Novel UBA5 compounds and methods of use of the novel compounds

Abstract

Provided herein are compounds having the formula (I) for treating, preventing or managing cancer. Also provided are pharmaceutical compositions comprising the compounds and methods of use of the compounds and compositions. In certain embodiments, the methods encompass treating, preventing or managing cancer, including solid tumors and blood borne tumors using the compounds provided herein.

Description

[0001] NOVEL UBA5 COMPOUNDS AND METHODS OF USE OF THE NOVEL COMPOUNDS

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U. S. provisional patent application serial number 63 / 789,164, filed April 15, 2025, which is incorporated herein by reference in its entirety.

[0003] FIELD OF THE INVENTION

[0004] Provided herein are compounds for treating, preventing or managing cancer. Also provided are pharmaceutical compositions comprising the compounds and methods of use of the compounds and compositions. In certain embodiments, the methods encompass treating, preventing or managing cancer, including solid tumors and blood borne tumors using the compounds provided herein.

[0005] BACKGROUND OF THE INVENTION

[0006] Cancer is characterized primarily by an increase in the number of abnormal cells derived from a given normal tissue, invasion of adjacent tissues by these abnormal cells, or lymphatic or blood-borne spread of malignant cells to regional lymph nodes and to distant sites (metastasis). Clinical data and molecular biologic studies indicate that cancer is a multistep process that begins with minor preneoplastic changes, which may under certain conditions progress to neoplasia. The neoplastic lesion may evolve clonally and develop an increasing capacity for invasion, growth, metastasis, and heterogeneity, especially under conditions in which the neoplastic cells escape the host's immune surveillance. Roitt, I., Brostoff, J and Kale,

[0007] D., Immunology, 17.1-17.12 (3rd ed., Mosby, St. Louis, Mo., 1993).

[0008] There is an enormous variety of cancers which are described in detail in the medical literature. Examples include cancer of the lung, colon, rectum, prostate, breast, brain, and intestine. The incidence of cancer continues to climb as the general population ages, as new cancers develop, and as susceptible populations grow. A tremendous demand therefore exists for new methods and compositions that can be used to treat patients with cancer. There exists a significant need for safe and effective compounds and methods for treating, preventing, and managing cancer, including for cancers that are refractory to standard treatments, such as surgery, radiation therapy, chemotherapy and hormonal therapy, while reducing or avoiding the toxicities and / or side effects associated with the conventional therapies.The UBA5 enzyme belongs to the El family of activating enzymes, which are responsible for initiating the labeling of intracellular proteins with small protein modifiers. These ubiquitin (Ub) and Ub-like (Ubl) modifiers destine target proteins for a variety of fates within the cell, including degradation by the 26S proteasome, depending on the nature and number of Ubl molecules attached (J. Biol. Chem. 1983, 258, 8206-8214, Nat. Rev. Mol. Cell Biol., 2009, 10, 319-331). In order to maintain fidelity and specificity of protein labeling, each Ubl modifier is activated by one specific El that catalyzes the adenylation of the C-terminal glycine carboxylate of the Ubl, followed by covalent attachment to an active site cysteine through a thioester bond to the El (J. Biol. Chem. 1983, 258, 8206-8214). The El catalyzes a second round of Ubl adenylation prior to binding to a specific subset of >30 conjugating E2 enzymes, which relieves the El of the first Ubl molecule through a transthiolation reaction that occurs between the thioester in the El-Ubl conjugate and the active site cysteine residue of the E2 (J. Biol. Chem. 1983, 258, 8206-8214, Nat. Rev. Mol. Cell Biol., 2009,10, 319-331). The conjugating enzyme shuttles the Ubl to one of around 600 E3 ligase enzymes (Nat. Rev. Mol. Cell Biol., 2009, 10, 319-331). The E3 mediates the final step of protein labeling by binding to both the Ubl-E2 complex and the protein substrate, facilitating the transfer of the Ubl from the E2 to an exposed lysine residue on the target protein in the formation of an isopeptide linkage (Nat. Rev. Mol. Cell Biol., 2009, 10, 319-331).

