregulation of the cell division cycle in one of two ways - making stimulatory genes hyperactive or inhibitory genes inactive. Protein kinase inhibitors, regulators or modulators alter the function of kinases such as cyclin-dependent kinases (CDKs), mitogen activated protein kinase (MAPK/ERK), glycogen synthase kinase 3 (GSK3beta), Checkpoint (Chk) (e.g., CHK-1 , CHK-2 etc.) kinases, AKT kinases, JNK, and the like. Examples of protein kinase inhibitors are described in WO02/22610 A1 and by Y. Mettey et al in J. Med. Chem., (2003) 46 222-236.
The cyclin-dependent kinases are serine/threonine protein kinases, which are the driving force behind the cell cycle and cell proliferation. Misregulation of CDK function occurs with high frequency in many important solid tumors. Individual CDK's, such as, CDK1 , CDK2, CDK3, CDK4, CDK5, CDK6 and CDK7, CDK8 and the like, perform distinct roles in cell cycle progression and can be classified as either G1 , S, or G2M phase enzymes. CDK2 and CDK4 are of particular interest because their activities are frequently misregulated in a wide variety of human cancers. CDK2 activity is required for progression through G1 to the S phase of the cell cycle, and CDK2 is one of the key components of the G1 checkpoint. Checkpoints serve to maintain the proper sequence of cell cycle events and allow the cell to respond to insults or to proliferative signals, while the loss of proper checkpoint control in cancer cells contributes to tumorgenesis. The CDK2 pathway influences tumorgenesis at the level of tumor suppressor function (e.g. p52, RB, and p27) and oncogene activation (cyclin E). Many reports have demonstrated that both the coactivator, cyclin E, and the inhibitor, p27, of CDK2 are either over- or underexpressed, respectively, in breast, colon, nonsmall cell lung, gastric, prostate, bladder, non-Hodgkin's lymphoma, ovarian, and other cancers. Their altered expression has been shown to correlate with increased CDK2 activity levels and poor overall survival. This observation makes CDK2 and its regulatory pathways compelling targets for the development of cancer treatments.
A number of adenosine 5'-triphosphate (ATP) competitive small organic molecules as well as peptides have been reported in the literature as CDK inhibitors for the potential treatment of cancers. U.S. 6,413,974, col. 1 , line 23- col. 15, line 10 offers a good description of the various CDKs and their relationship to various types of cancer. Flavopiridol (shown below) is a nonselective CDK inhibitor that is currently undergoing human clinical trials, A. M. Senderowicz et al, J. Clin. Oncol. (1998) 16, 2986-2999.
Figure imgf000003_0001
Other known inhibitors of CDKs include, for example, olomoucine (J. Vesely et al, Eur. J. Biochem., (1994) 224, 771-786) and roscovitine (I. Meijer et al, Eur. J. Biochem., (1997) 243, 527-536). U.S. 6,107,305 describes certain pyrazolo[3,4-b] pyridine compounds as CDK inhibitors. An illustrative compound from the '305 patent is:
K. S. Kim et al, J. Med. Chem. 45 (2002) 3905-3927 and WO 02/10162 disclose certain aminothiazole compounds as CDK inhibitors.
Imidazopyrazines are known. For example, U.S. 6,919,341 (the disclosure of which is incorporated herein by reference) and US2005/0009832 disclose various imidazopyrazines. Also being mentioned are the following: WO2005/047290;
US2005/095616; WO2005/039393; WO2005/019220; WO2004/072081 ; WO2005/014599; WO2005/009354; WO2005/005429; WO2005/085252;
US2005/009832; US2004/220189; WO2004/074289; WO2004/026877;
WO2004/026310; WO2004/022562; WO2003/089434; WO2003/084959;
WO2003/051346; US2003/022898; WO2002/060492; WO2002/060386;
WO2002/028860; JP (1986)61-057587; J. Burke et al., J. Biological Chem., Vol. 278(3). 1450-1456 (2003); and F. Bondavalli et al, J. Med. Chem., Vol. 45 (22), 4875-
4887 (2002).
Also made reference to are US 2004/0220189 (published November 4, 2004);
US 2005/0009832 (published January 13, 2005); US 2006/0084650 (published April
20, 2006) which describe kinase inhibitors, and US 2006/0106023 (published May 18, 2006) which describe imidazopyrazines as cyclin dependent kinase inhibitors. In addition, US 2007/0117804 (published May 24,
2007), describes imidazopyrazines as protein kinase inhibitors of the following structure:
A compound of the Formula:
Figure imgf000005_0001
or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein: R is H, CN, -NR5R6, cycloalkyl, cycloalkenyl, heterocyclenyl, heteroaryl,
-C(O)NR5R6, -N(R5)C(O)R6, heterocyclyl, heteroaryl substituted with (CH2)1-3 NR5R6, unsubstituted alkyl, or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR5, heterocyclyl,
-N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2)i-3-N(R5R6) and -NR5R6; R1 is H, halo, aryl or heteroaryl, wherein each of said aryl and heteroaryl can be unsubstituted or substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, - CH2OR5, -C(O)NR5R6, -C(O)OH, -C(O)NH2, -NR5R6 (wherein the R5 and R6, together with the N of said -NR5R6, form a heterocyclyl ring), -S(O)R5, -S(O2)R5, -CN, -CHO, -SR5, -
C(O)OR5, -C(O)R5 and -OR5; R2 is H, halo, aryl, arylalkyl or heteroaryl, wherein each of said aryl, arylalkyl and heteroaryl can be unsubstituted or optionally independently be substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
-C(O)OH, -C(O)NH2, -NR5R6 (wherein the R5 and R6, together with the N of said -NR5R6, form a heterocyclyl ring), -CN, arylalkyl,
-CH2OR5, -S(O)R5, -S(O2)R5, -CN, -CHO, -SR5, -C(O)OR5, -C(O)R5, heteroaryl and heterocyclyl;
R3 is H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein:
- said alkyl shown above for R3 can be unsubstituted or substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR5, alkoxy, heteroaryl, and -NR5R6;
- said aryl shown above for R3 is unsubstituted, or optionally substituted, or optionally fused, with halo, heteroaryl, heterocyclyl, cycloalkyl or heteroarylalkyl, wherein each of said heteroaryl, heterocyclyl, 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 alkyl, -OR5, -N(R5R6) and -S(O2)R5; and
- said heteroaryl shown above for R3 can be unsubstituted or optionally substituted, or optionally fused, with one or more moieties which can be the same or different with each moiety being independently selected from the group consisting of halo, amino, alkoxycarbonyl, -OR5, alkyl, - CHO, - NR5R6, -S(O2)N(R5R6),
-C(O)N(R5R6), -SR5, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclenyl, and heterocyclyl;
R5 is H, alkyl, aminoalkyl, aryl, heteroaryl, heterocyclyl or cycloalkyl; and R6 is H, alkyl, aryl, arylalkyl, heteroaryl, heterocyclyl or cycloalkyl; further wherein in any -NR5R6 in Formula I, said R5 and R6 can optionally be joined together with the N of said -NR5R6 to form a cyclic ring.
Another series of protein kinases are those that play an important role as a checkpoint in cell cycle progression. Checkpoints prevent cell cycle progression at inappropriate times, such as in response to DNA damage, and maintain the metabolic balance of cells while the cell is arrested, and in some instances can induce apoptosis (programmed cell death) when the requirements of the checkpoint have not been met. Checkpoint control can occur in the G1 phase (prior to DNA synthesis) and in G2, prior to entry into mitosis.
One series of checkpoints monitors the integrity of the genome and, upon sensing DNA damage, these "DNA damage checkpoints" block cell cycle progression in G1 & G2 phases, and slow progression through S phase. This action enables DNA repair processes to complete their tasks before replication of the genome and subsequent separation of this genetic material into new daughter cells takes place. Inactivation of CHK1 has been shown to transduce signals from the DNA-damage sensory complex to inhibit activation of the cyclin B/Cdc2 kinase, which promotes mitotic entry, and abrogate G.sub.2 arrest induced by DNA damage inflicted by anticancer agents or endogenous DNA damage, as well as result in preferential killing of the resulting checkpoint defective cells. See, e.g., Peng et al., Science, 277, 1501- 1505 (1997); Sanchez et al., Science, 277, 1497-1501 (1997), Nurse, Cell, 91 , 865- 867 (1997); Weinert, Science, 277, 1450-1451 (1997); Walworth et al., Nature, 363, 368-371 (1993); and Al-Khodairy et al., Molec. Biol. Cell., 5, 147-160 (1994). Selective manipulation of checkpoint control in cancer cells could afford broad utilization in cancer chemotherapeutic and radiotherapy regimens and may, in addition, offer a common hallmark of human cancer "genomic instability" to be exploited as the selective basis for the destruction of cancer cells. A number of factors place CHK1 as a pivotal target in DNA-damage checkpoint control. The elucidation of inhibitors of this and functionally related kinases such as CDS1/CHK2, a kinase recently discovered to cooperate with CHK1 in regulating S phase progression (see Zeng et al., Nature, 395, 507-510 (1998); Matsuoka, Science, 282, 1893-1897 (1998)), could provide valuable new therapeutic entities for the treatment of cancer. Another group of kinases are the tyrosine kinases. Tyrosine kinases can be of the receptor type (having extracellular, transmembrane and intracellular domains) or the non-receptor type (being wholly intracellular). Receptor-type tyrosine kinases are comprised of a large number of transmembrane receptors with diverse biological activity. In fact, about 20 different subfamilies of receptor-type tyrosine kinases have been identified. One tyrosine kinase subfamily, designated the HER subfamily, is comprised of EGFR (HER1 ), HER2, HER3 and HER4. Ligands of this subfamily of receptors identified so far include epithelial growth factor, TGF-alpha, amphiregulin, HB-EGF, betacellulin and heregulin. Another subfamily of these receptor-type tyrosine kinases is the insulin subfamily, which includes INS-R, IGF-IR, IR, and IR-R. The PDGF subfamily includes the PDGF-alpha and beta receptors, CSFIR, c-kit and FLK-II. The FLK family is comprised of the kinase insert domain receptor (KDR), fetal liver kinase-1(FLK-1 ), fetal liver kinase-4 (FLK-4) and the fms-like tyrosine kinase-1 (flt-1 ). For detailed discussion of the receptor-type tyrosine kinases, see Plowman et al., DN&P 7(6): 334-339, 1994.
At least one of the non-receptor protein tyrosine kinases, namely, LCK, is believed to mediate the transduction in T-cells of a signal from the interaction of a cell- surface protein (Cd4) with a cross-linked anti-Cd4 antibody. A more detailed discussion of non-receptor tyrosine kinases is provided in Bolen, Oncogene, 8, 2025- 2031 (1993). The non-receptor type of tyrosine kinases is also comprised of numerous subfamilies, including Src, Frk, Btk, Csk, AbI1 Zap70, Fes/Fps, Fak, Jak, Ack, and LIMK. Each of these subfamilies is further sub-divided into varying receptors. For example, the Src subfamily is one of the largest and includes Src, Yes, Fyn, Lyn, Lck, BIk, Hck, Fgr, and Yrk. The Src subfamily of enzymes has been linked to oncogenesis. For a more detailed discussion of the non-receptor type of tyrosine kinases, see Bolen, Oncogene, 8:2025-2031 (1993).
In addition to its role in cell-cycle control, protein kinases also play a crucial role in angiogenesis, which is the mechanism by which new capillaries are formed from existing vessels. When required, the vascular system has the potential to generate new capillary networks in order to maintain the proper functioning of tissues and organs. In the adult, however, angiogenesis is fairly limited, occurring only in the process of wound healing and neovascularization of the endometrium during menstruation. On the other hand, unwanted angiogenesis is a hallmark of several diseases, such as retinopathies, psoriasis, rheumatoid arthritis, age-related macular degeneration, and cancer (solid tumors). Protein kinases which have been shown to be involved in the angiogenic process include three members of the growth factor receptor tyrosine kinase family; VEGF-R2 (vascular endothelial growth factor receptor 2, also known as KDR (kinase insert domain receptor) and as FLK 1 ); FGF-R (fibroblast growth factor receptor); and TEK (also known as Tie-2).
VEGF-R2, which is expressed only on endothelial cells, binds the potent angiogenic growth factor VEGF and mediates the subsequent signal transduction through activation of its intracellular kinase activity. Thus, it is expected that direct inhibition of the kinase activity of VEGF-R2 will result in the reduction of angiogenesis even in the presence of exogenous VEGF (see Strawn et al, Cancer Research, 56, 3540-3545 (1996)), as has been shown with mutants of VEGF-R2 which fail to mediate signal transduction. Millauer et al, Cancer Research, 56, 1615-1620 (1996). Furthermore, VEGF-R2 appears to have no function in the adult beyond that of mediating the angiogenic activity of VEGF. Therefore, a selective inhibitor of the kinase activity of VEGF-R2 would be expected to exhibit little toxicity. Similarly, FGFR binds the angiogenic growth factors aFGF and bFGF and mediates subsequent intracellular signal transduction. Recently, it has been suggested that growth factors such as bFGF may play a critical role in inducing angiogenesis in solid tumors that have reached a certain size. Yoshiji et al., Cancer Research, 57, 3924-3928 (1997). Unlike VEGF-R2, however, FGF-R is expressed in a number of different cell types throughout the body and may or may not play important roles in other normal physiological processes in the adult. Nonetheless, systemic administration of a small molecule inhibitor of the kinase activity of FGF-R has been reported to block bFGF-induced angiogenesis in mice without apparent toxicity. Mohammad et al., EMBO Journal, 17, 5996-5904 (1998). TEK (also known as Tie-2) is another receptor tyrosine kinase expressed only on endothelial cells which has been shown to play a role in angiogenesis. The binding of the factor angiopoietin-1 results in autophosphorylation of the kinase domain of TEK and results in a signal transduction process which appears to mediate the interaction of endothelial cells with peri-endothelial support cells, thereby facilitating the maturation of newly formed blood vessels. The factor angiopoietin-2, on the other hand, appears to antagonize the action of angiopoietin-1 on TEK and disrupts angiogenesis. Maisonpierre et al., Science, 277, 55-60 (1997). The kinase, JNK, belongs to the mitogen-activated protein kinase (MAPK) superfamily. JNK plays a crucial role in inflammatory responses, stress responses, cell proliferation, apoptosis, and tumorigenesis. JNK kinase activity can be activated by various stimuli, including the proinflammatory cytokines (TNF-alpha and interleukin- 1 ), lymphocyte costimulatory receptors (CD28 and CD40), DNA-damaging chemicals, radiation, and Fas signaling. Results from the JNK knockout mice indicate that JNK is involved in apoptosis induction and T helper cell differentiation. Pim-1 is a small serine/threonine kinase. Elevated expression levels of Pim-1 have been detected in lymphoid and myeloid malignancies, and recently Pim-1 was identified as a prognostic marker in prostate cancer. K. Peltola, "Signaling in Cancer: Pim-1 Kinase and its Partners", Annales Universitatis Turkuensis, Sarja - Ser. D Osa - Tom. 616, (August 30, 2005), http://kiriasto.utu.fi/iulkaisupalvelut/annaalit/2004/D616.html. Pim-1 acts as a cell survival factor and may prevent apoptosis in malignant cells. K. Petersen Shay et al., Molecular Cancer Research 3: 170-181 (2005).
Yet another group of kinases are Aurora kinases. Aurora kinases (Aurora-A, Aurora-B, Aurora-C) are serine/threonine protein kinases that have been implicated in human cancer, such as colon, breast and other solid tumors. Aurora-A (also sometimes referred to as AIK) is believed to be involved in protein phosphorylation events that regulate the cell cycle. Specifically, Aurora-A may play a role in controlling the accurate segregation of chromosomes during mitosis. Misregulation of the cell cycle can lead to cellular proliferation and other abnormalities. In human colon cancer tissue, Aurora-A, Aurora-B, Aurora-C have been found to be over-expressed (see, Bischoff et al., EMBO J., 17:3052-3065 (1998); Schumacher et al., J. Cell Biol. 143:1635-1646 (1998); Kimura et al., J. Biol. Chem., 272:13766-13771 (1997)).
There is a need for effective inhibitors of protein kinases, especially Aurora kinases, in order to treat or prevent disease states associated with abnormal cell proliferation. Moreover, it is desirable to have kinase inhibitors, especially small- molecule compounds that may be readily synthesized.
Summary of the Invention
In its many embodiments, the present invention provides a novel class of imidazo[1 ,2-a]pyrazine compounds, methods of preparing such compounds, pharmaceutical compositions comprising one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition or amelioration of one or more diseases associated with protein kinases using such compounds or pharmaceutical compositions.
In one aspect, the present invention provides compounds represented by Formula I:
Figure imgf000011_0001
Formula I or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein: R is H, CN, -NR5R6, cycloalkyl, cycloalkenyl, heterocyclenyl, heteroaryl, -C(O)NR5R6, -N(R5)C(O)R6, heterocyclyl, heteroaryl substituted with (CH2)i.3
NR5R6, unsubstituted alkyl, or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR5, heterocyclyl,
-N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2)i-3-N(R5R6) and -NR5R6; R1 is H, halo, aryl or heteroaryl, wherein each of said aryl and heteroaryl can be unsubstituted or substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, - CH2OR5, -C(O)NR5R6, -C(O)OH, -C(O)NH2, -NR5R6 (wherein the R5 and R6, together with the N of said
-NR5R6, form a heterocyclyl ring), -S(O)R5, -S(O2)R5, -CN, -CHO, -SR5, - C(O)OR5, -C(O)R5 and -OR5; R2 is H, halo, aryl, arylalkyl or heteroaryl, wherein each of said aryl, arylalkyl and heteroaryl can be unsubstituted or optionally independently be substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
-C(O)OH, -C(O)NH2, -NR5R6 (wherein the R5 and R6, together with the N of said -NR5R6, form a heterocyclyl ring), -CN, arylalkyl, -CH2OR5, -S(O)R5, -S(O2)R5, -CN, -CHO, -SR5, -C(O)OR5, -C(O)R5, heteroaryl and heterocyclyl;
R3 is heterocyclyl-(CR7R8)n-X, heterocyclenyl-(CR7R8)n-X, heteroaryl-(CR7R8)n-X or aryl-(CR7R8)n-X wherein each of the heterocyclyl-, heterocyclenyl-, heteroaryl- or aryl- moieties of said R3 can be unsubstituted or substituted with one or more moieties, independently selected from the group consisting Of -CONR5R6,
-OR5 and alkyl, n is 1-6,
X is selected from the group consisting of -NR5R6, -OR5, -SO-R5, -SR5, SO2R5, heteroaryl, heterocyclyl and aryl, wherein said heteroaryl or aryl can be unsubstituted or substituted with one or more moieties, independently selected from the group consisting of -O-alkyl, alkyl, halo, or NR5R6;
R7 and R8 are each independently hydrogen, alkyl, heterocyclyl, aryl, heteroaryl or cycloalkyl; R5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxyalkyl,
-alkyl-S-alkyl, aminoalkyl, aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S- alkylheterocyclyl, heterocyclyl, heterocyclenyl, alkylN(alkyl)2, alkylNH(alkyl), alkylN(alkenyl)2, -alkylN(alkoxyl)2, -alkyl-SH, hydroxyalkyl, trihaloalkyl, dihaloalkyl, monohaloalkyl, wherein each of said alkyl, alkenyl, alkoxyalkyl, -alkyl-S-alkyl, aminoalkyl, aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S-alkylheterocyclyl, heterocyclyl, heterocyclenyl, alkylN(alkyl)2, alkylNH(alkyl), alkylN(alkenyl)2, -alkylN(alkoxyl)2, -alkyl-SH, hydroxyalkyl, trihaloalkyl, dihaloalkyl, monohaloalkyl can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkylSH, alkoxyl, -S- alkyl, hydroxyalkyl, and aminoalkyl;
R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkylSH, alkoxyl, -S- alkyl, hydroxyalkyl, aminoalkyl, -alkyl-OC(O)alkyl, -alkylOC(O)cycloalkyl, -alkylOC(O)aryl, -alkylOC(O)aralkyl, -alkylOC(O)NR5aryl, - alkylOC(O)NR5alkyl, -alkylOC(O)NR5heterocyclyl, - alkylOC(O)NR5heteroaryl -alkylOC(O)NR5cycloalkyl, - alkylOC(O)heterocyclyl, alkylC(O)OH, alkylC(O)Oalkyl, - alkylC(O)Ocycloalkyl, -alkylC(O)Oaryl, -alkylC(O)Oaralkyl, - alkylC(O)ONR5aryl, -alkylC(O)ONR5alkyl, -alkylCfOJONR^eterocyclyl, - alkylC(O)ONR5heteroaryl -alkylC(O)ONR5cycloalkyl, - alkylC(O)Oheterocyclyl, alkylC(O)OH, and alkylC(O)Oalkyl wherein each of said aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, -alkyl-OC(O)alkyl, - alkylOC(O)cycloalkyl, -alkylOC(O)aryl, -alkylOC(O)aralkyl, - alkylOC(O)NR5aryl, -alkylOC(O)NR5alkyl, -alkylOC(O)NR5heterocyclyl, - alkylOC(0)NR5heteroaryl -alkylOC(O)NR5cycloalkyl, - alkylOC(O)heterocyclyl, alkylC(O)OH, alkylC(O)Oalkyl, - alkylC(O)Ocycloalkyl, -alkylC(O)Oaryl, -alkylC(O)Oaralkyl, - alkylC(O)ONR5aryl, -alkylC(O)ONR5alkyl, -alkylC(O)ONR5heterocyclyl, - alkylC(O)ONR5heteroaryl -alkylC(O)ONR5cycloalkyl, - alkylC(O)Oheterocyclyl, alkylC(O)OH, and alkylC(O)Oalkyl,can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkylSH, alkoxyl, -S- alkyl, hydroxyalkyl, aminoalkyl, amino, aminodialkyl, aminocycloalkyl, halo, trihaloalkyl, dihaloalkyl, and monohaloalkyl; further wherein in any -NR5R6 in Formula I, said R5 and R6 can optionally be joined together with the N of said -NR5R6 to form a cyclic ring or bridged cyclic ring, wherein each of said cyclic ring or bridged cyclic ring, can be unsubstituted or substituted with one or more moieties, which can be the same or different, independently selected from the group consisting of hydroxyl, -SH, alkyl, alkenyl, hydroxyalkyl, -alkyl-SH, alkoxyl, -S-alkyl, - CO2-alkyl, -CO2-alkenyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, heteroaryl, aryl, cyclenyl, cycloalkyl, spiroheterocyclyl, spiroheterocyclenyl, spiroheteroaryl, spirocyclyl, spirocyclenyl, spiroaryl, alkoxyalkyl, -alkyl-S- alkyl, heterocyclyl, heterocyclenyl, halo, trihaloalkyl, dihaloalkyl, CN and monohaloalkyl.
The compounds of Formula I can be useful as protein kinase inhibitors. The compounds of Formula I can also be useful as Aurora kinase inhibitors. The compounds of Formula I can be useful in the treatment and prevention of proliferative diseases, for example, cancer, inflammation and arthritis, neurodegenerative diseases such Alzheimer's disease, cardiovascular diseases, viral diseases and fungal diseases.
Detailed Description
In an embodiment, the present invention provides imidazopyrazine compounds, especially imidazo[1 ,2-a]pyrazine compounds which are represented by structural Formula I, or pharmaceutically acceptable salts, solvates, esters or prodrug thereof, wherein the various moieties are as described above.
In another embodiment, the present invention provides compounds represented by Formula I:
Figure imgf000014_0001
Formula I or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein: R is H, CN, -NR5R6, cycloalkenyl, heterocyclenyl, -C(O)NR5R6, -N(R5)C(O)R6, or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR5 and - NR5R6;
R1 is H, halo, aryl or heteroaryl, wherein each of said aryl and heteroaryl can be unsubstituted or substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, - C(O)NR5R6 and -OR5; R2 is H, halo, or heteroaryl, wherein said 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 and heterocyclyl;
R3 is heterocyclyl-(CR7R8)n-X, heterocyclenyl-(CR7R8)n-X, heteroaryl-<CR7R8)n-X or aryl-(CR7R8)n-X wherein each of the heterocyclyl-, heterocyclenyl-, heteroaryl- or aryl- moieties of said R3 can be unsubstituted or substituted with one or more moieties, independently selected from the group consisting Of -CONR5R6,
-OR5 and alkyl, n is 1 ,
X is selected from the group consisting of, -NR5R6, -OR5, -SO-R5 and -SR5, R7 and R8 are each independently hydrogen or alkyl; R5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxyalkyl,
-alkyl-S-alkyl, aminoalkyl, aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S- alkylheterocyclyl, heterocyclyl, heterocyclenyl, alkylN(alkyl)2, alkylNH(alkyl), alkylN(alkenyl)2, -alkylN(alkoxyl)2, -alkyl-SH and hydroxyalkyl, wherein each of said aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S- alkylheterocyclyl, heterocyclyl, heterocyclenyl can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of alkyl, alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkylSH, alkoxyl, -S-alkyl, hydroxyalkyl, and aminoalky;
R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkylSH, alkoxyl, -S- alkyl, hydroxyalkyl, and aminoalkyl, wherein each of said aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of alkyl, alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, - alkylSH, alkoxyl, -S-alkyl, hydroxyalkyl, and aminoalkyl; further wherein in any -NR5R6 in Formula I, said R5 and R6 can optionally be joined together with the N of said -NR5R6 to form a cyclic ring or bridged cyclic ring, wherein each of said cyclic ring or bridged cyclic ring, can be unsubstituted or substituted with one or more moieties, which can be the same or different, independently selected from the group consisting of hydroxyl, -SH, alkyl, alkenyl, hydroxyalkyl, -alkyl-SH, alkoxyl, -S-alkyl, -
CO2-alkyl, -CO2-alkenyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, heteroaryl, aryl, cyclenyl, cycloalkyl, spiroheterocyclyl, spiroheterocyclenyl, spiroheteroaryl, spirocyclyl, spirocyclenyl, spiroaryl, alkoxyalkyl, -alkyl-S- alkyl, heterocyclyl, and heterocyclenyl.
In an embodiment, R, R1 and R2 are not all H simultaneously. In another embodiment, in Formula I, R2 is unsubstituted heteroaryl or heteroaryl substituted with alkyl.
In another embodiment, in Formula I, R2 is heteroaryl substituted with alkyl. In another embodiment, in Formula I, R2 is pyrazolyl.
In another embodiment, in Formula I, R2 is pyrazolyl substituted with alkyl. In another embodiment, in Formula I, R2 is 1-methyl-pyrazol-4-yl. In another embodiment, in Formula I, R is H. In another embodiment, in Formula I, R is CN. In another embodiment, in Formula I, R is -C(O)NR5R6.
In another embodiment, in Formula I, R is -C(O)NH2. In another embodiment, in Formula I, R is heterocyclenyl. In another embodiment, in Formula I, R is tetrahydropyridinyl.
In another embodiment, in Formula I, R is 1 ,2,3,6-tetrahydropyridinyl.
In another embodiment, in Formula I, R is alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR1 and -NR5R6.
In another embodiment, in Formula I, R is alkyl substituted with one or more - NR5R6.
In another embodiment, in Formula I, R is alkyl substituted with -NH2.
In another embodiment, in Formula I, R is alkyl substituted with -NH(methyl). In another embodiment, R is unsubstituted alkyl.
In some embodiments, both R and R1 are not H simultaneously.
In another embodiment, in Formula I, R3 is heteroaryl-CH2-X, wherein X is - OR5, -SOR5, -NR5R6, or -SR5; R5 is hydrogen, -alkylN(alkyl)2, heterocyclylalkyl or heterocyclenylalkyl; or R5 and R6 can optionally be joined together with the N of said - NR5R6 to form a cyclic ring or bridged cyclic ring, wherein said cyclic ring or bridged cyclic ring can be unsubstituted or substituted one or more moities, which can be the same or different, independently selected from the group consisting of hydroxy!, alkyl, alkoxyl, alkoxylalkyl, hydroxyalkyl, arylalkyl, aryl, heterospirocyclyl, heterospirocyclenyl, heterospiroaryl and -CO2alkyl. In another embodiment, in Formula I, R3 is heteroaryl-CH2-X or heteroaryl-
CHMethyl-X, wherein X is -NR5R6, R5 is -alkylN(alkyl)2, alkyl, alkoxyalkyl, hydroxyalkyl, arylalkyl, heterocyclenylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, or -alkylSH, R6 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or -alkylN(alkyl)2; or R5 and R6 can optionally be joined together with the N of said -NR5R6 to form a cyclic ring or bridged cyclic ring, wherein said cyclic ring or bridged cyclic ring can be unsubstituted or substituted one or more moities, which can be the same or different, independently selected from the group consisting of hydroxyl, alkyl, alkoxyl, alkoxylalkyl, hydroxyalkyl, arylalkyl, aryl, heterospirocyclyl, heterospirocyclenyl, heterospiroaryl and -CO2alkyl. In another embodiment, in Formula I, R3 is heteroaryl-CH2-X , wherein the heteroaryl of said heteroaryl-CH2-X is substituted with alkyl or -CONR5R6, wherein X is -NR5R6, R5 is alkyl, R6 is alkyl, or R5 and R6 are optionally joined together with the N of said -NR5R6 to form a cyclic ring.
In another embodiment, in Formula I1 R3 is aryl-CH2-X , wherein the aryl of said aryl-CH2-X is substituted with alkyl, wherein X is heterocyclyl.
Y^ Vvs> In another embodiment, in Formula I,
Figure imgf000018_0001
R5 is s C- ** .
Figure imgf000018_0002
or
Figure imgf000018_0003
wherein X is selected from the group consisting of, -NR5R6, -OR5 -SO-R5 and -SR5,
R5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxyalkyl, -alkyl-S-alkyl, aminoalkyl, aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S- alkylheterocyclyl, heterocyclyl, heterocyclenyl, alkylN(alkyl)2, alkylNH(alkyl), alkylN(alkenyl)2, -alkylN(alkoxyl)2, -alkyl-SH and hydroxyalkyl, wherein each of said aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S- alkylheterocyclyl, heterocyclyl, heterocyclenyl can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of alkyl, alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkylSH, alkoxyl, -S-alkyl, hydroxyalkyl, and aminoalky; R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkylSH, alkoxyl, -S- alkyl, hydroxyalkyl, and aminoalkyl, wherein each of said aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of alkyl, alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, - alkylSH, alkoxyl, -S-alkyl, hydroxyalkyl, and aminoalkyl; further wherein in any -NR5R6 in Formula I, said R5 and R6 can optionally be joined together with the N of said -NR5R6 to form a cyclic ring or bridged cyclic ring, wherein each of said cyclic ring or bridged cyclic ring, can be unsubstituted or substituted with one or more moieties, which can be the same or different, independently selected from the group consisting of hydroxyl, -SH, alkyl, alkenyl, hydroxyalkyl, -alkyl-SH, alkoxyl, -S-alkyl, - CO2-alkyl, -CO2-alkenyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, heteroaryl, aryl, cyclenyl, cycloalkyl, spiroheterocyclyl, spiroheterocyclenyl, spiroheteroaryl, spirocyclyl, spirocyclenyl, spiroaryl, alkoxyalkyl, -alkyl-S- alkyl, heterocyclyl, and heterocyclenyl.
In another embodiment, in Formula I, R3 is isothiazole, thiophene or pyrimidine substituted with:
Figure imgf000019_0001
Figure imgf000020_0001
In another embodiment, in Formula I, R3 is pyrimidinyl substituted with heterocyclylmethyl.
In another embodiment, in Formula I, R3 is pyrimidinyl substituted with morpholinylmethyll or pyrrolidinylmethyl.
In another embodiment, in Formula I, R3 is phenyl substituted with heterocyclylalkyl, wherein said heterocyclylalkyl 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 alkyl.
