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WO2014088519A1 - Composés comprenant des modulateurs des kinases interagissant avec les map kinases 1 et 2 (mnk1 et mnk2) et des inhibiteurs d'abl et abl (t315i), et leurs utilisations - Google Patents

Composés comprenant des modulateurs des kinases interagissant avec les map kinases 1 et 2 (mnk1 et mnk2) et des inhibiteurs d'abl et abl (t315i), et leurs utilisations Download PDF

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WO2014088519A1
WO2014088519A1 PCT/SG2013/000519 SG2013000519W WO2014088519A1 WO 2014088519 A1 WO2014088519 A1 WO 2014088519A1 SG 2013000519 W SG2013000519 W SG 2013000519W WO 2014088519 A1 WO2014088519 A1 WO 2014088519A1
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alkyl
phenyl
compound
methyl
abl
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Joseph Cherian
Athisayamani Jeyaraj DURAISWAMY
Kassoum Nacro
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Agency for Science Technology and Research Singapore
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Definitions

  • the present invention relates to certain piperazine-based compounds that act as inhibitors of the MAP kinase interacting kinases and/or as inhibitors of ABL or ABL (T315I).
  • the invention further relates to pharmaceutical compositions comprising these compounds, and to the use of the compounds for the preparation of a medicament for the prophylaxis and treatment of cancer, inflammatory and Alzheimer disease conditions, as well as methods of treatment of these disorders.
  • MNKs 1 The human MAP Kinase-interacting kinases, also known as MAP Kinase signal- integrating kinases, (MNKs 1 ), are ubiquitously expressed protein-serine/threonine kinases that are directly activated by ERK or p38 MAP kinases ' . They comprise a group of four proteins derived from two genes (Gene symbols: MKNKl and MKNK2) by alternative splicing. MNKla/b and MNK2a/b proteins differ at their C-termini, in each case the a-form possessing a longer C-terminal region than the b-form which lacks the MAP Kinase-binding region. The N-termini of all forms contain a polybasic region which binds Importin a and the translation factor scaffold protein eukaryotic Initiation
  • eIF4G kinases Factor 4G.
  • MNK isoforms differ markedly in their activity, regulation, and in subcellular localization.
  • the best-characterized MNK substrate is eIF4E. Although the cellular role of eIF4E phosphorylation remains unclear, it may promote export of a defined set of mRNAs from the nucleus.
  • Other MNK substrates bind to AU-rich elements that modulate the stability/translation of specific mRNAs.
  • MNK1 is highly expressed in hematological malignancies 4 ' 5 and both MN 1 and MNK2 are up-regulated in solid tumors such as gliomas and ovarian cancers 6'7
  • the Eukaryotic Initiation Factor-4 E regulates the expression of genes involved in proliferation and survival as a cap dependent mRNA translation and mRNA export factor.
  • eIF4E is dysregulated in several human cancers, including breast 8 , prostate 9 , and some leukemias 10 , and elevated levels of eIF4E are a marker of poor prognosis 10 ' 11 .
  • overexpression and dysregulation of eIF4E leads to an increased tumor number, invasion, and metastases in mouse models and transgenic expression of eIF4E leads to a variety of cancers 11 ' 12.
  • eIF4E overexpression results in a specific increase in the translation of these weakly competitive mRNAs, many of which encode products that stimulate cell growth and angiogenesis, e.g., fibroblast growth factor 2 and vascular endothelial growth factor 13 " 15 , cyclin Dl 16 , and ri *bonucleotide reductase 17.
  • reducing eIF4E with antisense RNA or reducing its function by overexpression of the inhibitory 4E-BP proteins can suppress the oncogenic properties of many cell lines 8 ' 20 ' 21 .
  • both the expression and activity of eIF4E are regulated at multiple levels by growth factors and oncogenes 30 , suggesting that the protein is a nexus of converging transformation signaling pathways.
  • eIF4E is phosphorylated by the MN 1/2 serine/threonine kinases in response to activation by mitogenic and stress signals downstream of ERK1/2 and p38 MAP kinase respectively 2 ' 3 .
  • eIF4E phosphorylation at serine 209 by MNK1/2 is required to promote its transformation activity 31 ' 32 .
  • MNK1/2 is dispensable for normal cell growth and development 33 ' 34
  • MNK phosphorylation of eIF4E on Ser-209 is believed to be critical to eIF4E oncogenic activity 32.
  • the current consensus is that a high level of either eIF4E or phosphorylated eIF4E leads to tumorigenesis by promoting the translation of low affinity oncogenic mRNA.
  • Mcl-l is a Bcl2 family member with a very short half-life, and Mcl-l mRNA translation highly depends on eIF4E.
  • Blast crisis chronic myeloid leukemia is characterized by an expansion of a population of granulocyte macrophage progenitor-like cells (GMPs) that have acquired self-renewal capacity, a feature not seen in normal or chronic phase (CP) GMPs.
  • GMPs granulocyte macrophage progenitor-like cells
  • CP chronic phase
  • the ability to self-renew is thought to be mediated by ⁇ -catenin activation, and may contribute to disease persistence, as well as activity as a reservoir for drug resistance.
  • the mechanisms contributing to ⁇ -catenin activation remain obscure, and will need to be identified to improve the control of BC-CML.
  • the role of the translation machinery in mediating ⁇ -catenin-mediated self-renewal was investigated, since prior work had implicated aberrant mRNA translation in drug-resistance and BC
  • eIF4E activates beta-catenin signaling via a two-step mechanism. First, eIF4E overexpression increased total cell beta-catenin. Second, eIF4E phosphorylation facilitated beta-catenin nuclear translocation.
  • mice were treated with vehicle, CGP-53780 (40 mg kg/d), or Dasatinib (5mg/kg/d) for three consecutive weeks.
  • human CD34+ cells were isolated from the mice, and transplanted into a second recipient mouse.
  • CGP57380 but not Dasatinib
  • BC cells from serially transplanting NSG mice.
  • MNK inhibition prevents, eIF4E phosphorylation and beta-catenin signaling in BC GMPs; and 4. MNK inhibition prevents BC GMPs from functioning as leukemia stem cells.
  • eIF4E and the degree of eIF4E phosphorylation is regulated by pathways that include the P38 kinase, MAPK kinase and Akt/mTOR pathways as shown in Figure 1.
  • Inhibitors of mTOR such as rapamycin, decrease the level of phosphorylated eIF4E .
  • mTOR inhibitors as single agents, have proven efficacious in several cancer types such as transplant-associated lymphoma 43;44 and Kaposi sarcoma 43;44 , tuberous sclerosis-related astrocytoma 41 ' 42 , and mantle cell and other non-Hodgkin lymphomas 46 .
  • Two mTOR inhibitors are currently marketed for the treatment of the renal cell carcinoma 47,48 .
  • rapamycin Inhibition of mTOR by rapamycin also suppresses mTOR catalyzed phosphorylation of EBP1 leading to an increased level eIF4E-EBPl. Consequently, rapamycin inhibits translation initiation by decreasing the phosphorylation of eIF4E- binding proteins, thus decreasing eIF4E availability to the initiation complex.
  • Combination therapy with MNK1/2 and mTOR kinases inhibitors could be a viable strategy to treat certain types of cancer 52.
  • a Novartis patent claimed MNK and mTOR combination therapy with small molecules, antibodies and siRNA for the treatment of cancer 55 , and recent findings support that MNK and mTOR combination induces apoptosis in cutaneous T cell lymphoma cells 40 .
  • Macrophages are major effectors of innate immunity, stimulated by a broad variety of bacterial products through specific TLRs on the cell surface to produce proinflammatory cytokines, such as TNF.
  • E. coli LPS is a potent stimulus to macrophage gene expression, especially TNF, by engaging the TLR4 membrane signaling complex 54 . It was shown that TLR signaling pathways require MNK expression through the use of a panel of commercial TLR agonist panel on macrophage.
  • TNF production was increased as a response to Salmonella LPS (TLR4), ODN2006 (TLR9), HKLM (TLR2), FSL (TLR6/2) and imiquimod (TLR7) stimulation.
  • TLR4 Salmonella LPS
  • TLR9 ODN2006
  • HKLM TLR2
  • FSL TLR6/2
  • imiquimod TLR7
  • hnRNPAl heterogeneous nuclear ribonucleoprotein Al
  • MNKl/2 cytoplasmic stress granules
  • hnRNPAl exit the nucleus bound to poly(A) mRNA and this complex is required for hnRNPAl phosphorylation by MNKl/2 and for its relocalization to the cytoplasmic SGs.
  • Phosphorylation of hnRNPAl by MNKl/2 reduces its binding affinity to 3'UTR mRNA and consequently MNK inhibition enhances hnRNAPAl association with TNF mRNA.