[0009] The El enzymes are classified as canonical or non-canonical, depending on their tertiary structure (Nat. Rev. Mol. Cell Biol., 2009, 10, 319-331, J. Biol. Chem. 2010, 285, 20273-20280) The non-canonical UBA5 enzyme regulates the covalent modification of proteins with Ub-fold modifier 1 (UFM1), an 85 amino acid (~9.1 kDa) protein that exhibits strong structural homology with the Ub tertiary structure (J. Biol. Chem. 2010, 285, 20273-20280, EMBO J. 2004, 23, 1977-1986). Physiologically, the UFM1 system has been implicated in erythroid development, where UBA5 knockout mice died in utero as a result of severe anemia brought upon by defective megakaryocyte and erythrocyte differentiation (Nat. Comm. 2011, DOI: 10.1038 / ncomms1182). The ribosomal protein RPL26 is a primary target of the UFM1 conjugation pathway (UFMylation) (Proc. Natl. Acad. Sci. U. S. A. 2019, 116, 1299-1308). Proteins of the UFM1 conjugation pathway are also upregulated in secretory cells that undergo endoplasmic reticulum (ER) stress, such as those found in the pancreatic islets of Langerhans, pancreatic acini, and seminal vesicles (PIoS ONE. 2011, 6, 4, e18517). It has been found that conjugation of UFM1 to its downstream substrates, UFM1-binding protein 1 containing a Pd domain (UFBP1) and CDK5RAP3, produces an anti-apoptotic effect in pancreatic islet cellsupon the induction of ER stress (PIoS ONE. 2011, 6, 4, el8517). In breast cancer, estrogen receptor-α (ERα) is prevalent. UFMylation of activating signal cointegrator 1 (ASC1) is crucial for ERa transactivation triggered by 17 -estradiol, highlighting the significance of ASCI UFMylation in breast cancer development (Mol. Cell. 2014, 56, 261-274). The UFMylation system thus appears to play a protective role in maintaining cell survival in times of stress.

[0010] Considering the higher protein turnover and resultant ER stress that also occurs in cancer cells, the UBA5 enzyme is a target for disrupting cancer progression, by inhibiting UFMylation through the sensitization of cancer cells to principal drugs responsible for inducing ER stress (Nat. Rev. Mol. Cell Biol., 2009, 10, 319-331, PIoS ONE. 2011, 6, 4, e18517). Furthermore, UFM1 conjugation is unique from other Ubl systems as it involves only one El (UBA5), one E2 (UFC1), and one E3 ligase (UFL1), compared to related pathways that rely on multiple E2s and up to hundreds of E3s (J. Biol. Chem. 2010, 285, 20273-20280, EMBO J. 2004, 23, 1977-1986, Biochem. Biophys. Res. Commun. 2007, 362, 1079-1084). Inhibition of UFM1 conjugation by targeting UBA5 upstream in the pathway could therefore be achieved without affecting off-target proteins.

[0011] SUMMARY OF THE INVENTION

[0012] Provided herein are compounds, pharmaceutical compositions containing the compounds and methods of use thereof in treating cancer, including solid tumors and blood borne tumors.

[0013] In a first embodiment, the present invention comprises a compound having a Formula (I),

[0014]

[0015] wherein: A is aryl or heterocyclyl, with the proviso that if A is aryl, then R2 must be alkyl;

[0016] Ri is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl; R2 is H or alkyl;

[0017] R3 is alkyl; R4 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted -alkyl-NHC(O)-aryl, substituted or unsubstituted -alkyl-NHC(O)- heteroaryl, or substituted or unsubstituted -alkyl-NHSO2-aryl. with the proviso that if R.4 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, then R2 must be alkyl, or a pharmaceutically acceptable salt thereof

[0018] In one embodiment, the compound provided herein is a compound of Formula I.

[0019] In one embodiment, the compound provided herein is a pharmaceutically acceptable salt of the compound of Formula I.

[0020] In one embodiment, the compound provided herein is a solvate of the compound of Formula I.

[0021] In one embodiment, the compound provided herein is a hydrate of compound of Formula I.

[0022] In one embodiment, the compound provided herein is a clathrate of the compound of Formula I.

[0023] Also provided are pharmaceutical compositions formulated for administration by an appropriate route and means containing effective concentrations of one or more of the compounds provided herein, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, and optionally comprising at least one pharmaceutical carrier.

[0024] In one embodiment, the pharmaceutical compositions deliver amounts effective for the treatment of cancer, including solid tumors and blood borne tumors.

[0025] In one embodiment, the pharmaceutical compositions deliver amounts effective for the prevention of cancer, including solid tumors and blood borne tumors.

[0026] In one embodiment, the pharmaceutical compositions deliver amounts effective for the amelioration of cancer, including solid tumors and blood borne tumors.

[0027] Also provided herein are combination therapies using one or more compounds or compositions provided herein, or an enantiomer or a mixture of enantiomers thereof, or an diastereomer or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof in combination with a therapy e.g., another pharmaceutical agent with activity against cancer or its symptoms. Examples of therapies within the scope of the methods include, but are not limited to, surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy, immunotherapy, and combinations thereof.The compounds or compositions provided herein, or pharmaceutically acceptable derivatives thereof, may be administered simultaneously with, prior to, or after administration of one or more of the above therapies. Pharmaceutical compositions containing a compound provided herein and one or more of the above agents are also provided.

[0028] In certain embodiments, provided herein are methods of treating, preventing or ameliorating cancer, including solid tumors and blood borne tumors, or one or more symptoms or causes thereof.

[0029] In certain embodiments, provided herein are methods of preventing cancer, including solid tumors and blood borne tumors, or one or more symptoms or causes thereof.