In another embodiment, in Formula I, R3 is phenyl-CHmethyl-X or phenyl-CH2- X , wherein X is piperazinyl, piperadinyl, pyrrolidinyl, morpholinyl or thiomorpholinyl wherein said piperazinyl, piperadinyl, pyrrolidinyl, morpholinyl or thiomorpholinyl 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 alkyl.
In another embodiment, in Formula I, R3 is phenyl substituted with heterocyclylmethyl, wherein said phenyl group is further substituted with alkyl.
In another embodiment, in Formula I, R3 is phenyl substituted with piperidinylmethyl, morpholinylmethyl or thiomorpholinylmethyl, wherein said phenyl group is further substituted with methyl.
In another embodiment, in Formula I, R3 is x
Figure imgf000021_0004
Figure imgf000021_0003
.wherein X is heterocyclyl wherein said heterocyclyl 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 hydroxyl, alkyl, hydroxyalkyl, alkoxyl, -CO2alkyl, arylalkyl, aryl, alkoxyalkyl, and heterocyclyl.
M
In another embodiment, in Formula I1 R3 is
Figure imgf000021_0002
wherein X is heterocyclyl wherein said heterocyclyl 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 alkyl.
In another embodiment, this invention discloses a compound of the formula:
Figure imgf000021_0001
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is heteroaryl, wherein said 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, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -C(O)OH, -C(O)NH2, -NR5R6 (where R5 and R6 form a cyclic amine together with the N of said -NR5R6), -CN, arylalkyl, -CH2OR5, -S(O)R5, -S(O2)R5, -CN, -CHO, -SR5, - C(O)OR5, -C(O)R5, heteroaryl and heterocyclyl; R is unsubstituted alkyl or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR5, heterocyclyl,
-N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2)1-3-N(R5R6) and -NR5R6; R1 is H; R3 is heteroaryl-CH2-X or heteroaryl-CHMethyl-X, wherein X is -NR5R6, R5 is - alkylN(alkyl)2, alkyl, alkoxyalkyl, hydroxyalkyl, arylalkyl, heterocyclenylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, or-alkylSH, R6 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or -alkylN(alkyl)2; or R5 and R6 can optionally be joined together with the N of said -NR5R6 to form a cyclic ring or bridged cyclic ring, wherein said cyclic ring or bridged cyclic ring can be unsubstituted or substituted one or more moities, which can be the same or different, independently selected from the group consisting of hydroxyl, alkyl, alkoxyl, alkoxylalkyl, hydroxyalkyl, arylalkyl, aryl, heterospirocyclyl, heterospirocyclenyl, heterospiroaryl and -CO2alkyl; wherein R5 and R6 are as defined above.
In another embodiment, this invention discloses a compound of the formula:
Figure imgf000022_0001
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is heteroaryl, wherein said 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, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -C(O)OH, -C(O)NH2, -NR5R6 (where R5 and R6 form a cyclic amine together with the N of said -NR5R6), -CN, arylalkyl, -CH2OR5, -S(O)R5, -S(O2)R5, -CN, -CHO, -SR5, - C(O)OR5, -C(O)R5, heteroaryl and heterocyclyl; R is unsubstituted alkyl or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR5, heterocyclyl, -N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2)i.3-N(R5R6) and -NR5R6; R1 is H; R3 is heteroaryl-CH2-X , wherein the heteroaryl of said heteroaryl-CH2-X is substituted with alkyl Or -CONR5R6, wherein X is -NR5R6 or R5 and R6 are optionally joined together with the N of said -NR5R6 to form heterocyclyl; wherein R5 and R6 are as defined above.
In another embodiment, this invention discloses a compound of the formula:
Figure imgf000023_0001
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is heteroaryl, wherein said 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, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -C(O)OH, -C(O)NH2, -NR5R6 (where R5 and R6 form a cyclic amine together with the N of said -NR5R6), -CN, arylalkyl, -CH2OR5, -S(O)R5, -S(O2)R5, -CN, -CHO, -SR5, - C(O)OR5, -C(O)R5, heteroaryl and heterocyclyl; R is unsubstituted alkyl or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR5, heterocyclyl,
-N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2)1-3-N(R5R6) and -NR5R6; R1 is H; R3 is isothiazole, thiophene or pyrimidine substituted with:
Figure imgf000023_0002
Figure imgf000024_0002
Figure imgf000024_0003
; wherein R and R are as defined above. In another embodiment, this invention discloses a compound of the formula:
R1 R2
Figure imgf000024_0001
R3 % or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is heteroaryl, wherein said 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, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -C(O)OH, -C(O)NH2, -NR5R6 (where R5 and R6 form a cyclic amine together with the N of said -NR5R6), -CN, arylalkyl, -CH2OR5, -S(O)R5, -S(O2)R5, -CN, -CHO, -SR5, - C(O)OR5, -C(O)R5, heteroaryl and heterocyclyl; R is unsubstituted alkyl or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR5, heterocyclyl,
-N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CHz)1-3-N(R5R6) and -NR5R6; R1 is H; R3 is phenyl-CHmethyl-X or phenyl-CH2-X , wherein said phenyl of each of said phenyl- CHmethyl-X or phenyl-CH2-X can be unsubstituted or substituted with alkyl, further wherein X is piperazinyl, piperadinyl, pyrrolidinyl, morpholinyl or thiomorpholinyl wherein each of said piperazinyl, piperadinyl, pyrrolidinyl, morpholinyl or thiomorpholinyl can be unsubstituted or substituted with alkyl; wherein R5 and R6 are as defined above. In another embodiment, this invention discloses a compound of the formula:
R1 R2
Figure imgf000025_0001
R3 N-H or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is heteroaryl, wherein said 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, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -C(O)OH, -C(O)NH2, -NR5R6 (where R5 and R6 form a cyclic amine together with the N of said -NR5R6), -CN, arylalkyl, -CH2OR5, -S(O)R5, -S(O2)R5, -CN, -CHO, -SR5, - C(O)OR5, -C(O)R5, heteroaryl and heterocyclyl; R is unsubstituted alkyl or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR5, heterocyclyl, -N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2)1-3-N(R5R6) and -NR5R6; R1 is H; R3 is
■ N
Figure imgf000025_0002
-N , ^" V
Xwherein X is selected from the group consisting of, -NR5R6, -OR5 -SO-R5
Figure imgf000025_0003
and -SR5,
R5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxyalkyl, -alkyl-S-alkyl, aminoalkyl, aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S- alkylheterocyclyl, heterocyclyl, heterocyclenyl, alkylN(alkyl)2, alkylNH(alkyl), alkylN(alkenyl)2, -alkylN(alkoxyl)2, -alkyl-SH and hydroxyalkyl, wherein each of said aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S- alkylheterocyclyl, heterocyclyl and heterocyclenyl can be unsubstituted or substituted with one or more alkyl, R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkylSH, alkoxyl, -S- alkyl, hydroxyalkyl, and aminoalkyl, wherein each of said aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl and heterocycloalkylalkyl can be unsubstituted or substituted with one or more alkyl, further wherein in any -NR5R6 in Formula I, said R5 and R6 can optionally be joined together with the N of said -NR5R6 to form a cyclic ring or bridged cyclic ring, wherein each of said cyclic ring or bridged cyclic ring, can be unsubstituted or substituted with one or moieties, which can be the same or different, independently selected from the group consisting of hydroxyl, -SH, alkyl, alkenyl, hydroxyalkyl, -alkyl-SH, alkoxyl, -S-alkyl, - CO2-alkyl, -CO2-alkenyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, heteroaryl, aryl, cyclenyl, cycloalkyl, spiroheterocyclyl, spiroheterocyclenyl, spiroheteroaryl, spirocyclyl, spirocyclenyl, spiroaryl, alkoxyalkyl, -alkyl-S- alkyl, heterocyclyl, and heterocyclenyl. In another embodiment, this invention discloses a compound of the formula:
Figure imgf000026_0001
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is heteroaryl, wherein said 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, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -C(O)OH, -C(O)NH2, -NR5R6 (where R5 and R6 form a cyclic amine together with the N of said -NR5R6), -CN, arylalkyl, -CH2OR5, -S(O)R5, -S(O2)R5, -CN, -CHO, -SR5, - C(O)OR5, -C(O)R5, heteroaryl and heterocyclyl; R is unsubstituted alkyl or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR5, heterocyclyl, -N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2)i-3-N(R5R6) and -NR5R6; R1 is H; R3 is, P
Figure imgf000027_0002
wherein R5 and R6 are as defined above.
In another embodiment, this invention discloses a compound of the formula:
R1 R2
Figure imgf000027_0001
R3 % or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is pyrazolyl, wherein said pyrazolyl 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, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -C(O)OH, - C(O)NH2, -NR5R6 (where R5 and R6 form a cyclic amine together with the N of said - NR5R6), -CN1 arylalkyl, -CH2OR5, -S(O)R5, -S(O2)R5, -CN, -CHO, -SR5, -C(O)OR5, - C(O)R5, heteroaryl and heterocyclyl; R is unsubstituted alkyl or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR5, heterocyclyl,
-N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2)1-3-N(R5R6) and -NR5R6; R1 is H; R3 is heteroaryl-CH2-X or heteroaryl-CHMethyl-X, wherein X is -NR5R6, R5 is - alkylN(alkyl)2, alkyl, alkoxyalkyl, hydroxyalkyl, arylalkyl, heterocyclenylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, or -alkylSH, R6 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or -alkylN(alkyl)2; or R5 and R6 can optionally be joined together with the N of said -NR5R6 to form a cyclic ring or bridged cyclic ring, wherein said cyclic ring or bridged cyclic ring can be unsubstituted or substituted one or more moities, which can be the same or different, independently selected from the group consisting of hydroxyl, alkyl, alkoxyl, alkoxylalkyl, hydroxyalkyl, arylalkyl, aryl, heterospirocyclyl, heterospirocyclenyl, heterospiroaryl and -Cθ2alkyl, wherein R5 and R6 are as defined above; wherein R5 and R6 are as defined above.
In another embodiment, this invention discloses a compound of the formula:
Figure imgf000028_0001
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is pyrazolyl, wherein said pyrazolyl 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, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -C(O)OH, - C(O)NH2, -NR5R6 (where R5 and R6 form a cyclic amine together with the N of said - NR5R6), -CN, arylalkyl, -CH2OR5, -S(O)R5, -S(O2)R5, -CN, -CHO, -SR5, -C(O)OR5, - C(O)R5, heteroaryl and heterocyclyl; R is unsubstituted alkyl or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR5, heterocyclyl, -N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2J1-3-N(R5R6) and -NR5R6; R1 is H; R3 is heteroaryl-CH2-X , wherein the heteroaryl of said heteroaryl-CH2-X is substituted with alkyl Or -CONR5R6, wherein X is -NR5R6, R5 is alkyl, R6 is alkyl, or R5 and R6 are optionally joined together with the N of said -NR5R6 to form heterocyclyl; wherein R5 and R6 are as defined above. In another embodiment, this invention discloses a compound of the formula:
Figure imgf000028_0002
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is pyrazolyl, wherein said pyrazolyl 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, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -C(O)OH, - C(O)NH2, -NR5R6 (where R5 and R6 form a cyclic amine together with the N of said - NR5R6), -CN, arylalkyl, -CH2OR5, -S(O)R5, -S(O2)R5, -CN, -CHO, -SR5, -C(O)OR5, - C(O)R5, heteroaryl and heterocyclyl; R is unsubstituted alkyl or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR5, heterocyclyl,
-N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2)1-3-N(R5R6) and -NR5R6; R1 is H; R3 is isothiazole, thiophene or pyrimidine substituted with:
Figure imgf000029_0001
or
Figure imgf000030_0003
; wherein R5 and R6 are as defined above.
In another embodiment, this invention discloses a compound of the formula:
Figure imgf000030_0001
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is pyrazolyl, wherein said pyrazolyl 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, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -C(O)OH, - C(O)NH2, -NR5R6 (where R5 and R6 form a cyclic amine together with the N of said - NR5R6), -CN, arylalkyl, -CH2OR5, -S(O)R5, -S(O2)R5, -CN, -CHO, -SR5, -C(O)OR5, - C(O)R5, heteroaryl and heterocyclyl; R is unsubstituted alkyl or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR5, heterocyclyl, -N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2J1-3-N(R5R6) and -NR5R6; R1 is H; R3 is phenyl-CHmethyl-X or phenyl-CH2-X , wherein said phenyl of each of said phenyl- CHmethyl-X or phenyl-CH2-X can be unsubstituted or substituted with alkyl, further wherein X is piperazinyl, piperadinyl, pyrrolidinyl, morpholinyl or thiomorpholinyl wherein each of said piperazinyl, piperadinyl, pyrrolidinyl, morpholinyl or thiomorpholinyl can be unsubstituted or substituted with alkyl; wherein R5 and R6 are as defined above. In another embodiment, this invention discloses a compound of the formula:
Figure imgf000030_0002
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is pyrazolyl, wherein said pyrazolyl 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, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -C(O)OH, - C(O)NH2, -NR5R6 (where R5 and R6 form a cyclic amine together with the N of said - NR5R6), -CN, arylalkyl, -CH2OR5, -S(O)R5, -S(O2)R5, -CN, -CHO, -SR5, -C(O)OR5, - C(O)R5, heteroaryl and heterocyclyl; R is unsubstituted alkyl or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR5, heterocyclyl, -N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2)1-3-N(R5R6) and -NR5R6; R1 is H; R3 is,
Figure imgf000031_0001
wherein R5 and R6 are as defined above.
In another embodiment, this invention discloses a compound of the formula:
Figure imgf000031_0002
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is 1-H- pyrazol-4-yl; R is unsubstituted alkyl or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR5, heterocyclyl, -N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2)1-3- N(R5R6) and -NR5R6; R1 is H; R3 is heteroaryl-CH2-X or heteroaryl-CHMethyl-X, wherein X is -NR5R6, R5 is -alkylN(alkyl)2, alkyl, alkoxyalkyl, hydroxyalkyl, arylalkyl, heterocyclenylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, or -alkylSH, R6 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or -alkylN(alkyl)2; or R5 and R6 can optionally be joined together with the N of said -NR5R6 to form a cyclic ring or bridged cyclic ring, wherein said cyclic ring or bridged cyclic ring can be unsubstituted or substituted one or more moities, which can be the same or different, independently selected from the group consisting of hydroxyl, alkyl, alkoxyl, alkoxylalkyl, hydroxyalkyl, arylalkyl, aryl, heterospirocyclyl, heterospirocyclenyl, heterospiroaryl and -CO2alkyl; wherein R5 and R6 are as defined above.
In another embodiment, this invention discloses a compound of the formula:
Figure imgf000032_0001
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is 1-A7- pyrazol-4-yl; R is unsubstituted alkyl or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR5, heterocyclyl, -N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2)1-3- N(R5R6) and -NR5R6; R1 is H; and R3 is heteroaryl-CH2-X , wherein the heteroaryl of said heteroaryl-CH2-X is substituted with alkyl Or -CONR5R6, wherein X is -NR5R6, R5 is alkyl, R6 is alkyl, or R5 and R6 are optionally joined together with the N of said - NR5R6 to form heterocyclyl. ; wherein R5 and R6 are as defined above. In another embodiment, this invention discloses a compound of the formula:
Figure imgf000032_0002
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is 1- H-pyrazol-4-yl; R is unsubstituted alkyl or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR5, heterocyclyl, -N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2)1-3- N(R5R6) and -NR5R6; R1 is H; R3 is isothiazole, thiophene or pyrimidine substituted with:
Figure imgf000033_0001
or
Figure imgf000033_0003
;wherein R5 and R6 are as defined above. In another embodiment, this invention discloses a compound of the formula:
Figure imgf000033_0002
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is 1- H-pyrazol-4-yl; R is unsubstituted alkyl or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR5, heterocyclyl, -N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2)1-3- N(R5R6) and -NR5R6; R1 is H; R3 is phenyl-CHmethyl-X or phenyl-CH2-X , wherein said phenyl of each of said phenyl-CHmethyl-X or phenyl-CH2-X can be unsubstituted or substituted with alkyl, further wherein X is piperazinyl, piperadinyl, pyrrolidinyl, morpholinyl or thiomorpholinyl wherein each of said piperazinyl, piperadinyl, pyrrolidinyl, morpholinyl or thiomorpholinyl can be unsubstituted or substituted with alkyl; wherein R5 and R6 are as defined above.
In another embodiment, this invention discloses a compound of the formula:
Figure imgf000034_0001
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is 1-H- pyrazol-4-yl; R is unsubstituted alkyl or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR5, heterocyclyl, -N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2)1-3-
N(R5R6) and -NR5R6; R1 is H; R3 is,
Figure imgf000034_0002
Figure imgf000034_0003
Figure imgf000035_0001
and
Figure imgf000035_0002
wherein R5 and R6 are as defined above.
In another embodiment, this invention discloses a compound of the formula:
Figure imgf000035_0003
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is 1-H- pyrazol-4-yl; R is unsubstituted alkyl; R1 is H; R3 is heteroaryl-CH2-X or heteroaryl- CHMethyl-X, wherein X is -NR5R6, R5 is -alkylN(alkyl)2) alkyl, alkoxyalkyl, hydroxyalkyl, arylalkyl, heterocyclenylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, or -alkylSH, R6 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or -alkylN(alkyl)2; or R5 and R6 can optionally be joined together with the N of said -NR5R6 to form a cyclic ring or bridged cyclic ring, wherein said cyclic ring or bridged cyclic ring can be unsubstituted or substituted one or more moities, which can be the same or different, independently selected from the group consisting of hydroxyl, alkyl, alkoxyl, alkoxylalkyl, hydroxyalkyl, arylalkyl, aryl, heterospirocyclyl, heterospirocyclenyl, heterospiroaryl and -CO2alkyl; wherein R5 and R6 are as defined above.
In another embodiment, this invention discloses a compound of the formula:
Figure imgf000035_0004
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is 1-H- pyrazol-4-yl; R is unsubstituted alkyl; R1 is H; R3 is heteroaryl-CH2-X , wherein the heteroaryl of said heteroaryl-CH2-X is substituted with alkyl or -CONR5R6, wherein X is -NR5R6, R5 is alkyl, R6 is alkyl, or R5 and R6 are optionally joined together with the N of said -NR5R6 to form heterocyclyl; wherein R5 and R6 are as defined above.
In another embodiment, this invention discloses a compound of the formula:
Figure imgf000036_0001
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is 1- H-pyrazol-4-yl; R is unsubstituted alkyl; R1 is H; R3 is isothiazole, thiophene or pyrimidine substituted with:
Figure imgf000036_0002
or
Figure imgf000037_0005
; wherein R5 and R6 are as defined above.
In another embodiment, this invention discloses a compound of the formula:
Figure imgf000037_0001
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is 1- H-pyrazol-4-yl; R is unsubstituted alkyl; R1 is H; R3 is phenyl-CHmethyl-X or phenyl- CH2-X , wherein said phenyl of each of said phenyl-CHmethyl-X or phenyl-CH2-X can be unsubstituted or substituted with alkyl, further wherein X is piperazinyl, piperadinyl, pyrrolidinyl, morpholinyl or thiomorpholinyl wherein each of said piperazinyl, piperadinyl, pyrrolidinyl, morpholinyl or thiomorpholinyl can be unsubstituted or substituted with alkyl; wherein R5 and R6 are as defined above.
In another embodiment, this invention discloses a compound of the formula:
Figure imgf000037_0002
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is λ-H-
pyrazol-4-yl; R is unsubstituted alkyl; R1 is H; and R3 is,
Figure imgf000037_0003
, ,
Figure imgf000037_0004
Figure imgf000038_0001
In another embodiment, this invention discloses a compound of the formula:
Figure imgf000038_0002
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is 1-H- pyrazol-4-yl; R is methyl, R1 is H; R3 is heteroaryl-CH2-X or heteroaryl-CHMethyl-X, wherein X is -NR5R6, R5 is -alkylN(alkyl)2, alkyl, alkoxyalkyl, hydroxyalkyl, arylalkyl, heterocyclenylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, or -alkylSH, R6 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or -alkylN(alkyl)2; or R5 and R6 can optionally be joined together with the N of said -NR5R6 to form a cyclic ring or bridged cyclic ring, wherein said cyclic ring or bridged cyclic ring can be unsubstituted or substituted one or more moities, which can be the same or different, independently selected from the group consisting of hydroxyl, alkyl, alkoxyl, alkoxylalkyl, hydroxyalkyl, arylalkyl, aryl, heterospirocyclyl, heterospirocyclenyl, heterospiroaryl and -Cθ2alkyl; wherein R5 and R6 are as defined above.
In another embodiment, this invention discloses a compound of the formula:
Figure imgf000038_0003
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is 1-H- pyrazol-4-yl; R is methyl, R1 is H; R3 is heteroaryl-CH2-X , wherein the heteroaryl of said heteroaryl-CH2-X is substituted with alkyl or -CONR5R6, wherein X is -NR5R6, R5 is alkyl, R6 is alkyl, or R5 and R6 are optionally joined together with the N of said - NR5R6 to form heterocyclyl; wherein R5 and R6 are as defined above.
In another embodiment, this invention discloses a compound of the formula:
Figure imgf000039_0001
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is 1- H-pyrazol-4-yl; R is methyl, R1 is H; R3 is isothiazole, thiophene or pyrimidine substituted with:
Figure imgf000039_0002
Figure imgf000040_0001
In another embodiment, this invention discloses a compound of the formula:
Figure imgf000040_0002
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R2 is 1-
H-pyrazol-4-yl; R is methyl, R1 is H; R3 is phenyl-CHmethyl-X or phenyl-CH2-X , wherein said phenyl of each of said phenyl-CHmethyl-X or phenyl-CH2-X can be unsubstituted or substituted with alkyl, further wherein X is piperazinyl, piperadinyl, pyrrolidinyl, morpholinyl or thiomorpholinyl wherein each of said piperazinyl, piperadinyl, pyrrolidinyl, morpholinyl or thiomorpholinyl can be unsubstituted or substituted with alkyl.
In another embodiment, this invention discloses a compound of the formula:
Figure imgf000040_0003
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R is λ-H-
pyrazol-4-yl; R is methyl, R1 is H; R3 is,
Figure imgf000040_0004
Figure imgf000040_0005
Figure imgf000041_0001
In another embodiment, this invention discloses a compound of the formula:
Figure imgf000041_0002
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R5 is alkyl; R6 is selected from the group consisting of alkoxyalkyl, hydroxyalkyl, cycloalkyl, wherein said cycloalkyl is substituted by hydroxyalkyl; or R5 and R6 together with the N of said -NR5R6 to form a cyclic ring, wherein said cyclic ring is substituted by one or more moieties independently selected from the group consisting of alkoxyalkyl, hydroxyalkyl, and alkyl.
In another embodiment, this invention discloses a compound of the formula:
Figure imgf000041_0003
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R5 is methyl, ethyl, or propyl; R6 is selected from the group consisting of ethoxyethyl, 1 ,1- dimethylhydroxyethyl, cyclopentyl, cyclohexyl, wherein each of said cyclopentyl and cyclohexyl is substituted by hydroxymethyl; or R5 and R6 together with the N of said - NR5R6 to form a cyclic ring, wherein said cyclic ring is substituted by one or more moieties independently selected from the group consisting of ethoxymethyl, methoxymethyl, hydroxymethyl, and methyl.
Non-limiting examples of compounds of Formula I include:
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000043_0002
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
and
Figure imgf000046_0002
or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
As used above, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings, including any possible substitutions of the stated groups or moieties: "Patient" includes both human and animals. "Mammal" means humans and other mammalian animals. "Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more, lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. "Alkyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, oxime (e.g., =N-OH), - NH(alkyl), -NH(cycloalkyl), -N(alkyl)2, -O-C(O)-alkyl, -O-C(O)-aryl, -O-C(O)-cycloalkyl, carboxy and -C(O)O-alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.
"Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon- carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more, lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. "Lower alkenyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. "Alkenyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl. aryl, cycloalkyl, cyano, alkoxy and -S(alkyl). Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut- 2-enyl, n-pentenyl, octenyl and decenyl.
"Alkylene" means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above. Non-limiting examples of alkylene include methylene, ethylene and propylene.
"Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon- carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more, lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3- methylbutynyl. "Alkynyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl. "Aryl" means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. "Bridged cyclic ring" is a hydrocarbon ring such as cycloalkyl, cyclenyl, or aryl or heteroatom containing ring such as, heterocyclyl, heterocyclenyl, or heteroaryl as described herein, that contains a bridge, which is a valence bond or an atom or an unbranched chain of atoms connecting two different parts of the ring. The two tertiary carbon atoms connected through the bridge are termed "bridgeheads". "Heteroaryl" means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl" can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. "Heteroaryl" may also include a heteroaryl as defined above fused to an aryl as defined above. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1 ,2,4- thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1 ,2- a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1 ,2,4-triazinyl, benzothiazolyl and the like. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.
"Aralkyl" or "arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.
"Alkylaryl" means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non-limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl.
"Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbomyl, adamantyl and the like.
"Cycloalkylalkyl" means a cycloalkyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyl and the like.
"Cycloalkenyl" means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contain at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. The cycloalkenyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-1 ,3-dienyl, and the like. Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.
"Cycloalkenylalkyl" means a cycloalkenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable cycloalkenylalkyls include cyclopentenylmethyl, cyclohexenylmethyl and the like.
"Halogen" means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.
"Ring system substituent" means a substituent attached to an aromatic or non- aromatic ring system which, for example, replaces an available hydrogen on the ring system. Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, amide, -CHO, -O-C(O)-alkyl, -O-C(O)-aryl, - O-C(O)-cycloalkyl, -C(=N-CN)-NH2, -C(=NH)-NH2) -C(=NH)-NH(alkyl), oxime (e.g., =N-OH), YiY2N-, WzN-alkyl-, Y1Y2NC(O)-, Y1Y2NSO2- and -SO2NY1Y2, wherein Y1 and Y2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. "Ring system substituent" may also mean a single moiety which simultaneously replaces two available hydrogen on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moiety are methylene dioxy, ethylenedioxy, -C(CH3)2- and the like which form moieties such as, for example:
Figure imgf000050_0001
"Heteroarylalkyl" means a heteroaryl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl and the like.
"Heterocyclyl" means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), -N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention. The heterocyclyl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S- dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4- dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like. "Heterocyclyl" may also mean a single moiety (e.g., carbonyl) which simultaneously replaces two available hydrogen on the same carbon atom on a ring system. Example of such moiety is pyrrolidone:
Figure imgf000051_0001
"Heterocyclylalkyl" means a heterocyclyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable heterocyclylalkyls include piperidinylmethyl, piperazinylmethyl and the like. "Heterocyclenyl" means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above. The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non- limiting examples of suitable heterocyclenyl groups include 1 ,2,3,4- tetrahydropyridinyl, 1 ,2-dihydropyridinyl, 1 ,4-dihydropyridinyl, 1 ,2,3,6- tetrahydropyridinyl, 1 ,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2- imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, 7- oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like. "Heterocyclenyl" may also mean a single moiety (e.g., carbonyl) which simultaneously replaces two available hydrogen on the same carbon atom on a ring system. Example of such moiety is pyrrolidinone:
Figure imgf000052_0001
"Heterocyclenylalkyl" means a heterocyclenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
It should be noted that in hetero-atom containing ring systems of this invention, there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom. Thus, for example, in the ring:
Figure imgf000052_0002
there is no -OH attached directly to carbons marked 2 and 5.
It should also be noted that tautomeric forms such as, for example, the moieties:
Figure imgf000052_0003
are considered equivalent in certain embodiments of this invention.
"Alkynylalkyl" means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl.
"Heteroaralkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin-3- ylmethyl. The bond to the parent moiety is through the alkyl.
"Spiro ring systems" have two or more rings linked by one common atom. Preferred spiro ring systems include spiroheteroaryl, spiroheterocyclenyl, spiroheterocyclyl, spirocycloalkyl, spirocyclenyl, and spiroaryl. The spiro ring systems can be optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above. Non-limiting examples of suitable spiro ring
systems include
Figure imgf000053_0001
H spiro[4.5]decane,
Figure imgf000053_0002
8-azaspiro[4.5]dec-2-ene, and
Figure imgf000053_0003
spiro[4.4]nona-2,7-diene.
"Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
"Acyl" means an H-C(O)-, alkyl-C(O)- or cycloalkyl-C(O)-, group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propanoyl.
"Aroyl" means an aryl-C(O)- group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1- naphthoyl.
"Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen. "Aryloxy" means an aryl-O- group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen.
"Aralkyloxy" means an aralkyl-O- group in which the aralkyl group is as previously described. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to the parent moiety is through the ether oxygen.
"Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The bond to the parent moiety is through the sulfur. "Arylthio" means an aryl-S- group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The bond to the parent moiety is through the sulfur.
"Aralkylthio" means an aralkyl-S- group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur.
"Alkoxycarbonyl" means an alkyl-O-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl. "Aryloxycarbonyl" means an aryl-O-C(O)- group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.
"Aralkoxycarbonyl" means an aralkyl-O-C(O)- group. Non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl.
"Alkylsulfonyl" means an alkyl-S(O2)- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.
"Arylsulfonyl" means an aryl-S(O2)- group. The bond to the parent moiety is through the sulfonyl.
The term "substituted" means that one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties.
The term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof. Thus, the term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like) , in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.
When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in organic Synthesis (1991 ), Wiley, New York.
When any variable (e.g., aryl, heterocycle, R2, etc.) occurs more than one time in any constituent or in Formula I, its definition on each occurrence is independent of its definition at every other occurrence. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
Prodrugs and solvates of the compounds of the invention are also contemplated herein. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press. The term "prodrug" means a compound (e.g., a drug precursor) that is transformed in vivo to yield a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. For example, if a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (C1-CβJalkyI, (C2- C12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1- methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4- crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(CrC2)alkylamino(C2-C3)alkyl (such as β-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di (C1-C2)alkylcarbamoyl-(C1- C2)alkyl and piperidino-, pyrrolidine- or morpholino(C2-C3)alkyl, and the like.
Similarly, if a compound of Formula (I) contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C1-C6)alkanoyloxymethyl, 1-((Cr C6)alkanoyloxy)ethyl, 1 -methyl-1 -((C1-C6)alkanoyloxy)ethyl, (Cr C6)alkoxycarbonyloxymethyl, N-(C1-C6)alkoxycarbonylaminomethyl, succinoyl, (C1- C-6)alkanoyl, α-amino(C1-C4)alkanyl, arylacyl and α-aminoacyl, or α-aminoacyl-α- aminoacyl, where each α-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(C1-C6)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.
If a compound of Formula (I) incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (C1-C-ιO)alkyl, (C3-C7) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl or natural α-aminoacyl, — C(OH)C(O)OY1 wherein Y1 is H, (C1- C6)alkyl or benzyl, — C(OY2)Y3 wherein Y2 is (CrC4) alkyl and Y3 is (C1-Cβ)alkyl, carboxy (C1-C6)alkyl, amino(C1-C4)alkyl or mono-N — or di-N,N-(C1-C6)alkylaminoalkyl, -C(Y4JY5 wherein Y4 is H or methyl and Y5 is mono-N— or di-N,N-(C1-C6)alkylamino morpholino, piperidin-1-yl or pyrrolidin-1-yl, and the like. One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H2O.
One or more compounds of the invention may optionally be converted to a solvate. Preparation of solvates is generally known. Thus, for example, M. Caira et al, J. Pharmaceutical Sd., 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£\}, 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 Formula I can form salts which are also within the scope of this invention. Reference to a compound of Formula I herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of Formula I 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 Formula I may be formed, for example, by reacting a compound of Formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization. Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates.) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1 ) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D. C. on their website). These disclosures are incorporated herein by reference thereto.
Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others. All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
Pharmaceutically acceptable esters of the present compounds include the following groups: (1 ) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n- propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, C-i^alkyl, or C-i^alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a C-i^o alcohol or reactive derivative thereof, or by a 2,3-di (Cβ-24)acyl glycerol.
Compounds of Formula I, and salts, solvates, esters and prodrugs thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.