  • TNF gene transcript level is undetectable in unstimulated TCell and greatly increased upon stimulation.
  • MNK inhibition effect on TNF appears to be more at the translation level as MNK inhibition has no influence on the level of TNF mRNA 57 .
  • the formation of SG is reported to be prevented by MNK inhibition thus removing the protection that was offered by the SGs where the phosphorylated hnRNPAl bound mRNA could localize.
  • MNK inhibitors can regulate the innate immune response in macrophage.
  • a compound with anti-inflammatory properties will inhibit the release of proinflammatory cytokines. It has been shown that CGP57380, a MNK inhibitor, inhibits the release of TNF alpha by macrophage 59 (and not eIF4E). According to WO2005/003785 A2 MNK kinases are promising targets for anti-inflammatory therapy.
  • MNKs was also reported to phosphorylate a number of different proteins in addition to eIF4E. Three of these are hnRNPAl 58 , cPLA2 and Sprouty2 60;61 . Their role and function is still being investigated. Of these substrates hnRNPAl is overexpressed in colorectal cancer and it could contribute to maintenance of telomere repeats in cancer cells with enhanced cell proliferation 62. It is also reported that the expression levels of hnRNPA/B is deregulated in non-small cell lung cancer 63 .
  • MNK inhibitors are useful in the treatment of cancers including breast 66 , protate 11 , hematological malignancies (CML, AML), head and neck, colon 67 , bladder, prostatic adenocarcinoma, lung, cervical, and lymphomas 68 ' 69 .
  • the Philadelphia chromosome genetic abnormality is a hallmark of CML. This genetic abnormality arises from the chromosomal translocation, in which parts of two chromosomes, 9 and 22, swap places. This fusion gene created by juxtaposing the ABL 1 gene on chromosome 9 (region q34) to a part of the BCR ("breakpoint cluster region") gene on chromosome 22 (region ql l), functions as a constitutively activated
  • BCR-ABL tyrosine kinase tyrosine kinase. 71 ' 72
  • various molecular weight isoforms of BCR-ABL are
  • BCR-ABL hyper activity triggers intracellular signal transduction pathways that promote proliferation and genetic instability while suppressing apoptosis
  • BCR-ABL Biochemical signaling pathways known to be activated by BCR-ABL include RAS, mitogen activated protein kinase, c-Jun NH 2 - terminal kinase/stress activated protein kinase, phosphatidylinositol 3 -kinase (PI3-K), nuclear factor- ⁇ , CRK oncogene-like protein/focal adhesion kinase, and signal transducer and activator of transcription. These and other pathways are activated by BCR-ABL kinase activity. Based on its role in malignant transformation, BCR-ABL has served as a target for therapeutic intervention in CML. Imatinib, Dasatinib, Nilotinib and Bosutinib are some of the clinically used therapies, inhibiting Bcr-Abl in addition to other kinases. 79 ' 80
  • T315I represents about 15-20 percent of all clinically observed BCR-ABL mutations. Therefore, development of a T315I inhibitor represents a significant unmet medical need in CML.
  • the present invention relates to compounds that act as kinase inhibitors, in particular as inhibitors of the MAP kinase interacting kinases 1 and 2 (MNK1 and MNK2).
  • the present invention relates to compounds that act as ABL or ABL (T315I) inhibitors, in particular as inhibitors BCR-ABL kinase activity.
  • a compound of the present invention is of Formula (I):
  • R is hydrogen or alkyl
  • X is O, N(R 1 ) 2 , or C(R 2 ) 2 , wherein each R 1 and R 2 can be the same or different and is hydrogen or alkyl;
  • Y is hydrogen, halo, or alkyl
  • Z is an optionally substituted heterocyclyl.
  • Y is hydrogen, fluoro, chloro, or methyl.
  • Z is pyridyl, azaindolyl, or azaindazolyl, any of which is optionally substituted.
  • Z is pyridyl, 7-azaindole, 7-azaindazole, any of which is optionally substituted.
  • Z is:
  • the present invention relates to pharmaceutical compositions comprising these compounds and to their use for the preparation of a medicament for the prophylaxis and treatment diseases associated with a dysfunction linked to MNKl and MNK2 pathway, where MNKl and MNK2 play a role (MNK overexpression, eIF4E overexpression, P38 MAPK kinase pathway), such as but not limited to, neoplastic diseases (leukemias and other hematological magnilancies and solid tumors), inflammatory and autoimmune conditions, Alzheimer's disease, metabolic disorders (obesity, diabetes) as well as methods of treatment of these disorders using compounds described herein as single agents or in combination with one or more additional agents.
  • MNK overexpression, eIF4E overexpression, P38 MAPK kinase pathway such as but not limited to, neoplastic diseases (leukemias and other hematological magnilancies and solid tumors), inflammatory and autoimmune conditions, Alzheimer's disease, metabolic disorders (obesity, diabetes) as well as methods of
  • an additional agent is a kinase inhibitor. In some embodiments, an additional agent is an mTOR inhibitor. In some embodiments, an additional agent is a PI3-kinase inhibitor.
  • Exemplary PI3-kinase inhibitors include wortmannin, demethoxyviridin, LY294002, perifosine, CAL101, PX-886, BEZ235, SF1126, INK1117, INK1 197, IPI-145, GDC-0941, BKM120, XL147, XL765, palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100-115, CAL263, PI-103, GNE-477, CUDC-907, GSK 2126458, GDC-0980, PF-46915032, CAL263, SF1126 and PX-886.
  • the PI3-kinase inhibitor inhibits ⁇ 3 ⁇ - ⁇ , ⁇ 3 ⁇ - ⁇ , PI3K- ⁇ , and/or PI3K-5.
  • an additional agent is an inhibitor of KIT, RET, PDGFR, EGFR, VEGFR, FLT3, BRAF or SRC.
  • the present invention relates to pharmaceutical compositions comprising these compounds and to their use for the preparation of a medicament for the prophylaxis and treatment diseases associated with a dysfunction linked to ABL or ABL (T3151) activity, in particular BCR-ABL kinase activity.
  • the present invention describes methods for the synthesis and isolation of compound of formula (I).
  • FIG. 1 Pathway connection between MNK and mTOR. Schematic illustration depicting the cellular pathways that lead to eIF4E activation and phosphorylation by Mnkl/2.
  • the PI3K/Akt/mTORCl pathway which is frequently activated in human cancers, releases 4E-BPs from eIF4E, and enables eIF4E to bind eIF4G, which, in turn, assembles the eIF4F complex comprising eIF4E, eIF4G, eIF4A, and eIF3.
  • Mnkl and Mnk2 which are activated by Erk and by the stress inducible kinase p38, use eIF4G as a docking site to phosphorylate efficiently eIF4E.
  • the phosphorylation of eIF4E is critical for its oncogenic activity, probably through the differential translation of proteins that are required for oncogenesis.
  • the phosphorylation of eIF4E by Mnkl/2 provides a new avenue for cancer therapy.
  • the inhibition of eIF4E phosphorylation could have similar consequences as the inhibition mTORCl by rapalaogs, but with the advantage that it does not elicit the activation of Akt as a result of the inhibition of the negative feedback loops mediated by mTORCl. Reproduced from PNAS 2010, 107 (32), 13975-13976.
  • Figure 2 Results from the effects of ETC036 and ETC037 on serial replating efficiency of Blast Crisis Chronic Myelogenous Leukemia (BC-CML) primary cells.
  • Colony forming and serial replating assays were performed on normal and BC- CML primary samples.
  • CD34+ from (A) cord blood and (B) BC-CML were treated with various ETC drugs for 48 hr. 48 hr post drug treatment, 1 x 104 cells were plated for CFC; colonies were enumerated and individually picked for serial replating. The serial replating efficiency will be assessed by the ability of individual clones to replate to the third plating over 8 weeks and displayed as percentage relative to the first colony forming assay readout.
  • ETC-027 and ETC-219 inhibited K562-eIF4E tumor growth in a dose response manner.
  • ETC-027 achieves a tumor growth inhibition of 43%; 83% and lOP/o for 50, 100 and 200 mg kg respectively.
  • ETC-219 achieves a tumor growth inhibition of 98% and 110%o for 50 and 100 mg/kg respectively.
  • ETC-027 and ETC-219 inhibit self renewal at a concentration as low as 0.5 nM and no colony is seen after the third replating. No colony grows at concentrations, >50 nM for ETC-027 and > 1 nM for ETC-219, respectively.
  • ETC-027 and ETC-219 show superior ability to inhibit GMPs self renewal as compared to commercial TKIs.