[0030] In certain embodiments, provided herein are methods of ameliorating cancer, including solid tumors and blood borne tumors, or one or more symptoms or causes thereof.

[0031] In certain embodiments, the blood borne tumor is leukemia. In certain embodiments, methods provided herein encompass methods of treating various forms of leukemias such as chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, acute myeloid leukemia and acute myeloblastic leukemia.

[0032] In certain embodiments, methods provided herein encompass methods of preventing various forms of leukemias such as chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, acute myeloid leukemia and acute myeloblastic leukemia.

[0033] In certain embodiments, methods provided herein encompass methods of managing various forms of leukemias such as chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, acute myeloid leukemia and acute myeloblastic leukemia.

[0034] The methods provided herein include treatment of leukemias that are relapsed, refractory or resistant.

[0035] The methods provided herein include prevention of leukemias that are relapsed, refractory or resistant.

[0036] The methods provided herein include management of leukemias that are relapsed, refractory or resistant.

[0037] In one embodiment, methods provided herein encompass methods of treating acute myeloid leukemia.

[0038] In one embodiment, methods provided herein encompass methods of preventing acute myeloid leukemia.

[0039] In one embodiment, methods provided herein encompass methods of managing acute myeloid leukemia.In practicing the methods, effective amounts of the compounds or compositions containing therapeutically effective concentrations of the compounds are administered to an individual exhibiting the symptoms of the disease or disorder to be treated. The amounts are effective to ameliorate or eliminate one or more symptoms of the disease or disorder.

[0040] Further provided is a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use of sale for human administration. The pack or kit can be labeled with information regarding mode of administration, sequence of drug administration (e.g., separately, sequentially or concurrently), or the like.

[0041] These and other aspects of the subject matter described herein will become evident upon reference to the following detailed description.

[0042] DETAILED DESCRIPTION OF THE INVENTION

[0043] Provided herein are compounds of formula I.

[0044] Provided herein is an enantiomer of compounds of formula I.

[0045] Provided herein is a mixture of enantiomers of compounds of formula I.

[0046] Provided herein is a pharmaceutically acceptable salt of a compound of formula I.

[0047] Provided herein is a pharmaceutically acceptable solvate of a compound of formula I. Provided herein is a pharmaceutically acceptable hydrate of a compound of formula I. Provided herein is a pharmaceutically acceptable co-crystal of a compound of formula I. Provided herein is a pharmaceutically acceptable clathrate of a compound of formula I. Provided herein is a pharmaceutically acceptable polymorph of a compound of formula I. Further provided are methods of treating cancer, including solid tumors blood borne tumors, and pharmaceutical compositions and dosage forms useful for such methods.

[0048] Further provided are methods of preventing cancer, including solid tumors blood borne tumors, and pharmaceutical compositions and dosage forms useful for such methods.

[0049] Further provided are methods of ameliorating cancer, including solid tumors blood borne tumors, and pharmaceutical compositions and dosage forms useful for such methods. The compounds, methods and compositions are described in detail in the sections below.

[0050] A. DefinitionsUnless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications are incorporated by reference in their entirety. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0051] Definitions Abbreviations:

[0052] The Following Abbreviations May be Used Herein

[0053] Bn = benzyl

[0054] t-Bu or tert-Bu = tertiary butyl

[0055] BINAP = ([l,l'-binaphthalene]-2,2'-diyl)bis(diphenylphosphane)

[0056] Boc = tert-butyloxycarbonyl

[0057] BOC2O = di-tert-butyl dicarbonate

[0058] BSA = bovine serum albumin

[0059] CHCh = chloroform

[0060] CN = cyano

[0061] Cs2CO3 = cesium carbonate

[0062] DCM or CH2Cl2 = dichloromethane

[0063] DIPEA or z-Pr2NEt = diisopropylethylamine (Hunig’s base)

[0064] DMAP = 4-dimethylaminopyridine

[0065] DMF = dimethyl formamide

[0066] DMSO = dimethyl sulfoxide

[0067] EDTA = ethylenediaminetetraacetic acidESI = electrospray ionization

[0068] Et = ethyl

[0069] Et3N = triethylamine

[0070] EtI = iodoethane

[0071] EtOH = ethanol

[0072] Et2O = diethyl ether

[0073] EtOAc = ethyl acetate

[0074] HATU = hexafluorophosphate azabenzotriazole tetramethyl uronium HC1 = hydrochloric acid