The compounds of Formula (I) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula (I) as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Moshei^s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column. It is also possible that the compounds of Formula (I) may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.
All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.) Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate", "ester", "prodrug" and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds. The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 180, 170, 31P, 32P, 35S, 18F, and 36CI, respectively.
Certain isotopically-labelled compounds of Formula (I) (e.g., those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances, 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 Formula I can be inhibitors, regulators or modulators of protein kinases. Non-limiting examples of protein kinases that can be inhibited, regulated or modulated include cyclin-dependent kinases (CDKs), such as, CDK1 , CDK2, CDK3, CDK4, CDK5, CDK6 and CDK7, CDK8, mitogen activated protein kinase (MAPK/ERK), glycogen synthase kinase 3 (GSK3beta), Pim-1 kinases, Chk kinases (such as Chk1 and Chk2), tyrosine kinases, such as the HER subfamily (including, for example, EGFR (HER1 ), HER2, HER3 and HER4), the insulin subfamily (including, for example, INS-R, IGF-IR, IR, and IR-R), the PDGF subfamily (including, for example, PDGF-alpha and beta receptors, CSFIR, c-kit and FLK-II), the FLK family (including, for example, kinase insert domain receptor (KDR), fetal liver kinase-1(FLK-1), fetal liver kinase-4 (FLK-4) and the fms-like tyrosine kinase-1 (flt-1)), non-receptor protein tyrosine kinases, for example LCK, Src, Frk, Btk, Csk, AbI, Zap70, Fes/Fps, Fak, Jak, Ack, and LIMK, growth factor receptor tyrosine kinases such as VEGF-R2, FGF-R, TEK1 Akt kinases, Aurora kinases (Aurora A, Aurora B, Aurora C) and the like.
The compounds of Formula I can be inhibitors of protein kinases such as, for example, the inhibitors of the checkpoint kinases such as Chk1 , Chk2 and the like. Preferred compounds can exhibit IC5O values of less than about 5μm, preferably about 0.001 to about 1.0 μm, and more preferably about 0.001 to about 0.1 μm. The assay methods are described in the Examples set forth below.
The compounds of Formula I can be useful in the therapy of proliferative diseases such as cancer, autoimmune diseases, viral diseases, fungal diseases, neurological/neurodegenerative disorders, arthritis, inflammation, anti-proliferative (e.g., ocular retinopathy), neuronal, alopecia and cardiovascular disease. Many of these diseases and disorders are listed in U.S. 6,413,974 cited earlier, incorporated by reference herein.
More specifically, the compounds of Formula I can be useful in the treatment of a variety of cancers, including (but not limited to) the following: tumor of the bladder, breast (including BRCA-mutated breast cancer, colorectal, colon, kidney, liver, lung, small cell lung cancer, non-small cell lung cancer, head and neck, esophagus, bladder, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T- cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma and Burkett's lymphoma; chronic lymphocytic leukemia ("CLL"), acute and chronic myelogenous leukemia, myelodysplastic syndrome and promyelocytic leukemia; fibrosarcoma, rhabdomyosarcoma; head and neck, mantle cell lymphoma, myeloma; astrocytoma, neuroblastoma, glioma, glioblastoma, malignant glial tumors, astrocytoma, hepatocellular carcinoma, gastrointestinal stromal tumors ("GIST") and schwannomas; melanoma, multiple myeloma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.
Due to the key role of kinases in the regulation of cellular proliferation in general, inhibitors could act as reversible cytostatic agents which may be useful in the treatment of any disease process which features abnormal cellular proliferation, e.g., benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, endotoxic shock, and fungal infections. Compounds of Formula I 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 Formula I may induce or inhibit apoptosis. The apoptotic response is aberrant in a variety of human diseases. Compounds of Formula I, as modulators of apoptosis, will be useful in the treatment of cancer (including but not limited to those types mentioned hereinabove), viral infections (including but not limited to herpevirus, poxvirus, Epstein- Barr virus, Sindbis virus and adenovirus), prevention of AIDS development in HIV-infected individuals, autoimmune diseases (including but not limited to systemic lupus, erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes mellitus), neurodegenerative disorders (including but not limited to Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration), myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol related liver diseases, hematological diseases (including but not limited to chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including but not limited to osteoporosis and arthritis) aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain.
Compounds of Formula I, as inhibitors of kinases, can modulate the level of cellular RNA and DNA synthesis. These agents would therefore be useful in the treatment of viral infections (including but not limited to HIV, human papilloma virus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus).
Compounds of Formula I 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 Formula I may also be useful in inhibiting tumor angiogenesis and metastasis.
Compounds of Formula I may also act as inhibitors of cyclin dependent kinases and other protein kinases, e.g., protein kinase C, her2, raf 1 , MEK1 , MAP kinase, EGF receptor, PDGF receptor, IGF receptor, PI3 kinase, weel kinase, Src, AbI and thus be effective in the treatment of diseases associated with other protein kinases.
Another aspect of this invention is a method of treating a mammal (e.g., human) having a disease or condition associated with kinases (e.g., CDKs, CHK and Aurora kinases) by administering a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound to the mammal.
A preferred dosage is about 0.001 to 1000 mg/kg of body weight/day of the compound of Formula I. An especially preferred dosage is about 0.01 to 25 mg/kg of body weight/day of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound.
The compounds of this invention may also be useful in combination (administered together or sequentially) with one or more of anti-cancer treatments such as radiation therapy, and/or one or more anti-cancer agents different from the compound of Formula I. The compounds of the present invention can be present in the same dosage unit as the anti-cancer agent or in separate dosage units.
Another aspect of the present invention is a method of treating one or more diseases associated with a kinase (such as CDK, CHK and Aurora), comprising administering to a mammal in need of such treatment: an amount of a first compound, which is a compound of Formula 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; and an amount of at least one second compound, the second compound being an anti-cancer agent different from the compound of Formula 1 , wherein the amounts of the first compound and the second compound result in a therapeutic effect.
Non-limiting examples of suitable anti-cancer agent is selected from the group consisting of a cytostatic agent, cisplatin, doxorubicin, liposomal doxorubicin (e.g., Caelyx®, Myocet®, Doxil®), taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, R115777®, L778.123®, BMS 214662®, Iressa®, Tarceva®, antibodies to EGFR, antibodies to IGFR (including, for example, those published in US 2005/0136063 published June 23, 2005), KSP inhibitors (such as, for example, those published in WO 2006/098962 and WO 2006/098961 ; ispinesib, SB-743921 from Cytokinetics), centrosome associated protein E ("CENP- E") inhibitors (e.g., GSK-923295), Gleevec®, intron, ara-C, adriamycin, Cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN™, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, Avastin, herceptin, Bexxar, bortezomib ("Velcade"), Zevalin, Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane, Fulvestrant, Ifosfomide, Rituximab, C225®, satriplatin, mylotarg, Avastin, Rituxan, panitubimab, Sutent, sorafinib, Sprycel (dastinib), nilotinib, Tykerb (lapatinib) and Campath.
If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent or treatment within its dosage range. For example, the CDC2 inhibitor olomucine has been found to act synergistically with known cytotoxic agents in inducing apoptosis (J. Cell Sci., (1995) 108, 2897. Compounds of Formula I 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 Formula I may be administered either prior to or after administration of the known anticancer or cytotoxic agent. For example, the cytotoxic activity of the cyclin-dependent kinase inhibitor flavopiridol is affected by the sequence of administration with anticancer agents. Cancer Research, (1997) 57, 3375. Such techniques are within the skills of persons skilled in the art as well as attending physicians.
Accordingly, in an aspect, this invention includes combinations comprising an amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an amount of one or more anti-cancer treatments and anti-cancer agents listed above wherein the amounts of the compounds/ treatments result in desired therapeutic effect.
Another aspect of the present invention is a method of inhibiting one or more Aurora kinases in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of at least one compound of Formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
Another aspect of the present invention is a method of treating, or slowing the progression of, a disease associated with one or more Aurora kinases in a patient in need thereof, comprising administering a therapeutically effective amount of at least one compound of Formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
Yet another aspect of the present invention is a method of treating one or more diseases associated with Aurora kinase, comprising administering to a mammal in need of such treatment an amount of a first compound, which is a compound of Formula 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; and an amount of at least one second compound, the second compound being an anti-cancer agent, wherein the amounts of the first compound and the second compound result in a therapeutic effect.
Another aspect of the present invention is a method of treating, or slowing the progression of, a disease associated with one or more Aurora kinases in a patient in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising in combination at least one pharmaceutically acceptable carrier and at least one compound according to Formula 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
In the above methods, the Aurora kinase to be inhibited can be Aurora A, Aurora B and/or Aurora C.
Another aspect of the present invention is a method of inhibiting one or more Checkpoint kinases in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
Another aspect of the present invention is a method of treating, or slowing the progression of, a disease associated with one or more Checkpoint kinases in a patient in need thereof, comprising administering a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
Yet another aspect of the present invention is a method of treating one or more diseases associated with Checkpoint kinase, comprising administering to a mammal in need of such treatment an amount of a first compound, which is a compound of formula 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; and an amount of at least one second compound, the second compound being an anti-cancer agent, wherein the amounts of the first compound and the second compound result in a therapeutic effect. Another aspect of the present invention is a method of treating, or slowing the progression of, a disease associated with one or more Checkpoint kinases in a patient in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising in combination at least one pharmaceutically acceptable carrier and at least one compound according to formula 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
In the above methods, the checkpoint kinase to be inhibited can be Chk1 and/or Chk2.
Another aspect of the present invention is a method of inhibiting one or more cyclin dependent kinases in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. Another aspect of the present invention is a method of treating, or slowing the progression of, a disease associated with one or more cyclin dependent kinases in a patient in need thereof, comprising administering a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. Yet another aspect of the present invention is a method of treating one or more diseases associated with cyclin dependent kinase, comprising administering to a mammal in need of such treatment an amount of a first compound, which is a compound of formula 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; and an amount of at least one second compound, the second compound being an anti-cancer agent, wherein the amounts of the first compound and the second compound result in a therapeutic effect.
Another aspect of the present invention is a method of treating, or slowing the progression of, a disease associated with one or more cyclin dependent kinases in a patient in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising in combination at least one pharmaceutically acceptable carrier and at least one compound according to formula 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
In the above methods, the checkpoint kinase to be inhibited can be CDK1 and/or CDK2. Another aspect of the present invention is a method of inhibiting one or more tyrosine kinases in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of at least one compound of Formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
Yet another aspect of the present invention is a method of treating, or slowing the progression of, a disease associated with one or more tyrosine kinases in a patient in need thereof, comprising administering a therapeutically effective amount of at least one compound of Formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
Another aspect of the present invention is a method of treating one or more diseases associated with tyrosine kinase, comprising administering to a mammal in need of such treatment an amount of a first compound, which is a compound of
Formula 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; and an amount of at least one second compound, the second compound being an anti-cancer agent, wherein the amounts of the first compound and the second compound result in a therapeutic effect. Another aspect of the present invention is a method of treating, or slowing the progression of, a disease associated with one or more tyrosine kinases in a patient in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising in combination at least one pharmaceutically acceptable carrier and at least one compound according to Formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
In the above methods, the tyrosine kinase can be VEGFR (VEGF-R2), EGFR,
HER2, SRC, JAK and/or TEK.
Another aspect of the present invention is a method of inhibiting one or more
Pim-1 kinases in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of at least one compound of Formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
Yet another aspect of the present invention is a method of treating, or slowing the progression of, a disease associated with one or more Pim-1 kinases in a patient in need thereof, comprising administering a therapeutically effective amount of at least one compound of Formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. Another aspect of the present invention is a method of treating one or more diseases associated with Pim-1 kinase, comprising administering to a mammal in need of such treatment an amount of a first compound, which is a compound of Formula 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; and an amount of at least one second compound, the second compound being an anti-cancer agent, wherein the amounts of the first compound and the second compound result in a therapeutic effect.
Another aspect of the present invention is a method of treating, or slowing the progression of, a disease associated with one or more Pim-1 kinases in a patient in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising in combination at least one pharmaceutically acceptable carrier and at least one compound according to Formula 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
The pharmacological properties of the compounds of this invention may be confirmed by a number of pharmacological assays. The exemplified pharmacological assays which are described herein below have been carried out with compounds according to the invention and their salts, solvates, esters or prodrugs.
This invention is also directed to pharmaceutical compositions which comprise at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound and at least one pharmaceutically acceptable carrier.
For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania. Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.
Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
The compounds of this invention may also be delivered subcutaneously.
Preferably the compound is administered orally or intravenously.
Also contemplated are delivery methods that are combinations of the above- noted delivery methods, Such methods are typically decided by those skilled in the art. Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg, according to the particular application.
The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required. The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two to four divided doses.
Another aspect of this invention is a kit comprising a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound and a pharmaceutically acceptable carrier, vehicle or diluent.
Yet another aspect of this invention is a kit comprising an amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound and an amount of at least one anticancer therapy and/or anti-cancer agent listed above, wherein the amounts of the two or more ingredients result in desired therapeutic effect.
The invention disclosed herein is exemplified by the following preparations and examples which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures will be apparent to those skilled in the art.
Where NMR data are presented, 1 H spectra were obtained on either a Varian
VXR-200 (200 MHz, 1H), Varian Gemini-300 (300 MHz) or XL-400 (400 MHz) and are reported as ppm down field from Me4Si with number of protons, multiplicities, and coupling constants in Hertz indicated parenthetically. Where LC/MS data are presented, analyses was performed using an Applied Biosystems API-100 mass spectrometer and Shimadzu SCL-10A LC column: Altech platinum C18, 3 micron, 33mm x 7mm ID; gradient flow: 0 min - 10% CH3CN, 5 min - 95% CH3CN, 7 min - 95% CH3CN, 7.5 min - 10% CH3CN, 9 min - stop. The retention time and observed parent ion are given. The following solvents and reagents may be referred to by their abbreviations in parenthesis: Thin layer chromatography: TLC dichloromethane: CH2CI2 ethyl acetate: AcOEt or EtOAc methanol: MeOH trifluoroacetate: TFA triethylamine: Et3N or TEA butoxycarbonyl: n-Boc or Boc nuclear magnetic resonance spectroscopy: NMR liquid chromatography mass spectrometry: LCMS high resolution mass spectrometry: HRMS milliliters: mL millimoles: mmol microliters: μl grams: g milligrams: mg room temperature or rt (ambient): about 25°C. dimethoxyethane: DME
The synthesis of the inventive compounds is illustrated below. Also, it should be noted that the disclosure of commonly-owned U.S. 6,919,341 and U.S. Appl. No. 11/598186 is incorporated herein by reference.
EXAMPLE 1
Figure imgf000073_0001
Figure imgf000074_0001
Part A: 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 (Siθ2, 40% ethyl acetate/hexanes) afforded compound 4 as a white solid 2.30 g (76%). 1H-NMR (400- MHz, DMSO-de ) δ 8.3 (s, 1 H), 7.8 (s, 1 H), 2.6 (s, 3H). HPLC-MS tR = 1.87 Min (UV 254nm)- Mass calculated for formula C7H5BrlN3S 370.01 , observed LC/MS m/z 370.9 (M+H).
Part C: A suspension of bromide from Part B (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 mL) was heated overnight under nitrogen at 105C. After cooling, the mixture was diluted with ethyl acetate (1 L), washed with brine (2 x 500 mL), dried (magnesium sulfate), filtered, concentrated and purified by chromatography on silica gel. The title compound was obtained as a pale yellow solid (21.4 g, 64%). Part D: To a DMF (400 mL) solution of compound from Example 1 , Part C (21.8 g) was added N-iodosuccinimide (26.9 g) and the resulting mixture was heated overnight at 6OC. The mixture was concentrated and water (400 mL) was added. After stirring 1 hr at rt, saturated sodium carbonate was added (250 mL) and subsequently stirred an additional 30 min at rt. The mixture was filtered, washed with water, methanol (100 mL) and the filter cake was dried overnight under vacuum. A brown solid was obtained (31.4 g, 87%). Part E: A flask was charged with iodide from Part D (1.00 equiv), Bpin-compound 5a (1.3 equiv), PdCI2(dppf) (0.1 equiv) and potassium phosphate monohydrate (3.0 equiv). After purging the flask with argon, 1 ,4-dioxane (50 mL) and water (5) were added and the resulting mixture was heated at 8OC overnight (23 h). The reaction was cooled to room temperature. EtOAc was added to the reaction mixture and filtered through Celite. After concentration the residue was purified by column chromatography (silica gel, 25% EtOAc/hexane) to give the title compound. Part F: To a solution of compound from Example 1 , Part E (1.0 equiv) in DCM (10 mL) was added m-CPBA (2.05 equiv) in one portion. The resulting mixture was stirred at room temperature for 30 min. The mixture was concentrated and then partitioned between EtOAc and water. The organic layer was washed with NaHCO3 (sat. aq., twice), brine and dried (Na2SO4). After concentration, the title compound was obtained and used in the next step directly without further purification.
EXAMPLE 2
Figure imgf000075_0001
1 2
To a solution of 11 (1.04 g, 5.98 mmol) in 20 mL of DMF, was added K2CO3 (2.48 g, 17.9 mmol) and MeI (1.27 g, 8.96 mmol). The reaction was stirred at room temperature overnight. It was diluted with 200 mL of 50% EtOAc/hexanes and washed with water (200 mL) and brine (100 mL). The organic was concentrated. To the residue was added 20 mL of hexanes. The solid was collected by filtration to give 2. The filtrate was concentrated and purified by column eluting with 25% EtOAc/hexanes to give additional amount of 2. The combined yield of 2 is 1.05 g. 1H NMR (400 MHz, CDCI3) δ 8.37 (s, 1 H), 4.05 (s, 3H). EXAMPLE 3
Figure imgf000076_0001
To a solution of 2 (260 mg, 1.38 mmol) in 6 mL of AcOH was added iron powder (774 mg, 13.8 mmol). The reaction mixture was heated at 70-75 °C for 12 min. The mixture was cooled to room temperature and then added 20 mL of MeOH. The resulting mixture was filtered through celite (the celite was rinsed with additional amount MeOH). The filtrate was concentrated to remove most of AcOH. To the residue was added 15 mL of 20% MeOH/CH2CI2 followed by 20 mL of saturated aqueous NaHCO3. The mixture was stirred until it stops bobbling. The mixture was extracted by EtOAc (60 mL x 2), dried over Na2SO4, and then concentrated. To the residue was added 5 mL of ether followed by 5 mL of hexanes. The solid was collected by filtration to give 160 mg of crude 3 which contains a little acylated amine but pure enough for the sulfone displacement reaction. The filtrate was purified by column with 20% of AcOEt/ CH2CI2 to give additional 30 mg of 3. 1H NMR (400 MHz, CDCI3) δ 6.85 (s, 1 H), 4.61 (brs, 2H), 3.92 (s, 3H).
EXAMPLE 4
Figure imgf000076_0002
4 To a solution of compound 3 (89 mg, 0.56 mmol) and 6-bromo-8-methanesulfonyl-3- [1-(2-trimethylsilanyl-ethoxymethyl)-1 H-pyrazol-4-yl]-imidazo[1 ,2-a]pyrazine (258 mg, 0.55 mmol) in 2 mL of DMF, was added NaH (60% dispersion in oil, 44 mg, 1.1 mmol). The reaction was stirred at room temperature for 15 min. It was quenched with 5 mL of saturated aqueous NH4CI and diluted with 30 mL of water. The solid was collected by filtration, washed with water and MeOH. It was dried under vacuum to give 255 mg of compound 4. 1H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1 H), 8.22 (s, 1 H), 8.15 (s, 1 H), 7.96 (s, 1 H)1 7.62 (s, 1 H), 5.50 (s, 2H), 3.85 (s, 3H), 3.60 (t, 2H), 1.83 (t, 2H), 0.00 (s, 9H).
EXAMPLE 5
Figure imgf000077_0001
Step A: To a solution of 4 (76 mg, 0.14 mmol) in 6 mL of THF was added Pd(PPh3J4 (16 mg, 0.014 mmol) and 0.35 mL of MeZnCI (2 M solution in THF, 0.69 mmol). The reaction was stirred at 80 °C for 20 min. It was cooled to room temperature and quenched by adding 0.5 mL of MeOH. It was diluted with 30 mL of CH2CI2 and washed with 20 mL of 0.5 N aqueous HCI solution. The solvent was removed under vacuum. The residue was purified by flash chromatography eluting with 5% MeOH/CH2CI2 to give 50 mg of 5-{6-methyl-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1 H- pyrazoM-ylJ-imidazofi ^^pyrazin-δ-ylaminoJ-isothiazole-S-carboxylic acid methyl ester contaminated by a small amount of triphenylphosphine oxide. Step B: The above crude material was dissolved in 5 mL of THF. To the solution was added 0.5 mL of LiBHEt3 (1 M solution in THF). The reaction was stirred at room temperature for 30 min. It was quenched by adding 5 mL of saturated aqueous NH4CI solution. The mixture was extracted by 30 mL of CH2CI2. The organic was concentrated and purified by flash chromatography eluting with 5% MeOH/CH2CI2 to give 25 mg of compound 5. NMR (400 MHz, CDCI3) δ 7.90 (s, 1 H), 7.82 (s, 1 H), 7.60 (s, 1 H), 7.48 (s, 1 H), 6.90 (s, 1 H), 5.55 (s, 2H), 4.75 (brs, 2H), 3.65 (t, 2H), 2.50 (s, 3H), 1.00 (t, 2H), 0.00 (s, 9H). EXAMPLE 6
Figure imgf000078_0001
To a solution of compound 5 (200 mg, 0.438 mmol) in 20 mL of THF, was added triethylamine (0.21 mL, 1.5 mmol) and methanesulfonylchloride (0.10 mL, 1.3 mmol). The reaction was stirred at room temperature for 30 min. It was quenched by adding 1 mL of MeOH. The solution was diluted by 30 mL of CH2Cb, washed consecutively with 15 mL of 2 N aqueous HCI, water, and brine. The solvent was removed under vacuum to give 230 mg of crude compound 6 which was used in further transformations without further purification.
EXAMPLE 7
Figure imgf000078_0002
Step A: Mixture of compound 6 (17 mg, 0.032 mmol) and sodium azide (15 mg, 0.23 mmol) in 1 mL of DMF was heated at 70 °C for 3 h. It was cooled to room temperature and added 10 mL of water. The resulting solid was collected by filtration and purified by flash chromatography eluting with 5% MeOHZCH2CI2 to give 12 mg of (3- azidomethyl-isothiazol-5-yl)-{6-methyl-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1 H- pyrazol-4-yl]-imidazo[1 ,2-a]pyrazin-8-yl}-amine. Step B: The above material was dissolved in 3 mL of MeOH. To the solution was added 15 mg of 10% wt. Pd/C. The mixture was stirred under H2 (1 atm) for 1 h. It was filtered through celite. The filtrate was concentrated under vacuum to give 12 mg of compound 7. NMR (400 MHz, CDCI3) δ 7.88 (s, 1 H), 7.80 (s, 1 H), 7.60 (s, 1 H), 7.47 (s, 1 H), 6.86 (s, 1 H), 5.55 (s, 2H), 4.00 (brs, 2H), 3.65 (t, 2H), 2.50 (s, 3H), 1.00 (t, 2H), 0.00 (s, 9H).
EXAMPLE 8
Figure imgf000079_0001
To a solution of compound 7 (12 mg, 0.026 mmol) in 2 mL of THF heated at 70 °C, was added 0.5 mL of 4 N HCI in dioxane. To the resulting mixture was added MeOH until it became homogeneous. The reaction was stirred at 70 °C for 1 h and then cooled to room temperature. The solid was collected by filtration and washed with ether to give 9 mg of compound 8 as its HCI salt form. NMR (400 MHz, CD3OD) δ 8.23 (s, 1 H), 8.20 (s, 2H), 8.03 (s, 1 H), 7.20 (s, 1 H), 4.22 (s, 2H), 2.59 (s, 3H). HPLC- MS t.R = 1.82 min (UV 254nm)- Mass calculated for formula C14Hi4N8S 326.1 ; observed MH+ (LCMS) 327.2 (m/z).
EXAMPLE 9
Figure imgf000080_0001
Step A: To a solution of compound 7 (9 mg, 0.02 mmol) in 1 mL of MeOH/CH2Cl2 (1 :1 ), was added formaldehyde (40% wt. in water, 6 mg, 0.2 mmol). It was stirred at room temperature for 15 min when NaBH4 (16 mg, 0.4 mmol) was added in two portions. The mixture was purified by flash chromatography eluting with NH4CI (aq.)/MeOH/CH2CI2 (1 :5:190) to give 5 mg of (3-dimethylaminomethyl-isothiazol-5-yl)- {6-methyl-3-[1 -(2-trimethylsilanyl-ethoxymethyl)-1 H-pyrazol-4-yl]-imidazo[1 ,2- a]pyrazin-8-yl}-amine.
Step B: The above material was then dissolved in 2 mL of THF. The resulting solution was heated at 70 °C when 0.5 mL of 4 N HCI in dioxane was added. To the resulting mixture was added 1 mL of MeOH. The reaction was stirred at 70 °C for 1 h and then cooled to room temperature. Most of the solvent was removed under vacuum. To the residue was added 5 mL of ether. The solid was collected by filtration and washed with ether to give 5 mg of compound 9 as its HCI salt form. NMR (400 MHz, CD3OD) δ 8.21 (s, 1 H), 8.18 (s, 2H), 8.08 (s, 1 H), 7.30 (s, 1 H), 4.42 (s, 2H), 2.95 (s, 6H), 2.59 (s, 3H). HPLC-MS tR = 2.04 min (UV 254nm). Mass calculated for formula C16H18N8S 354.1 ; observed MH+ (LCMS) 355.2 (m/z). EXAMPLE 10
Figure imgf000081_0001
5 10
To a solution of compound 5 (2.50 g, 5.47 mmol) in 100 mL of THF, was added 0.3 mL of water followed by Dess-Martin periodinane (6.96 g, 16.4 mmol). The reaction was stirred at room temperature for 30 min. The solid was filtered off. The filtrate was diluted with 200 mL of CH2CI2, and washed with 100 mL of saturated aqueous NH4CI solution. The organic was dried over anhydrous Na2SO4 and then concentrated. To the residue was added 30 mL of acetonitrile. The solid was collected by filtration to give 2.05 g of compound 10. NMR (400 MHz, DMSO-Gf6) δ 12.38 (s, 1 H), 9.84 (s, 1 H),
8.60 (s, 1 H), 8.11 (s, 1 H), 7.96 (s, 1 H), 7.91 (s, 1 H), 7.55 (s, 1 H), 5.50 (s, 2H), 3.60 (t,
2H), 2.45 (s, 3H), 1.83 (t, 2H), 0.00 (s, 9H).
EXAMPLE 11
Figure imgf000081_0002
Step A: A solution of compound 10 (100 mg, 0.220 mmol) and pyrrolidine (156 mg, 2.20 mmol) in 14 mL of CH2CI2 was stirred at room temperature for 20 min. To the solution was added two drops of acetic acid, followed by NaBH4 (67 mg, 1.8 mmol). The resulting mixture was stirred at room temperature for 5 min when 3 mL of MeOH was added. The stirring was continued for additional 20 min. The reaction was quenched by adding 15 mL of saturated aqueous NaHCO3 solution. After diluted with 20 mL of CH2Ck, the organic was isolated. The solvent was removed under vacuum. The residue was purified by flash chromatography eluting with NH4CI (aq.)/MeOH/CH2CI2 (1 :10:190) to give 98 mg of {6-methyl-3-[1-(2-trimethylsilanyl- ethoxymethyl)-1 H-pyrazol-4-yl]-imidazo[1 ,2-a]pyrazin-8-yl}-(3-pyrrolidin-1 -ylmethyl- isothiazol-5-yl)-amine. NMR (400 MHz, CDCI3) δ 7.88 (s, 1 H), 7.81 (s, 1 H), 7.60 (s, 1 H), 7.48 (s, 1 H), 6.96 (s, 1 H), 5.55 (s, 2H), 3.80 (s, 2H), 3.65 (t, 2H), 2.70 (brs, 4H), 2.50 (s, 3H), 1.85 (brs, 4H), 0.96 (t, 2H), 0.00 (s, 9H).
Step B: To a solution of {6-methyl-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1 H-pyrazol-4- yl]-imidazo[1 ,2-a]pyrazin-8-yl}-(3-pyrrolidin-1-ylmethyl-isothiazol-5-yl)-amine (98 mg, 0.19 mmol) in 8 mL of THF heated at 70 °C, was added 2 mL of 4 N HCI in dioxane. To the resulting mixture was added MeOH until it became homogeneous. The reaction was stirred at 70 °C for 1 h and then cooled to room temperature. To the mixture was added 3 mL of ether. The solid was collected by filtration and washed with ether to give 79 mg of compound 11 as its HCI salt form. NMR (400 MHz, CD3OD) δ 8.18 (s, 2H), 8.13 (s, 1 H), 8.00 (s, 1 H), 7.22 (s, 1 H), 4.50 (s, 2H), 3.62-3.68 (m, 2H), 3.06-3.15 (m, 2H), 2.58 (s, 3H)1 1.95-2.22 (m, 4H). HPLC-MS tR = 2.03 min (UV 254nm)- Mass calculated for formula C18H2oN8S 380.2; observed MH+ (LCMS) 381.2 (m/z).
EXAMPLE 12 By essentially the same procedure set forth in Example 11 , only replacing pyrrolidine with other respective aliphatic amines in step A, compounds shown in column 2 of Table 1 were prepared.
Figure imgf000083_0001
TABLE 1
Figure imgf000083_0002
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
EXAMPLE 13
Figure imgf000093_0001
13
By essentially the same procedure set forth in Example 4, only replacing 6-bromo-8- methanesulfonyl-3-[1 -(2-trimethylsilanyl-ethoxymethyl)-1 H-pyrazol-4-yl]-imidazo[1 ,2- a]pyrazine with 8-methanesulfonyl-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1 H-pyrazol- 4-yl]-imidazo[1 ,2-a]pyrazine, compound 13 was prepared. NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1 H), 8.22 (d, 1 H), 8.21 (s, 1 H), 8.03 (s, 1 H), 7.82 (d, 1 H), 5.58 (s, 2H), 3.96 (s, 3H), 3.69 (t, 2H), 3.40 (s, 1 H), 0.95 (t, 2H), 0.02 (s, 9H).
EXAMPLE 14
Figure imgf000093_0002
13 14
To a solution of compound 13 (830 mg, 1.76 mmol) in 50 mL of CH2CI2 stirred at 0 °C, was added 7.05 mL of LiBHEt3 (1 M solution in THF). The reaction was stirred at room temperature for 10 min. It was quenched by adding saturated aqueous NH4CI solution. The organic was separated and washed with saturated aqueous NaHCO3 solution. The solvent was removed under vacuum. To the residue was added 10 mL of MeOH. The solid was collected by filtration to give 530 mg of compound 14. NMR (400 MHz, CD3OD) δ 8.38 (s, 1 H), 7.98 (s, 1 H), 7.97 (d, 2H), 7.78 (s, 1 H), 7.69 (d, 2H), 7.15 (s, 1 H), 5.55 (s, 2H), 4.62 (s, 2H), 3.66 (t, 2H), 0.92 (t, 2H), 0.00 (s, 9H). EXAMPLE 15
Figure imgf000094_0001
14 15
To a solution of compound 14 (258 mg, 0.582 mmol) in 20 mL of THF, was added 0.05 ml. of water followed by Dess-Martin periodinane (740 mg, 1.75 mmol). The reaction was stirred at room temperature for 1.5 h. The solid was filtered off. The filtrate was diluted with 100 mL of CH2CI2, and washed with water and brine. The solvent was removed under vacuum, the residue was purified by flash chromatography eluting with 5% of MeOH/CH2CI2 to give 230 mg of compound 15.