  • Table 17 Compounds synthesized according to method of Example 19 [00055] Table 18 Compounds synthesized according to method of Example 20 [00056] Table 1 Compounds synthesized according to method of Example 23 [00057] Table 20 Compounds synthesized according to method of Example 24 [00058] Table 21 Summary of biological activity of several compounds. Shown are the IC 50 values for various compounds in the inhibition of MNK1 and MNK2, as well as in the inhibition of phosphorylation of eIF4E in HeLa cells.
  • the phrase "at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.
  • This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase "at least one" refers, whether related or unrelated to those elements specifically identified.
  • At least one of A and SET can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
  • HPLC high pressure liquid chromatography
  • aliphatic includes both saturated and unsaturated, nonaromatic, straight chain (i.e., unbranched), branched, acyclic, and cyclic (i.e., carbocyclic) hydrocarbons.
  • an aliphatic group is optionally substituted with one or more functional groups.
  • "aliphatic” is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl moieties.
  • Ci_ alkyl is intended to encompass, C 1; C 2 , C 3 , C 4 , C 5 , C 6 , Ci_ 6 , Ci_ 5 , Q ⁇ -A, Ci_ 3 , Ci_ 2 , C 2 _ 6 , C _ 5 , C _ , C 2 _ 3 , C 3 _ 6 , C 3 _ 5 , C 3 ⁇ , C4_ 6 , C4_ , and C 5 _ 6 alkyl.
  • Alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C ⁇ o alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“ ⁇ _ 10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“Ci_9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci_ 8 alkyl”).- In some embodiments, an alkyl group has 1 to 7 carbon atoms (“Ci_ 7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C ⁇ alkyl”).
  • an alkyl group has 1 to 5 carbon atoms (“Ci_ 5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1 -4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C ⁇ alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C ⁇ alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2 _ 6 alkyl").
  • C ⁇ alkyl groups include methyl (CO, ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ), and n-hexyl (C 6 ).
  • alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 ) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i. e. , unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents. In certain embodiments, the alkyl group is unsubstituted Ci-to alkyl (e.g., -CH 3 ). In certain embodiments, the alkyl group is substituted C ⁇ -io alkyl.
  • alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C 2 _ 2 o alkenyl”).
  • an alkenyl group has 2 to 10 carbon atoms ("C 2 _i 0 alkenyl”).
  • an alkenyl group has 2 to 9 carbon atoms (“C 2 _9 alkenyl”).
  • an alkenyl group has 2 to 8 carbon atoms (“C 2 _8 alkenyl”).
  • an alkenyl group has 2 to 7 carbon atoms ("C 2 _ 7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C 2 _ alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2 - 5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2 _ 3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms ("C 2 alkenyl”).
  • the one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1 -butenyl).
  • Examples of C 2 _ alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2- butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • Examples of C 2 _6 alkenyl groups include the aforementioned C 2 ⁇ t alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C ), and the like.
  • alkenyl examples include heptenyl (C 7 ), octenyl (C ), octatrienyl (C 8 ), and the like.
  • each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkenyl") or substituted (a "substituted alkenyl") with one or more substituents.
  • the alkenyl group is unsubstituted C 2 _ 10 alkenyl.
  • the alkenyl group is substituted C 2 _ 10 alkenyl.
  • Alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds ("C 2 _ 2 o alkynyl”).
  • an alkynyl grou has 2 to 10 carbon atoms ("C2-10 alkynyl”).
  • an alkynyl group has 2 to 9 carbon atoms (“C 2 _9 alkynyl”).
  • an alkynyl group has 2 to 8 carbon atoms (“C 2 _ 8 alkynyl”).
  • an alkynyl group has 2 to 7 carbon atoms ("C 2 _ 7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2 _ 6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C 2 _ 5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2 ⁇ alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2 _ 3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms ("C 2 alkynyl”).
  • the one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
  • Examples of C 2 ⁇ alkynyl groups include, without limitation, ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
  • Examples of C 2 _ 6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like.
  • alkynyl examples include heptynyl (C 7 ), octynyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with one or more substituents. In certain embodiments, the alkynyl group is unsubstituted C 2 _io alkynyl. In certain embodiments, the alkynyl group is substituted C 2 _ 10 alkynyl.
  • Carbocyclyl or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms ("C 3 _!o carbocyclyl") and zero heteroatoms in the non-aromatic ring system.
  • a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3 _ 8 carbocyclyl”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3 _ £ carbocyclyl”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3 _ ⁇ carbocyclyl”).
  • a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5 _ 10 carbocyclyl").
  • Exemplary C ⁇ carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
  • Exemplary C 3 _g carbocyclyl groups include, without limitation, the aforementioned carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 j, cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), and the like.
  • Exemplary C 3 _ 10 carbocyclyl groups include, without limitation, the aforementioned C 3 _ 8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-lH-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like.
  • the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated.
  • “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
  • each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl") with one or more substituents.
  • the carbocyclyl group is unsubstituted C 3 _ 10 carbocyclyl.
  • the carbocyclyl group is a substituted C 3 _ 10 carbocyclyl.
  • carbocyclyl is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms ("C 3 _ 10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3 _ 8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3 _ cycloalkyl").
  • a cycloalkyl group has 5 to 6 ring carbon atoms ("Cs- ⁇ cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms W 201
  • C 5 _ 10 cycloalkyl (“C 5 _ 10 cycloalkyl").
  • Examples, of Cs_ 6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ).
  • Examples of C3--5 cycloalkyl groups include the aforementioned C 5 _ ⁇ cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
  • Examples of C 3 _ 3 ⁇ 4 cycloalkyl groups include the aforementioned C 3 _ ⁇ 5 cycloalkyl groups as well as cycloheptyl (C ) and cyclooctyl (C 8 ).
  • each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents.
  • the cycloalkyl group is unsubstituted C 3 _i 0 cycloalkyl.
  • the cycloalkyl group is substituted C 3 _ 10 cycloalkyl.
  • Heterocyclyl refers to a radical of a 3- to 10- membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3-10 membered heterocyclyl").
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic ("monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated.
  • Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
  • each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents.
  • the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3-10 membered heterocyclyl.
  • a heterocyclyl group is a 5-10 membered non- aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heterocyclyl").
  • a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl").
  • a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1—4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl").
  • the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl.
  • Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5- dione.
  • Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.
  • Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6- membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7- membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl, and thiocanyl.
  • Exemplary 5-membered heterocyclyl groups fused to a C 6 aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
  • Exemplary 6-membered heterocyclyl groups fused to an aryl ring include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
  • Aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C ⁇ u aryl").
  • an aryl group has six ring carbon atoms ("C 6 aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms ("Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms ("C 14 aryl”; e.g., anthracyl).
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents.
  • the aryl group is unsubstituted C ⁇ H aryl.
  • the aryl group is substituted Ce-i 4 aryl.
  • Heteroaryl refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl").
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system.
  • Heteroaryl also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system.
  • Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
  • a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl").
  • a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl").
  • a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl").
  • the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted ("substituted heteroaryl") with one or more substituents.
  • the heteroaryl group is unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl.
  • Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
  • Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl.
  • Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Partially unsaturated refers to a group that includes at least one double or triple bond.
  • the term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic groups (e.g., aryl or heteroaryl groups) as herein defined.
  • saturated refers to a group that does not contain a double or triple bond, i.e., contains all single bonds.
  • Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted (e.g., "substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, "substituted” or “unsubstituted” alkynyl, "substituted” or “unsubstituted” carbocyclyl, "substituted” or “unsubstituted” heterocyclyl, "substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group).
  • substituted means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a "substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
  • substituted is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound.
  • the present invention contemplates any and all such combinations in order to arrive at a stable compound.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
  • each instance of R aa is, independently, selected from Ci_i 0 alkyl, Ci_i 0 perhaloalkyl, C 2 _ 10 alkenyl, C 2 _ 10 alkynyl, C 3 _ 10 carbocyclyl, 3-14 membered heterocyclyl, C -u aryl, and 5-14 membered heteroaryl, or two R aa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1 , 2, 3, 4, or 5 R dd groups;
  • each instance of R bb is, independently, selected from hydrogen, -OH, -OR aa , -
  • each instance of R cc is, independently, selected from hydrogen, Ci-io alkyl, d- t o perhaloalkyl, C 2 _ 10 alkenyl, C 2 _io alkynyl, C 3 _ 10 carbocyclyl, 3-14 membered heterocyclyl, J-M aryl, and 5-14 membered heteroaryl, or two R cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
  • each instance of R ee is, independently, selected from C 1--6 alkyl, Ci_6 perhaloalkyl, C 2 _6 alkenyl, C 2 _ 6 alkynyl, C 3 _i 0 carbocyclyl, C ⁇ o aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
  • each instance of R ff is, independently, selected from hydrogen, C ⁇ alkyl, Ci_6 perhaloalkyl, C 2 _ 6 alkenyl, C2-6 alkynyl, C 3 _ 10 carbocyclyl, 3-10 membered heterocyclyl, C6- 10 aryl and 5-10 membered heteroaryl, or two R groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1 , 2, 3, 4, or 5 R 8S groups; and
  • each instance of R gs is, independently, halogen, -CN, -N0 2 , -N 3 , -S0 2 H, -
  • a "counterion” or “anionic counterion” is a negatively charged group associated with a cationic quaternary amino group in order to maintain electronic neutrality.