[0075] His6 = polyhistidine tag

[0076] HO Ac or AcOH = acetic acid

[0077] H2SO4 = sulfuric acid

[0078] HTRF = homogeneous time-resolved fluorescence

[0079] IC50 = half-maximal inhibitory concentration

[0080] Int = intermediate

[0081] K2CO3 = potassium carbonate

[0082] LiCl = lithium chloride

[0083] LiOH = lithium hydroxide

[0084] Me = methylMeCN or ACN = acetonitrile

[0085] Mel = iodomethane

[0086] MeOH = methanol

[0087] MgCl2 = magnesium chloride

[0088] MgSO4 = magnesium sulfate

[0089] NaCl = sodium chloride

[0090] NaH = sodium hydride

[0091] NaOH = sodium hydroxide

[0092] NaHCO3 = sodium bicarbonate

[0093] Na2SO4 = sodium sulfate

[0094] NH4CI = ammonium chloride

[0095] NH4OAc = ammonium acetate

[0096] NMI= 1 -methylimidazole

[0097] NMP = N-methyl-2-pyrrolidone

[0098] Ph = phenyl

[0099] Pd / C = palladium on carbon

[0100] Pd(OAc)2 = palladium(II) acetate

[0101] PdCl2(dtbpf) = [1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium(0)POCl3 = phosphorus oxychloride

[0102] iPrOH = isopropanol

[0103] Pyr or py = pyridine

[0104] K3PO4 = tripotassium phosphate

[0105] TCEP = tris(2-carboxyethyl)phosphine

[0106] TCFH = N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate THF = tetrahydrofuran

[0107] tert = tertiary

[0108] TFA = trifluoroacetic acid

[0109] rt = room temperature

[0110] min = minute(s)

[0111] hr or hrs = hour(s)

[0112] L = liter

[0113] mL = milliliter

[0114] pL = microliter

[0115] pM = micromolar

[0116] g = gram(s)

[0117] mg = milligram(s)

[0118] mol = molesmmol = millimole(s)

[0119] mM = millimolar

[0120] sat or sat’d = saturated

[0121] aq = aqueous

[0122] HPLC = high performance liquid chromatography

[0123] LC / MS = high performance liquid chromatography / mass spectrometry

[0124] MS or Mass Spec = mass spectrometry

[0125] NMR = nuclear magnetic resonance

[0126] mHz = megahertz

[0127] UV = ultraviolet

[0128] nm = nanometer

[0129] tR = retention time

[0130] δ = chemical shift in ppm

[0131] The use of the terms “a,” “an,” “the,” and similar referents in the context of describing the invention (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated. Recitation of ranges of values herein merely are intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended to better illustrate the invention and is not a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.“Alkyl” refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten, one to eight, one to six or one to four carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and the like.

[0132] “Alkylene” and “alkylene chain” refer to a straight or branched divalent hydrocarbon chain consisting solely of carbon and hydrogen, containing no unsaturation and having from one to eight carbon atoms, e.g., methylene, ethylene, propylene, n-butylene and the like. The alkylene chain may be attached to the rest of the molecule through any two carbons within the chain.

[0133] “Alkenylene” or “alkenylene chain” refers to a straight or branched chain unsaturated divalent radical consisting solely of carbon and hydrogen atoms, having from two to eight carbon atoms, wherein the unsaturation is present only as double bonds and wherein the double bond can exist between any two carbon atoms in the chain, e.g., ethenylene, prop-l-enylene, but-2-enylene and the like. The alkenylene chain may be attached to the rest of the molecule through any two carbons within the chain.

[0134] “Alkoxy” refers to the group having the formula — OR wherein R is alkyl or haloalkyl. An “optionally substituted alkoxy” refers to the group having the formula — OR wherein R is an optionally substituted alkyl as defined herein.

[0135] “Amino” refers to a radical having the formula — NR'R" wherein R' and R" are each independently hydrogen, alkyl or haloalkyl. An “optionally substituted amino” refers to a radical having the formula — NR'R" wherein one or both of R' and R" are optionally substituted alkyl as defined herein.

[0136] “Aryl” refers to a group of carbocylic ring system, including monocyclic, bicyclic, tricyclic, tetracyclic C6-C18 ring systems, wherein at least one of the rings is aromatic. The aryl may be fully aromatic, examples of which are phenyl, naphthyl, anthracenyl, acenaphthylenyl, azulenyl, fluorenyl, indenyl and pyrenyl. The aryl may also contain an aromatic ring in combination with a non-aromatic ring, examples of which are acenaphene, indene, and fluorene.

[0137] “Cycloalkyl” refers to a stable monovalent monocyclic or bicyclic hydrocarbon group consisting solely of carbon and hydrogen atoms, having from three to ten carbon atoms which is saturated, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalinyl, norbornane, norbomene, adamantyl, bicyclo[2.2.2]octane and the like.

[0138] “Halo, “halogen” or “halide” refers to F, Cl, Br or I.“Haloalkyl” refers to an alkyl group, in certain embodiments, Ci-6alkyl group in which one or more of the hydrogen atoms are replaced by halogen. Such groups include, but are not limited to, chloromethyl, trifluoromethyl l-chloro-2-fluoroethyl, 2,2-difluoroethyl, 2-fluoropropyl, 2-fluoropropan-2-yl, 2,2,2-trifluoroethyl, 1,1 -difluoroethyl, l,3-difluoro-2-methylpropyl, 2,2-difluorocyclopropyl, (trifluoromethyl)cyclopropyl, 4,4-difluorocyclohexyl and 2,2,2-trifluoro- 1, 1 -dimethylethyl.