EXAMPLE 16
Figure imgf000094_0002
By essentially the same procedure set forth in Example 11 , compounds shown in column 2 of Table 2 were prepared by replacing compound 10 with compound 15, and replacing pyrrolidine with other respective aliphatic amines in step A. TABLE 2
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0002
1 ) Walsh R.J.A.; Wooldridge, K. R. H. J. Chem. Soc. Perkin Trans. 1972, 1247.
EXAMPLE 17
Figure imgf000097_0001
Part A: A solution of ester (2.38 g, 4.91 mmol, 1 equivalent) in DMF (40 mL) was treated with NaH (60% dispersion in oil, 1.5 equivalents) for 20 min at rt, at which time, the reaction mixture was cooled to -10C and 2-(trimethylsilyl)ethoxymethyl chloride ( 0.87 mL, 1 equivalent) added to the reaction mixture. The resulting solution was allowed to slowly warm to rt and continued to stir at rt for a further 1 h. LC-MS analysis indicated the reaction was complete. The reaction was quenched with methanol (15 mL), diluted with ethyl acetate (300 mL) and washed with sat. sodium bicarbonate, water, brine, dried (sodium sulfate) and concentrated. Purification by column chromatography (Siθ2 40% ethyl acetate / hexanes) afforded the desired product as a yellow solid 1.2 g (40%). HPLC-MS tR = 2.79 Min (UV 254nm)- Mass calculated for formula C27H41 N7O4SSi2 615.25, observed LC/MS m/z 616.2 (M+H). Part B: To a solution of compound from Part A (1.2 g, 1.90 mmol, 1 equivalent) in THF (100 mL) was added superhydride solution (4 equivalents) at rt. The resulting solution was stirred at rt for 30 minutes at which time LC-MS analysis indicated the reaction was complete. The reaction was quenched with sat. aq. ammonium chloride and then extracted with dichloromethane (x2). The combined organic layers were dried (sodium sulfate) and concentrated. Purification by column chromatography (SiO2 60 % ethyl acetate / hexanes) afforded alcohol as a clear oil (47%). HPLC-MS tR = 2.49 Min (UV 254nm). Mass calculated for formula C26H41N7O3SSΪ2 587.25, observed LC/MS m/z 588.3 (M+H).
Part C: A solution of alcohol from Part B (0.52 g, 0.88 mmol, 1 equivalent) in DCM (15 mL) was treated with triethylamine (1.5 equivalents) for 15 min at OC (ice-bath), at which time, methanesulfonyl chloride (1.2 equivalents) was added to the reaction at OC. The resulting solution was allowed to slowly warm to rt and continued to stir at rt for a further 3h. LC-MS analysis indicated the reaction was complete. The reaction mixture was diluted with ethyl acetate (10OmL) and washed with water, brine, dried (anh. sodium sulfate) and concentrated to afford mesylate as a red/brown oil 0.59 g (100%) which was used without further purification. HPLC-MS tR = 2.66 Min (UV 254nm). Mass calculated for formula C27H43N7O5S2Si2 665.23, observed LC/MS m/z 666.1 (M+H).
Part D: A solution of the respective alcohol (3 equivalents) in THF (1.5 mL) was treated with NaH (60% dispersion in oil, 2 equivalents) for 15 min at rt, at which time, mesylate from Part C (40 mg, 0.06 mmol, 1 equivalent) was added to the reaction mixture. After stirring at rt for 1h, LC-MS analysis indicated the reaction was complete. The reaction was quenched with sat. aq. ammonium chloride and then extracted with ethyl acetate (twice). The combined organic layer was dried (sodium sulfate) and concentrated to afford crude ether, which was used without further purification. Part E: A solution of compound from Part D in 1 ,4-dioxane (1 mL) was treated with 4N HCI in 1 ,4-dioxane solution (1 mL) at 6OC for 10 min at which time HPLC-MS indicated that the reaction was complete. The solvent was removed and the residue was purified by Prep-LC. Conversion to a hydrochloric salt afforded compounds listed in Table 3.
TABLE 3
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000110_0002
By essentially the same procedures given in Preparative Example 17, compounds given in Table 4 can be prepared.
TABLE 4
Figure imgf000111_0001
Figure imgf000112_0003
EXAMPLE 19
Figure imgf000112_0001
Example 19 was prepared in similar manner to Example 4. 1H NMR (300 MHz, DMSO-de) δ 12.4 (bs, 1 H), 7.81 (s, 1 H), 7.75 (s, 1 H), 7.59 (s, 1 H), 3.85 (s, 3H), 2.49 (s, 3H).
EXAMPLE 20
Figure imgf000112_0002
Example 20 was prepared in similar manner to Example 17, Part A. 1H NMR (300 MHz, CDCI3) δ 7.81 (s, 1 H)1 7.73 (s, 1 H), 7.63 (s, 1 H), 6.61 (s, 2H), 3.98 (s, 3H), 3.74 (t, J = 8 Hz, 2H), 2.62 (s, 3H), 0.94 (t, J = 8 Hz1 2H), -0.83 (s, 9H). EXAMPLE 21
Figure imgf000113_0001
To a stirring solution of ester (2.40 g, 4.40 mmol) in tetrahydrofuran (96 mL) at -78 °C was added DIBAL-H (1 M in dichloromethane, 11.0 mL, 11.0 mmol) dropwise. The mixture was stirred at -78 °C for 3 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 (2*250 mL), the organic layers were combined, washed with brine (100 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure affording compound 21 as a yellow solid 2.20 g (97%). 1H NMR (300 MHz, CDCI3) δ 9.99 (s, 1 H), 7.74 (s, 1 H), 7.73 (s, 1 H), 7.65 (s, 1 H), 6.60 (s, 2H), 3.74 (t, J = 8 Hz, 2H)1 2.64 (s, 3H), 0.94 (t, J = 8 Hz, 2H), -0.07 (s, 9H).
EXAMPLE 22
Figure imgf000113_0002
To a stirring solution of aldehyde (1.30 g, 2.52 mmol), piperidine (257 mg, 3.02 mmol), and acetic acid (150 μL, 2.52 mmol) in 1 ,2-dichloroethane (17 mL) at room temperature was added sodium triacetoxyborohydride (801 mg, 3.78 mmol) in one portion. The mixture was stirred at room temperature for 2 hours at which time thin layer chromatography (40% ethyl acetate/hexanes) indicated the reaction was complete. The reaction was quenched with 1 N sodium hydroxide (25 mL) and stirred for 20 minutes. The mixture was extracted with chloroform (3*20 mL), the organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Afforded compound 22 as a yellow solid 1.35 g (92%). 1H NMR (300 MHz, CDCI3) δ 7.70 (s, 1 H), 7.59 (s, 1 H), 7.23 (s, 1 H), 6.58 (s, 2 H), 3.72 (t, J = 8 Hz, 2H), 3.62 (s, 2H), 2.58 (s, 3H), 2.47 (m, 4H), 1.58 (m, 6H), 0.93 (t, J = 8 Hz, 2H), - 0.086 (s, 9H).
EXAMPLE 23
Figure imgf000114_0001
Example 23 was prepared in a similar manner to example 22 with the substitution of 3-methylpiperidine for piperidine. 1H NMR (300 MHz, CDCI3) δ 7.70 (s, 1 H), 7.59 (s, 1 H), 7.23 (s, 1 H), 6.58 (s, 2H), 3.72 (t, J = 8 Hz1 2H), 3.62 (s, 2H), 2.85 (m, 2H), 2.59 (s, 3H), 1.98 (m, 1 H), 1.65 (m, 6H), 0.93 (t, J = 8 Hz, 2H), 0.84 (d, J = 6 Hz, 3H), - 0.076 (s, 9H).
EXAMPLE 24
Figure imgf000114_0002
Example 24 was prepared in a similar manner to example 23 with the substitution of pyrrolidine for piperidine. 1H NMR (300 MHz, CDCI3) δ 7.70 (s, 1 H), 7.59 (s, 1 H), 7.23 (S1 1 H), 6.58 (S1 2H)1 3.77 (s, 2H)1 3.72 (t, J = 8 Hz1 2H)1 2.61 (m, 4H)1 2.59 (s, 3H)1 1.81 (m, 4H)1 0.92 (t, J = 8 Hz1 2H), -0.90 (s, 9H).
EXAMPLE 25
Figure imgf000115_0001
A solution of iodide from Example 24 (20 mg, 0.035 mmol) in 1 ,4-dioxane (1 mL) was treated with 4N HCI in 1 ,4-dioxane (1 mL). The mixture was sonicated at room temperature for 2.5 hours, at which time HPLC indicated the reaction was complete. The mixture was concentrated under reduced pressure and the resulting residue was purified by prep-HPLC and conversion to the hydrochloride salt afforded compound 25 as a white solid 15 mg (83%). 1H NMR (300 MHz1 CD3OD) δ 7.88 (s, 1 H), 7.79 (s, 1 H)1 7.17 (S1 1 H)1 4.51 (s, 2H)1 3.71 (m, 2H)1 3,22 (m, 2H), 2.57 (s, 3H), 2.07 (m, 4H). HPLC tR = 4.83 min (UV 254 J. Mass calculated for formula C15H17IN6S 440.03; observed MH+ (MS) 441.5 (m/z). EXAMPLE 26
Figure imgf000115_0002
Example 26 was prepared in a similar manner to example 25. 1H NMR (300 MHz, CD3OD) δ 7.87 (s, 1 H), 7.79 (s, 1H), 7.22 (s, 1H), 4.39 (s, 2H), 3.52 (m, 2H), 2.96 (m,
1 H)1 2.70 (m, 1 H), 2.57 (s, 3H)1 1.90 (m, 4H), 1.21 (m, 1 H), 0.99 (d, J = 6 Hz, 3H). HPLC tR = 5.06 min (UV 254nm). Mass calculated for C17H2ilN6S 468.3; observed MH+ (MS) 469.7 (m/z).
EXAMPLE 27 The compounds shown in column 2 of Table 5 were prepared as follows:
Figure imgf000116_0001
A flask containing the prepared aryl iodide scaffolds (compound from Example 22, 23, or 24, 1 equivalent), commercially available or readily prepared in 1 to 3 steps aryl/heteroaryl/alkyl boronic acid/ester/boroxine or aryl/heteroaryl/alkyl magnesium bromide or aryl/heteroaryl/alkyl zinc chloride (1.5 - 3 equivalents), potassium phosphate or potassium carbonate (2- 3 equivalents) and Pd(PPh3J4 or PdCI2dppf (0.05 - 0.10 equivalents) was evacuated, backfilled with nitrogen and repeated. 1 ,4- Dioxane or N,N-dimethylformamide or 1 ,2-dimethoxyethane (1 - 3 mL) was added and the mixture was stirred at 50 - 130 °C until reaction was complete as judged by thin layer chromatography (ethyl acetate/hexanes) or HPLC. The mixture was diluted with water (3 - 10 mL) and extracted with ethyl acetate (2-3 * 10-30 mL). The organic layers were combined, washed with brine (15 - 30 mL), dried over magnesium sulfate, filtered, concentrated, and purified by column chromatography (SiO2, ethyl acetate/hexanes). The product obtained was dissolved in 1 ,4-dioxane (1 mL) and treated with 4 N HCI in 1 ,4-dioxane (1 mL) and sonicated at room temperature for 1-5 hours, at which time HPLC indicated the reaction was complete. The mixture was concentrated under reduced pressure and the resulting residue was purified by prep- HPLC and conversion to the hydrochloride salt afforded compounds 27-1 to 27-7. TABLE 5
Figure imgf000117_0001
Figure imgf000118_0002
EXAMPLE 28
Figure imgf000118_0001
A mixture of iodide (60 mg, 0.103 mmol), trimethyl(trifluoromethyl)silane (44 mg, 0.308 mmol), copper iodide (73 mg, 0.385 mmol), potassium fluoride (15 mg, 0.257 mmol), and anhydrous DMF (1.0 ml.) was degassed with nitrogen then heated at 80 °C in a sealed tube overnight. The mixture was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (Siθ2, 90:10:0.25 methylene chloride/methanol/concentrated ammonium hydroxide). The resulting residue was dissolved in anhydrous 1 ,4-dioxane (1mL) and 4 M HCI in dioxane (1 mL) was added. The resulting solution was sonicated at room temperature for 2 hours and concentrated under reduced pressure to dryness. Purification by preparative HPLC and conversion to the hydrochloride salt afforded the title compound as an off-white solid 3.1 mg (6%). 1H NMR (300 MHz, CD3OD) δ 8.07 (s, 1 H), 7.85 (s, 1 H), 7.24 (s, 1 H), 4.40 (s, 2H), 3.61 (d, J = 12.3 Hz, 2H), 3.07 (t, J= 12.3 Hz, 2H), 2.55 (s, 3H), 1.75-2.03 (m, 5H), 1.56 (m, 1 H). HPLC tR = 7.19 min. Mass calculated for formula C17H19F3N6S 396.13; observed MH+ 397.2 (m/z).
EXAMPLE 29
Figure imgf000119_0001
A mixture o iodide (100 mg, 0.171 mmol) in anhydrous THF (2.0 mL) was cooled to -78 °C and n-butyl lithium (2.5 M solution in hexanes, 89 μL, 0.222 mmol) was added dropwise. After stirring for 15 minutes a solution of hexachloroethane (45 mg, 0.188 mmol) in THF (1.0 mL) was added dropwise. After stirring the reaction at - 78 °C for 30 minutes the solution was quenched with a saturated aqueous solution of ammonium chloride (3.0 mL) and warmed to room temperature. The reaction was concentrated under reduced pressure, extracted with ethyl acetate (50 mL) and the organic layer dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (Siθ2, 90:10:0.25 methylene chloride/methanol/concentrated ammonium hydroxide). The resulting residue was dissolved in anhydrous 1 ,4-dioxane (1 mL) and 4 M HCI in dioxane (1 mL) was added. The resulting solution was sonicated at room temperature for 2 hours and concentrated under reduced pressure to dryness. Purification by preparative HPLC and conversion to the hydrochloride salt afforded the title compound as an off-white solid 30 mg (40%). 1H NMR (300 MHz, CD3OD) δ 7.80 (s, 1 H), 7.73 (s, 1 H), 7.22 (s, 1 H), 4.39 (s, 2H), 3.59 (d, J = 12.3 Hz, 2H), 3.08 (t, J= 12.3 Hz, 2H), 2.55 (s, 3H)1 1.75-2.03 (m, 5H), 1.56 (m, 1 H). HPLC tR = 4.79 min. Mass calculated for formula C16H19CIN6S 362.11 ; observed MH+ 363.7 (m/z).
EXAMPLE 30
Figure imgf000120_0001
Example 30 was prepared in a similar manner as Example 29. 1H NMR (300 MHz, CD3OD) δ 7.77 (s, 1 H), 7.68 (s, 1 H), 7.20 (s, 1 H), 4.39 (s, 2H), 3.47-3.67 (m, 2H), 2.97 (m, 1 H), 2.71 (m, 1 H), 2.55 (s, 3H)1 1.77-2.01 (m, 4H), 1.20 (m, 1 H), 1.00 (d, J = 6.4 Hz, 3H). HPLC tR = 4.98 min. Mass calculated for formula C17H2iCIN6S 376.12; observed MH+ 377.6 (m/z).
EXAMPLE 31
Figure imgf000120_0002
Example 31 was prepared in a similar manner to compound 29 with the substitution of tetrachlorodibromoethane for hexachloroethane. 1H NMR (300 MHz, CD3OD) δ 7.84 (s, 1 H), 7.83 (s, 1 H), 7.25 (s, 1 H), 4.41 (s, 2H), 3.61 (d, J = 12.3 Hz, 2H), 3.08 (t, J= 12.3 Hz, 2H), 2.57 (s 3H), 1.77-2.03 (m, 5H), 1.55 (m, 1 H). HPLC tR = 5.19 min. Mass calculated for formula C16Hi9BrN6S 406.06; observed MH+ 407.4 (m/z).
EXAMPLE 32
Figure imgf000121_0001
To a solution of aminopyrimidine (100 mg, 0.452 mmol) in anhydrous pyridine (2.0 mL) was added 3-fluorobenzoyl chloride (72 mg, 0.452 mmol). After stirring at room temperature overnight, the reaction was concentrated under reduced pressure, diluted with water (30 mL), and extracted with methylene chloride (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to afford the title compound as an off-white solid 124 mg (80%). 1H NMR (300 MHz, CDCI3) δ 8.95 (s, 2H), 8.72 (s, 1 H), 7.66-7.72 (m, 2H), 7.49 (m, 2H), 1.36 (s, 12H).
EXAMPLE 33
Figure imgf000121_0002
Prepared in a similar manner as compound 31 affording the title compound as an off- white solid 131 mg (80%). 1H NMR (300 MHz, CDCI3) δ 8.93 (s, 2H), 8.65 (s, 1 H), 7.83 (m, 1 H), 7.69 (m, 1 H), 7.30 (m, 1 H), 1.34 (s, 12H). EXAMPLE 34
Figure imgf000122_0001
A mixture of iodide (60 mg, 0.103 mmol), tri-n-butyl(pyridyl)tin (57 mg, 0.154 mmol), dichloro[1 ,1 '-bis(diphenylphosphino)ferrocene]palladium(ll) dichloromethane adduct (8 mg, 0.0103 mmol), and potassium fluoride (18 mg, 0.309 mmol) in anhydrous 1 ,4- dioxane (1.0 mL) was degassed with nitrogen then heated at 85 °C in a sealed tube overnight. The mixture was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (2 * 100 mL). The organic layer was then separated, dried over sodium sulfate, filtered, concentrated under reduced pressure to residue, and purified by column chromatography (Siθ2, 90:10:0.25 methylene chloride/methanol/ concentrated ammonium hydroxide). The resulting residue was then dissolved in anhydrous 1 ,4-dioxane (1 mL) and 4 M HCI in dioxane (1 mL) was added. The resulting solution was sonicated at room temperature for 2 hours and then concentrated under reduced pressure to dryness. Purification by preparative HPLC and conversion to the hydrochloride salt afforded de-halogenated product 3.2 mg (10%) as an off-white solid: 1H NMR (300 MHz, CD3OD) δ 8.23 (s, 1 H), 8.13 (s, 2H), 7.29 (s, 1 H), 4.55 (s, 2H), 3.72 (br s, 2H)1 3.29 (m, 2H), 2.61 (s, 3H), 2.05-2.18 (m, 4H). HPLC tR =3.49 min. Mass calculated for formula C15H16N6S 314.13; observed MH+ 315.2 (m/z). Also afforded coupling product 5.0 mg (10%) as an off-white solid: 1H NMR (300 MHz, CD3OD) δ 8.95 (s, 1 H), 8.86 (d, J = 5.1 Hz, 1 H), 8.50 (s, 1 H), 8.28 (t, J = 7.5 Hz, 1 H), 8.18 (d, J = 7.8 Hz, 1 H), 7.70 (t, J = 6.3 Hz, 1 H), 7.26 (s, 1 H), 4.54 (s, 2H), 3.74 (m, 2H), 3.29 (m, 2H), 1.99-2.30 (m, 4H). HPLC tR =4.80 min. Mass calculated for formula C20H2-IN7S 391.16; observed MH+ 392.5 (m/z). EXAMPLE 35
Figure imgf000123_0001
Sodium borohydride (3 mg, 0.073 mmol) was added to a room temperature suspension of iodide (15 mg, 0.037) in methanol (1 mL). The reaction was allowed to stir for 30 minutes then quenched with water (20 mL). The mixture was diluted with diethyl ether (20 mL) and the phases were allowed to separate. The organic layer was dried (sodium sulfate), filtered and concentrated to afford a protected de- halogenated intermediate. The reduced product (7 mg, 0.017 mmol) was subjected to the acidic conditions outlined previously to afford the title compound as a yellow solid 2 mg (17%). 1H NMR (300 MHz, CD3OD) δ 7.94 (s, 1 H), 7.90 (s, 1 H), 7.74 (s, 1 H), 7.55 (s, 1 H), 3.94 (s, 3H), 2.50 (s, 3H). HPLC tR = 4.67 min (UV 254nm). Mass calculated for formula C12HnN5O2S 289.06; observed MH- (ESI MS) 288.0 (m/z).
EXAMPLE 36
Figure imgf000123_0002
Example 36 was prepared in a similar manner to Example 31. 1H NMR (300 MHz, CD3OD) δ 7.72 (s, 1 H), 7.69 (s, 1 H), 7.15 (s, 1 H), 4.38 (s, 2H)1 3.69-3.52 (m, 2H), 3.17-2.96 (m, 2H), 2.54 (s, 3H), 2.06-1.70 (m, 5H), 1.65-1.44 (m, 1 H). HPLC tR = 5.00 min (UV 254nm)- Mass calculated for formula C16H19IN6S 454.04; observed MH+ (ESI MS) 455.0 (m/z). EXAMPLE 37
Figure imgf000124_0001
Pd2(dba)3 (5 mg, 0.005 mmol) was added to a room temperature solution of
DPPF (6 mg, 0.103 mmol) in N,N'-dimethylformamide (1 mL) and stirred for 10 minutes. The mixture was then added to a solution of iodide (60 mg, 0.103 mmol), Zn(CN)2 (12 mg, 0.103 mmol) in N,N'dimethylformamide (4 mL). The reaction was heated to 150 °C in the microwave for 30 minutes, cooled to room temperature then. concentrated to dryness. Purification of the resultant residue by flash chromatography' (SiO2; 12 g; 10% methanol in methylene chloride) afforded impure nitrile as a yellow solid. The impure nitrile (22 mg, 0.045 mmol) was dissolved in 2 N HCI (4 mL) without further purification. The resultant solution was sonicated at 45 °C for 2 hours. Upon completion, the reaction was concentrated to dryness. Purification of the resultant residue by prep-HPLC afforded the title compound as a white solid 8 mg (18%). 1H NMR (300 MHz, CD3OD) δ 8.22 (s, 1 H), 7.93 (s, 1 H)1 7.22 (s, 1 H), 4.40 (s, 2H), 3.73- 3.52 (m, 2H), 3.20-2.97 (m, 2H), 2.55 (s, 3H)1 2.06-1.71 (m, 5H), 1.66-1.42 (m, 1 H). HPLC tR = 4.50 min (UV 254nm)- Mass calculated for formula C17Hi9N7S 353.14; observed MH+ (ESI MS) 354.3 (m/z).
EXAMPLE 38
Figure imgf000124_0002
A mixture of iodide (70 mg, 0.12 mmol), Pd(dppf)CI2 (9 mg, 0.012 mmol), sodium tert-butoxide (35 mg, 0.36 mmol) and sodium thiomethoxide (17 mg, 0.24 mmol) was flushed with nitrogen then dissolved into 1 ,4-dioxane (5 mL). The solution was heated to 95 °C in the microwave for 90 minutes. The reaction was cooled to room temperature, diluted with ethyl acetate (100 mL), and filtered through celite. The organic layer was washed with water (50 mL) and brine (50 mL) then dried (sodium sulfate), filtered and concentrated to dryness. Purification of the resultant residue by prep-HPLC afforded the protected thiomethylether. The thiomethylether (35 mg, 0.07 mmol) was subjected to the reaction conditions outlined in example 110 to afford the title compound as a white solid 6 mg (11 %). 1H NMR (300 MHz, CD3OD) δ 8.28 (s, 1 H), 8.25 (s, 1 H), 7.34 (s, 1 H), 4.43 (s, 2H), 3.68-3.52 (m, 2H), 3.18-2.98 (m, 2H), 2.67 (s, 3H), 2.49 (s, 3H), 2.05-1.71 (m, 5H), 1.65-1.44 (m, 1 H). HPLC tR = 4.74 min (UV 254nm). Mass calculated for formula C17H22N6S2 374.13; observed MH+ (ESI MS) 375.3 (m/z).
EXAMPLE 39
Figure imgf000125_0001
A combined mixture of iodide (70 mg, 0.12 mmol), sodium thioethoxide (20 mg,
0.24 mmol), Pd(dppf)CI2 (9 mg, 0.012 mmol) and sodium te/t-butoxide (35 mg, 0.36 mmol) was flushed with nitrogen gas then dissolved into 1 ,4-dioxane (5 mL). The reaction was heated to 95 °C and stirred for 72 hours. The reaction was then cooled to room temperature, diluted with ethyl acetate (100 ml), and filtered through celite. The filtrate was washed with water (50 mL) and brine (50 mL) then dried (sodium sulfate), filtered and concentrated to dryness. Purification of the resultant residue by flash chromatography (SiO2; 12 g; 0% to 10% methanol in methylene chloride) afforded a thioethylether intermediate as a yellow solid. The thioethylether (10 mg, 0.019 mmol) was subjected to the reaction conditions outlined in example 110 to afford the title compound as a white solid 2 mg (4%). 1H NMR (300 MHz, CD3OD) δ 8.32 (s, 1 H), 8.28 (s, 1 H), 7.35 (s, 1 H), 4.43 (s, 2H), 3.68-3.55 (m, 2H), 3.17-3.01 (m, 2H), 2.90 (q, J = 7.3 Hz, 2H), 2.67 (s, 3H), 2.07-1.71 (m, 5H), 1.65-1.42 (m, 1 H), 1.28 (t, J = 7.3 Hz, 3H). HPLC tR = 5.27 min (UV 254nm)- Mass calculated for formula C18H24N6S2 388.15; observed MH+ (ESI MS) 389.7 (m/z).
EXAMPLE 40
Figure imgf000126_0001
Part A: To a stirred solution of 2-Bromo-thiazole-5-carboxylic acid (2.0 g, 9.615 mmol) in t-Butanol (30 mL) and triethyl amine (1.5 mL, 10.57 mmol) was added diphenylphosphoryl azide (2.9 g, 10.57 mmol) and reaction mixture was heated to 80 °C and stirred for 12 hrs, LCMS showed the complete disappearance of the starting material. Reaction mixture was cooled to room temp., solvent removed under vacuum, water (100 mL) added and extracted with ethyl acetate (3 x 100 mL). Organic layer was washed with water, brine, dried over sodium sulfate and concentrated, crude material was passed through small pad of silica gel and resultant (2-Bromo-thiazol-5- yl)-carbamic acid tert-butyl ester (solid) was used as such in the next step, yield 2.5 g (90%). 1H NMR (400 MHz, DMSO-d6 δ 7.10 (s, 1 H), 7.05 (s, 1 H), 1.51 (s, 9H).Mass calculated for formula C8H11BrN2O2S 277.97; observed MH+ (LCMS) 279.0 (m/z). Part B: To a stirred solution of (2-Bromo-thiazol-5-yl)-carbamic acid tert-butyl ester (2.5 g, 8.9928 mmol) in 1 ,4-dioxane (20.0 mL) were added tributy(vinyl)tin (2.9 mL, 9.892 mmol), 2,6-di-tert-butyl-4-methylphenol (cat. amt) and tetrakis(triphenyl phosphine) palladium(O) (506.0 mg, 0.4496 mmol). The reaction mixture was heated to 100 °C and stirred for 12 hrs, LCMS showed the complete disappearance of the starting material. Reaction mixture was cooled to room temp, filtered and solid washed with ethyl acetate, combined filtrate (organic solvent) was removed under vacuum, crude material was purified using biotage HPLC using hexane / ethyl acetate gradient 0.0 to 100 % to yield (2-Vinyl-thiazol-5-yl)-carbamic acid tert-butyl ester (solid) 1.1 g (54%). 1H NMR (400 MHz, CDCI3 δ 7.27 (d, J = 12.7 Hz,2H), 7.19 (brs, 1 H), 6.84-6.77 (m, 1 H), 6.87 (d, J = 17.0 Hz, 1 H), 5.43 (d, J = 10.5 Hz,1 H), 1.52 (s, 9H). Mass calculated for formula C10H14N2O2S 226.08; observed MH+ (LCMS) 227.1 (m/z). Part C: To a stirred solution of (2-Vinyl-thiazol-5-yl)-carbamic acid tert-butyl ester (0.76 g, 2.857 mmol) in 1 ,4-dioxane : water (30 : 9 mL), were added sodium periodate (2.5 g, 11.43 mmol) osmium tetroxide (2.5% solution in 2-propanol) (0.5 mL) and 2,6- lutidine (0.663 mL, 5.714 mmol) and reaction mixture was stirred for 4 hrs, LCMS showed the almost disappearance of the starting material. Reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate, organic layer was washed with water, brine, dried over sodium sulfate and concentrated under high vacuum to yield aldehyde 710 mg (92%). Crude product was used as such in the next reaction. 1H NMR (400 MHz, DMSO-d6 δ 11.45 (s, 1 H), 9.76 (s, 1 H), 7.58 (s, 1 H), 1.40 (s, 9H). Mass calculated for formula C9H12N2O3S 228.06; observed MH+ (LCMS) 229.1 (m/z). Part D: To a stirred solution of (2-Formyl-thiazol-5-yl)-carbamic acid tert-butyl ester (0.76 g, 2.857 mmol) in 1 ,2-dichloroethane(10 mL) were added Morpholine (250 mg, 1.1135 mmol) triacetoxysodium borohydride (472 mg, 2.227 mmol) and Cat amount acetic acid (three drops) and stirred for two hrs at room temp. To the reaction mixture was added sodium borohydride (126 mg, 3.3405 mmol) and stirred for one hrs. LCMS showed the disappearance of the starting material. Reaction mixture was diluted with water (100 mL) and extracted with dichloromethane, organic layer was washed with water, brine, dried over sodium sulfate and concentrated under high vacuum to yield (2-Morpholin-4-ylmethyl-thiazol-5-yl)-carbamic acid tert-butyl ester 298 mg (91 %). Crude product was used as such in the next reaction. Mass calculated for formula C14H25N3O3S 315.43; observed MH+ (LCMS) 300.3 (m/z).
Part E: To a stirred solution of (2-Mθrpholin-4-ylmethyl-thiazol-5-yl)-carbamic acid tert- butyl ester (80.0 mg, 0.268 mmol) in dichloromethane(5 mL) was added iodotirmethylsilane ( 44 μl_, 0.321 mmol) and stirred for 10 min. LCMS showed the disappearance of the starting material. Reaction mixture was diluted with water (10 mL), 1 N aqueous NaOH solution (5 mL) and extracted with 10% 2-propanol in DCM (3 x 25 mL) and organic layer dried over sodium sulfate and concentrated under high vacuum to yield 2-Morpholin-4-ylmethyl-thiazol-5-ylamine 30.0 mg (56%). Crude product was used as such in the next reaction. Mass calculated for formula C8H13N3OS 199.27; observed MH+ (LCMS) 200.1 (m/z).
Part F: To a stirred solution of 2-Morpholin-4-ylmethyl-thiazol-5-ylamine (30.0 mg, 0.151 mmol) in DMSO (2.5 mL) was added 8-Methanesulfonyl-6-methyl-3-(1 H- pyrazol-4-yl)-imidazo[1 ,2-a]pyrazine ( 25.0 mg, 0.09045 mmol) followed by NaH 60% in mineral oil (48 mg, 1.206 mmol) and stirred for 30 min. LCMS showed the disappearance of the starting material. Reaction mixture was quenched 1 :1 mixture of acetonitrile and saturated ammonium chloride (10 mL), and extracted with 10% 2- propanol in DCM (3 x 25 mL) and organic layer was concentrated under high vacuum to yield crude [6-Methyl-3-(1 H-pyrazol-4-yl)-imidazo[1 ,2-a]pyrazin-8-yl]-(2-morpholin- 4-ylmethyl-thiazol-5-yl)-amine which was subsequently purified by Agilent reverse phase HPLC using formic acid method to yield 10 mg (28%). HPLC-MS (10 min method) tR = 2.06 min (UV 254nm)- Mass calculated for formula C18H20N8OS 396.47; observed MH+ (LCMS) 397.5 (m/z).