  • exemplary counterions include halide ions (e.g., F ⁇ , Cl ⁇ , Br ⁇ , ⁇ ), N0 3 ⁇ , C10 4 ⁇ , OH-, H 2 P0 4 ⁇ , HS0 4 -, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-l-sulfonic acid-5-sulfonate, ethan-l-sulfonic acid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate,
  • Halo or "halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -CI), bromine (bromo, -Br), or iodine (iodo, -I).
  • Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms.
  • R aa , R bb , R cc and R dd are as defined above.
  • the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group).
  • Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • Amide nitrogen protecting groups include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifiuoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3- pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, ⁇ p- phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide,
  • Carbamate nitrogen protecting groups include, but are not limited to, methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(l 0, 10-dioxo-l 0, 10, 10, 10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l-adamantyl)-l-methylethyl carba
  • Sulfonamide nitrogen protecting groups include, but are not limited to, -toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl— 4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6- dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl- ⁇ 4- methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6- trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5, 7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms),
  • Ts -toluenesulfonamide
  • nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivative, N'- -toluenesulfonylaminoacyl derivative, N - phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-l, 1,4,4- tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1 ,3-dimethyl- 1 ,3 ,5-triazacyclohexan-2-one, 5-substituted 1 ,3-dibenzyl-l ,3 ,5— triazacyclo
  • the substituent present on an oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group).
  • Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,
  • the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a thiol protecting group).
  • Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • pharmaceutically acceptable form thereof refers to pharmaceutically acceptable salts, solvates, hydrates, prodrugs, tautomers, isomers, enantiomers, diastereomers, and/or polymorphs of a compound of the present invention.
  • the pharmaceutically acceptable form is a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al, describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Cl ⁇ -alkyl)4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • the pharmaceutically acceptable form is a hydrate or solvate.
  • hydrate refers to a compound non-covalently associated with one or more molecules of water.
  • solvate refers to a compound non-covalently associated with one or more molecules of an organic solvent.
  • the pharmaceutically acceptable form is a prodrug.
  • prodrug refers to a derivative of a parent compound that requires transformation within the body in order to release the parent compound. In certain cases, a prodrug has improved physical and/or delivery properties over the parent compound. Prodrugs are typically designed to enhance pharmaceutically and/or pharmacokinetically based properties associated with the parent compound.
  • prodrug can lie in its physical properties, such as enhanced water solubility for parenteral administration at physiological pH compared to the parent compound, or it enhances absorption from the digestive tract, or it may enhance drug stability for long-term storage.
  • esters as a prodrug type for compounds containing a carboxyl or hydroxyl functionality is known in the art as described, for example, in The Organic Chemistry of Drug Design and Drug Interaction by Richard Silverman, published by Academic Press (1992).
  • the pharmaceutically acceptable form is a tautomer.
  • tautomer includes two or more interconvertable compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base.
  • Exemplary tautomerizations include keto-to-enol; amide-to-imide; lactam-to-lactim; enamine-to-imine; and enamine-to- (a different) enamine tautomerizations.
  • the pharmaceutically acceptable form is an isomer.
  • the term "isomer” as used herein includes any and all geometric isomers and stereoisomers (e.g., enantiomers, diasteromers, etc.).
  • “isomer” include cis- and trans-isomers, E- and Z- isomers, R- and S-enantiomers, diastereomers, (D)- isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • an isomer/enantiomer may, in some embodiments, be provided substantially free of the corresponding enantiomer, and may also be referred to as "optically enriched.”
  • “Optically-enriched,” as used herein, means that the compound is made up of a significantly greater proportion of one enantiomer.
  • the compound of the present invention is made up of at least about 90% by weight of a preferred enantiomer. In other embodiments the compound is made up of at least about 95%, 98%, or 99% by weight of a preferred enantiomer.
  • Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by asymmetric syntheses.
  • the pharmaceutically acceptable form is a polymorph.
  • polymorph refers to a crystalline compound existing in more than one crystalline form/structure. When polymorphism exists as a result of difference in crystal packing it is called packing polymorphism. Polymorphism can also result from the existence of different conformers of the same molecule in conformational polymorphism. In pseudopolymorphism the different crystal types are the result of hydration or solvation.
  • a "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs; and/or birds, including commercially relevant birds such as chickens, ducks, geese, and/or turkeys.
  • humans i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other primates (e.g.,
  • cancer refers to the development and growth of abnormal cells in an uncontrolled manner as is commonly understood by those of skill in the art, brought about by aberration of the cellular growth cycle and/or cellular differentiation.
  • Cancers include benign cancers, malignant cancers, and pre-cancerous lesions, as well as both solid tumors and non- solid cancers such as leukemias.
  • the cancer may be breast cancer, prostate cancer, cervical cancer, ovarian cancer, gastric cancer, colorectal cancer, pancreatic cancer, liver cancer, brain cancer, neuroendocrine cancer, gastric cancer, glioblastomas, head and neck cancer, lung cancer, kidney cancer, hematological malignancies, melanoma and sarcomas.
  • the terms “treat,” “treating” and “treatment” refer to partially or completely halting, reducing, delaying, or diminishing the severity of symptoms related to a disease or condition from which the subject is suffering. Prophylaxis means that regiment is undertaken to prevent a possible occurrence, such as where a pre-cancerous lesion is identified
  • prevent contemplate an action that occurs before a subject begins to suffer an infection or symptoms related to an infection.
  • inhibitors refer to the ability of a compound to reduce, slow, halt or prevent activity of a particular biological process in a cell relative to vehicle.
  • the biological process is in vitro (e.g., cellular assay). In certain embodiments, the biological process is in vivo.
  • an "effective amount” refers to the minimal amount or concentration of an inventive compound or pharmaceutical composition thereof that, when administered, is sufficient in treating or preventing an infection in the subject.
  • an "effective amount" of the inventive compound or pharmaceutical composition thereof is that amount effective for killing, inhibiting, or preventing, the growth of the causative microbial organism (e.g., a bacterium, virus, parasite, or fungus).
  • an effective amount is the amount administered to a subject to achieve a concentration at the site of infection sufficient to inhibit the growth of the causative microbial organism.
  • an effective amount is the amount administered to a subject to achieve the mean inhibitory concentration at the site of infection for the causative microbial organism.
  • a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of an infection or to delay or minimize one or more symptoms associated with the infection.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the infection.
  • the term "therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of infection, or enhances the therapeutic efficacy of another therapeutic agent.
  • a prophylactically effective amount of a compound is an amount sufficient to prevent an infection, or one or more symptoms associated with the infection or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the infection.
  • the term "prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • a compound of the present invention is of , Formula (I): or a pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R is hydrogen or alkyl
  • X is O, N(R 1 ) 2 , or C(R 2 ) 2 , wherein each R 1 and R 2 can be the same or different and is hydrogen or alkyl;
  • Y is hydrogen, halo, or alkyl
  • Z is an optionally substituted heterocyclyl.
  • R is H, methyl, ethyl, or cyclopropyl.
  • X is O or NH.
  • Y is hydrogen, fluoro, chloro, or methyl.
  • Z is pyridyl, pyrimidinyl, azaindolyl, diazaindolyl, azaindazolyl, diazaindazolyl, imidazolyl, or pyrazolyl, any of which is optionally substituted.
  • Z is pyridyl, azaindolyl, or azaindazolyl, any of which is optionally substituted.
  • Z is pyridyl, 7-azaindole, 7-azaindazole, any of which is optionally substituted.
  • Z is:
  • the present invention also provides pharmaceutical compositions comprising an effective amount of a compound described herein, or a pharmaceutically acceptable form (e.g., pharmaceutically acceptable salt or prodrug) thereof, and, optionally, a pharmaceutically acceptable excipient.
  • a pharmaceutically acceptable form e.g., pharmaceutically acceptable salt or prodrug
  • compositions agents include any and all solvents, diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • General considerations in formulation and/or manufacture of pharmaceutical compositions agents can be found, for example, in Remington 's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005).
  • compositions described herein can be prepared by any method known in the art of pharmacology.
  • preparatory methods include the steps of bringing the compound of the present invention (the "active ingredient") into association with a carrier and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping and/or packaging the product into a desired single- or multi-dose unit.
  • compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
  • a "unit dose" is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
  • compositions of the invention will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the composition may comprise between 0.1% and
  • compositions used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils.
  • Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
  • Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc., and combinations thereof.
  • Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked polyvinylpyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, etc., and combinations thereof.
  • crospovidone cross-linked polyvinylpyrrolidone
  • sodium carboxymethyl starch sodium starch glycolate
  • Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols
  • natural emulsifiers e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin
  • colloidal clays e.g. bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate
  • stearyl alcohol e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol
  • carbomers e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer
  • carrageenan e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose
  • sorbitan fatty acid esters e.g.
  • polyoxyethylene sorbitan monolaurate Tween 20
  • polyoxyethylene sorbitan Tween 60
  • polyoxyethylene sorbitan monooleate Tween 80
  • sorbitan monopalmitate Span 40
  • sorbitan monostearate Span 60
  • sorbitan tristearate Span 65
  • polyoxyethylene esters e.g. polyoxyethylene monostearate (Myrj 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxym ethylene stearate, and Solutol
  • sucrose fatty acid esters e.g.
  • Cremophor polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether (Brij 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F-68, Poloxamer PI 88, cetrimonium bromide, cetylpyndinium chloride, benzalkonium chloride, docusate sodium, etc. and/or combinations thereof.
  • polyoxyethylene ethers e.g. polyoxyethylene lauryl ether (Brij 30)
  • poly(vinyl-pyrrolidone) poly(vinyl-pyrrolidone)
  • diethylene glycol monolaurate triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate
  • Exemplary binding agents include starch (e.g. cornstarch and starch paste), gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g.
  • acacia sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, polyvinylpyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, etc., and/or combinations thereof.
  • Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
  • antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
  • Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
  • EDTA ethylenediaminetetraacetic acid
  • salts and hydrates thereof e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
  • citric acid and salts and hydrates thereof e.g., citric acid mono
  • antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
  • Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
  • Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
  • Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
  • preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BH A), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl.
  • the preservative is an anti-oxidant.
  • the preservative is a chelating agent.
  • Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D- gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic sa
  • Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, etc., and combinations thereof.
  • Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea
  • Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof.
  • Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents
  • the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • the conjugates of the invention are mixed with solubilizing agents such as Cremophor, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and combinations thereof.
  • solubilizing agents such as Cremophor, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and combinations thereof.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol.
  • a nontoxic parenterally acceptable diluent or solvent for example, as a solution in 1 ,3-butanediol.
  • acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and g
  • Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
  • Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active ingredients can be in micro-encapsulated form with one or more excipients as noted above.
  • the solid , dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • opacifying agents include polymeric substances and waxes.
  • Dosage forms for topical and/or transdermal administration of a compound of this invention may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and/or patches.
  • the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and/or any needed preservatives and/or buffers as can be required.
  • the present invention contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body.
  • Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium.
  • the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.
  • Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices such as those described in U.S. Patents 4,886,499; 5,190,521; 5,328,483; 5,527,288; 4,270,537; 5,015,235; 5,141,496; and 5,417,662.
  • Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin, such as those described in PCT publication WO 99/34850 and functional equivalents thereof.
  • Jet injection devices which deliver liquid vaccines to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable.
  • Jet injection devices are described, for example, in U.S. Patents 5,480,381; 5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189; 5,704,911; 5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335; 5,503,627; 5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880; 4,940,460; and PCT publications WO 97/37705 and WO 97/13537.
  • Ballistic powder/particle delivery devices which use ⁇ compressed gas to accelerate vaccine in powder form through the outer layers of the skin to the dermis are suitable.
  • conventional syringes can be used in the classical mantoux method of intradermal administration.
  • Formulations suitable for topical administration include, but are not limited to, liquid and/or semi liquid preparations such as liniments, lotions, oil in water and/or water in oil emulsions such as creams, ointments and/or pastes, and/or solutions and/or suspensions.
  • Topically-administrable formulations may, for example, comprise from about 1 % to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent.
  • Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition of the invention can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity.
  • a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers or from about 1 to about 6 nanometers.
  • Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self- propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container.
  • Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers.
  • Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.
  • Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure.
  • the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition.
  • the propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).
  • compositions of the invention formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension.
  • Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device.
  • Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate.
  • the droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.
  • Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition of the invention.
  • Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered, by rapid inhalation through the nasal passage from a container of the powder held close to the nares.
  • Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition of the invention can be prepared, packaged, and/or sold in a formulation for buccal administration.
  • Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein.
  • formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient.
  • Such powdered, aerosolized, and/or aerosolized formulations when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition of the invention can be prepared, packaged, and/or sold in a formulation for ophthalmic administration.
  • Such formulations may, for example, be in the form of eye drops including, for example, a 0.1/1.0%» (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier.
  • Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein.
  • Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are contemplated as being within the scope of this invention.
  • compositions suitable for administration to humans are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation.
  • kits e.g., pharmaceutical packs
  • the kits provided may comprise an inventive pharmaceutical composition or compound and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container).
  • a container e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container.
  • provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of an inventive pharmaceutical composition or compound.
  • the inventive pharmaceutical composition or compound provided in the container and the second container are combined to form one unit dosage form.
  • a single container may comprise one or more compartments for containing an inventive pharmaceutical composition or compound, and/or a pharmaceutically acceptable excipient for suspension or dilution.
  • a single container can be appropriate for modification such that the container may receive a physical modification so as to allow combination of compartments and/or components of individual compartments.
  • a foil or plastic bag may comprise two or more compartments separated by a perforated seal which can be broken so as to allow combination of contents of two individual compartments once the signal to break the seal is generated.
  • a kit may thus comprise such multi-compartment containers providing an inventive pharmaceutical composition or compound and one or more pharmaceutically acceptable excipients.
  • instructions for use are additionally provided in such kits of the invention.
  • Such instructions may provide, generally, for example, instructions for dosage and administration.
  • instructions may further provide additional detail relating to specialized instructions for particular containers and/or systems for administration.
  • instructions may provide specialized instructions for use in conjunction and/or in combination with an additional therapeutic agent.
  • compositions of the present invention are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease, disorder, or condition being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
  • the compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol.
  • enteral e.g., oral
  • parenteral intravenous, intramuscular, intraarterial, intramedullary
  • intrathecal subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal
  • topical as by powders, ointments, creams, and/or drops
  • mucosal nasal, bucal
  • Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/of direct administration to an affected site.
  • intravenous administration e.g., systemic intravenous injection
  • regional administration via blood and/or lymph supply e.g., via blood and/or lymph supply
  • direct administration e.g., via blood and/or lymph supply
  • direct administration to an affected site.
  • the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).
  • the exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like.
  • the desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks.
  • the desired dosage can be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).
  • an effective amount of a compound for administration one or more times a day to a 70 kg adult human may comprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.
  • the compounds of the invention may be at dosage levels sufficient to deliver from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult.
  • the amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
  • a compound or composition, as described herein, can be administered in combination with one or more additional therapeutically active agents.
  • the compounds or compositions can be administered in combination with additional therapeutically active agents that improve their bioavailability, reduce and/or modify their metabolism, inhibit their excretion, and/or modify their distribution within the body.
  • additional therapeutically active agents that improve their bioavailability, reduce and/or modify their metabolism, inhibit their excretion, and/or modify their distribution within the body.
  • the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects.
  • the compound or composition can be administered concurrently with, prior to, or subsequent to, one or more additional therapeutically active agents.
  • each agent will be administered at a dose and/or on a time schedule determined for that agent.
  • the additional therapeutically active agent utilized in this combination can be administered together in a single composition or administered separately in different compositions.
  • the particular combination to employ in a regimen will take into account compatibility of the inventive compound with the additional therapeutically active agent and/or the desired therapeutic effect to be achieved.
  • additional therapeutically active agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.
  • Patents on MNK inhibitors to treat cancer US20110280886 (Novartis, combination with mTOR to treat glioblastoma multiform); WO 2011058139; WO 2011104338 (treatment of diseases); WO 2011 104340 (treatment of diseases); WO 2010055072 A2 (Novartis, combination with mTOR); WO 2007147874 Al (treatment of diseases), WO 2007/104053 A3 (treatment of metabolic disorders)
  • AUC area under the curve
  • DIEA diisopropyl-ethyl-amine
  • HATU 2-(lH-7-Azabenzotriazol- 1 -yl)- 1 , 1 ,3 ,3-tetramethyl uronium hexafluorophosphate
  • HBTU 0-Benzotriazole-N,N,N',N'-tetramethyl-uronium- ⁇ hexafluoro- phosphate
  • LC-MS Liquid chromatography-mass spectrometry
  • MS mass spectrometry
  • NBS N-Bromosuccinimide
  • NIS N-iodosuccinimide
  • NMM N-methylmorpholine
  • THF tetrahydrofuran
  • TFA trifluoroacetic acid
  • the crude compound was purified by column chromatography over neutral alumina using a solvent gradient of 1% methanol-dichlorom ethane as eluent to afford 200 mg of ethyl 2-(4-(6- (methylamino)pyridin-3-yl)phenoxy)acetate.