[0139] “Heterocycle” or “Heterocyclyl” refers to a stable 3- to 15-membered non-aromatic ring radical which consists of carbon atoms and from one to five heteroatoms selected from a group consisting of nitrogen, oxygen and sulfur. In one embodiment, the heterocyclic ring system radical may be a monocyclic, bicyclic or tricyclic ring or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen or sulfur atoms in the heterocyclic ring system radical may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or fully saturated. The heterocyclic ring system may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Exemplary heterocylic radicals include, morpholinyl, piperidinyl, piperazinyl, pyranyl, pyrrolidinyl, oxetanyl, azetidinyl, quinuclidinyl, octahydroquinolizinyl, decahydroquinolizinyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.2.2]octanyl, isoindolinyl, indolinyl and others.

[0140] “Heteroaryl” refers to a heterocyclyl group as defined above which is aromatic. The heteroaryl groups include, but are not limited to monocyclyl, bicyclyl and tricyclyl groups, and may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of such heteroaryl groups include, but are not limited to: furanyl, imidazolyl, oxazolyl, isoxazolyl, pyrimidinyl, pyridinyl, pyridazinyl, thiazolyl, thienyl, benzimidazolyl, imidazo[4,5-b]pyridinyl, imidazo[l,2-a]pyridinyl, imidazo[l,2-b]pyridazinyl, imidazo[l,2-a]pyrazinyl and others.

[0141] “IC50” refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as cell growth or proliferation, measured via any of the in vitro or cell-based assay described herein.

[0142] Pharmaceutically acceptable salts include, but are not limited to, amine salts, such as but not limited to N, N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzyl phenethylamine, l-para-chlorobenzyl-2-pyrrolidin-l'-ylmethyl-benzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkalimetal salts, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not limited to zinc; and other metal salts, such as but not limited to sodium hydrogen phosphate and disodium phosphate; and also including, but not limited to, salts of mineral acids, such as but not limited to hydrochlorides and sulfates; and salts of organic acids, such as but not limited to acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrates, valerates, fumarates and organic sulfonates.

[0143] As used herein and unless otherwise indicated, the term “hydrate” means a compound provided herein or a salt thereof, that further includes a stoichiometric or non-stoichiometeric amount of water bound by non-covalent intermolecular forces.

[0144] As used herein and unless otherwise indicated, the term “solvate” means a solvate formed from the association of one or more solvent molecules to a compound provided herein. The term “solvate” includes hydrates (e.g., mono-hydrate, dihydrate, trihydrate, tetrahydrate and the like).

[0145] Unless stated otherwise specifically described in the specification, it is understood that the substitution can occur on any atom of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group.

[0146] Where the number of any given substituent is not specified (e.g., haloalkyl), there may be one or more substituents present. For example, “haloalkyl” may include one or more of the same or different halogens.

[0147] When the groups described herein are said to be “substituted,” they may be substituted with any appropriate substituent or substituents. Illustrative examples of substituents are those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine; aryloxyamine, aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (=0); B(0H)2, O(alkyl)aminocarbonyl; cycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocyclyl, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl); monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl,furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl) aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclyl alkoxy. When the alkyl groups described herein are said to be “substituted,” they may be substituted with any substituent or substituents as those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine; aryloxyamine, aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(0H)2, or O(alkyl)aminocarbonyl.

[0148] Unless specifically stated otherwise, where a compound may assume alternative tautomeric, regioisomeric and / or stereoisomeric forms, all alternative isomers are intended to be encompassed within the scope of the claimed subject matter. For example, where a compound is described as having one of two tautomeric forms, it is intended that both tautomers be encompassed herein.

[0149] Thus, the compounds provided herein may be enantiomerically pure, or be stereoisomeric or diastereomeric mixtures.

[0150] It is to be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R) or (S) configuration, or may be a mixture thereof. It is to be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. As such, one of skill in the art will recognize that administration of a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (S) form.

[0151] Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography on a chiral stationary phase.

[0152] In the description herein, if there is any discrepancy between a chemical name and chemical structure, the structure controls.

[0153] As used herein and unless otherwise indicated, the terms “treat,” “treating” and “treatment” refer to alleviating or reducing the severity of a symptom associated with the disease or condition being treated.The term “prevention” includes the inhibition of a symptom of the particular disease or disorder. In some embodiments, patients with familial history of cancer, including solid tumors and blood borne tumors, are candidates for preventive regimens. Generally, the term “preventing” refers to administration of the drug prior to the onset of symptoms, particularly to patients at risk of cancer, including solid tumors and blood borne tumors.