The compounds shown in Table 6 were prepared using procedures described in Example 40. TABLE 6
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0002
EXAMPLE 41
Figure imgf000131_0001
To a solution of 5-nitrothiophene-3-carboxylic acid (5.00 g, 28.88 mmol) in dimethylformamide (40 mL) was added potassium carbonate (11.98 g, 86.71 mmol) and iodomethane (2.70 mL, 43.37 mmol). The reaction mixture was stirred at RT for 16 hr. After the starting material had been consumed, the reaction was diluted with 50% ethyl acetate/hexanes (350 mL) and extracted with H2O (350 mL). The organic layer was washed with brine (150 mL) and concentrated. Hexanes (50 mL) was added to the solid and concentrated again to yield 5.456 g (99%) of product. 1H NMR (400 MHz) CDCI3 δ 8.30 (s, 1 H), 8.25 (s, 1 H)1 3.93 (s, 3H). Mass calculated for formula C6H5NO4S 187.17; observed M4H+ (MS) 191.15 (m/z)
EXAMPLE 42
Figure imgf000132_0001
To a solution of the nitro-ester (1.006 g, 5.375 mmol) in TFA (15 mL), Fe powder (1.5135 g, 27.10 mmol) was slowly added to the round bottom flask. The reaction was heated to 60°C for 45 min at which time TLC (1 :1 , ethyl acetate to hexanes) showed consumption of starting material. The reaction was diluted with ethyl acetate and the Fe was filtered off. The filtrate was neutralized with aqueous Na2CO3 and allowed to stir for 1 hr. The aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give 0.701 g (83%) of a yellow solid. 1H NMR (400 MHz) CD3OD δ 7.29 (s, 1 H), 6.44 (s, 1 H), 3.79 (s, 3H). Mass calculated for formula C6H7NO2S 157.19; observed MH+ (LCMS) 158.1 (m/z).
EXAMPLE 43
Figure imgf000132_0002
A solution of the sulfone (1.27 g, 3.11 mmol) and 2-aminothiophene-4- carboxylate methyl ester (0.701 g, 4.46 mmol) in DMF (35 mL) were treated with NaH
(60% dispersion in oil, 0.402 g, 10.05 mmol) at room temperature until mass spectrometry and thin layer chromatography (50% ethyl acetate/hexanes) indicated that the reaction was complete. Saturated ammonium chloride (15 mL) and water (50 mL) were added to the reaction. The reaction was stirred for 10 minutes. The precipitated solid was collected via filtration to yield the desired product. 1H NMR (400 MHz) CDCI3 δ 8.78 (s, 1 H), 7.88 (s, 1 H), 7.82 (s, 3H), 7.68 (s, 1 H), 7.58 (s, 1 H), 7.44 (s, 1 H), 7.16 (s, 3H), 5.54 (s, 2H), 3.87 (s, 3H), 3.67 (t, 2H), 2.46 (s, 3H), 0.97 (t, 2H), 0.01 (s, 9H). Mass calculated for formula 0-22H2SN6O3SSi 484.65; observed MH+ (MS) 485.1 (m/z).
EXAMPLE 44
Figure imgf000133_0001
A solution of the ester prepared in Example 43 (0.565 g, 1.17 mmol) in THF (10 mL) and MeOH (3 mL) was treated with solid NaOH (9 pellets) followed by H2O (5 mL). The reaction was stirred vigorously at room temperature for 16 hr. The THF and MeOH were removed in vacuo and the residue was extracted with EtOAc (3 x 20 mL). The aqueous phase was brought to a pH of 3-4 with aqueous HCI. The acidified aqueous phase was extracted with EtOAc (5 x 20 mL) and concentrated in vacuo to give 0.393 g (71 %) of the desired carboxylic acid.
EXAMPLE 45
Figure imgf000133_0002
A solution of the carboxylic acid (prepared in Example 4) (0.054 g, 0.115 mmol) in DMF (3 mL) was treated with amine (0.03 mL, 0.262 mmol), NMM (0.07 mL, 0.637 mmol) and then HATU (0.141 g, 0.372 mmol). The reaction was stirred at room temperature for 16 hr. Water (15 ml.) was added and the reaction was stirred for 10 minutes. The precipitated solid was collected via filtration to yield 0.038 g (60%) of the desired amide. 1H NMR (400 MHz) CDCI3 δ 9.13 (s, 1 H), 7.86 (s, 1 H), 7.80 (s, 3H), 7.54 (s, 1 H), 7.41 (s, 1 H), 7.31 (s, 1 H), 7.08 (s, 3H), 5.83 (d, 1 H), 5.53 (s, 2H), 3.93 (m, 1 H), 3.67 (t, 2H), 2.44 (s, 3H), 1.70 (m, 10H), 0.96 (t, 2H), 0.00 (s, 9H). Mass calculated for formula C27H37N7O2SSi 551.78; observed MH+ (MS) 552.1 (m/z).
By essentially the same procedure set forth in Example 45, only substituting the amines shown in Column 2 of Table 7, the compounds in Column 3 were prepared:
TABLE 7
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
EXAMPLE 46
Figure imgf000139_0001
To a solution of the amide (0.038 g, 0.069 mmol) in dichloromethane (4 mL) was added lithium aluminum hydride (0.029 g, 0.775 mmol) and ethyl ether (0.8 mL). The reaction mixture was stirred at RT for 10 min then refluxed at 40° C for 5 hr. The reaction was monitored by mass spectrometry. Upon consumption of the starting amide, the reaction was cooled to RT and quenched with H2O (2 mL). The reaction was diluted with DCM and filtered. The filtrate was washed with H2O (≤ 8 mL). The organic layer was concentrated to give 0.019 g (52 %) of the amine. The above amine in THF was further treated with 4 N HCI/dioxane at 60 °C for 1 hr. Upon cooling to RT, Et2O was added and the mixture was stirred for 10 min. The precipitated solid was collected giving 13.9 mg (96 % yield) of the desired amine.
By essentially the same procedure set forth in Example 46, the following compounds shown in Column 2 of Table 8 were prepared:
TABLE 8
Figure imgf000139_0002
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0003
EXAMPLE 47
Figure imgf000143_0001
Ethyl 4-chloro-3-oxobutanoate (14.15 g, 86 mmol), cyanoacetic acid (8.00 g, 86 mmol), NH4OAc (1.32 g, 17.2 mmol), AcOH (2.46 mL, 43 mmol), and benzene (40 mL) was stirred overnight at reflux with a Dean-Stark trap. The mixture was cooled to room temperature, diluted with EtOAc, washed with sat. NaHCO3, brine, dried with Na2SO4, and concentrated to afford crude product 1 (9.29g, 58%). HPLC-MS tR =1.67 Min (UV 254nm)- Mass calculated for M+ 187.0, observed LC/MS m/z 188.1(M+H).
EXAMPLE 48
Figure imgf000143_0002
Morpholine (580 uL, 6.65 mmol) was added dropwise to a mixture of ethyl 3- (chloromethyl)-4-cyanobut-3-enoate (622 mg, 3.33 mmol) and S-flakes (116 mg, 3.63mmol) in EtOH (5 mL). The reaction stirred at room temperature overnight. The mixture was concentrated. The mixture was diluted with EtOAc, washed with brine, dried with Na2SO4, and concentrated to afford crude product. Purification by Prep-LC afforded the title compound (182 mg, 20%). HPLC-MS tR = 0.80 Min (UV 254nm)- Mass calculated for M+ 270.1 , observed LC/MS m/z 271.1(M+H).
EXAMPLE 49
Figure imgf000144_0001
A solution of ethyl 5-amino-3-(morpholinomethyl)thiophene-2-carboxylate (61.0 mg, 0.225 mmol) and sulfone (71.0 mg, 0.173 mmol) in DMF (2 mL) was treated with NaH (60% dispersion in oil, 20.9 mg, 0.521 mmol) at room temperature. The mixture was stirred at room temperature until LCMS indicate the reaction was complete. The reaction mixture was diluted with EtOAc, washed with sat NH4CI, dried with Na2SO4, and concentrated to afford title compound. HPLC-MS tR = 1.79 Min (UV 254nm)- Mass calculated for M+ 597.2, observed LC/MS m/z 598.3(M+H).
EXAMPLE 50
Figure imgf000144_0002
A solution of /-PrMgCI in THF (0.78 uL, 1.56 mmol) was added dropwise to a solution of crude compound from example 49 (104.2 mg, 0.173 mmol) and diethylamine (91 uL, 0.782 mmol) in THF (3 mL) at -20°C The mixture was slowly warmed up to room temperature and stirred at this temperature until LCMS indicate the reaction was complete. The reaction mixture was cooled to O°C and quenched with Sat. NH4CI. The reaction mixture was extracted with EtOAc and the organic layer was dried with Na2SO4 and concentrated to afford crude product 4. HPLC-MS \R = 1.81 Min (UV 254nm). Mass calculated for M+ 624.3, observed LC/MS m/z 625.3(M+H).
EXAMPLE 51
Figure imgf000145_0001
4N HCI in dioxane (1 mL) was added to crude compound 4 (17mg, 0.027 mmol) at 0°C The mixture was warmed to room temperature and stirred at this temperature until LCMS indicate the reaction was complete. Concentration and purification by
Prep-LC and conversion to a hydrochloric salt afforded the title compound. HPLC-MS tR = 1.14 Min (UV 254nm). Mass calculated for M+ 494.2, observed LC/MS m/z
495.2(M+H).
By essentially the same procedure, compounds given in Column 2 of Table 9 can be prepared.
TABLE 9
Figure imgf000146_0002
EXAMPLE 52
Figure imgf000146_0001
A solution of thiophene-2,5-dicarboxylic acid (2.73 g, 15.84 mmol), diphenylphosphoryl azide (3.41 mL g, 15.84 mmol) and triethylamine (4.4 mL, 31.68 mmol) in tert-butanol (80 mL) was heated at refluxing 5h. The reaction mixture was cooled to room temperature and then concentrated to afford the crude title compound. HPLC-MS tR =1.52 Min (UV 254nm)- Mass calculated for M+ 243.0, observed LC/MS m/z 244.1 (M+H). EXAMPLE 53
Figure imgf000147_0001
Et3N (1261.6 uL, 9.05 mmol) was added at O°C to a mixture of 5-tert- Butoxycarbonylamino- thiophene-2-carboxylic acid (550 mg, 2.26mmol), EDCI (1086 mg, 5.65 mmol) , and piperidine (447 uL, 4.52 mmol) in DMF (6ml). The reaction mixture was warmed up to room temperature and stirred at this temperature overnight.
The mixture was diluted with EtOAc, washed with brine (2X), dried over Na2SO4 and concentrated to afford crude residue. Purification by Biotage afforded compound 2 (368 mg, 53%). HPLC-MS tR =1.89 Min (UV 254nm)- Mass calculated for M+ 310.1 , observed LC/MS m/z 311.2(M+H). HPLC-MS tR =2.4 Min (UV 254nm)-
EXAMPLE 54
Figure imgf000147_0002
Compound from Example 53 (90 mg, 0.29 mmol) was stirred in 20% TFA / CH2CI2 solution (5 mL) at room temperature for 1.5 hrs. The reaction mixture was concentrated to afford compound 3. The crude product was used without further purification. HPLC-MS tR =1.16 Min (UV 254nm)- Mass calculated for M+210.0, observed LC/MS m/z 211.1(M+H).
EXAMPLE 55
Figure imgf000147_0003
A solution of crude material from Example 54 and sulfone (98.0 mg, 0.241 mmol) in DMF (2 mL) was treated with NaH (60% dispersion in oil, 29.0 mg, 0.725 mmol) at room temperature. The mixture was stirred until LCMS indicate the reaction was complete. The reaction mixture was diluted with EtOAc, washed with sat NH4CI, dried with Na2SO4, and concentrated to afford crude product 4. Purification by Biotage afforded the title compound (82 mg, 63%). HPLC-MS tR = 2.30 Min (UV 254nm). Mass calculated for M+ 537.2, observed LC/MS m/z 538.2(M+H).
EXAMPLE 56
Figure imgf000148_0001
To a solution of the amide (47.6 mg, 0.089 mmol) in dichloromethane (5 mL) was added lithium aluminum hydride (39.9 mg, 1.0 mmol) and ethyl ether (1 mL). The reaction mixture was stirred at room temperature for 10 min then refluxed at 40° C until LCMS indicate the reaction was complete. The reaction was cooled to room temperature and quenched with H2O (0.5 mL). The reaction was diluted with dichloromethane, dried over Na2SO4 and concentrated to afford crude title compound. HPLC-MS tR = 1.52 Min (UV 254nm). Mass calculated for M+ 523.2, observed LC/MS m/z 524.2 (M+H).
EXAMPLE 57
Figure imgf000148_0002
4N HCI in dioxane (2mL) was added to crude compound from example 56 at 0°C The mixture was warmed to room temperature and stirred at this temperature until LCMS indicate the reaction was complete. Concentration afforded crude title compound. Purification by Prep-LC and conversion to a hydrochloric salt afforded the title compound. HPLC-MS tR = 0.91 Min (UV 254nm). Mass calculated for M+ 393.1 , observed LC/MS m/z 394.1 (M+H).
By essentially the same procedure, the compounds in Table 10 were prepared.
TABLE 10
Figure imgf000149_0001
Figure imgf000150_0001
EXAMPLE 58
Figure imgf000151_0001
To a solution of 8-methanesulfonyl-6-methyl-3-thiazol-2-yl-imidazo [1 , 2-a] pyrazine (0.070 g; 0.24 mmol) and 5-amino-3-carbomethoxy-isothiazole (0.039g; 0.25 mmol) in dimethyl formamide (DMF; 0.8 mL) was added sodium hydride (NaH; 60% in oil; 0.024 g). The reaction mixture was stirred at room temperature for 0.5 hr and then quenched with saturated aqueous solution of ammonium chloride (NH4CI). Diluted with more water and filtered. The filter cake was washed with water and hexanes. The filter cake was dried in vacuo to obtain the title compound as yellow solid (0.078 g;
87%). 1H NMR (400 MHz, DMSO-d6): 8.85 (s, 1 H), 8.42 (s, 1 H), 8.1 (s, 1 H), 7.9 (s,
1 H), 7.65 (s, 1 H), 3.85 (s, 3H) 2.5 (s, 3H). HPLC-MS tR = 4.35 (UV254n.*). Mass CaIc. for C15H12N6O2S2 372.04; obsd MH+ (LCMS) 373.2 (m/z).
EXAMPLE 59
Figure imgf000151_0002
A solution of lithium triethylborohydride (Super Hydride; 1 M in THF; 0.32 mL) was added dropwise to a solution of the methyl ester (0.03 g; 0.08 mmol) in dry THF (0.8 mL). After stirring at room temperature for 1.5 hr, the reaction mixture was quenched with saturated aqueous NH4CI solution (8 mL) and diluted with water. Small amount of the precipitated yellow solid was filtered and washed with water and ether. The solid was dried in vacuo to obtain -10 mg (36%) of the alcohol. 1H NMR (400 MHz, DMSO-de): 8.8 (s, 1 H), 8.4 (s, 1 H), 8.1 (s, 1 H), 7.9 (s, 1 H), 7.2 (s, 1 H), 5.4 (t, 1 H). 4.5 (d, 2H), 2.5 (s, 3H). HPLC-MS tR = 2.98 (UV254nm). Mass CaIc. for C14Hi2N6OS2 344.05; obsd MH+ (LCMS) 345.2 (m/z).
EXAMPLE 60
Figure imgf000152_0001
A solution of ester (0.113 g; 0.3 mmol) in DMF (1.5 mL) was treated with NaH (60% in oil; 0.03 g; 0.76 mmol) followed by 2-(Trimethylsilyl) ethoxymethyl chloride (SEM-CI; 0.1 mL; 0.61 mmol). The reaction mixture was stirred at room temperature for 3 hr and quenched with saturated aqueous NH4CI and water. The precipitated yellow solid was collected by filtration, washed with water and dried. The title compound was obtained as yellow solid (0.142 g; 92%). 1H NMR (400 MHz, CDCI3): 9.1 (s, 1 H), 8.1 (s, 1 H), 7.98 (s, 1 H), 7.8 (s, 1 H), 7.4 (s, 1 H), 6.65 (s, 2H), 4.0 (s, 3H), 3.78 (t, 2H), 2.65 (s, 3H), 1.0 (t, 2H), 0.0 (s, 9H). HPLC-MS tR = 5.98 (UV254nm). Mass CaIc. for C21H26N6O3S2Si 502.13; obsd MH+ (LCMS) 503.3 (m/z).
EXAMPLE 61
Figure imgf000152_0002
A solution of lithium triethylborohydride (Super Hydride; 1 M in THF; 1 mL) was added dropwise to a solution of the methyl ester 2 in dry THF. After stirring at room temperature for 1 hr, the reaction mixture was quenched with saturated aqueous NH4CI solution (8 mL) and saturated aqueous solution of Rochelle salt. The organic product was extracted with dichloromethane (CH2CI2), washed with water and brine. Concentration in vacuo gave -120 mg (100%) of the alcohol. HPLC-MS tR = 4.22 (UV254nm). Mass CaIc. for C20H26N6O2S2Si 474.13; obsd MH+ (LCMS) 475.3 (m/z). EXAMPLE 62
Figure imgf000153_0001
Dess-Martin periodinane (0.147 g; 0.35 mmol) was added to a solution of alcohol (0.11 g; 0.23 mmol) in dry THF and stirred at room temperature for 40 minutes. The reaction mixture was diluted with 30 mL of CH2Cb, washed with saturated sodium bicarbonate (NaHCOa) solution, water and dried. Concentration furnished a yellow solid which was re-dissolved in CH2CI2 and filtered. The filtrate was concentrated to obtain 120 mg of crude title compound as a yellow solid which was used as is in the next step. 1H NMR (400 MHz, CDCI3): 10 (s, 1 H), 9.1 (s, 1 H), 8.1 (s,
1 H), 7.98 (s, 1 H), 7.78 (s, 1 H), 7.4 (s, 1 H), 6.6 (s, 2H), 3.78 (t, 2H), 2.65 (s, 3H), 1.0 (t,
2H), 0.0 (s, 9H). HPLC-MS tR = 6.14 (UV254Hm). Mass CaIc. for C20H24N6O2S2Si
472.12; obsd MH+ (LCMS) 473.3 (m/z).
EXAMPLE 63
Figure imgf000153_0002
A solution of aldehyde (0.05 g; 0.1 mmol) and piperidine (0.05 mL; 0.5 mmol) in CH2CI2 (1 mL) was treated with glacial acetic acid (AcOH; 1 drop) and stirred at room temperature (RT) for 3 hr. Solid sodium borohydride (NaBH4; 0.016 g; 0.42 mmol) was added and the reaction mixture was cooled in an ice/brine bath (-5°C) and methanol (0.2 mL) was added dropwise. After stirring at low temperature for 30 minutes, the reaction was quenched with saturated NH4CI and extracted into CH2CI2. The organic extract was washed with saturated NH4CI, water and brine. Removal of solvent gave the crude product which was purified by preparative thin layer chromatography (Prep TLC) using CH2CI2 with 4% CH3OH and 1% ammonium hydroxide. The title compound was isolated as yellow film (25 mg; 45%). 1H NMR (400 MHz, CDCI3): 9.1 (s, 1 H), 8.1 (s, 1H), 7.98 (s, 1 H), 7.4 (s, 1 H),7.3 (s, 1 H), 6.6 (s, 2H), 3.8 (t, 2H), 3.6 (s, 2H), 2.65 (s, 3H), 2.5 (br-s, 4H),1.7 (br-s, 4H), 1.45 (br-s, 2H), 0.98 (t, 2H), 0.0 (s, 9H). HPLC-MS tR = 3.82 (UV254nm). Mass CaIc. for C25H35N7OS2Si 541.21 ; obsd MH+ (LCMS) 542.3 (m/z).
EXAMPLE 64
Figure imgf000154_0001
A solution of compound from Example 63 (0.013 g; 0.02 mmol) in 0.5 mL of
THF was treated with HCI in dioxane (4M; 0.5 mL) and placed in an oil bath at 70°C After heating for 30 min, a precipitate formed which dissolved upon adding 0.5 mL of methanol. The reaction mixture was heated at a bath temperature of 7O°C for an additional 1 hr. The contents of the reaction were cooled to RT and all the volatiles were removed on a rotary evaporator. The residue was suspended in THF and triturated with ether. The precipitate was collected by filtration, washed with ~ 10 mL of ether and dried in air (0.5 hr) and in vacuo (16 hr) to furnish 10 mg (93%) of the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): 9.0 (s, 1 H), 8.3 (s, 1 H), 8.05 (s, 1 H), 7.7 (s, 1 H), 7.25 (s, 1 H), 4.4 (s, 2H), 3.6 (d, 2H), 3.1 (t, 2H), 2.6 (s, 3H), 2.0 (d, 2H)1 1.85 (t, 4H), 1.6 (t, 1 H). HPLC-MS tR = 2.96 (UV254nm). Mass CaIc. for C19H21N7S2 411.13; obsd MH+ (LCMS) 412.2 (m/z).
Compounds in the Table 11 were prepared as per above examples: TABLE 11
Figure imgf000155_0001
Figure imgf000156_0002
EXAMPLE 65
Figure imgf000156_0001
Part A: Lithium hexamethyldisilazide (1 M in THF; 0.18 mL) was added to an amber solution of 4-morpholin-4-ylmethyl phenylamine (0.013g; 0.068 mmol) and 8- methanesulfonyl-6-methyl-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1/-/-pyrazol-4-yl]- imidazo[1 , 2-a]pyrazine (0.025g; 0.061 mmol) in 2 mL of THF at RT resulting in a burgundy solution. After stirring at RT for 20 minutes, the reaction mixture was quenched with saturated aqueous NH4CI solution. The contents were diluted with ethyl acetate and washed with water and brine. The crude material from the organic extract was purified by prep TLC (5% methanol-CH2CI2) to obtain the title compound as pale yellow oil (0.025 g; 80%). 1H NMR (400 MHz, CDCI3): 8 (s, 1 H), 7.9 (d, 2H), 7.85 (s, 1 H), 7.8 (s, 1 H), 7.5 (s, 1 H), 7.4 (s, 1 H), 7.35 (d, 2H), 5.55 (s, 2H), 3.75 (br-s, 4H), 3.7 (t, 2H), 3.5 (br-s, 2H), 2.5 (br-s, 2H), 2.4 (s, 3H)1 1.6 (br-s, 2H), 0.95 (t, 2H), 0.0 (s, 9H). HPLC-MS tR = 3.05 (UV254nm). Mass CaIc. for C27H37N7O2Si 519.27; obsd MH+ (LCMS) 520.3 (m/z).
Part B: The compound from Part A (0.025g; 0.048 mmol) was suspended in dry THF and treated with HCI in dioxane (4M; 1 mL) and heated in an oil bath set to 7O°C for 15 minutes when a white precipitate was formed. Methanol was added to dissolve some of the solid and the reaction mixture was continued to be heated for 45 minutes more. After cooling to RT, the volatiles were removed on the rotary evaporator. The residue was suspended in THF and the precipitated solid was collected by filtration, washed with ether and dried in vacuo overnight. The title compound was isolated as a beige solid (14 mg; 78%). All the analogues in Table 12 were similarly prepared. TABLE 12
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0002
EXAMPLE 66
Figure imgf000159_0001
Part A: A solution of 4-Amino-2-methyl-benzoic acid methyl ester (0.33 g; 2 mmol; prepared from commercially available 4-nitro-2-methyl-benzoic acid) and 8- methanesulfonyl-6-bromo-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1/-/-pyrazol-4-yl]- imidazo[1 , 2-a]pyrazine (0.472 g; 1.0 mmol) was treated with LiHMDS (1 M in THF; 2 mL) at RT. The resulting burgundy solution was stirred at RT for 20 minutes and then quenched with saturated aqueous NH4CI solution. Standard work up as described for Example 65 and flash silicagel chromatography (25% EtOAc in CH2CI2) provided the title compound as pale yellow foam (0.48 g; 86%).
NMR (400 MHz, CDCI3): 8.18 (s, 1 H), 8 (d, 1 H), 7.9 (s, 1 H), 7.85 (d, 1 H), 7.78 (s, 1 H), 7.7 (s, 1 H), 7.62 (s, 1 H), 7.58 (s, 1 H), 5.5 (s, 2H), 3.9 (s, 3H), 3.65 (t, 2H), 2.6 (s, 3H), 0.98 (t, 2H), 0.0 (s, 9H). Mass CaIc. for C24H29BrN6O3Si 556.13; Obsd MH+ (CI-MS) 557 / 559 (m/z).
Part B: A solution of compound from Part A (0.48 g; 0.86 mmol) in 2 mL of dry THF was treated with a solution of dimethyl zinc (2M; 4 mL) dropwise. After the effervescence ceased, solid Pd(PPh3)4 was added and the reaction was flushed with nitrogen, fitted with a reflux condenser and heated in an oil bath at 65-70°C After 0.5 hr, the reaction mixture had turned from yellow orange to deep red and after 4 more hours, it had become an opaque black. TLC (25% EtOAc- CH2CI2) indicated the formation of a slightly more polar spot. The reaction was cooled to RT, quenched with saturated aqueous NH4CI solution and extracted with EtOAc. Flash silicagel chromatography of the crude material gave the 6-methyl title compound as yellow solid (0.38 g; 90%). NMR (400 MHz, CDCI3): 8.1 (s, 1 H), 8 (d, 1 H), 7.9 (d, 1 H), 7.85 (S, 1 H), 7.8 (s, 1 H), 7.7 (s, 1 H), 7.58 (s, 1 H), 7.4 (s, 1 H), 5.5 (s, 2H), 3.9 (s, 3H), 3.65 (t, 2H), 2.65 (s, 3H), 2.4 (s, 3H), 0.98 (t, 2H), 0.0 (s, 9H). Mass CaIc. for C25H32N6O3Si 492.23; Obsd MH+ (CI-MS) 493.11 (m/z).
Figure imgf000160_0001
Part A: Ester was first reduced to the alcohol using LiBEt3H in THF at RT and subsequently oxidized using Dess-Marin periodinane to the aldehyde as described previously. The reductive amination of aldehyde with various secondary amines was carried out provided SEM-protected title compound. Removal of the SEM protecting group was carried out under conditions described previously. In a similar manner, other tertiary amines listed in Table 13 were also prepared by the similar reaction scheme with the corresponding secondary amines followed by removal of the SEM protecting group.
TABLE 13
Figure imgf000161_0001
EXAMPLE 68
Figure imgf000162_0001
The substrate (1 g, 5.07 mmol) was dissolved in THF:H2O (12 mL, 1 :1 , v/v) and treated with K2CO3 (1.4 g, 10.15 mmol) at room temperature. Then benzyl chloroformate (0.79 ml, 5.58 mmol) in THF (2 mL) was slowly added. The mixture was stirred for 16 h. It was diluted with ethyl acetate (25 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (2 * 25 mL). The combined organic layer was washed with brine (1 * 30 mL), dried (Na2SO4), filtered and evaporated under reduced pressure to give the crude product which was purified by column chromatography (SiO2) eluting ethyl acetate-hexane.
EXAMPLE 69
Figure imgf000162_0002
The substrate acetal (1.2 g, 3.64 g) was dissolved in acetone (20 mL), and treated with 1 N aqueous HCI (2 mL) at room temperature, and the mixture was stirred for 7 h. Then acetone was evaporated off, and the residue was diluted with saturated aqueous NaHCO3 (30 mL). The aqueous layer was extracted with ethyl acetate (2 * 30 mL). The combined organic layer was washed with brine (1 * 30 mL), dried (Na2SO4), filtered and evaporated under reduced pressure to give the crude product as solid which was used in the next step without any further purification. EXAMPLE 70
Figure imgf000163_0001
The substrate (1 eq.), amine (4 eq.), catalytic AcOH, NaB(OAc)3H (2 eq.) in 1 ,2- dichloroethane was stirred at room temperature for 2 h. Then sodium borohydride (3 eq.) was added and the mixture was stirred for 30 min at which point LC-MS analysis indicate complete consumption of starting material to product. Then the reaction was quenched with 2N aqueous NaOH, and the mixture was stirred vigorously until two clear layer separated. The organic layer was washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure to give the product.
The crude product was hydrogenated in ethyl acetate using 10% Pd/C at 1 atmosphere hydrogen pressure. The catalyst was filtered off, and solvent was evaporated under reduce pressure to give the crude product.
EXAMPLE 71
Figure imgf000163_0002
Part A: The substrate (1 eq.), amine (4 eq.), catalytic AcOH, NaB(OAc)3H in 1 ,2- dichloroethane was stirred at room temperature for 2 h. Then sodium borohydride (3 eq.) was added and the mixture was stirred for 30 min at which point LC-MS analysis indicate complete consumption of starting material to product. Then the reaction was quenched with 2N aqueous NaOH, and the mixture was stirred vigorously until two clear layer separated. The organic layer was washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure to give the product. Part B: The crude product was hydrogenated in ethyl acetate using 10% Pd/C at 1 atmosphere hydrogen pressure. The catalyst was filtered off, and solvent was evaporated under reduce pressure to give the crude product.
EXAMPLE 72
Figure imgf000164_0001
Part A: The substrate (1 eq.), amine (4 eq.), catalytic AcOH, NaB(OAc)3H in 1 ,2- dichloroethane was stirred at room temperature for 2 h. Then sodium borohydride (3 eq.) was added and the mixture was stirred for 30 min at which point LC-MS analysis indicate complete consumption of starting material to product. Then the reaction was quenched with 2N aqueous NaOH, and the mixture was stirred vigorously until two clear layer separated. The organic layer was washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure to give the product. Part B: The crude product was hydrogenated in ethyl acetate using 10% Pd/C at 1 atmosphere hydrogen pressure. The catalyst was filtered off, and solvent was evaporated under reduce pressure to give the crude product.
EXAMPLE 73
Figure imgf000164_0002
Part A: The substrate (1 eq.) and amine (1.5-2 eq.) was dissolved in DMSO under argon, and treated with NaH (5 eq., 60% dispersion in oil). After 30 min, LC-MS analysis indicated complete consumption of starting material. The reaction was quenched by addition of saturated aqueous NH4CI-acetonitrile (1 :1 , v/v). The two layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to give the crude product. Part B: The substrate was dissolved in 4N HCI in dioxane, and stirred at room temperature for 30 min. The solvent was then evaporated, and the residue was purified by Prep-LC. Conversion to hydrochloride salt afforded the product as solid.
TABLE 14
Figure imgf000165_0001
Figure imgf000166_0002
EXAMPLE 74
Figure imgf000166_0001
Part A: By essentially the same procedure as described for Example 1 and 13. Part B: To a solution of compound from Example 74, Part A (0.16 g, 0.57 mmol) in THF (20 mL) and water (0.025 mL) was added Dess-Martin periodinane (3 equivalents). The resulting solution was stirred at rt for 1.5h at which time LC-MS analysis indicated the reaction was complete. The reaction mixture was diluted with dichloromethane (75 mL), washed with water, dried (sodium sulfate) and concentrated. Purification by column chromatography (Siθ2 10% methanol / DCM) afforded the title compound as a yellow solid 0.08 g (49%). HPLC-MS tR = 1.59 Min (UV 254nm). Mass calculated for formula C13H11 N5OS 285.07, observed LC/MS m/z 286.1 (M+H).
Part C: To a solution of compound from Part B (30 mg, 0.105 mmol, 1 equivalent), 3- methylpiperidine (10 equivalents) in dichloromethane:methanol (5:1 ) (3 ml) was added acetic acid (1 drop). The resulting solution was stirred at rt for 30 minutes, and then sodium borohydride (8 equivalents) added to the reaction. The reaction mixture was stirred at rt for 1 hour at which time LC-MS analysis indicated the reaction was complete. The reaction was quenched with sat. aq. sodium bicarbonate and then extracted with dichloromethane (x2). The combined organic layer was dried (sodium sulfate) and concentrated. Purification by Prep-LC and conversion to a hydrochloric salt afforded the title compound. HPLC-MS tR = 3.73 Min (UV 254nm)- Mass calculated for formula C19H24N6S 368.18, observed LC/MS m/z 369.2 (M+H). EXAMPLE 75
Figure imgf000167_0001
Part A: To a solution of compound 1 (30 mg, 0.105 mmol, 1 equivalent), piperidine (10 equivalents) in dichloromethane:methanol (5:1 ) (3 ml) was added acetic acid (1 drop). The resulting solution was stirred at rt for 30 minutes, and then sodium borohydride (8 equivalents) added to the reaction. The reaction mixture was stirred at rt for 1 h at which time LC-MS analysis indicated the reaction was complete. The reaction was quenched with sat. aq. sodium bicarbonate and then extracted with dichloromethane (x2). The combined organic layer was dried (sodium sulfate) and concentrated. Purification by Prep-LC and conversion to a hydrochloric salt afforded compound 2. HPLC-MS tR = 3.47 Min (UV 254nm)- Mass calculated for formula C18H22N6S 354.16, observed LC/MS m/z 355.1 (M+H).