  • Ethyl (3S)-3-(4-bromophenyl)butanoate was synthesized as reported previously (J. Org. Chem. 2009, 74, 929) from (4-bromophenyl)boronic acid and ethyl- (2E)-but-2-enoate.
  • a solution of ethyl (35 -3-(4-bromophenyl)butanoate (1.0 g, 3.7 mmol) and LiOH.H 2 0 (488 mg, 11.1 1 mmol) in THF-water (15 mL, 15 mL), MeOH (1 mL) was stirred for 15 h. After completion of reaction, THF and MeOH were distilled off.
  • (3R)-3-(4-bromophenyl)butanoic acid was also synthesized using (i?)-Binap.
  • reaction mixture was stirred at room temperature for 2 hours and partitioned between H 2 0 (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL x 2). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuum.
  • tert-butyl 4-( ⁇ 4-[3-(4- bromophenyl)propanamido]-2-(trifluoromethyl)phenyl ⁇ methyl)-piperazine-l- carboxylate was synthesized from 3-(4-Bromophenyl)propionic acid and tert-butyl 4- ⁇ [4- amino-2-(trifluoromethyl)phenyl]methyl ⁇ -piperazine-l -carboxylate.
  • ESI MS m/z 571.1 [M+H]V
  • tert-butyl 4-( ⁇ 4-[3-(4-bromo- 2-fluorophenyl)propanamido]-2-(trifluoromethyl)phenyl ⁇ -methyl)piperazine-l- carboxylate was synthesized from 3-(4-Bromo-2-fluorophenyl)propanoic acid and tert- butyl 4- ⁇ [4-amino-2-(trifluoromethyl)phenyl]methyl ⁇ -piperazine- 1 -carboxylate.
  • ESI MS m/z 588.4 [M+H] + .
  • tert-butyl 4-( ⁇ 4-[(3R)-3-(4- bromophenyl)butanamido] -2-(trifluoromethyl)phenyl ⁇ methyl)piperazine- 1 -carboxylate was synthesized from 3-(4-bromophenyl)butanoic acid and tert-butyl 4- ⁇ [4-amino-2- (trifluoromethyl)phenyl]methyl ⁇ -piperazine- 1 -carboxylate.
  • ESI MS m/z 583.3[M-H] + .
  • tert-butyl 4-( ⁇ 4-[(3S 3-(4-bromophenyl)butanamido]-2- (trifluoromethyl)phenyl ⁇ methyl)piperazine- 1 -carboxylate [000246] According to the method described in A-6, tert-butyl 4-( ⁇ 4-[(35)-3-(4- bromophenyl)butanamido]-2-(trifiuoromethyl)phenyl ⁇ methyl)piperazine-l-carboxylate was synthesized from (35)-3-(4-bromophenyl)butanoic acid and tert-butyl 4- ⁇ [4-amino- 2-(trifluoromethyl)phenyl]methyl ⁇ -piperazine-l -carboxylate.
  • A-8 SYNTHESIS OF N- ⁇ 4-[(4-ETHYLPIPERAZIN-l-YL)METHYL]-3- (TRJFLUOROMETHYL)PHENYL ⁇ -2-[4-(TETRAMETHYL-l,3,2-DIOXABOROLAN-2- YL)PHENOXY]A CETAMIDE:
  • reaction mixture was cooled to room temperature, filtered through celite and washed with methanol (100 mL). The filtrate was concentrated and the residue partitioned between water (50 ml) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL).
  • N- ⁇ 4-[(4-ethylpiperazin-l-yl)methyl]-3-(trifluoromethyl)phenyl ⁇ -2-(2- fluoro-4- ⁇ lH-pyrrolo[2,3-b]pyridin-5-yl ⁇ phenoxy)acetamide was synthesized in a similar method as described in example 3 from 2-(4-bromo-2-fluorophenoxy)-N- ⁇ 4-[(4- ethylpiperazin-l-yl)methyl]-3-(trifluoromethyl)phenyl ⁇ acetamide and 5-(tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrrolo[2,3-b]pyridine.
  • ⁇ lH-pyrrolo[2,3-b]pyridin-5-yl ⁇ phenoxy)acetamide was synthesized in a similar method as described in example 3 from 2-(4-bromophenoxy)-N- ⁇ 4-[(4-methylpiperazin-l- yl)methyl]-3-(trifluoromethyl)phenyl ⁇ acetamide and 5-(tetramethyl-l,3,2-dioxaborolan- 2-yl)-lH-pyrrolo[2,3-b]pyridine.
  • N- ⁇ 4-[(4-methylpiperazin- 1 -yl)methyl] -3 -(trifluoromethyl)phenyl ⁇ -2-(2-fluoro-4- ⁇ lH-pyrrolo[2,3-b]pyridin-5-yl ⁇ phenoxy)acetamide was synthesized in a similar method as described in example 3 from 2-(4-bromo-2-fluorophenoxy)-N- ⁇ 4-[(4-methylpiperazin- 1 -yl)methyl]-3-(trifluoromethyl)phenyl ⁇ -acetamide and 5-(tetramethyl-l ,3,2- dioxaborolan-2-yl)-lH-pyrrolo[2,3-b]pyridine.
  • the crude compound was purified by column chromatography over silica (100-200 mesh) using a solvent gradient of 1% MeOH:CHCl 3 in TEA (1 mL) as eluent to afford 400 mg (0.644 mmol) of the product (ESI-MS: m/z 622.13 (M+H) + ) which was dissolved in DCM (10 mL) and treated with TFA (4 mL) and stirred at room temperature for 3 h.
  • reaction mixture was concentrated under reduced pressure and purified by prep HPLC to afford 250 mg of N-[4-(piperazin-l-ylmethyl)-3-(trifluoromethyl)phenyl]-3-(4- ⁇ lH- pyrrolo[2,3-b]pyridin-5-yl ⁇ phenyl)butanamide.
  • N-(5- ⁇ 4-[(2S)-l- ⁇ [4-(piperazin- 1 -ylmethyl)-3-(trifluoromethyl)phenyl] carbamoyl ⁇ propan-2- yl]phenyl ⁇ pyridin-2-yl)cyclopropanecarboxamide was synthesized from tert-butyl 4-( ⁇ 4- [(35)-3-(4-bromophenyl)butanamido]-2-(trifluoromethyl)phenyl ⁇ methyl)piperazine-l- carboxylate and N-(5-bromopyridin-2-yl)acetamide.
  • N-(5- ⁇ 4-[(2R)-l- ⁇ [4-(piperazin- 1 -ylmethyl)-3 -(trifluoromethyl)phenyl] carbamoyl ⁇ propan-2- yl]phenyl ⁇ pyridin-2-yl)cyclopropanecarboxamide was synthesized from tert-butyl 4-( ⁇ 4- [(3i?)-3-(4-bromophenyl)butanamido]-2-(trifluoromethyl)phenyl ⁇ methyl)piperazine-l - carboxylate and N-(5-bromopyridin-2-yl)acetamide.
  • Enzymatic and cell-based eIF4E phosphorylation assays The compounds described in this invention bind to and inhibit the kinases MNKl and MNK2. They were analyzed using both in vitro and in vivo assays that are known in the art.
  • MNKl and MNK2 inhibitor activity was determined using recombinant kinase domains expressed in E.coli.
  • MNKl and MNK2 were expressed as GST fusion proteins and the GST tag was removed using PreScission protease. After concentration to 10-15 mg/ml the proteins were flash frozen in liquid nitrogen and stored at -80 °C.
  • MNKl and MNK2 were activated using recombinant ERK2 which was activated using a constitutively active mutant of MEKl, both ERK2 and MEKl were expressed in E.coli as N-terminally his tagged proteins.
  • Recombinant ERK2 was activated by incubating 11.3 ⁇ of the kinase with 1 ⁇ MEKl and 100 ⁇ ATP. This reaction mixture was then used immediately for the activation of the MNKs.
  • the activation of the MNKl was performed by incubating 5.0 ⁇ of MNKl with 0.3 ⁇ of activated ERK2 and 500 ⁇ ATP at 30°C for 6 hours.
  • the activation of MNK2 was performed by incubating 50 ⁇ of MNK2 with 3.0 ⁇ of activated ERK2 and 500 ⁇ ATP at 30°C for 2 hours.