[0154] As used herein and unless otherwise indicated, the term “managing” encompasses preventing the recurrence of the particular disease or disorder in a patient who had suffered from it, lengthening the time a patient who had suffered from the disease or disorder remains in remission, reducing mortality rates of the patients, and / or maintaining a reduction in severity or avoidance of a symptom associated with the disease or condition being managed.

[0155] As used herein, “subject” is an animal, typically a mammal, including a human, such as a human patient.

[0156] As used herein, the term “tumor,” refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues.

[0157] “Neoplastic,” as used herein, refers to any form of dysregulated or unregulated cell growth, whether malignant or benign, resulting in abnormal tissue growth. Thus, “neoplastic cells” include malignant and benign cells having dysregulated or unregulated cell growth.

[0158] As used herein, “hematologic malignancy” refers to cancer of the body's blood-forming and immune system — the bone marrow and lymphatic tissue. Such cancers include leukemias, lymphomas (Non-Hodgkin's Lymphoma), Hodgkin's disease (also called Hodgkin's Lymphoma) and myeloma.

[0159] The term “leukemia” refers to malignant neoplasms of the blood-forming tissues. The leukemia includes, but is not limited to, chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, and acute myeloblastic leukemia. The leukemia can be relapsed, refractory or resistant to conventional therapy.

[0160] As used herein, “promyelocytic leukemia” or “acute promyelocytic leukemia” refers to a malignancy of the bone marrow in which there is a deficiency of mature blood cells in the myeloid line of cells and an excess of immature cells called promyelocytes. It is usually marked by an exchange of regions of chromosomes 15 and 17.

[0161] As used herein, “acute lymphocytic leukemia (ALL)”, also known as “acute lymphoblastic leukemia” refers to a malignant disease caused by the abnormal growth and development of early nongranular white blood cells, or lymphocytes.As used herein, “T-cell leukemia” refers to a disease in which certain cells of the lymphoid system called T lymphocytes or T cells are malignant. T cells are white blood cells that normally can attack virus-infected cells, foreign cells, and cancer cells and produce substances that regulate the immune response.

[0162] The term “relapsed” refers to a situation where patients who have had a remission of leukemia after therapy have a return of leukemia cells in the marrow and a decrease in normal blood cells.

[0163] The term “refractory or resistant” refers to a circumstance where patients, even after intensive treatment, have residual leukemia cells in their marrow.

[0164] As used herein, and unless otherwise specified, the terms “therapeutically effective amount” and “effective amount” of a compound refer to an amount sufficient to provide a therapeutic benefit in the treatment, prevention and / or management of a disease, to delay or minimize one or more symptoms associated with the disease or disorder to be treated. The terms “therapeutically effective amount” and “effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent.

[0165] The terms “co-administration” and “in combination with” include the administration of two therapeutic agents (for example, a compound provided herein and another anti-cancer agent) either simultaneously, concurrently or sequentially with no specific time limits. In one embodiment, both agents are present in the cell or in the patient's body at the same time or exert their biological or therapeutic effect at the same time. In one embodiment, the two therapeutic agents are in the same composition or unit dosage form. In another embodiment, the two therapeutic agents are in separate compositions or unit dosage forms.

[0166] The term “the supportive care agent” refers to any substance that treats, prevents or manages an adverse effect from treatment with the compound of Formula I.

[0167] The term “biological therapy” refers to administration of biological therapeutics such as cord blood, stem cells, growth factors and the like.

[0168] The term “about,” as used herein, unless otherwise indicated, refers to a value that is no more than 10% above or below the value being modified by the term. For example, the term “about 10 mg / m2” means a range of from 9 mg / m2to 11 mg / m2.

[0169] “Anti-cancer agents” refers to anti-metabolites (e.g., 5-fluoro-uracil, methotrexate, fludarabine), antimicrotubule agents (e.g., vinca alkaloids such as vincristine, vinblastine; taxanes such as paclitaxel, docetaxel), alkylating agents (e.g., cyclophosphamide, melphalan,carmustine, nitrosoureas such as bischloroethylnitrosurea and hydroxyurea), platinum agents (e.g. cisplatin, carboplatin, oxaliplatin, JM-216 or satraplatin, CI-973), anthracyclines (e.g., doxorubicin, daunorubicin), antitumor antibiotics (e.g., mitomycin, idarubicin, adriamycin, daunomycin), topoisomerase inhibitors (e g., etoposide, camptothecins), anti-angiogenesis agents (e.g. Sutent® and Bevacizumab) or any other cytotoxic agents, (estramustine phosphate, prednimustine), hormones or hormone agonists, antagonists, partial agonists or partial antagonists, kinase inhibitors, and radiation treatment.

[0170] As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature

[0171] (see, Biochem. 1972, 11:942-944).

[0172] B. Compounds

[0173] EMBODIMENTS

[0174] The embodiments listed below are presented in numbered form for convenience and for ease and clarity of reference in referring back to multiple embodiments.