EXAMPLE 76
(95%)
Figure imgf000167_0002
Step A: Sodium hydride (60% dispersion in mineral oil, 6.68 g, 3.40 equiv) was slowly added in one portion to a stirring mixture of compound sulfone (20.0 g, 1.00 equiv) and aminoisothiazole (11.5 g, 1.20 equiv, as HCI salt) in DMF (490 mL) at room temperature (with aid of a room temperature water bath). Reaction was allowed to stir for 1 hour at which time HPLC analysis indicated the reaction was complete. The reaction was carefully quenched with saturated aqueous sodium bicarbonate (200 mL) and then diluted with water (1 L). This mixture was stirred for 20 minutes at room temperature, and then the resulting precipitate was collected by filtration, washed with water (200 mL), and dried under high vacuum for 16 hours. The resulting waxy solid was dissolved in 1.8 L of 1 :1 chloroform : methanol, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (22.3 g, 93%) as a dark yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 12.3 (bs, 1 H), 8.60 (s, 1 H), 8.10 (s, 1 H), 7.88 (s, 2H), 7.59 (s, 1 H), 5.51 (s, 2H), 3.85 (s, 3H), 3.63 (d, J = 8 Hz, 2H), 2.48 (s, 3H), 0.88 (d, J = 8 Hz, 2H), -0.026 (s, 9H). Mass calculated for formula C21 H27N7O3SSi 485.63; observed MH+ (MS) 486.6 (m/z).
Step B: A mixture of compound from Step A (4.27g, 3.73 mmol) was dissolved in 180 mL of THF. The resulting solution was cooled to 0 °C and LiAIH4 powder (2.6 g, 68.5 mmol) was carefully added. The cooling bath was removed and the reaction was stirred at RT under a N2 atmosphere for 1.5 hr. The reaction was cooled to 0 °C and carefully quenched by the sequential addition of 2.6 mL of H2O; 2.6 mL of 15 % NaOH (aq); 7.8 mL H2O. After stirring for 10 min, the reaction was filtered through a very thin pad of Celite (rinsing with THF, EtOAc and DCM). Concentration of the filtrate yielded a light yellow solid. Pure alcohol (2.66 g, 66 % yield) was obtained via triturating with MeOH and used directly in Step C. Step B (Alternative procedure; e.g. Example 76-39): A solution of 4,4- difluoropiperidine hydrochloride (25.1 mg, 0.16 mmol) in THF (2.0 mL) was added NaH (60% dispersion in mineral oil, 12 mg, 0.30 mmol). The mixture was stirred under a N2 atmosphere at room temperature for 10 min, then mesylate (31.4 mg, 0.06 mmol) and NaI (4 mg, 0.03 mmol) were added to the reaction flask. The reaction was heated at 80 °C under a N2 atmosphere for 8 hr. The reaction was cooled to room temperature and 15 mL of saturated NH4CI (aq) solution was added. The reaction was diluted with dichloromethane (20 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (2 x 20 mL). The organic phase was washed with 15 mL of saturated NaHCO3 (aq), then brine (15 mL). The organic phase was dried over NaSO4 and concentrated in vacuo. Purification via preparative TLC (10% MeOH/CH2CI2) gave 19.7 mg (60% yield) of the title compound. Step C: A mixture of compound from Step B (2.40 g, 4.49 mmol), amine (1.57 g, 13.46 mmol), and NaI (63.0 mg, 0.449 mmol) in 45 mL of THF was heated at 80 °C for 12 h. It was diluted with 200 mL of CH2CI2, and washed with 100 mL of saturated aqueous NaHCO3 solution, then with brine (100 mL). The solvent was removed under vacuum. The residue was purified by flash chromatography eluting with 5% to 10% MeOH/CH2CI2 to give 1.68 g of the title compound. 1H NMR (400 MHz, CDCI3) δ 9.49 (brs, 1 H), 7.89 (s, 1 H), 7.82 (s, 1 H), 7.60 (s, 1 H), 7.49 (s, 1 H), 6.86 (s, 1 H), 5.54 (s, 2H), 3.79 (brs, 3H), 3.67 (t, J = 8.3 Hz, 2H), 3.36 (s, 2H), 2.65-2.80 (m, 2H), 2.50 (s, 3H), 1.11 (s, 6H), 1.02(t, J = 7.1 Hz, 2H), 0.96 (t, J = 8.2 Hz, 2H), 0.01 (s, 9H). To a solution of Sem-protected compound (2.0 g, 3.6 mmol) in 36 mL of MeOH/CH2CI2 (1 :1 ) stirred at 80 °C, was added 36 mL of 4 N HCI in dioxane. The reaction was stirred at 80 °C for 30 min. After it was cooled to the room temperature, 120 mL of ether was added. The solid was collected by filtration, washed with ether and dried under vacuum to give 2.0 g of the title compound as its HCI salt form. Mass calculated for formula C20H26N8OS 426.2; observed MH+ (LCMS) 427.2 (m/z).
Using essentially the same procedures as described for Example 76, the following compounds were prepared.
TABLE 15
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0002
Figure imgf000200_0001
Example 76-1 : 1H NMR (400 MHz, CD3OD) δ 8.24 (s, 1 H), 8.23 (s, 2H), 8.07 (s, 1 H), 7.35 (s, 1 H), 4.57 (d, J = 12.8 Hz, 2H), 3.81 (t, J = 4.8, 2H), 3.57 (q, J = 14.0, 6.8 Hz, 2H)1 3.52 (m, 2H), 3.41 (m, 2H), 2.60 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H), 1.21 (t, J = 6.8 Hz, 3H). HPLC-MS tR = 2.28 min (UV 254nm). Mass calculated for formula C20H26N8OS 426.2; observed MH+ (LCMS) 427.2 (m/z).
Example 76-2: 1H NMR (400 MHz, CD3OD) δ 8.31 (s, 1 H)1 8.29 (s, 2H), 7.32 (s, 1 H), 4.88 (d, 1 H), 4.46 (d, J = 16.1 Hz, 1 H), 3.82 (d, J = 12.3 Hz1 1 H), 3.71 (d, J = 12.3 Hz, 1 H), 3.64 (m, 1 H), 2.65 (s, 3H), 1.42 (s, 3H), 1.40 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H). HPLC-MS tR = 2.26 min (UV 254nm).
Example 76-3: 1H NMR (400 MHz, CD3OD) δ 8.16 (s, 2H), 8.13 (s, 1 H), 7.99 (s, 1 H),
7.25 (s, 1 H), 4.72 (d, J = 15.6 Hz, 1 H), 4.53 (t, J = 15.6, 1 H), 3.66 (s, 2H), 3.61 (m, 1 H), 3.40 (m, 1 H), 2.57 (s, 3H), 1.33-0.95 (8H), 1.17 (t, J = 6.8 Hz, 3H). HPLC-MS tR =
2.26 min (UV 254nm)- Mass calculated for formula C20H26N8OS 452.2; observed MH+ (LCMS) 453.2 (m/z).
Example 76-4: 1H NMR (400 MHz, CD3OD) δ 8.16 (s, 2H), 8.15 (s, 1 H), 8.00 (s, 1 H), 7.21 (s, 1 H), 4.95 (d, J = 16.0 Hz, 1 H), 4.35 (d, J = 16.8 Hz, 1 H), 4.07 (d, J = 12.4 Hz 1 H), 3.82 (d, J = 12.8 Hz 1H), 3.52 (m, 2H), 2.57 (s, 3H), 1.96-1.58 (10H), 1.26 (t, J = 6.8 Hz, 3H). HPLC-MS tR = 2.48 min (UV 254nm)- Mass calculated for formula C20H26N8OS 466.3; observed MH+ (LCMS) 467.3 (m/z). Example 76-5: 1H NMR (400 MHz, CD3OD) δ 8.28 (s, 1H), 8.25 (s, 2H), 8.10 (s, 1H),
7.39 (s, 1 H), 4.65 (d, J = 14.0 Hz, 1 H), 4.52 (d, J = 10.8 Hz, 1 H), 4.24 (d, J = 14.0 Hz 1 H), 3.85 (d, J = 18.0 Hz 1 H), 3.65-3.44 (4H), 2.65 (s, 3H), 1.97-1.58 (6H), 1.29 (t, J = 7.2 Hz, 3H). HPLC-MS tR = 2.35 min (UV 254nm). Mass calculated for formula C20H26N8OS 452.2; observed MH+ (LCMS) 453.2 (m/z).
Example 76-61H NMR (400 MHz, CD3OD) δ 8.21 (s, 3H), 8.03 (s, 1H), 7.23 (s, 1H), 4.38 (d, J = 5.6 Hz, 1H), 3.79 (d, J = 5.4 Hz, 1H), 3.63 (d, J = 12.4 Hz 1H), 3.53 (m, 1H), 3.10 (m, 1H), 2.58 (s, 3H)11.34 (s, 6H), 0.87 (t, J = 6.2 Hz, 3H). HPLC-MS tR = 2.39 min (UV 254nm). Mass calculated for formula C20H26N8OS 440.2; observed MH+ (LCMS) 441.2 (m/z).
Example 76-7: 1H-NMR (400 MHz, CD3OD ) δ 8.33 m (3H), 8.15 s (1H), 7.41 s (1H), 4.80 (d, 2H), 4.15 (d, 2H), 4.06 (d, 2H), 3.62 (d, 2H), 3.58 (m, 1H), 2.68 (d, 3H), 2.21 (m, 1H), 1.81 (m , 6H) and 1.45 (s, 3H). HPLC-MS tR =1.80Min (UV 254nm). Mass calculated for formula C21H26N8OS 438.55, observed LC/MS m/z 439.1 (M+H).
Example 76-8: 1H-NMR (400 MHz, DMSO-d6 ) δ 12.73 bs (1H), 9.2 bs (1H), 8.28 s (2H), 8.09 s (1H), 8.08 s (1H), 7.36 s (1H), 4.71 m (1H), 4.05 m (1H), 3.82 m (1H), 3.63 m (1 H), 3.25 m (2H), 1.97 m (1 H), 1.65 m (6H) and 1.30 s (3H).
Example 76-9: 1H-NMR (400 MHz, DMSO-d6 ) δ 8.28 (1H), 8.25 (2H), 8.08 (1 H), 7.32 (1 H), 4.71 (1 H), 4.08 (1 H), 3.84 (1 H), 3.52 (3 H), 3.46 (1 H), 2.63 (3 H), 2.17 (2 H), 1.87-1.73(6H), 1.45(3H).
Example 76-10: 1H-NMR (400 MHz, DMSO-d6 ) δ 8.28 (1H), 8.25 (2H), 8.08 (1 H), 7.32 (1 H), 4.71 (1 H), 4.08 (1 H), 3.84 (1 H), 3.52 (3 H), 3.46 (1 H), 2.63 (3 H), 2.17 (2 H), 1.87-1.73(6H), 1.45(3H).
Example 76-11: 1HNMR (400 MHz, CD3OD) δ 8.20 (s, 2H), 8.14 (s, 1H), 8.03 (s, 1H), 7.25 (s, 1H), 4.48 (d, 1H), 4.37 (d, 1H), 3.46 (s, 3H), 2.91-3.60 (m, 6H), 2.62 (s, 3H),
1.40 - 1.89 (m, 4H), 0.92 (s, 3H). Example 76-12: 1HNMR (400 MHz, CD3OD) δ 8.20 (s, 2H), 8.14 (s, 1 H)1 8.03 (s, 1 H), 7.25 (s, 1 H)1 4.48 (d, 1 H), 4.37 (d, 1 H)1 3.46 (s, 3H)1 2.91-3.60 (m, 6H)1 2.62 (s, 3H), 1.40 - 1.89 (m, 4H), 0.92 (s, 3H).
Example 76-40: 1H NMR (400 MHz1 CD3OD) δ 8.28 (s, 1 H), 8.25 (s, 2H), 8.10 (s, 1 H), 7.38 (s, 1 H), 4.59 (s, 2H)1 3.3-3.9 (m, 4H), 2.64 (s, 3H), 2.3-2.5 (m, 4H).
Example 76-42: 1H NMR (400 MHz1 CD3OD) δ 8.13 (broad s, 2H), 7.85 (s, 1 H)1 7.78 (s, 1 H)1 7.15 (s, 1 H), 4.10 (d, J ~ 14 Hz, 1 H), 3.96 (d, J -14 Hz1 1 H)1 3.54-3.66 (m, 1 H), 3.07-3.17 (m, 1 H), 2.62-2.72 (m, 1 H), 2.53 (s, 3H), 1.82-2.21 (m, 4H).
EXAMPLE 77
Figure imgf000202_0001
A mixture of iodoethane (52.5 g, 336.5 mmol) and 2-amino-2-methyl-1-propanol (30.0 g, 336.5 mmol) was stirred at 60 °C for 15 min. It was diluted with 500 mL of ether, and basified by adding 5 N aqueous NaOH until it reaches pH =10. The organic layer was separated. The aqueous layer was extracted with ether (500 mL X 3). The combined organic was washed sequentially with 100 mL of water, and 100 mL of brine, then dried over anhydrous Na2SO4. The solvent was removed to provide 20 g of the crude product, which was purified by recrystallization in 150 mL of hexanes to give 13 g of a white solid. The solid was further purified by sublimation under reduced pressure to give 12 g of the title compound. 1H NMR (400 MHz, CDCI3) δ 3.28 (s, 2H), 2.54 (qt, J = 7.1 Hz, 2H), 1.09 (t, J = 7.0 Hz, 3H), 1.07 (s, 6H). EXAMPLE 78
1. LiAlH4
Peak 2
Figure imgf000203_0001
2
Step A: The substrate (10 g) was suspended in THF (200 mL). Then lithium aluminum hydride solution (110 mL, 2M in THF) was slowly added. The mixture was stirred at room temperature for 12 h. The solution was cooled to 0 °C, and saturated aqueous Na2SO4 (200 mL) was slowly added. The mixture was filtered through Celite, and filtercake was washed with ethyl acetate (400 mL). The organic layer was washed with water (200 mL) and brine (200 mL). The organic layer was dried (anhydrous Na2SO4), filtered and evaporated to give the amino alcohol (6.9g). The amino alcohol (6.9 g) was dissolved in THF (80 mL) and water (80 mL) at room temperature. The potassium carbonate (14.76 g) was added. Then benzyl chloroformate (8.28 mL) in THF (40 mL) was added dropwise. The mixture was stirred at room temperature for 30 min. Solvent was evaporated off under reduced pressure, and ethyl acetate (100 mL) was added. Two layers were separated, and the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The combined organic layer was washed with brine (200 mL), dried (Na2SO4), filtered and evaporated under reduced pressure to give the crude product which was purified by column chromatography. The racemic aminoalcohol was chirally separated by SFC HPCL method. Then enatiomers corresponding to peak 1 and peak 2 were separately taken forward to prepare the corresponding building blocks.
Step B: The alcohol from Step A (1.936 g) was dissolved in dichloromethane (80 mL), and treated with proton sponge (8.32 g) at room temperature. Then trimethyloxonium tetrafluoroborate (5.69 g) was added. The mixture was stirred for 1 h. The reaction was quenched with saturated aqueous ammonium chloride solution (100 mL). The two layers were separated, and the aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organic layer was washed sequentially with hydrochloric acid (200 mL, 1 N)1 saturated sodium bicarbonate solution (200 mL), brine (200 mL), dried (Na2SO4), filtered and evaporated under reduced pressure to give the crude product which was purified by column chromatography. Step C: The enantiomerically pure methyl ether from Step B in EtOH was treated with Pd(OH)2 on carbon (20% wt) and stirred in hydrogen atmosphere at atmospheric pressure at room temperature for 2 h. The mixture was filtered off, and the filtrate was evaporated under reduced pressure to give the amine.
EXAMPLE 79
Figure imgf000204_0001
Step A: At -78°C, ester (6359 mg, 24.7 mmol) in THF (50ml) was added dropwise to LDA (1.8 M in THF, 27.5 ml, 49.4 mmol) in THF (200ml). The reaction mixture was slowly warmed up to room temperature and stirred at that temperature overnight. The reaction was cooled to O°C and quenched with saturated NH4CI solution. The mixture was diluted with H2O and extracted with EtOAc (x2). The combined organic layer was dried over anhydrous Na2SO4 and concentrated. Purification by column chromatography afforded the title compound (6221 mg, 93%). LCMS tR =2.27 Min.
Mass calculated for, M+ 271.1 , observed LC/MS m/z 216.1 (M+H-C4H8). To a solution of ester (4659 mg, 17.2 mmol) in THF (300 ml) was added LiBHEt3 (69 ml, 1 M in
THF). The reaction was stirred at room temperature for 30 min. It was quenched by adding saturated NH4CI. The mixture was extracted with CH2CI2. The combined organic layer was dried over anhydrous Na2SO4 and concentrated. Purification by column chromatography afforded the title compound (3032mg, 77%). LCMS tR =1.82 Min. Mass calculated for, M+ 229.1 , observed LC/MS m/z 174.1 (M+H-C4H8). Step B: NaH (1324 mg, 60% dispersion in mineral oil, 33.1 mmol) was added portion wise to a mixture of compound from Step A and MeI (3.3 ml, 52.9 mmol) in DMF (66 mL) at 0°C The reaction mixture was slowly warmed up to room temperature and stirred at that temperature overnight. The reaction was cooled to O°C and quenched with saturated NH4CI solution. The mixture was diluted with H2O and extracted with EtOAc (x2). The combined organic layer was dried over anhydrous Na2SO4 and concentrated. Purification by column chromatography afforded the title compound (2633 mg, 82%). LCMS tR =2.32 Min. Mass calculated for, M+ 243.1 , observed LC/MS m/z 188.1 (M+H-C4H8). A solution of compound 4 (901 mg, 3.71 mmol) was stirred in 20 % TFA in CH2CI2 (20 mL) at O°C for 30 min and then room temperature for 15 min. The reaction mixture was concentrated. The crude residue was used for example without further purification. LCMS tR =0.26 Min. Mass calculated for, M+ 143.1 , observed LC/MS m/z 144.1 (M+H).
Step C: CbzCI (604 ul, 4.08 mmol) in THF (1 ml) was added to a mixture of compound from Step B and K2CO3 (1125 mg, 8.15 mmol) in THF (20 ml) and H2O (20 ml) at 0°C After stirring at room temperature for 30 min, the reaction mixture was extracted with EtOAc (x2). The combined organic layer was dried over anhydrous Na2SO4 and concentrated. Purification by column chromatography afforded the titlte compound (965mg, 94%). LCMS tR =2.28 Min (UV 254nm). Mass calculated for, M+ 277.1 , observed LC/MS m/z 278.1 (M+H). The title amines were chirally separated utilizing a Gilson GX-281 liquid handling system with HPLC capabilities. Separation was accomplished with the following conditions: Chiral Technologies Chiral PAK AD column (5 x 50 cm; 20 μ); flow = 50 mL/min; 7.5% isopropanol in hexanes (isocratic); observed at 210 nm.
Step D: The enatiomerically pure isomers from Step C were dissolved in (1 mmol, 277 mg) in EtOH (6 ml) was mixed with 20% Pd(OH)2 (51 mg) and stirred under H2 balloon at room temperature for 2h. Filtration through celite and concentration afforded the title compound, which was used for next step without further purification. LCMS tR =0.26 Min. Mass calculated for, M+ 143.1 , observed LC/MS m/z 144.1 (M+H). EXAMPLE 80
Figure imgf000206_0001
Step A: The parent compounds were prepared from Example 76-2 using acid chlorides, acids, ureas and isocyanates using standard reaction conditions. Step B: Sem-protected material from Step A was dissolved in 1 ,4-dioxane (1 mL) and treated with 4 N HCI in 1 ,4-dioxane (1 mL). then heated at 6OC for 1 hr.. The mixture was concentrated under reduced pressure and the resulting residue was purified by prep-HPLC and conversion to the hydrochloride salt afforded the title compound as a colorless solid.
Using essentially the same procedures as described for Example 80, the following compounds were prepared. TABLE 16
Figure imgf000206_0002
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
EXAMPLE 81
Figure imgf000218_0001
Step A: The starting sulfone was prepared by essentially the same procedure described in Example 6 except that ethylboronic acid or cyclopropylboronic acid was used. Final products listed in Table 17 were obtained by using the procedures described for Example 76.
TABLE 17
Figure imgf000218_0002
Figure imgf000219_0001
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0002
EXAMPLE 82
Figure imgf000223_0001
Step A: The title compound was prepared using as described for Example 7 except that f-butylamine was used.
Step B: To a solution of the product of Step A (1 equivalent) in THF (3 mL) was added DIEA (3 equivalents), and the respective trifilate (1.2 equivalents) at room temperature. The reaction was heated at reflux until consumption of starting material was observed by LC-MS analysis. The solution was cooled to room temperature and concentrated under reduced pressure. Purification by column chromatography (Siθ2, 30% ethyl acetate/dichloromethane) afforded the desired coupled intermediate. 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 18.
TABLE 18
Figure imgf000224_0002
EXAMPLE 83
Figure imgf000224_0001
Step A: Sodium thiomethoxide (39 mg, 3.00 equiv) was added to a stirring mixture of mesylate prepared in example 7 (100 mg, 1.00 equiv) and sodium iodide (14 mg, 0.50 equiv) in DMF (6 ml.) at room temperature. The resulting mixture was allowed to stir for 2.5 hours at which time LC-MS analysis indicated the reaction was complete. The reaction was quenched with saturated aqueous sodium bicarbonate (30 mL) and then extracted with dichloromethane (2 * 70 mL). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound as a yellow solid, 100 mg (>99%). Step B: m-Chloroperbenzoic acid (66 mg, 2.05 equiv) was added to a stirring solution of compound from Step A (91 mg, 1.00 equiv) in dichloromethane (3 mL) at room temperature. The mixture was allowed to stir for 2 hours at which time thin layer chromatography indicated the reaction was complete. The mixture was diluted with ethyl acetate (40 mL) and then washed with saturated aqueous sodium bicarbonate (15 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 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 compound as an off-white solid, 18 mg (27%). 1H NMR (300 MHz, DMSO-de) δ 12.19 (s, 1 H), 8.24 (s, 2H), 7.96 (s, 1 H), 7.83 (s, 1 H), 7.28 (s, 1 H), 4.61 (s, 2H), 3.01 (s, 3H), 2.53 (s, 3H). HPLC tr = 4.04 min (UV 254nm). Mass calculated for C15H15N7O2S2 389.1 ; observed MH+ (MS) 390.7 (m/z).
EXAMPLE 84
Figure imgf000226_0001
Step A: EtN(JPr)2 (10.55 mL, 60.69 mmol) was added at O°C to acid (2953 mg, 20.23 mmol, prepared according to Bioorganic & Medicinal Chemistry, 11(20), 4333-4340; 2003), EDCI (5817 mg, 30.34 mmol), HOBT (4100 mg, 30.34 mmol) and piperidine (2398 uL, 24.28 mmol) in DMF (100 mL). After stirring at room temperature overnight, the crude reaction material was diluted with EtOAc and washed with brine (2X). The organic layer was dried over Na2SO4, filtered, and concentrated to give the crude product which was chromatographed to give the product amide. HPLC-MS tR =1.57 Min (UV 254nm).Mass calculated for formula, M+ 213.0, observed LC/MS m/z 214.1 (M+H).
Step B: Powdered KNO3 (1100.8 mg, 10.89 mmol) was added portionwise to a stirred solution of amide (927.6 mg, 4.356 mmol) in cone. H2SO4 (20 mL) at 0°C After stirring at 0°C for 30 min, the reaction mixture was poured onto ice. Extraction with CH2CI2 and the combined organic lawyer was washed with H2O, dried over Na2SO4 and concentrated. Purification by column chromatography afforded first the undesired nitration product 545.5 mg (48.5%), HPLC-MS tR = 1.79 Min (UV 254nm). Mass calculated for M+ 258.0, observed LC/MS m/z 259.1 (M+H), 1HNMR (400 MHz, CDCI3) δ 7.58 (d, 1 H, J = 0.4 Hz), 3.67 (m, 4H), 1.73 (m, 6H), then the desired nitration product 435.6 mg (38.8%), HPLC-MS tR = 1.68 Min (UV 254nm)- Mass calculated for M+ 258.0, observed LC/MS m/z 259.1(M+H). 1H NMR (400 MHz, CDCI3) δ 8.37 (d, 1 H, J = 3.2 Hz), 3.67 (m, 4H), 1.71 (m, 6H). Step C: To a solution of nitroamide (435.6 mg, 1.69 mmol) in HOAc (20 mL) was added iron powder (471.5 mg, 8.44 mmol). The reaction mixture was heated at 7O°C for 30 min. The mixture was cooled to room temperature and concentrated to dryness. To the residue was added 3OmL of 20% MeOH/CH2CI2 followed by 20 mL of saturated aqueous NaHCO3. The mixture was stirred until it stoped bobbling. The mixture was extracted by EtOAc (x 2), dried over Na2SO4, and then concentrated. The crude amine was used for displacement reaction without further purification. HPLC- MS tR = 1.32 Min (UV 254nm)- Mass calculated for M+ 228.0, observed LC/MS m/z 229.1 (M+H). Step D: A solution of crude amine from Step C (491.5 mg, 2.156 mmol) and sulfone (292 mg, 0.719 mmol) in DMSO (10 mL) was treated with NaH (60% dispersion in oil, 172.5 mg, 4.312 mmol) at room temperature. The mixture was stirred until LCMS indicated the reaction was complete. The reaction mixture was diluted with EtOAc, washed with sat NH4CI, dried with Na2SO4, and concentrated to afford crude product 4. Purification afforded compound 4. HPLC-MS tR = 2.503 Min (UV 254nm). Mass calculated for M+ 555.2, observed LC/MS m/z 556.3(M+H).
Step E: To a solution of the amide from Step D (120 mg, 0.216 mmol) in dichloromethane (12 mL) was added lithium aluminum hydride (86.4 mg, 2.162 mmol) and ethyl ether (3 mL) at 0°C The reaction mixture was stirred at room temperature until LCMS indicate the reaction was complete. The reaction was quenched with H2O (86 uL), 3N NaOH (86 uL) and H2O (264 uL). The reaction was filtered and concentrated to afford crude compound 5. HPLC-MS tR = 1.738 Min (UV 254nm)- Mass calculated for M+ 541.2, observed LC/MS m/z 542.2 (M+H). Step F: 4N HCI in dioxane (3mL) was added to crude product from Step E at 0°C The mixture was stirred at room temperature until LCMS indicated the reaction was complete. Concentration afforded crude product. Purification by Prep-LC and conversion to a hydrochloric salt afforded the title compound. HPLC-MS tR = 0.923 Min (UV 254nm). Mass calculated for M+ 411.1 , observed LC/MS m/z 412.2 (M+H). EXAMPLE 85
Figure imgf000228_0001
By essentially the same procedure given in Example 84, the title compound can be prepared. HPLC-MS tR = 1.005 Min (UV 254nm)- Mass calculated for M+ 425.1 , observed LC/MS m/z 426.2 (M+H).
EXAMPLE 86
Figure imgf000228_0002
Step A: To a solution of nitroester (2285 mg, 12.22 mmol) in HOAc (55 mL) was added iron powder (6825 mg, 122.20 mmol). The reaction mixture was heated at 75°C for 10 min. The mixture was cooled to room temperature and then added 200 mL of MeOH. The resulting mixture was filtered through celite (the celite was rinsed with additional amount MeOH). The filtrate was concentrated to remove most of AcOH. To the residue was added 50 mL of 20% MeOH/CH2CI2 followed by saturated aqueous NaHCθ3 until it stoped bubbling. The mixture was extracted by EtOAc (x 2), dried over Na2SO4, and then concentrated. The crude amine was used without further purification. HPLC-MS tR = 1.07 Min (UV 254nm)- Mass calculated for M+ 157.0.0, observed LC/MS m/z 158.1(M+H). Step B: To a solution of the aminoester (850 mg, 5.414 mmol)) and sulfone from Example 1 (1 equivalent, 1469 mg, 3.609 mmol) in DMSO (36 mL) was treated with NaH (60% dispersion in oil, 14.43 mmol, 577 mg) at room temperature portionwise. After 10 min, LC-MS analysis of the reaction indicated the reaction was complete. While cooling by water bath, the reaction was quenched with sat. NH4CI dropwise (5 ml) and then added H2O (160 ml) extracted with ethyl acetate (2x). The combined organic layers were washed with brine and dried (sodium sulfate). Evaporation and purification by column chromatography (0 to 100% EtOAc/Hexane) afforded title compound (1492 mg, 85%). HPLC-MS tR = 2.41 Min (UV 254nm)- Mass calculated for M+ 484.1 , observed LC/MS m/z 485.2 (M+H). Step C: To a solution of the product of Step B (206 mg, 0.4271 mmol) in THF (8 mL) was treated with DIBAL (1.0 M in CH2CI2, 2.56 mL) at -78°C dropwise. After stirring at -78°C for 4.5h, LCMS indicated the existence of small amount of starting material.. Two more equivalents DIBAL (0.85 mL) were added. After stirring at -78°C for another 0.5 h, brine (6 mL) was added portionwise at -78°C to quench the excess reagents. The reaction mixture was extracted with CH2CI2 (3X). Evaporation of solvent and purification by column chromatography (0 -> 100% 2% MeOH in EtOAc/Hexane) afforded alcohol (153 mg, 79%). HPLC-MS tR = 2.01 Min (UV 254nm)- Mass calculated for M+ 456.1 , observed LC/MS m/z 457.1 (M+H). Step D: To a solution of alcohol from Step C (537 mg, 1.17 mmol) in THF (26 mL), was added H2O (0.078 mL) followed by Dess-Martin periodinane (599 mg, 1.41 mmol) at 0°C The reaction was stirred at room temperature until LCMS indicated the reaction was complete. The reaction mixture was diluted with CH2CI2, and washed with saturated aqueous NH4CI solution. The organic was dried over anhydrous Na2SO4 and then concentrated. Purification by column chromatography afforded aldehyde (237.1 mg, 44%). HPLC-MS tR = 2.15 Min (UV 254nm). Mass calculated for M+ 454.1 , observed LC/MS m/z 455.1 (M+H). Step E: To a mixture of aldehyde (94 mg, 0.21 mmol) and 4-fluoropiperidine hydrochloride (58 mg, 0.41 mmol) in DCE (10 mL) was added DIEA (144 uL, 0.828 mmol), followed by NaBH(OAc)3 (139 mg, 0.62 mmol). The reaction mixture was stirred at room temperature overnight and then diluted with CH2CI2, and washed with saturated NaHCO3 solution. The organic was dried over anhydrous Na2SO4 and then concentrated. The crude product was used without purification for next step. HPLC- MS tR = 1.57 Min (UV 254nm). Mass calculated for M+ 541.2, observed LC/MS m/z 542.2 (M+H).
Step F: 4N HCI in dioxane (5mL) was added to crude amine at 0°C The mixture was stirred at room temperature until LCMS indicated the reaction was complete. Concentration and purification by Prep-LC the title compound. HPLC-MS tR = 0.89 Min (UV 254nm). Mass calculated for M+ 411.1 , observed LC/MS m/z 412.1 (M+H).