  • the activated MNKs were stored at -20 °C until required for assay.
  • Substrate buffer 245mM HEPES/NaOH pH7.5, 0.003% Brij® L23, 0.004% TWEEN® 20, 26mM MgCl 2 .
  • Termination buffer lOOmM HEPES/NaOH pH7.3, 0.022% Brij® L23, 5.6% DMSO, 0.16% CR3, 11.2mM EDTA pH8.0.
  • Separation buffer lOOmM HEPES/NaOH pH7.3, 0.02% Brij® L23, 5% DMSO, 0.1% CR3, ImM EDTA pH8.0.
  • Peptide substrate JH3: 5-FAM-TATKSGSTTKNRFW-CONH 2 .
  • the MNKl assay was performed by adding 65nM of activated MNK1 and ⁇ ⁇ of test compound to a microtitre plate in a volume of 15 ⁇ 1 of reconstitution buffer. The plate was incubated at 22°C for 15 minutes before the addition of 3.9 ⁇ of JH3 and 3.12mM ATP in ⁇ of substrate buffer and a further incubation period of 60 minutes at 28°C. The reaction was stopped by the addition of 45 ⁇ 1 of termination buffer. The final concentration of MNKl, JH3 peptide, ATP and compound in a 26 ⁇ 1 assay volume was 40nM, 1.5 ⁇ , 1.2mM, and IX respectively.
  • the MNK2 assay was performed by adding 32.5 nM of activated MNKl and 1 ⁇ of test compound to a microtitre plate in a volume of 15 ⁇ of reconstitution buffer. The plate was incubated at 22 °C for 15 minutes before the addition of 3.9 ⁇ of JH3 and 650 ⁇ ATP in 10 ⁇ of substrate buffer and a further incubation period of 60 minutes at 28 °C. The reaction was stopped by the addition of 45 ⁇ 1 of termination buffer. The final concentration of MNK2, JH3 peptide, ATP and compound in a 26 ⁇ assay volume was 20 nM, 1.5 ⁇ , 250 ⁇ , and IX respectively.
  • Inhibition constants were determined by plotting kinase activity versus log compound concentration and fitting with a non-linear regression algorhithm using GraphPad Prism (GraphPad Software Inc.).
  • ABL assay was performed by adding 2.44 nM of ABL (Carna biosciences, Full-length human ABL [2-1130(end) amino acids of accession number
  • NP_005148.2 was expressed as N-terminal His-tagged protein (126 kDa) using baculovirus expression system. His-tagged ABL was purified by using Ni-NTA affinity chromatography and anion exchange chromatography) and 1 ⁇ of test compound to a microtitre plate in a volume of 15 ⁇ of reconstitution buffer. The plate was incubated at 22 °C for 15 minutes before the addition of 3.9 ⁇ of FL-peptide2 (5-FAM- EAIYAAPFAKKK-CONH2) and 36.4 ⁇ ATP in 10 ⁇ of substrate buffer and a further incubation period of 150 minutes at 28 °C. The reaction was stopped by the addition of 45 ⁇ of termination buffer. The final concentration of ABL, FL-peptide2, ATP and compound in a 26 ⁇ assay volume was 1.5 nM, 1.5 ⁇ , 14 ⁇ , and IX respectively.
  • the ABL(T315I) assay was performed by adding 3.25 nM of ABL(T315I) (Carna biosciences, Full-length human ABL [2-1 130(end) amino acids and T315I of accession number NP_005148.2] was expressed as N-terminal His-tagged protein (126 kDa) using baculovirus expression system. His-tagged ABL[T315I] was purified by using Ni-NTA affinity chromatography) and ⁇ ⁇ of test compound to a microtitre plate in a volume of 15 ⁇ of reconstitution buffer.
  • the plate was incubated at 22°C for 15 minutes before the addition of 3.9 ⁇ of FL-peptide2 (5-FAM- EAIYAAPFAKKK-CONH2) and 31.2 ⁇ ATP in ⁇ of substrate buffer and a further incubation period of 150 minutes at 28°C. The reaction was stopped by the addition of 45 ⁇ of termination buffer. The final concentration of ABL(T315I), FL-peptide2, ATP and compound in a 26 ⁇ assay volume was 2 nM, 1.5 ⁇ , 12 ⁇ , and IX respectively.
  • Inhibition constants were determined by plotting kinase activity versus log compound concentration and fitting with a non-linear regression algorhithm using GraphP ad Prism (GraphPad Software Inc.).
  • Ser209 of eIF4E is solely phosphorylated by the MNK enzymes.
  • the ability of compounds to inhibit this process in Hela cells was investigated using the AlphaScreen SureFire® assay platform from Perkin Elmer (Waltham, MA).
  • eIF4E phosphorylated on Ser209 is recognized by two antibodies, the first which is fused to a streptavidin coated donor bead binds to an epitope away from Ser209, the second which is fused to a protein A conj ⁇ gated acceptor bead binds to phosphorylated Ser209.
  • HeLa cells were seeded into microtitre plates (30,000 cells per well) in 100 ⁇ of culture medium and incubated at 37 °C for 24 hours. The media was then removed by aspiration and the cells resuspended in 50 ⁇ 1 of serum free medium containing the test compound and incubated at 37 °C for 2 hours.
  • the culture medium was again removed by aspiration and the cells resuspended in lysis buffer (provided in Perkin Elmer SureFire® Assay Kit). After agitation at 350 rpm for 20 minutes at 22 °C, 4 ⁇ was transferred to a 384 well OptiPlateTM (Perkin Elmer, Waltham, MA). To each well was added 5 ⁇ of acceptor mix; the plate was sealed and agitated gently at 22 °C for 2 hours. Then, in subdued light, 2 ⁇ of donor mix was added to each well, the plate was sealed, wrapped in aluminum foil and agitated gently at 22 °C for 2 hours. Emission was measured using the En Vision® plate reader (Perkin Elmer, Waltham, MA).
  • Inhibition constants were determined by plotting AlphaScreen signal versus log compound concentration and fitting with a non-linear regression algorhithm using GraphPad Prism (GraphPad Software Inc.).
  • Methodology Cell lines derived from subjects with blast crisis chronic myeloid leukemia, BV-173, EM-2, KCL-22, JURL-MK1 and TMM were purchased from DSMZ. The cells were cultured according to the supplier's recommendations. For the dose response study, 5000 cells were seeded in 100 ⁇ of growth media in black, flat- bottom 96-well plate (Greiner) and treated with compounds for 48 hours. Compounds synthesized by ETC were used for treatment with doses ranging from 0.01 ⁇ to 50 ⁇ . Imatinib was used as control.
  • cell viability was determined by CellTiter- Glo Luminescent Cell Viability Assay (Promega, Madison, WI) where 100 ⁇ of the reagent was added to the cells and luminescence was measured using Tecan Safire Reader. Data was analysed with Graphpad Prism software and the figures indicate the half maximal inhibitory concentration (IC 50 ). Error bars denote standard deviation (SD). Experiments were carried out on two different days to ensure reproducibility.
  • Cancer cell lines B16 (melanoma) and MDA-MB-231 (breast cancer) were purchased from ATCC and cultured according to supplier's recommendations.
  • K562 cells myelogenous leukemia
  • eIF4E myelogenous leukemia
  • 5000 cells were seeded in 70 ⁇ of growth medium in black, flat-bottom 96-well plate.
  • the compounds, Imatinib, ETC036 and ETC037 were treated with doses ranging from .0.003 ⁇ to 50 ⁇ . 50 ⁇ of the diluted compounds was added to the cells and incubated at 37 °C in 5% C0 2 .
  • Table 21 shows the IC 50 values for various compounds in the inhibition of MNK1 and MNK2, as well as in the inhibition of phosphorylation of eIF4E in HeLa cells.
  • IC 50 ( ⁇ ): Concentration of the compound required to inhibit 50% of the enzyme activity; MNKl and MNK2: MAP kinase interacting kinases 1 and 2; Abl: Abl tyrosine kinase; Abl(T315I): Abl tyrosine kinase T315I mutant; K562 (o/e eIF4E): human myelogenous leukemia cell line K562 overexpressing eIF4E; GI 50 : Concentration of the compound required to inhibit 50% of the growth of K562 cells overexpressing eIF4E. [000344] Table 22 shows the IC 50 values for various compounds after 48 hours of treatment.
  • ETC036 and ETC037 prevented growth of Blast Crisis Chronic Myelogenous Leukemia (BC-CML) cell panel tested, with GI50S in the range of 0.5-1.5 ⁇ and 0.08 - 0.36 ⁇ respectively.
  • BC-CML Blast Crisis Chronic Myelogenous Leukemia
  • GI50S in the range of 0.5-1.5 ⁇ and 0.08 - 0.36 ⁇ respectively.