[0175] In a first embodiment, the present invention comprises a compound having a Formula (I),

[0176]

[0177] wherein: A is aryl or heterocyclyl, with the proviso that if A is aryl, then R2 must be alkyl; Ri is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl; R2 is H or alkyl; Ra is alkyl;

[0178] R4 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted - alkyl-NHC(O)-aryl, substituted or unsubstituted -alkyl-NHC(O)-heteroaryl, or substituted or unsubstituted -alkyl-NHSO2-aryl, with the proviso that if R4 is substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, then R2 must be alkyl, or a pharmaceutically acceptable salt thereof.

[0179] In a second embodiment, the invention is a compound according to the first embodiment, wherein the compound is of Formula (II),

[0180]

[0181] wherein n is 1 or 2, or a pharmaceutically acceptable salt thereof.

[0182] In a third embodiment, the invention is a compound according to the first or second embodiments, wherein the compound is of Formula (IIB),

[0183]

[0184] pharmaceutically acceptable salt thereof.

[0185] In a fourth embodiment, the invention is a compound according to the first or second embodiments, wherein the compound is of Formula (IIC),

[0186]

[0187] pharmaceutically acceptable salt thereof.

[0188] In a fifth embodiment, the invention is a compound according to the first embodiment, wherein the compound is of Formula (III),

[0189]

[0190] pharmaceutically acceptable salt thereof.

[0191] In sixth embodiment, the invention is compound according to any of the preceding

[0192] embodiments, wherein Ri is selected from: H,

[0193]

[0194]

[0195] or a pharmaceutically acceptable salt thereof.

[0196] In a seventh embodiment, the invention is a compound according to any one of the

[0197] preceding embodiments wherein

[0198]

[0199] pharmaceutically acceptable salt thereof.

[0200] In an eighth embodiment, the invention is the compound according to any one of first

[0201] through sixth embodiments, wherein Ri is

[0202]

[0203] or a pharmaceutically acceptable salt thereof.

[0204] In a ninth embodiment, the invention is the compound according to any one of the preceding embodiments wherein R2 is Me, or a pharmaceutically acceptable salt thereof.

[0205] In a tenth embodiment, the invention is the compound according to any one of the preceding embodiments, wherein R3 is methyl, or a pharmaceutically acceptable salt thereof.

[0206] In an eleventh embodiment, the invention is the compound according to any one of the preceding embodiments wherein R4 is selected from:

[0207]

[0208]

[0209] thereof.

[0210] In a twelfth embodiment, the invention is the compound according to any one of the

[0211] preceding embodiments wherein

[0212]

[0213] pharmaceutically acceptable salt thereof.

[0214] In a thirteenth embodiment, the invention is the compound of the first embodiment, wherein the compound is selected from: ( )-4-(3-(2-(2,4-Dichlorobenzamido)-iV-methylacetamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-177-indole-7-carboxamide; (S)-4-(3-(2-Benzamido-JV-methylacetamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-l / / -indole-7-carboxamide; (5)-4-(3-(3-(ter / -Butyl)-jV-methyl-l 7 / -pyrazole-5-carboxamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-l / / -indole-7-carboxamide; (S)-5-Fluoro-4-(3-(2-((3-fluorophenyl)sulfonamido)-2V-methylacetamido)piperidin-l-yl)-2,3-dimethyl-lZf-indole-7-carboxamide; (5)-4-(3-(2-(2,3-Dimethylbenzamido)-7V-methylacetamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-l / / -indole-7-carboxamide; (S)-V-(2-((l-(7-Carbamoyl-5-fluoro-2,3-dimethyl-177-indol-4-yl)piperidin-3-yl)(methyl)amino)-2-oxoethyl)quinoline-8-carboxamide; (S)-7V-(2-((l-(7-Carbamoyl-5-fluoro-2,3-dimethyl-17 / -indol-4-yl)piperidin-3-yl)(methyl)amino)-2-oxoethyl)quinoline-4-carboxamide; (5)-V-(2-((l-(7-Carbamoyl-5-fluoro-2,3-dimethyl-l / / -indol-4-yl)piperidin-3-yl)(methyl)amino)-2-oxoethyl)quinoline-5-carboxamide; ( )-JV-(2-((l-(7-Carbamoyl-5-fluoro-2,3-dimethyl-l / / -indol-4-yl)piperidin-3-yl)(methyl)amino)-2-oxoethyl)isoquinoline-8-carboxamide; (S)-2V-(2-((l-(7-Carbamoyl-5-fluoro-2,3-dimethyl-l / 7-indol-4-yl)piperidin-3-yl)(methyl)amino)-2-oxoethyl)isoquinoline-4-carboxamide;

[0215]