EXAMPLE 87
Figure imgf000230_0001
By essentially the same procedure as Ex 86, the title compound can be prepared. HPLC-MS tR = 0.97 Min (UV 254nm)- Mass calculated for M+ 429.1 , observed LC/MS m/z 430.1 (M+H). EXAMPLE 88
Figure imgf000231_0001
By essentially the same procedure as Example 86, the title compound can be prepared. HPLC-MS tR = 0.99 Min (UV 254nm). Mass calculated for M+ 443.1 , observed LC/MS m/z 444.1 (M+H).
EXAMPLE 89
Figure imgf000231_0002
Part A: A mixture of 6-bromo compound (4562 mg, 10.39 mmol), PdCI2dppf (424.3 mg, 0.519 mmoL), CuI (296.9 mg, 1.56 mmol) and tributyl(1-ethoxyvinyl)tin (5617 uL, 16.627 mmol) in CH3CN (100 mL) was refluxing until LCMS indicate the reaction was complete. 1 N HCI (15 mL) was added and the mixture was stirred until LCMS indicate the conversion to ketone. The reaction mixture was diluted with EtOAc1 washed with sat NH4CI, dried with Na2SO4, and concentrated. Purification afforded ketone (3200 mg, 76%). HPLC-MS tR = 2.32 Min (UV 254nm). Mass calculated for M+ 403.1 , observed LC/MS m/z 404.2 (M+H).
Part B: Bis(2-methoxyethyl)aminosulfur trifluoride (2745 uL, 14.89 mmoL) was added dropwise to ketone from Part A (600 mg, 1.489 mmoL) in CH2CI2 (1 mL) at 0°C The mixture was stirred at room temperature for 1 week and then carefully added dropeise to Sat NaHCO3 solution. The mixture was extracted with CH2CI2 and the organic layer was dried over Na2SO4, and concentrated. Purification afforded di-fluoro compound. HPLC-MS tR = 2.52 Min (UV 254nm). Mass calculated for M+ 425.1 , observed LC/MS m/z 426.2 (M+H). Part C: m-CPBA (1515.7 mg, 6.76 mmoL) was added to a solution the product of Part B (1307 mg, 3.07 mmoL) in CH2CI2 (31 mL). After stirring at room temperature for 2h, the reaction mixture was diluted with EtOAc, washed with sat NaHCO3, dried with Na2SO4, and concentrated. The sulfone (5-A) was used directly without further purification. HPLC-MS tR = 2.17 Min (UV 254nm). Mass calculated for M+ 457.1 , observed LC/MS m/z 458.0 (M+H). Part D: To a solution of the aminoisothiazole (400 mg, 2.53 mmol) and sulfone from Part C (964 mg, 2.11 mmol) in DMF (13 mL) was treated with NaH (60% dispersion in oil, 4.64 mmol, 186 mg) at room temperature. The mixture was stirred until LCMS indicate the reaction was complete. The reaction mixture was diluted with EtOAc, washed with sat NH4CI, dried with Na2SO4, and concentrated. Purification afforded the displacement product (438.5 mg, 39%). HPLC-MS tR = 2.22 Min (UV 254nm). Mass calculated for M+ 535.1 , observed LC/MS m/z 536.1 (M+H).
Part E: To the solution of ester (406.5 mg, 0.759 mmol) in THF (39 mL) was added LiBHEtβ (3.79 mL, 1 M solution in THF). The reaction was stirred at room temperature for 30 min. It was quenched by adding saturated aqueous NH4CI (15 mL). The mixture was extracted by 30 mL of CH2CI2. The organic was concentrated and the crude alcohol was used for next step without further purification. HPLC-MS tR = 1.99 Min (UV 254nm). Mass calculated for M+ 507.1 , observed LC/MS m/z 508.1 (M+H). Part F: To a solution of crude alcohol from Part E in THF (40 mL), was added triethylamine (365 uL, 2.62 mmol) and methanesulfonylchloride (173 uL, 2.23 mmol). The reaction was stirred at room temperature for 30 min. It was quenched by adding MeOH. The solution was diluted by 30 mL of CH2CI2, washed consecutively with 15 mL of 2 N aqueous HCI, water, and brine. The solvent was removed under vacuum to give crude mesylate which was used in next transformations without further purification. HPLC-MS tR = 2.35 Min (UV 254nm). Mass calculated for M+ 585.1 , observed LC/MS m/z 586.1 (M+H).
Part G: A mixture of crude compound (30mg, 0.051 mmol), 3-methyl piperidine (24 uL, 0.205 mmol), EtN(JPr)2 (54 uL, 0.307 mmol) and NaI (1 mg) in THF (2ml) was heated at 8O°C for 1 h and 10 min. The mixture was cooled dot room temperature and then concentrated. 4N HCI in dioxane (3mL) was added to crude displacement product at 0°C The mixture was stirred at room temperature until LCMS indicated the reaction was complete. Concentration and purification afforded compound 5-1. HPLC-MS tR = 1.27 Min (UV 254nm). Mass calculated for M+ 458.1 , observed LC/MS m/z 459.1 (M+H).
By essentially the same procedure given in Example 89, the compounds listed in Table 19 can be prepared.
Table 19
Figure imgf000233_0001
Figure imgf000234_0001
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0002
EXAMPLE 90
Figure imgf000237_0001
Step A: To a solution of mesylate (1.1 g, 1.65 mmol) in DMSO (20 mL) at room temperature was added NaI (280 mg, 1.88 mmol) and NaCN (300 mg, 6.12 mmol). The mixture was stirred at 60 °C for 1 h. It was diluted with 200 mL of EtOAc and washed with water (200 mL X 2). The solvent was removed under vacuum. The residue was purified by column chromatography (Siθ2, 60% EtOAc/hexanes) to afford 980 mg of the title compound. 1H NMR (400 MHz, CDCI3) δ 7.90 (s, 1 H), 7.82 (s, 1 H), 7.63 (s, 1 H), 7.58 (s, 1 H), 7.20 (s, 1 H), 6.61 (brs, 2H)1 5.56 (s, 2H), 3.88 (s, 2H), 3.75 (t, 2H), 3.65 (t, 2H), 2.53 (s, 3H), 0.95 (m, 4H), 0.02 (s, 9H), -0.07 (s, 9H). Step B: A solution of compound from Step A (530 mg, 0.889 mmol) in 30 mL of CH2Cb was cooled to 0 °C. To this was slowly added DIBAL-H solution (1 M in CH2CI2, 3.56 mL, 3.56 mmol). The reaction was stirred at 0 °C for 20 min. It was quenched with 1 mL of MeOH, and the resulting solution was stirred at room temperature with 50 mL of saturated Rochelle salt solution for 2 h. The organic layer was isolated and the solvent was removed under vacuum. The residue was purified by column chromatography (SiO2, 10% 7N NH3 in MeOH/ CH2CI2) to give 450 mg of the title compound. 1H NMR (400 MHz, CDCI3) δ 7.90 (s, 1 H), 7:83 (s, 1 H), 7.63 (s, 1 H), 7.58 (s, 1 H)1 7.05 (s, 1 H), 6.65 (brs, 2H), 5.55 (s, 2H), 3.75 (t, 2H), 3.65 (t, 2H), 3.16 (t, 2H)1 2.95 (t, 2H), 2.52 (s, 3H), 0.95 (m, 4H), 0.02 (s, 9H), -0.08 (s, 9H). Step C: A solution of compound from Step B (400 mg, 0.667 mmol) and NaOAc (400 mg, 4.88 mmol) in 20 mL of AcOH was stirred at 60 °C. To this was slowly added t- butyl nitrite (1.40 mL, 11.8 mmol). The reaction was stirred at 60 °C for 20 min. It was cooled to room temperature and added 20 mL of CH2CI2. The solid was filtered off, and the solvent in the filtrate was removed under vacuum. The residue was diluted with 100 mL of CH2CI2 and washed with 50 mL of saturated NaHCO3 aqueous solution. The organic portion was concentrated. The residuw was dissolved in 10 mL of MeOH. To this solution was added a solution of NaOH (200 mg) in 1 mL of water. After stirred at room temperature for 30 min, it was diluted with 100 mL of CH2CI2 and washed with 100 mL of brine. The solvent was removed under vacuum. The residue was purified by column chromatography (SiO2, 75% EtOAc/hexanes) to give 240 mg of the title compound. 1H NMR (400 MHz, CDCI3) δ 7.90 (s, 1 H), 7.81 (s, 1 H), 7.63 (s, 1 H), 7.58 (s, 1 H), 7.05 (s, 1 H), 6.65 (brs, 2H), 5.57 (s, 2H), 4.03 (t, 2H), 3.75 (t, 2H), 3.65 (t, 2H), 3.01(t, 2H), 2.52 (s, 3H), 0.95 (m, 4H), 0.02 (s, 9H)1 -0.10 (s, 9H).
Figure imgf000238_0001
Step A: To a solution of Example 90 (200 mg, 0.333 mol) in 10 mL of THF, was added NEt3 (84 mg, 0.830 mmol) followed by methanesulfonyl chloride (76.4 mg, 0.667 mmol). The reaction was stirred at room temperature for 20 min. It was quenched by adding 10 mL of water and diluted with 50 mL of CH2CI2. The mixture was washed with 20 mL of 0.5 N aqueous HCI solution. The organic was dried over anhydrous Na2SO4. The solvent was removed under vacuum. The residue was purified by column chromatography (SiO2, 70% EtOAc/hexanes) to give 180 mg of the title compound.
Step B: A mixture of mesylate from Step A (42 mg, 0.062 mmol), thiomorpholine (16 mg, 0.16 mmol), K2CO3 (8.5 mg, 0.062 mmol) and a trace amount of NaI in 1.5 mL of THF was stirred at 80 °C for 24 h. It was cooled to room temperature. The solvent was removed under vacuum. The residue was purified by column chromatography (SiO2, 5% 7 N NH3 in MeOH/CH2CI2) to give 37 mg of the title compound. 1H NMR (400 MHz, CDCI3) δ 7.88 (s, 1 H), 7.81 (s, 1 H), 7.64 (s, 1 H), 7.57 (s, 1 H), 7.05 (s, 1 H), 6.64 (brs, 2H), 5.55 (s, 2H), 3.75 (t, 2H), 3.65 (t, 2H), 2.64-3.08(m, 8H)1 2.52 (s, 3H), 0.95 (m, 4H), 0.02 (s, 9H), -0.10 (s, 9H).
Step C: To a solution of product from Step B (37 mg, 0.054 mmol) in 2 mL of THF/MeOH (1 :1 ) stirred at 80 °C, was added 0.5 mL of 4 N HCI in dioxane solution. The reaction was stirred at 80 °C for 30 min. It was cooled to room temperature and diluted with 2 mL of THF and 1 mL of ether. The solid was collected by filtration and washed with ether to give 26 mg of the title compound as its HCI salt form. HPLC-MS tR = 2.21 min (UV 254nm)- Mass calculated for formula C19H2ONsOS 426.1 ; observed MH+ (LCMS) 427.2 (m/z).
By essentially the same procedure set forth in Example 91 only replacing thiomorpholine with other respective aliphatic amines in Step B, compounds shown in column 2 of Table 20 were prepared.
TABLE 20
Figure imgf000239_0001
Figure imgf000240_0001
Figure imgf000241_0002
EXAMPLE 92
Figure imgf000241_0001
Step A: To a solution of carbon tetrabromide (170 mg, 0.512 mmol) in 4 mL of CH2CI2 stirred at 0 °C, was added PPh3 (267 mg, 1.02 mmol). The reaction was stirred at 0 °C for 15 min when the aldehyde (200 mg, 0.341 mmol) was added. The resulting solution was further stirred at 0 °C for 15 min. It was quenched with 10 mL of saturated NaHCO3 aqueous solution. The mixture was extracted by 20 mL of CH2CI2. The aqueous phase was further extracted by CH2CI2 (10 mL X 2). The combined organics were concentrated and further purified by column chromatography (SiO2, 50% EtOAc/hexanes) to give 150 mg of the title compound.
Step B: A stirred solution of compound from Step A (40 mg, 0.054 mmol) and pyrrolidine (30 mg, 0.43 mmol) in 0.6 mL of DMSO and 0.15 mL of water was stirred at 100 °C for 3 h. It was cooled to room temperature and diluted with 15 mL of CH2CI2. The content was washed with water, saturated aqueous NaHCO3 and brine sequentially. The organic was concentrated and purified by column chromatography (SiO2, 3.5% 7 N NH3 in MeOH/ CH2CI2) to give 20 mg of the title compound. 1H NMR (400 MHz, CDCI3) δ 7.88 (s, 1 H), 7.81 (s, 1 H)1 7.64 (s, 1 H)1 7.57 (s, 1 H)1 7.18 (s, 1 H)1 6.62 (brs, 2H), 5.55 (s, 2H), 3.90 (s, 2H), 3.75 (t, 2H), 3.67 (t, 2H), 3.45-3.62 (m, 4H), 2.52 (s, 3H), 1.35-1.63 (m, 6H), 0.95 (m, 4H), 0.02 (s, 9H), -0.08 (s, 9H). Step C: A solution of compound from Part B (20 mg, 0.029 mmol) in 1 mL of THF and 2 mL of TFA was stirred at 60 °C for 2 h. The solvent was removed under vacuum. The residue was dissolved in 2 mL of THF. To the stirred solution was added 1 mL of 1 M HCI in ether.The solid was collected by filtration and washed with ether to give 10 mg of the title compound as its HCI salt form. HPLC-MS tR = 2.55 min (UV 254nm). Mass calculated for formula C19H20N8OS 408.2; observed MH+ (LCMS) 409.2 (m/z).
By essentially the same procedure set forth in Example 92, only replacing pyrrolidine with other respective aliphatic amines in Step B, compounds shown in column 2 of Table 21 were prepared.
TABLE 21
Figure imgf000242_0001
Figure imgf000243_0001
EXAMPLE 93
Figure imgf000244_0001
Step A: To a solution of mesylate (560 mg, 0.841 mmol) in 16 mL of acetone was added LiBr (730 mg, 8.41 mmol). The mixture was stirred at room temperature for 1.5 h. It was diluted with 100 mL of CH2Ck and washed with brine (100 mL). The solvent was removed under vacuum. The residue was purified by column chromatography (SiO2, 40% EtOAc/hexanes) to give 506 mg of the title compound, δ 7.88 (s, 1 H), 7.81 (s, 1 H), 7.65 (s, 1 H), 7.58 (s, 1 H), 7.30 (s, 1 H), 6.70 (brs, 2H), 5.57 (s, 2H), 4.55 (s, 2H), 3.78 (t, 2H), 3.68 (t, 2H), 2.56 (s, 3H), 0.95 (m, 4H), 0.02 (s, 9H), -0.08 (s, 9H). Step B: To a solution of compound from Step A (40 mg, 0.061 mmol) in 1.5 mL of THF, was added 2-tri-n-butylstannylpyridine (45 mg, 0.12 mmol), and Pd(PPh3J4 (17 mg, 0.015 mmol). The reaction was stirred at 80 °C in a sealed vial for 16 h. The solvent was removed under vacuum. The residue was purified by column chromatography (SiO2, 3% 7 N NH3 in MeOH/ CH2CI2) to give 32 mg of crude title compound contaminated by triphenylphosphine oxide. This material was used in Step C without further purification.
Step C: The product of Step B was dissolved in 2 mL of MeOH/THF (1 :1 ) at 80 °C. To this solution was added 0.5 mL of 4 N HCI in dioxane. The reaction was stirred at 80 °C for 30 min. It was cooled to room temperature and diluted with 1 mL of THF. The solid was collected by filtration and washed with THF and ether to give 15 mg of the title compound as its HCI salt form, δ 8.8(d, 1 H), 8.86 (t, 1 H), 8.10 (s, 3H), 7.92-8.08 (m, 3H), 7.22 (s, 1 H)1 4.60 (s, 2H), 2.58 (s, 3H). HPLC-MS tR = 2.00 min (UV 254nm). Mass calculated for formula C19H16N8S 388.1 ; observed MH+ (LCMS) 389.2 (m/z). By essentially the same procedure set forth in Example 93, only replacing 2-tri- n-butylstannylpyridine with other respective stannyl reagents in Step B, compounds shown in column 2 of Table 22 were prepared.
TABLE 22
Figure imgf000245_0001
Figure imgf000246_0001
Figure imgf000247_0001
Figure imgf000248_0001
Figure imgf000249_0003
EXAMPLE 94
Figure imgf000249_0001
Figure imgf000249_0002
Step A: To a mixture of 10 mL of THF/DMF (1 :1) was added NaH (39.3 mg, 1.64 mmol). It was cooled to -10 °C and a solution of trimethylsulfonium iodide (334 mg, 1.64 mmol) in 5 mL of DMSO was then slowly added. To the resulting mixture was added aldehyde. The reaction was stirred at room temperature for 40 min. It was quenched with ice water, and diluted with 50 mL of CH2Cb. The mixture was washed with water and brine. The solvent was removed under vacuum. The residue was purified by column chromatography (SiO2, 40% EtOAc/hexanes) to give 390 mg of the title compound, δ 7.90 (s, 1 H), 7.82 (s, 1 H), 7.67 (s, 1 H), 7.59 (s, 1 H), 7.10 (s, 1 H), 6.80 (brd, 1 H), 6.56 (brd, 1 H), 5.57 (s, 2H), 4.02-4.10 (m, 1 H), 3.78 (t, 2H), 3.69 (t, 2H), 3.07-3.25 (m, 2H), 2.58 (s, 3H), 0.95 (m, 4H), 0.02 (s, 9H), -0.08 (s, 9H). Step B: A solution of compound from Step A (270 mg, 0.450 mmol) in 4 mL of DMF was treated with sodium methanethiolate (100 mg, 1.43 mmol). The reaction was stirred at room temperature for 30 min. It was diluted with 15 mL of water. The mixture was extracted with EtOAc (20 mL x 3). The combined organics were washed with brine (20 mL) and then concentrated. The residue was purified by column chromatography (SiO2, 70% EtOAc/hexanes) to give 220 mg of the title compound, δ 7.90 (s, 1 H), 7.82 (s, 1H), 7.65 (s, 1 H), 7.58 (s, 1 H), 7.21 (s, 1 H)1 6.76 (brd, 1 H), 6.56 (brd, 1 H), 5.57 (s, 2H), 4.94 (m, 1 H), 3.40-3.80 (m, 5H), 2.80-3.15 (m, 2H), 2.58 (s, 3H), 2.12 (s, 3H), 0.95 (m, 4H), 0.02 (s, 9H), -0.10 (s, 9H).
Step C: To a solution of compound from Step B (30 mg, 0.046 mol) in 1 mL of THF, was added NEt3 (14 mg, 0.14 mmol) followed by methanesulfonyl chloride (16 mg, 0.14 mmol). The reaction was stirred at room temperature for 15 min. It was quenched by adding 2 mL of water and diluted with 15 mL of CH2CI2. The mixture was washed with 10 mL of 0.2 N aqueous HCI solution. The organic was dried over anhydrous Na2SO4 and then concentrated. The residue was treated with NaI (10 mg, 0.071 mmol) and piperidine (13 mg, 0.15 mmol) in 1 mL of THF. The resulting mixture was stirred at 80 °C for 12 h. It was diluted with 15 mL of CH2CI2 and washed with 15 mL of saturated aqueous NaHCO3 solution. The solvent was removed under vacuum, and the residue was purified by column chromatography (SiO2, 3% 7 N NH3 in MeOH/ CH2CI2) to give 12 mg of the title compound.
Step D: To a solution of compound from Step C (12 mg, 0.017 mmol) in 1 mL of THF/MeOH (1 :1 ), was added 0.5 mL of 4 N HCI in dioxane. The reaction was stirred at 80 °C for 1 h. It was cooled to room temperature and diluted with 10 mL of ether. The solid was collected by filtration and washed with ether to give 8 mg of the title compound as its HCI salt form. HPLC-MS tR = 2.88 min (UV 254nm)- Mass calculated for formula C21H26N8S2 454.2; observed MH+ (LCMS) 455.3 (m/z).
By essentially the same procedure set forth in Example 94, only replacing piperidine with other respective aliphatic amines in Step B, compounds shown in column 2 of Table 23 were prepared. TABLE 23
Figure imgf000251_0001
EXAMPLE 95
By essentially the same procedure set forth in Example 94, only replacing sodium methanethiolate with sodium benzenethiolate in Step A, and employing the respective aliphatic amines to replace piperidine in Step B, compounds shown in column 2 of Table 24 were prepared.
TABLE 24
Figure imgf000251_0002
Figure imgf000252_0002
EXAMPLE 96
Figure imgf000252_0001
A stirred solution of dimethylsulfone (281 mg, 2.99 mmol) in 5 mL of DMF was treated with sodium t-butoxide (287 mg, 2.99 mmol) at room temperature for 5 min. Aldehyde was then added. The reaction was stirred at room temperature for 15 min. It was quenched with saturated aqueous NH4CI solution (5 mL). The mixture was diluted with 50 mL of water and extracted with 50 mL of EtOAc/hexanes (1 :1 ), followed by 25 mL of EtOAc. The combined organic phase was washed with brine and then concentrated. The residue was purified by column chromatography (SiO2, 50% EtOAc/hexanes) to give 270 mg of the title compound, δ 7.90 (s, 1 H), 7.82 (s, 1 H)1 7.68 (s, 1 H), 7.60 (s, 1 H)1 7.20 (s, 1 H)1 6.67 (brs, 2H)1 5.55 (s, 2H)1 5.34-5.47 (brs, 1 H)1 3.90-3.98 (brs, 1 H)1 3.78 (t, 2H)1 3.68 (t, 2H)1 3.10 (s, 3H)1 2.58 (s, 3H), 0.95 (m, 4H), 0.02 (s, 9H), -0.10 (s, 9H). By essentially the same procedure set forth in Step B and Step C in Example pounds shown in column 2 of Table 25 were prepared.
TABLE 25
Figure imgf000253_0001
EXAMPLE 97
Figure imgf000254_0001
The compounds shown in column 2 of Table 24 were prepared according to the above reaction scheme and employing the following general procedures.
Step A: To a stirred solution of compound alcohol (1.00 g, 1.70 mmol) in 20 mL of THF, was added Dess-Martin periodinane (1.84 g, 4.26 mmol) and a trace amount of water. The reaction was stirred at room temperature for 40 min. It was diluted with 200 mL of CH2CI2, and washed with water and brine. The organic was dried over anhydrous Na2SO4. The solvent was removed under vacuum. The residue was purified by column chromatography (SiO2, 40% EtOAc/hexanes) to give 250 mg of the title compound.
Step B: To a solution of compound from Step A (0.05 mmol) in 1 mL of CH2CI2/MeOH (1 :1 ) was added the respective amine (5 equivalent) and a trace amount of trifluoroacetic acid. The mixture was stirred at room temperature for 30 min when NaBH4 (10 equivalent) was added. The stirring was continued for additional 10 min. The reaction was quenched with saturated aqueous NH4CI solution. The mixture was extracted with CH2CI2. The organic was concentrated and the residue was purified by column chromatography (SiO2, 5% 7 N NH3 in MeOH/ CH2CI2) to give title compound. Step C: To a solution of compound from Step B(0.05 mmol) in 1 mL of THF/MeOH (1 :1), was added 1 mL of 4 N HCI in dioxane. The reaction was stirred at 80 °C for 30 min. It was cooled to room temperature and diluted with 10 mL of ether. The solid was collected by filtration to afford compound 97-1 and 97-2, respectively. TABLE 26
Figure imgf000255_0001
EXAMPLE 98
Figure imgf000256_0001
Part A: To a solution of the isothiazole-aldehyde (534 mg; 0.9 mmol) in anhydrous THF (9 mL) was added methyl magnesium bromide (3M; 1.8 mL) at room temperature. After stirring for 20 min, the reaction mixture was quenched with 5 mL of saturated aqueous NH4CI solution and diluted with CH2Ck. The organic layer was washed with water and brine. The aqueous layer was back extracted with CH2CI2. The combined organic layers were dried over sodium sulfate and concentrated to obtain the crude product. Flash silica gel chromatography (EtOAc: CH2CI2 = 2:1 ) gave the desired carbinol as a white solid (460 mg; 84%) along with unreacted aldehyde (50 mg). 1H-NMR (CDCI3): 7.9 (s, 1 H); 7.8 (s, 1 H); 7.65 (s, 1 H); 7.55 (s, 1 H); 7.1 (s, 1 H); 6.75-6.65 (br-dd, 2H); 5.55 (s, 2H); 4.95 (t, J = 3 Hz, 1 H); 3.8 (t, J = 6 Hz, 2H); 3.7 (t, J = 6 Hz, 2H); 2.55 (s, 3H); 1.6 (d, J = 3 Hz, 3H); 1.0 (m, 2H); 0.05 (s, 9H); -0.05 (s, 9H). Part B: Triethylamine (136mg; 1.35mmol) and methanesulfonyl chloride (88 mg; 0.77 mmol) were added to a solution of the carbinol from Part A (232 mg; 0.39 mmol) in 12 mL of THF at room temperature. After 10 min, the reaction was quenched with water and diluted with CH2CI2. The organic layer was washed with water and brine, dried over Na2SO4_and concentrated to obtain crude product. Rapid elution with CH2CI2: EtOAc (2:1) from a flash silica gel column gave the desired mesylate as white solid (268 mg; 100%). 1H-NMR (CDCI3): 7.9 (s, 1 H); 7.8 (s, 1 H); 7.65 (s, 1 H); 7.55 (s, 1 H); 7.3 (S, 1 H); 6.7 (br-s, 2H); 5.85 (q, J = 4 Hz, 1 H); 5.55 (s, 2H); 3.8 (t, J = 6 Hz, 2H); 3.7 (t, J = 6 Hz, 2H); 2.95 (s, 3H); 2.6 (s, 3H); 1.85 (d, J = 4 Hz, 3H); 1.0 (m, 2H); 0.05 (s, 9H); -0.05 (s, 9H).
Part C: A solution of the mesylate (40 mg; 0.06 mmol) in 2 mL of anhydrous THF was treated with hexamethyleneimine (15 mg; 0.15 mmol) plus a catalytic amount of NaI and the mixture was heated at reflux in an oil bath (8O°C; 20 h). The reaction mixture was cooled to room temperature and diluted with water and CH2CI2. The organic layer was washed with water, brine and dried over Na2SO4. Concentration in vacuo gave the crude product. Purification was carried out on flash silica gel column, eluting the product with CH2CI2 containing 2-4% of 7N-Ammonia in methanol. The desired di- SEM protected amine product was obtained as a colorless film (31 mg; 75%). 1H-NMR (CDCI3): 7.9 (s, 1 H); 7.8 (s, 1 H); 7.65 (s, 1 H); 7.55 (s, 1 H); 7.3 (s, 1 H); 6.6 (br-s, 2H); 5.55 (s, 2H); 4.0 (br-s, 1 H); 3.8 (t, J = 6 Hz, 2H); 3.7 (t, J = 6 Hz, 2H); 2.8 (br-s, 4H); 2.6 (s, 3H); 1.75-1.5 (m, 11 H); 1.0 (m, 2H); 0.05 (s, 9H); -0.05 (s, 9H). Part D: To a solution of the above di-SEM protected amine from Part C (31 mg; 0.045 mmol) in 0.2 mL of THF and 0.2 mL of CH3OH was added 4N-HCI in dioxane (0.2 mL). The resulting mixture was heated at 8O°C in an oil bath for 30 min and then allowed to cool to room temperature. THF (2 mL) was added to the reaction mixture and the precipitated product was collected by filtration. The filer cake was washed with THF and ether and dried under vacuum to obtain the title product as white solid (23 mg). By using appropriate Grignard reagents in the first step and appropriate amine in the third step in the procedures described above, all the target compounds listed in Table 1 were prepared and characterized. TABLE 27
Figure imgf000258_0001
Figure imgf000259_0001
Figure imgf000260_0002
EXAMPLE 99
Figure imgf000260_0001
The substrate (500 mg) was suspended in f-BuOH (30 mL), and Et3N (0.45 mL) and DPPA (0.73 mL) was added sequentially at room temperature. Then the mixture was heated at 85 °C overnight. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was taken up in ethyl acetate (50 mL) and water (50 mL) was added. The biphasic mixture was stirred for 15 min. Then two layers were separated, and the aqueous layer was extracted with ethyl acetate (2 * 50 mL). The combined organic layer was washed with brine (50 mL), dried (Na2SO4), filtered and evaporated under reduced pressure to give the crude product which was purified by column chromatography (SiO2). HPLC-MS tR = 1.70. Mass calculated for CnH15NO3S 241.08; observed MH+ (LCMS) 242.2 (m/z) (UV254nm). EXAMPLE 100
Part C
Figure imgf000261_0001
Part A: Diacid (3 g) was suspended in CH2CI2 (50 mL), and N1O- dimethylhydroxylamine hydrochloride (1.69 g), HATU (6.6 g) and diisopropylethylamine (12.12 mL) was added sequentially at room temperature. The reaction mixture was stirred overnight, and quenched by addition of water (100 mL).
The two layers were separated. The aqueous layer was acidified to pH 4.0, and extracted with CHCb (5 * 100 mL). The organic layers were combined, and dried
(Na2SO4), filtered and evaporated under reduced pressure to give the product. HPLC- MS tR = 1.14. Mass calculated for C8H9NO4S 215.03; observed MH+ (LCMS) 216.1
(m/z) (UV254nm).
Part B: The substrate from Part A (3.2 g) was suspended in f-BuOH (100 mL), and EtβN (2.27 mL) and DPPA (3.64 mL) was added sequentially at room temperature. Then the mixture was heated at 85 CC overnight. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was taken up in ethyl acetate (100 mL) and water (100 mL) was added. The biphasic mixture was stirred for 15 min. Then two layers were separated, and the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The combined organic layer was washed with brine (150 mL), dried (Na2SO4), filtered and evaporated under reduced pressure to give the crude product which was purified by column chromatography (SiO2). HPLC-MS tR = 1.55. Mass calculated for C12H18N2O4S 286.1 ; observed MH+ (LCMS) 287.2 (m/z) (UV254Hm)-
Part C: The substrate from Part B (191 mg) was dissolved in THF/Et2O (3mL/6mL) and cooled to 0 °C. Then methylmagnesium bromide (0.83 mL, 2.0 M solution) was added dropwise. The reaction mixture was warmed to room temperature, and stirred for 12 h and quenched by addition of saturated ammonium chloride (10 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layer was washed with brine (30 mL), dried (Na2SO4), filtered and evaporated under reduced pressure to give the crude product which was purified by column chromatography (SiO2).
Part D: The substrate from Part C (10 mg) was dissolved in 30% TFA in CH2CI2 (2 mL), and the mixture was stirred for 30 min. Then the solvent was evaporated under reduced pressure and the residue was dried in vacuum. The crude product was used in the next step without further purification.
Part E: The sulfone (574.19 mg) and amine trifluoroacetic acid salt (514 mg) was dissolved in DMF (15 mL) under argon and treated with NaH (432 mg, 60% dispersion in oil). After LCMS indicated complete conversion of starting material to product, the reaction mixture was quenched with saturated ammonium chloride solution (15 mL). Then ethyl acetate (25 mL) was added. The two layers were separated, and the aqueous layer was extracted with ethyl acetate (25 mL). The combined organic layer was washed with brine (30 ml), dried (Na2SO4), filtered and evaporated under reduced pressure to give the crude product which was purified by column chromatography (SiO2). HPLC-MS tR = 2.31. Mass calculated for C22H28N6O2SSi 468.2; observed MH+ (LCMS) 469.1 (m/z) (UV254nm).
Part F: Ketone (25 mg) was suspended in Ti(O-Z-Pr)4 (1 mL) and treated with piperidine (0.2 mL) under argon. The mixture was stirred at room temperature overnight. Then methanol (2 mL) was added followed by NaBH4 (10 mg). The reaction mixture was stirred for additional 30 min. and quenched by addition of 2M aqueous NaOH (5 mL). It was filtered, and ethyl acetate (5 ml) was added to the filtrate. The two layers were separated, and the aqueous layer was extracted with ethyl acetate (5 ml). The combined organic layer was dried (Na2SO4), filtered and evaporated under reduced pressure to give the crude product which was taken to the next step without further purification.