  • the growth inhibitory effect of these compounds seem to be specific toward BC-CML cells as can be seen from the high micromolar IC 50 s for other cells tested (melanoma and breast cancer cells shown).
  • CB samples were purchased from the Singapore Cord Blood bank. CML samples were Singapore General Hospital after signed informed consent under local IRB-approved procedures. MNCs were obtained using Ficoll separation, and CD34 + cells selected by immunomagnetic beads (Miltenyi Biotech, Germany).
  • K562 cell line was obtained from the ATCC, and grown in RPMI supplemented with 10% FCS, L-glutamine, and penicillin/streptomycin.
  • ETC036 and 037 are non-selective MNK kinase inhibitors. In addition to dual MNK inhibition, they also inhibit Abl, Abl(T315I), PDGFR, FLT3 and FGFR2. It has been shown previously (Tiong et al., 2008) that a combination of MNK inhibitor and Bcr-Abl inhibitor prevents growth of BC CML cells more effectively than Bcr-Abl inhibitor Imatinib alone, including Imatinib resistant variants.
  • Fibroblast growth factor 9 has oncogenic activity and is a downstream target of Wnt signaling in ovarian endometrioid adenocarcinomas 1. Cancer Res. 2006, 66 (3), 1354-1362.
  • mice have reduced bone destruction following mixed anaerobic infection. Infect. Immun. 2000, 68 (8), 4681-4687.
  • Mnks are novel components in the control of TNF alpha biosynthesis and phosphorylate and regulate hnRNP Al. Immunity. 2005, 23 (2), 177-189.
  • the PSF.p54nrb complex is a novel Mnk substrate that binds the mRNA for tumor necrosis factor alpha. J. Biol.

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Abstract

La présente invention concerne certains composés à base de pipérazine qui agissent en tant qu'inhibiteurs des kinases interagissant avec les MAP kinases MNK2a, MNK2b, MNK1a et MNK1b, et/ou en tant qu'inhibiteurs d'ABL ou ABL (T315I). L'invention concerne également des compositions pharmaceutiques comprenant ces composés, et l'utilisation des composés pour la préparation d'un médicament pour la prophylaxie et le traitement du cancer, des maladies inflammatoires et de la maladie d'Alzheimer, ainsi que des procédés de traitement de ces troubles.
PCT/SG2013/000519 2012-12-07 2013-12-06 Composés comprenant des modulateurs des kinases interagissant avec les map kinases 1 et 2 (mnk1 et mnk2) et des inhibiteurs d'abl et abl (t315i), et leurs utilisations Ceased WO2014088519A1 (fr)

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WO2016172010A1 (fr) 2015-04-20 2016-10-27 Effector Therapeutics, Inc. Inhibiteurs de modulateurs de points de contrôle immunitaire destinés à être utilisés dans le traitement du cancer et d'infections
WO2017075367A1 (fr) * 2015-10-28 2017-05-04 Northwestern University Composés n-hétérocycliques aromatiques substitués en tant qu'inhibiteurs de protéine kinase activée par mitogène interagissant avec la kinase 1 (mnk1) et la kinase 2 (mnk2)
WO2017087808A1 (fr) * 2015-11-20 2017-05-26 Effector Therapeutics, Inc. Composés hétérocycliques inhibant l'activité kinase de mnk utiles pour le traitement de divers cancers
WO2017117052A1 (fr) 2015-12-31 2017-07-06 Effector Therapeutics, Inc. Biomarqueurs mnk et utilisations de ces biomarqueurs
US9814718B2 (en) 2014-06-25 2017-11-14 Effector Therapeutics, Inc. MNK inhibitors and methods related thereto
CN108349956A (zh) * 2015-10-22 2018-07-31 赛尔维他股份公司 吡啶酮衍生物及其作为激酶抑制剂的用途
US10112955B2 (en) 2015-10-29 2018-10-30 Effector Therapeutics, Inc. Isoindoline, azaisoindoline, dihydroindenone and dihydroazaindenone inhibitors of Mnk1 and Mnk2
WO2019013703A1 (fr) * 2017-07-14 2019-01-17 Agency For Science, Technology And Research (A*Star) Dérivés alcyne bicycliques et leurs utilisations
US10851082B2 (en) 2015-10-28 2020-12-01 Northwestern University Substituted aromatic n-heterocyclic compounds as inhibitors of mitogen-activated protein kinase interacting kinase 1 (MNK1) and 2 (MNK2)
WO2020263186A1 (fr) * 2019-06-25 2020-12-30 Sinopsee Therapeutics Composés pour le traitement du cancer
US11014926B2 (en) 2015-10-29 2021-05-25 Effector Therapeutics, Inc. Pyrrolo-, pyrazolo-, imidazo-pyrimidine and pyridine compounds that inhibit MNK1 and MNK2
US11083727B2 (en) 2017-02-14 2021-08-10 Effector Therapeutics Inc. Piperidine-substituted Mnk inhibitors and methods related thereto
US11952375B2 (en) 2018-10-24 2024-04-09 Effector Therapeutics Inc. Crystalline forms of Mnk inhibitors

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US9814718B2 (en) 2014-06-25 2017-11-14 Effector Therapeutics, Inc. MNK inhibitors and methods related thereto
US10702526B2 (en) 2015-04-20 2020-07-07 Effector Therapeutics Inc. Inhibitors of immune checkpoint modulators and related methods
WO2016172010A1 (fr) 2015-04-20 2016-10-27 Effector Therapeutics, Inc. Inhibiteurs de modulateurs de points de contrôle immunitaire destinés à être utilisés dans le traitement du cancer et d'infections
CN108349956A (zh) * 2015-10-22 2018-07-31 赛尔维他股份公司 吡啶酮衍生物及其作为激酶抑制剂的用途
WO2017075367A1 (fr) * 2015-10-28 2017-05-04 Northwestern University Composés n-hétérocycliques aromatiques substitués en tant qu'inhibiteurs de protéine kinase activée par mitogène interagissant avec la kinase 1 (mnk1) et la kinase 2 (mnk2)
US10851082B2 (en) 2015-10-28 2020-12-01 Northwestern University Substituted aromatic n-heterocyclic compounds as inhibitors of mitogen-activated protein kinase interacting kinase 1 (MNK1) and 2 (MNK2)
US10093668B2 (en) 2015-10-28 2018-10-09 Northwestern University Substituted aromatic N-heterocyclic compounds as inhibitors of mitogen-activated protein kinase interacting kinase 1 (Mnk1) and 2 (Mnk2)
US11014926B2 (en) 2015-10-29 2021-05-25 Effector Therapeutics, Inc. Pyrrolo-, pyrazolo-, imidazo-pyrimidine and pyridine compounds that inhibit MNK1 and MNK2
US10112955B2 (en) 2015-10-29 2018-10-30 Effector Therapeutics, Inc. Isoindoline, azaisoindoline, dihydroindenone and dihydroazaindenone inhibitors of Mnk1 and Mnk2
US10000487B2 (en) 2015-11-20 2018-06-19 Effector Therapeutics, Inc. Heterocyclic compounds that inhibit the kinase activity of Mnk useful for treating various cancers
WO2017087808A1 (fr) * 2015-11-20 2017-05-26 Effector Therapeutics, Inc. Composés hétérocycliques inhibant l'activité kinase de mnk utiles pour le traitement de divers cancers
WO2017117052A1 (fr) 2015-12-31 2017-07-06 Effector Therapeutics, Inc. Biomarqueurs mnk et utilisations de ces biomarqueurs
US11083727B2 (en) 2017-02-14 2021-08-10 Effector Therapeutics Inc. Piperidine-substituted Mnk inhibitors and methods related thereto
US11878015B2 (en) 2017-02-14 2024-01-23 Effector Therapeutics Inc. Piperidine-substituted Mnk inhibitors and methods related thereto
WO2019013703A1 (fr) * 2017-07-14 2019-01-17 Agency For Science, Technology And Research (A*Star) Dérivés alcyne bicycliques et leurs utilisations
US11952375B2 (en) 2018-10-24 2024-04-09 Effector Therapeutics Inc. Crystalline forms of Mnk inhibitors
WO2020263186A1 (fr) * 2019-06-25 2020-12-30 Sinopsee Therapeutics Composés pour le traitement du cancer
CN114450285A (zh) * 2019-06-25 2022-05-06 西诺普塞疗法公司 用于治疗眼部病症的化合物
US20220242863A1 (en) * 2019-06-25 2022-08-04 Sinopsee Therapeutics Compounds for treatment of eye disorders
CN114450285B (zh) * 2019-06-25 2024-04-09 西诺普塞疗法公司 用于治疗眼部病症的化合物

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