Part G: The substrate was dissolved in 4N HCI in dioxane and stirred for 30 min. LCMS indicated complete conversion of starting material to the product. Then solvent was evaporated under reduced pressure, and the crude material was purified by reverse phase HPLC. HPLC-MS tR = 1.28. Mass calculated for C21H25N7S 407.2; observed (M-84)+ (LCMS) 323 (m/z) (UV254nm).
The compounds in Table 28 were prepared following similar procedure.
TABLE 28
Figure imgf000263_0001
EXAMPLE 101
Figure imgf000264_0001
Step A: To a solution of 2-ethoxyethylamine (2.0 g, 22.4 mmol) in diethyl ether (40 mL) at 0 °C was added trifluoroacetic anhydride (4.7 g, 22.4 mmol) dropwise. The reaction was stirred at room temperature for 1 hr. Potassium carbonate (10 g) was added to the reaction solution. The reaction was stirred at room temperature for 1 hr. The mixture was filtered through Celite and the organic filtrate was concentrated to give 1.5 g (36% yield) of the title compound.
Step B: A solution of the (trifluoromethyl)acetamide from Step A (1.5 g, 8.1 mmol) in Et2θ (20 mL) was added to a flask charged with lithium aluminum hydride (0.92 g, 24.3 mmol) in Et2θ (20 mL). The reaction was stirred at room temperature for 30 min, then at reflux for 12 hr. The reaction was cooled to room temperature and quenched with MeOH until the bubbling ceased. The reaction was diluted with Et2θ (30 mL) and filtered through a pad of Celite. The filtrate was concentrated by distillation to give 0.5 g (36% yield) of title compound as a colorless liquid. The amine was used without further purification.
EXAMPLE 102
F
Figure imgf000264_0002
Step A: To a solution of 2-ethoxyethylamine (1.0 g, 11.2 mmol) in dichloromethane (50 mL) at 0 °C was added pyridine (2.2 g, 28.1 mmol). Difluoroacetic anhydride (2.3 g, 13.5 mmol) was then slowly added to the reaction solution. The reaction was further stirred at 0 °C for 15 min, then at room temperature for 2.5 hr. The reaction was diluted with dichloromethane (50 mL) and H2O (20 mL). The reaction was sequentially washed with 1 N HCI (aq); saturated NaHCO3 (aq); brine. The organic phase was dried over NaSCU and concentrated in vacuo to give 1.03 g (55% yield) of the (difluoromethyl)acetamide as a colorless liquid.
Step B: A solution of the (difluoromethyl)acetamide from Step A (1.04 g, 6.20 mmol) in Et2O (21 mL) was added to a flask charged with lithium aluminum hydride (0.47 g, 12.39 mmol) in Et2O (25 mL) at 0 °C while under a N2 atmosphere. The reaction was stirred under a N2 atmosphere at room temperature for 2 hr. The reaction was quenched by the sequential addition of 0.47 mL of H2O; 0.47 mL of 15 % NaOH (aq) solution; 1.4 mL H2O. The reaction was stirred at room temperature for 15 min then filtered through a pad of Celite. The filtrate was concentrated by distillation to give 0.79 g (83% yield) of the title compound as a colorless liquid. The amine was used without further purification.
EXAMPLE 103
Figure imgf000265_0001
Step A: To a solution of 1-amino-1-cyclopentane methanol (1.0 g, 8.68 mmol) in dichloromethane (35 mL) at 0 °C was added pyridine (2.4 g, 30.4 mmol). Trifluoroacetic anhydride (4.6 g, 21.7 mmol) was then slowly added to the reaction solution. The reaction was further stirred at 0 °C for 15 min, then at room temperature for 16 hr. The reaction was sequentially washed with 1 N HCI (aq); saturated NaHCO3 (aq); brine. The organic phase was dried over NaSO4 and concentrated in vacuo to give 1.07 g (60% yield) of the title compound as a light brown liquid. The title compound was used directly in the next reaction (Step B) without further purification. Step B: A solution of the (trifluoromethyl)acetamide from Step A (0.64 g, 3.06 mmol) in Et2O (10 mL) was added to a flask charged with lithium aluminum hydride (0.35 g, 9.1 mmol) in Et2O (30 mL) at 0 °C while under a N2 atmosphere. The reaction was stirred under a N2 atmosphere at 0 °C for 30 min, then at room temperature for 19 hr. The reaction was cooled to room temperature and stirred for 3 days. The reaction was then cooled to 0 °C and quenched by the sequential addition of 0.35 mL of H2O; 0.35 mL of 15 % NaOH (aq) solution; 1.05 mL H2O. The reaction was stirred at room temperature for 20 min then filtered through a pad of Celite. The filtercake was washed with Et2O and concentrated in vacuo to give 0.39 g (65% yield) of the title compound as a white solid. The amine was used without further purification.
EXAMPLE 104
Figure imgf000266_0001
Step A: To a solution of 2-amino-2-methyl-1-propanol (1.0 g, 11.2 mmol) in dichloromethane (100 mL) at 0 °C was added pyridine (3.1 g, 39.6 mmol). Trifluoroacetic anhydride (5.9 g, 28.1 mmol) was then slowly added to the reaction solution. The reaction was further stirred at 0 °C for 15 min, then at room temperature for 16 hr. The reaction was sequentially washed with 1 N HCI (aq); saturated NaHCO3 (aq); brine. The organic phase was dried over NaSO4 and concentrated in vacuo to give 0.79 g (38% yield) of the title compound as a white solid. Step B: A solution of the (trifluoromethyl)acetamide from Step A (0.79 g, 4.29 mmol) in Et2O (43 mL) was added to a flask charged with lithium aluminum hydride (0.49 g, 12.91 mmol) in Et2O (13 mL) at 0 °C while under a N2 atmosphere. The reaction was stirred under a N2 atmosphere at 0 °C for 30 min, then at reflux for 4 hr. The reaction was cooled to room temperature and stirred for 3 days. The reaction was then cooled to 0 °C and quenched by the sequential addition of 0.49 mL of H2O; 0.49 mL of 15 % NaOH (aq) solution; 1.47 mL H2O. The reaction was stirred at room temperature for 20 min, then filtered through a pad of Celite. The filtercake was washed with Et2O and concentrated in vacuo to give 0.67 g (92% yield) of the title compound as a white solid. The amine was used without further purification.
EXAMPLE105
Figure imgf000266_0002
Step A: To a solution of 2-amino-2-methyl-1-propanol (1.0 g, 11.2 mmol) in dichloromethane (50 mL) at 0 °C was added pyridine (2.7 g, 33.7 mmol). Difluoroacetic anhydride (3.9 g, 22.4 mmol) was then slowly added to the reaction solution. The reaction was further stirred at 0 °C for 15 min, then at room temperature for 2 hr. The reaction was diluted with dichloromethane (50 mL) and H2O (20 mL). The reaction was sequentially washed with 1 N HCI (aq); saturated NaHCO3 (aq); brine. The organic phase was dried over NaSO4 and concentrated in vacuo to give 2.04 g (74% yield) of the title compound as a colorless liquid.
Step B: A solution of the (difluoromethyl)acetamide from Step A (2.04 g, 8.31 mmol) in Et2O (17 mL) was added to a flask charged with lithium aluminum hydride (0.95 g, 24.92 mmol) in Et2O (50 mL) at 0 °C while under a N2 atmosphere. The reaction was stirred under a N2 atmosphere at room temperature for 2 hr. The reaction was quenched by the sequential addition of 0.95 mL of H2O; 0.95 mL of 15 % NaOH (aq) solution; 2.85 mL H2O. The reaction was stirred at room temperature for 15 min then filtered through a pad of Celite. The filtercake was washed with Et2O and concentrated in vacuo to give 1.23 g (97% yield) of the title compound as white needles. The amine was used without further purification.
EXAMPLE 106
Figure imgf000267_0001
Step A: Dess-Martin periodinane reagent (1.3 g; 3.1 mmol) was added to a solution of the isothiazole-alcohol (450 mg; 1 mmol) in 30 mL of THF containing 0.06 mL of water and the reaction mixture was stirred at room temperature for 45 min. The reaction was diluted with ether and filtered and washed with more ether. The filtrate was washed with saturated NaHCO3 solution, brine and dried. Concentration in vacuo gave the isothiazole aldehyde (418 mg; 93%). 1H-NMR (CDCI3): 10 (s, 1 H); 7.68 (s, 1 H); 7.65 (S, 1 H); 7.4 (s, 1 H); 7.3 (s, 1 H); 6.65 (s, 2H); 3.7 (t, J = 6 Hz, 2H); 2.6 (s, 3H); 1.95 (m,1 H); 1.1 (q, J = 2, 6 Hz, 2H); 1.0 (t, J = 6 Hz, 2H); 0.8 (q, J = 2, 6 Hz, 2H); -0.05 (s, 9H).
Step B: To a solution of sodium hydride (60% in mineral oil; 169 mg; 4.2 mmol) in a mixture of 3.6 mL of DMSO and 3.6 mL of THF cooled to -1O°C, was added a solution of trimethyl sulfonium iodide (863 mg; 4.2 mmol) in 3.6 mL of DMSO drop wise. This was followed by the addition of a solution of the aldyhyde (363 mg; 0.84 mmol) in 5.6 mL of anhydrous THF, added in one portion. After stirring at room temperature for one hour, the reaction mixture was quenched with ice water. The organic products were extracted with EtOAc. The combined aqueous layers were back extracted with ethyl acetate. All the organic extracts were pooled and washed with water, brine and dried over Na2SO4 and concentrated to obtain the crude product. Elution of the major spot from Flash silica gel using 25% EtOAc in hexanes gave the desired isothiazole epoxide (316 mg; 85%). 1H-NMR (CDCI3): 7.7 (s, 1 H); 7.35 (s, 1 H); 7.05 (s, 1 H); 6.8 (d, J = 4 Hz, 1 H); 6.5 (d, J = 4 Hz, 1 H); 4.05 (t, J = 2 Hz, 1 H); 3.7 (t, J = 6 Hz, 2H); 3.2 (t, J = 4 Hz, 1 H); 3.05 (t, J = 2 Hz, 1 H); 2.6 (s, 3H); 1.95 (m,1 H); 1.1 (q, J = 2, 6 Hz, 2H); 0.95 (t, J = 6 Hz, 2H); 0.8 (q, J = 2, 6 Hz, 2H); -0.05 (s, 9H). Step C: A solution of sodium methoxide in methanol (25% by wt; 4.5 mmol; 1 mL) was added to a solution of the epoxide (201 mg; 0.45 mmol) in a 1 :1 mixture of DMF- methanol (4 mL). The resulting solution was heated at 6O°C for 3.5 hr, then cooled to room temperature and quenched with water. Extracted the organic product with EtOAc, washed the organic extract with water and brine and dried over Na2SO4. Concentration gave the crude product. Purification by flash silica gel chromatography using 1 :1 mixture of CH2CI2 and EtOAc provided the desired methoxymethyl carbinol (180 mg; 84%) as colorless oil. 1H-NMR (CDCI3): 7.7 (s, 1 H); 7.35 (s, 1 H); 7.2 (s, 1 H); 6.7 (d, J = 4 Hz, 1 H); 6.58 (d, J = 4 Hz, 1 H); 5.0 (d, J = 2 Hz, 1 H); 3.7 (m, 3H); 3.5 (s, 3H); 2.95 (d, J = 14 Hz, 1 H); 2.6 (s, 3H); 1.95 (m,1 H); 1.05 (d, J = 4 Hz, 2H); 0.95 (t, J = 6 Hz, 2H); 0.8 (d, J = 4 Hz, 2H), -0.05 (s, 9H). Step D-F: This sequence of steps was carried out as described for Example 76 in 64% overall yield for the 3 step sequence. HPLC. HPLC-MS tR = 2.85. Mass calculated for C2IH27FN6OS = 430.2; observed (M-H)+ (LCMS) 431.2 (m/z) (UV254nm).
ASSAYS:
Aurora Enzyme Assay
An in vitro assay was developed that utilizes recombinant Aurora A or Aurora B as an enzyme source and a peptide based on PKA as the substrate. Aurora A Assay:
Aurora A kinase assays were performed in low protein binding 384-well plates (Corning Inc). All reagents were thawed on ice. Compounds were diluted in 100% DMSO to desirable concentrations. Each reaction consisted of 8 nM enzyme (Aurora A, Upstate cat#14-511), 100 nM Tamra-PKAtide (Molecular Devices, 5TAMRA- GRTGRRNSICOOH ), 25 μM ATP (Roche), 1 mM DTT (Pierce), and kinase buffer (10 mM Tris, 10 mM MgCI2, 0.01 % Tween 20). For each reaction, 14 μl containing TAMRA-PKAtide, ATP, DTT and kinase buffer were combined with 1 μl diluted compound. The kinase reaction was started by the addition of 5 μl diluted enzyme. The reaction was allowed to run for 2 hours at room temperature. The reaction was stopped by adding 60 μl IMAP beads (1 :400 beads in progressive (94.7% buffer A: 5.3% buffer B) 1X buffer, 24 mM NaCI). After an additional 2 hours, fluorescent polarization was measured using an Analyst AD (Molecular devices). Aurora B Assay:
Aurora B kinase assays were performed in low protein binding 384-well plates (Corning Inc). All reagents were thawed on ice. Compounds were diluted in 100% DMSO to desirable concentrations. Each reaction consisted of 26 nM enzyme (Aurora B, Invitrogen cat#pv3970), 100 nM Tamra-PKAtide (Molecular Devices, 5TAMRA-GRTGRRNSICOOH ), 50 μM ATP (Roche), 1 mM DTT (Pierce), and kinase buffer (10 mM Tris, 10 mM MgCI2, 0.01 % Tween 20). For each reaction, 14 μl containing TAMRA-PKAtide, ATP, DTT and kinase buffer were combined with 1 μl diluted compound. The kinase reaction was started by the addition of 5 μl diluted enzyme. The reaction was allowed to run for 2 hours at room temperature. The reaction was stopped by adding 60 μl IMAP beads (1 :400 beads in progressive (94.7% buffer A: 5.3% buffer B) 1X buffer, 24 mM NaCI). After an additional 2 hours, fluorescent polarization was measured using an Analyst AD (Molecular devices). ICgn Determinations:
Dose-response curves were plotted from inhibition data generated each in duplicate, from 8 point serial dilutions of inhibitory compounds. Concentration of compound was plotted against kinase activity, calculated by degree of fluorescent polarization. To generate IC50 values, the dose-response curves were then fitted to a standard sigmoidal curve and IC50 values were derived by nonlinear regression analysis.
Compounds of the present invention exhibit Aurora A IC50 values of about 4 nm to about 3000 nM, Aurora B IC50 values of about 13 nM to about 3000 nM, and p-HH3 IC50 values of about 1 nM to about 10,000 nM.
While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and other variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

Claims

CLAIMSWhat is claimed is:
1. A compound of Formula I:
Figure imgf000272_0001
Fo a I or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein: R is H, CN, -NR5R6, cycloalkyl, cycloalkenyl, heterocyclenyl, heteroaryl,
-C(O)NR5R6, -N(R5)C(O)R6, heterocyclyl, heteroaryl substituted with (CH2)i.3 NR5R6, unsubstituted alkyl, or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR5, heterocyclyl,
-N(R5)C(O)N(R5R6), -N(R5)-C(O)OR6, -(CH2)i-3-N(R5R6) and -NR5R6; R1 is H, halo, aryl or heteroaryl, wherein each of said aryl and heteroaryl can be unsubstituted or substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -
CH2OR5, -C(O)NR5R6, -C(O)OH, -C(O)NH2,
-NR5R6 (wherein the R5 and R6, together with the N of said -NR5R6, form a heterocyclyl ring), -S(O)R5, -S(O2)R5, -CN, -CHO, -SR5, -
C(O)OR5, -C(O)R5 and -OR5; R2 is H, halo, aryl, arylalkyl or heteroaryl, wherein each of said aryl, arylalkyl and heteroaryl can be unsubstituted or optionally independently be substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
-C(O)OH, -C(O)NH2, -NR5R6 (wherein the R5 and R6, together with the N of said -NR5R6, form a heterocyclyl ring), -CN, arylalkyl, -CH2OR5, -S(O)R5, -S(O2)R5, -CN, -CHO, -SR5, -C(O)OR5, -C(O)R5, heteroaryl and heterocyclyl; eterocyclyl-(CR7R8)n-X, heterocyclenyl-(CR7R8)n-XI heteroaryKCR7R8)n-X or aryl-(CR7R8)n-X wherein each of the heterocyclyl-, heterocyclenyl-, heteroaryl- or aryl- moieties of said R3 can be unsubstituted or substituted with one or more moieties, independently selected from the group consisting Of -CONR5R6, -OR5 and alkyl, n is 1-6,
X is selected from the group consisting of -NR5R6, -OR5, -SO-R5, -SR5, SO2R5, heteroaryl, heterocyclyl and aryl, wherein said heteroaryl or aryl can be unsubstituted or substituted with one or more moieties, independently selected from the group consisting of -O-alkyl, alkyl, halo, or NR5R6; R7 and R8 are each independently hydrogen, alkyl, heterocyclyl, aryl, heteroaryl or cycloalkyl; R5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxyalkyl,
-alkyl-S-alkyl, aminoalkyl, aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S- alkylheterocyclyl, heterocyclyl, heterocyclenyl, alkylN(alkyl)2, alkylNH(alkyl), alkylN(alkenyl)2, -alkylN(alkoxyl)2, -alkyl-SH, hydroxyalkyl, trihaloalkyl, dihaloalkyl, monohaloalkyl, wherein each of said alkyl, alkenyl, alkoxyalkyl, -alkyl-S-alkyl, aminoalkyl, aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S-alkylheterocyclyl, heterocyclyl, heterocyclenyl, alkylN(alkyl)2, alkylNH(alkyl), alkylN(alkenyl)2, -alkylN(alkoxyl)2, -alkyl-SH, hydroxyalkyl, trihaloalkyl, dihaloalkyl, monohaloalkyl can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkylSH, alkoxyl, -S- alkyl, hydroxyalkyl, and aminoalkyl; lected from the group consisting of hydrogen, alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkylSH, alkoxyl, -S- alkyl, hydroxyalkyl, aminoalkyl, -alkyl-OC(O)alkyl, -alkylOC(O)cycloalkyl,
-alkylOC(O)aryl, -alkylOC(O)aralkyl, -alkylOC(O)NR5aryl, - alkylOC(O)NR5alkyl, -alkylOC(O)NR5heterocyclyl, - alkylOC(O)NR5heteroaryl -alkylOC(O)NR5cycloalkyl, - alkylOC(O)heterocyclyl, alkylC(O)OH, alkylC(O)Oalkyl, - alkylC(O)Ocycloalkyl, -alkylC(O)Oaryl, -alkylC(O)Oaralkyl, - alkylC(O)ONR5aryl, -alkylC(O)ONR5alkyl, -alkylC(O)ONR5heterocyclyl, - alkylC(O)ONR5heteroaryl -alkylC(O)ONR5cycloalkyl, - alkylC(O)Oheterocyclyl, alkylC(O)OH, and alkylC(O)Oalkyl wherein each of said aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, -alkyl-OC(O)alkyl, - alkylOC(O)cycloalkyl, -alkylOC(O)aryl, -alkylOC(O)aralkyl, - alkylOC(O)NR5aryl, -alkylOC(O)NR5alkyl, -alkylOC(O)NR5heterocyclyl, - alkylOC(O)NR5heteroaryl -alkylOC(O)NR5cycloalkyl, - alkylOC(O)heterocyclyl, alkylC(O)OH, alkylC(O)Oalkyl, - alkylC(O)Ocycloalkyl, -alkylC(O)Oaryl, -alkylC(O)Oaralkyl, - alkylC(O)ONR5aryl, -alkylC(O)ONR5alkyl, -alkylC(O)ONR5heterocyclyl, - alkylC(O)ONR5heteroaryl -alkylC(O)ONR5cycloalkyl, - alkylC(O)Oheterocyclyl, alkylC(O)OH, and alkylC(O)Oalkyl,can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkylSH, alkoxyl, -S- alkyl, hydroxyalkyl, aminoalkyl, amino, aminodialkyl, aminocycloalkyl, halo, trihaloalkyl, dihaloalkyl, and monohaloalkyl; further wherein in any -NR5R6 in Formula I, said R5 and R6 can optionally be joined together with the N of said -NR5R6 to form a cyclic ring or bridged cyclic ring, wherein each of said cyclic ring or bridged cyclic ring, can be unsubstituted or substituted with one or more moieties, which can be the same or different, independently selected from the group consisting of hydroxyl, -SH, alkyl, alkenyl, hydroxyalkyl, -alkyl-SH, alkoxyl, -S-alkyl, - CO2-alkyl, -CO2-alkenyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, heteroaryl, aryl, cyclenyl, cycloalkyl, spiroheterocyclyl, spiroheterocyclenyl, spiroheteroaryl, spirocyclyl, spirocyclenyl, spiroaryl, alkoxyalkyl, -alkyl-S- alkyl, heterocyclyl, heterocyclenyl, halo, trihaloalkyl, dihaloalkyl, CN and monohaloalkyl.
2. The compound of claim 1 , wherein R2 is unsubstituted heteroaryl or heteroaryl substituted with alkyl.
3. The compound of claim 1 , wherein R2 is heteroaryl substituted with alkyl.
4. The compound of claim 1 , wherein R2 is pyrazolyl.
5. The compound of claim 1 , wherein R2 is pyrazolyl substituted with alkyl.
6. The compound of claim 1 , wherein R2 is 1-methyl-pyrazol-4-yl.
7. The compound of claim 1 , wherein R is H.
8. The compound of claim 1 , wherein R is CN.
9. The compound of claim 1 , wherein R is -C(O)NR5R6.
10. The compound of claim 1 , wherein R is -C(O)NH2.
11. The compound of claim 1 , wherein R is heterocyclenyl.
12. The compound of claim 1 , wherein R is tetrahydropyridinyl.
13. The compound of claim 1 , wherein R is 1 ,2,3,6-tetrahydropyridinyl.
14. The compound of claim 1 , wherein R is alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of -OR1 and -NR5R6.
15. The compound of claim 1 , wherein R is alkyl substituted with one or more - NR5R6.
16. The compound of claim 1 , wherein R is alkyl substituted with -NH2.
17. The compound of claim 1 , wherein R is alkyl substituted with -NH(methyl).
18. The compound of claim 1 , wherein R3 is heteroaryl substituted with heterocyclylmethyl.
19. The compound of claim 1 , wherein R3 is heteroaryl-CH2-X, wherein X is -OR5, -SOR5, -NR5R6, or -SR5; R5 is hydrogen, -alkylN(alkyl)2, heterocyclylalkyl or heterocyclenylalkyl; R6 is or R5 and R6 can optionally be joined together with the N of said -NR5R6 to form a cyclic ring or bridged cyclic ring, wherein said cyclic ring or bridged cyclic ring can be unsubstituted or substituted one or more moities, which can be the same or different, independently selected from the group consisting of hydroxyl, alkyl, alkoxyl, alkoxylalkyl, hydroxyalkyl, arylalkyl, aryl, heterospirocyclyl, heterospirocyclenyl, heterospiroaryl and -CO2alkyl.
20. The compound of claim 1 , wherein R3 is heteroaryl-CH2-X or heteroaryl- CHMethyl-X, wherein X is -NR5R6, R5 is -alkylN(alkyl)2, alkyl, alkoxyalkyl, hydroxyalkyl, arylalkyl, heterocyclenylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, or -alkylSH, wherein each of said arylalkyl, heterocyclenylalkyl, cycloalkyl, cycloalkylalkyl or heteroarylalkyl can be unsubstituted or substituted with hydroxyalkyl, alkoxyalkyl, alkyl, or hydroxyl; R6 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or - alkylN(alkyl)2; or R5 and R6 can optionally be joined together with the N of said -NR5R6 to form a cyclic ring or bridged cyclic ring, wherein said cyclic ring or bridged cyclic ring can be unsubstituted or substituted one or more moities, which can be the same or different, independently selected from the group consisting of hydroxyl, alkyl, alkoxyl, alkoxylalkyl, hydroxyalkyl, arylalkyl, aryl, heterospirocyclyl, heterospirocyclenyl, heterospiroaryl and -CO2alkyl.
21. The compound of claim 1 , wherein R3 is heteroaryl-CH2-X , wherein the heteroaryl of said heteroaryl-CH2-X is substituted with alkyl or -CONR5R6, wherein X is -NR5R6, R5 is alkyl, R6 is alkyl, or R5 and R6 are optionally joined together with the N of said -NR5R6 to form a cyclic ring.
22. The compound of claim 1 , wherein R3 is aryl-CH2-X , wherein the aryl of said aryl-CH2-X can be unsubsituted or substituted with alkyl, wherein X is heterbcyclyl.
23. The compound of claim 1 , wherein R3 is isothiazole, thiophene or pyrimidine substituted with:
Figure imgf000277_0001
\ /J \
24. The compound of claim
Figure imgf000278_0001
1 , wherein R3 is s— N ΓΛ x, \\ ^- a N
V wherein X is selected from the
Figure imgf000278_0002
Figure imgf000278_0003
group consisting of, -NR5R6, -OR5 -SO-R5 and -SR5,
R5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxyalkyl, -alkyl-S-alkyl, aminoalkyl, aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S- alkylheterocyclyl, heterocyclyl, heterocyclenyl, alkylN(alkyl)2, alkylNH(alkyl), alkylN(alkenyl)2, -alkylN(alkoxyl)2, -alkyl-SH and hydroxyalkyl, wherein each of said aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S- alkylheterocyclyl, heterocyclyl and heterocyclenyl can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of alkyl, alkoxyalkyl, and hydroxyalkyl; R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkylSH, alkoxyl, -S- alkyl, hydroxyalkyl, and aminoalkyl, wherein each of said aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl and heterocycloalkylalkyl can be unsubstituted or substituted with one or more alkyl, further wherein in any -NR5R6 in Formula I, said R5 and R6 can optionally be joined together with the N of said -NR5R6 to form a cyclic ring or bridged cyclic ring, wherein each of said cyclic ring or bridged cyclic ring, can be unsubstituted or substituted with one or moieties, which can be the same or different, independently selected from the group consisting of hydroxyl, -SH, alkyl, alkenyl, hydroxyalkyl, -alkyl-SH, alkoxyl, -S-alkyl, - CO2-alkyl, -CO2-alkenyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, heteroaryl, aryl, cyclenyl, cycloalkyl, spiroheterocyclyl, spiroheterocyclenyl, spiroheteroaryl, spirocyclyl, spirocyclenyl, spiroaryl, alkoxyalkyl, -alkyl-S- alkyl, heterocyclyl, and heterocyclenyl.
25. A compound represented by the formula:
Figure imgf000279_0001
Figure imgf000280_0001
Figure imgf000280_0002
Figure imgf000281_0001
Figure imgf000282_0001
Figure imgf000283_0001
Figure imgf000283_0002
or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
26. A compound according to claim 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, in purified form.
27. A compound according to claim 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, in isolated form.
28. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, in combination with at least one pharmaceutically acceptable carrier.
29. The pharmaceutical composition according to claim 28, further comprising one or more anti-cancer agents different from the compound of claim 2.
30. The pharmaceutical composition according to claim 29, wherein the one or more anti-cancer agents are 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, antibodies to IGFR (including, for example, those published in US 2005/0136063 published June 23, 2005), KSP inhibitors (such as, for example, those published in WO 2006/098962 and WO 2006/098961 ; ispinesib, SB-743921 from Cytokinetics), centrosome associated protein E ("CENP-E") inhibitors (e.g., GSK-923295), Gleevec®, intron, ara-C, adriamycin, Cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin,
Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN™, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine,
Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, Avastin, herceptin, Bexxar, bortezomib
("Velcade"), Zevalin, Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane, Fulvestrant, Ifosfomide, Rituximab, C225®, satriplatin, mylotarg, Avastin, Rituxan, panitubimab, Sutent, sorafinib, Sprycel (dastinib), nilotinib, Tykerb (lapatinib) and Campath.
31. A method of inhibiting one or more Aurora kinases, comprising administering a therapeutically effective amount of at least one compound of claim 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, to a patient.
32. A method of treating one or more diseases by inhibiting an Aurora kinase, comprising administering a therapeutically effective amount of at least one compound of claim 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, to a patient.
33. A method of treating one or more diseases by inhibiting an Aurora kinase, comprising administering to a mammal in need of such treatment an amount of a first compound, which is a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; and an amount of at least one second compound, the second compound being an anti-cancer agent different from the compound of claim 1 ; wherein the amounts of the first compound and the second compound result in a therapeutic effect.
34. The method according to any of claims 31 , 32, or 33, wherein the Aurora kinase is Aurora A.
35. The method according to any of claims 31 ,32, or 33, wherein the Aurora kinase is Aurora B.
36. The method according to any of claims 32 or 33, wherein the disease is selected from the group consisting of: tumor of the bladder, breast (including BRCA-mutated breast cancer, colorectal, colon, kidney, liver, lung, small cell lung cancer, non-small cell lung cancer, head and neck, esophagus, bladder, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T- cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma and Burkett's lymphoma; chronic lymphocytic leukemia ("CLL"), acute and chronic myelogenous leukemia, myelodysplastic syndrome and promyelocytic leukemia; fibrosarcoma, rhabdomyosarcoma; head and neck, mantle cell lymphoma, myeloma; astrocytoma, neuroblastoma, glioma, glioblastoma, malignant glial tumors, astrocytoma, hepatocellular carcinoma, gastrointestinal stromal tumors ("GIST") and schwannomas; melanoma, multiple myeloma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.
37. The method according to any of claims 31 , 32, or 33, further comprising radiation therapy.
38. The method according to claim 33, wherein the anti-cancer agent is selected from the group consisting of a cytostatic agent, cisplatin, doxorubicin, 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, Gleevec, intron, ara-C, adriamycin, Cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN™, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin,
Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone,
Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin, Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane, Fulvestrant, Ifosfomide, Rituximab, C225, Campath, Clofarabine, cladribine, aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine, SmM , fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, and MDL-101 ,731.
39. A method of inhibiting one or more kinases wherein said kinases are selected from the group consisting of cyclin dependent kinases, Checkpoint kinases, tyrosine kinases and Pim-1 kinases, comprising administering a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof to a patient in need of such inhibition.
40. A method of treating one or more diseases by inhibiting one or more kinases, wherein said kinases are selected from the group consisting of cyclin dependent kinases, Checkpoint kinases, tyrosine kinases and Pim-1 kinases, comprising administering a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof to a patient in need of such treatment.
41. The method of claim 39 or claim 40, wherein said cyclin dependent kinases are selected from CDK1 or CDK2, said Checkpoint kinases are selected from CHK-1 or CHK-2, and said tyrosine kinases are selected from the group consisting of VEGF-R2, EGFR, HER2, SRC, JAK and TEK.
42. A method of treating a cancer comprising administering a therapeutically effective amount of at least one compound of claim 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
43. A method of inhibiting one or more kinases wherein said kinases are selected from the group consisting of cyclin dependent kinases, Checkpoint kinases, tyrosine kinases and Pim-1 kinases, comprising administering a therapeutically effective amount of at least one compound of claim 25 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof to a patient in need of such inhibition.
44. A method of treating one or more diseases by inhibiting an Aurora kinase, comprising administering to a mammal in need of such treatment an amount of a first compound, which is a compound of claim 25, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; and an amount of at least one second compound, the second compound being an anti-cancer agent different from the compound of claim 25; wherein the amounts of the first compound and the second compound result in a therapeutic effect.
45. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim 25 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, in combination with at least one pharmaceutically acceptable carrier.
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