[0216] (7-Carbamoyl-5-fluoro-2,3-dimethyl-17 / -indol-4-yl)piperidin-3-yl)(methyl)amino)-2-oxoethyl)isoquinoline-l-carboxamide; (S)-5-Fluoro-JV,2,3-trimethyl-4-(3-(JV-methylbut-2-ynamido)piperidin-l-yl)-l / 7-indole-7-carboxamide; (5 -5-Fluoro-l,2,3-trimethyl-4-(3-(V-methylbut-2-ynamido)piperidin- 1 -yl)- 177-indole-7-carboxamide; ( )- 1 -Ethyl-5-fluoro-2,3-dimethyl-4-(3-(JV-methylbut-2-ynamido)piperidin-l-yl)-177-indole-7-carboxamide; (S)-4-(3-(3-Cyclopropyl-jV-methylpropiolamido)piperidin-l-yl)-5-fluoro-l,2,3-trimethyl-l / f-indole-7-carboxamide; (5)-5-Fluoro-l,2,3-trimethyl-4-(3-(? / -methylbut-2-ynamido)azepan-l-yl)-l / / -indole-7-carboxamide; 5-Fluoro-l,2,3-trimethyl-4-(3-(jV-methylbut-2-ynamido)phenyl)-l / 7-indole-7-carboxamide; (5)-4-(3-(5-(tert-butyl)-? / -methyl-177-pyrazole-3-carboxamido)piperidin-l-yl)-7V-(cyanomethyl)-5-fluoro-2,3-dimethyl-l / 7-indole-7-carboxamide; 4-((5)-3-(5-(tert-Butyl)-jV-methyl-l / 7-pyrazole-3-carboxamido)piperidin-l-yl)-5-fluoro-jV-((lS,27?)-2-hydroxycyclohexyl)-2,3-dimethyl-l / / -indole-7-carboxamide; (S)-4-(3-(5-( / er / -Butyl)-V-methyl-17 / -pyrazole-3-carboxamido)piperidin-l-yl)-A (3,3-difluoro-l-(hydroxymethyl)cyclobutyl)-5-fluoro-2,3-dimethyl-l / / -indole-7-carboxamide; (S)-4-(3-(5-(ter^Butyl)-A-methyl-l / / -pyrazole-3-carboxamido)piperidin-l-yl)-5-fluoro-JV-((l-hydroxycyclobutyl)methyl)-2,3-dimethyl-l / / -indole-7-carboxamide; ( )-4-(3-(5-(ter / -Butyl)-V-methyl-lZf-pyrazole-3-carboxamido)piperidin-l-yl)-7V-(l-cyclopropylpiperidin-4-yl)-5-fluoro-2,3-dimethyl-l / / -indole-7-carboxamide; 4-(( )-3-(2-(l-Naphthamido)-jV-methylacetamido)piperidin-l-yl)-5-fluoro-jV-((37?,4^)-4-hydroxytetrahydro-277-pyran-3-yl)-2,3-dimethyl-17 -indole-7-carboxamide; 4-((5)-3-(2-(l-Naphthamido)-jV-methylacetamido)piperidin-l-yl)-5-fluoro-iV-((3S,47?)-3-hydroxytetrahydro-2 / / -pyran-4-yl)-2, 3 -dimethyl- 17 / -indole-7-carboxamide; V-(2-(((5)-l-(5-Fluoro-7-(((37?,47?)-4-hydroxytetrahydro-2 / 7-pyran-3-yl)carbamoyl)-2,3-dimethyl-l / 7-indol-4-yl)piperidin-3-yl)(methyl)amino)-2-oxoethyl)quinoline-5-carboxamide; jV-(2-(((5)-l-(5-Fluoro-7-(((37?,4^)-4-hydroxytetrahydro-2 / 7-pyran-3-yl)carbamoyl)-2,3-dimethyl-17 / -indol-4-yl)piperidin-3-yl)(methyl)amino)-2-oxoethyl)quinoline-4-carboxamide; JV-(2-(((5)-l-(5-Fluoro-7-(((3S,47?)-3-hydroxytetrahydro-2 / 7-pyran-4-yl)carbamoyl)-2,3-dimethyl-l / 7-indol-4-yl)piperidin-3-yl)(methyl)amino)-2-oxoethyl)quinoline-4-carboxamide; JV-(2-(((5)-l-(5-Fluoro-7-(((37?,4^)-4-hydroxytetrahydro-2 / / -pyran-3-yl)carbamoyl)-l, 2, 3-trimethyl-l / / -indol -4-yl )piperi din-3-yl)(methyl)amino)-2-oxoethyl)quinoline-5-carboxamide; V-(2-(((S)-l-(5-Fluoro-7-(((37?,4^)-4-hydroxytetrahydro-2 / / -pyran-3-yl)carbamoyl)-l, 2, 3-trimethyl-17 / -indol -4-yl Jpiperi din-3-yl)(methyl)amino)-2-oxoethyl)quinoline-4-carboxamide; 4-((5)-3-(2-(l-Naphthamido)-JV-methylacetamido)piperidin-l-yl)-5-fluoro-A ((37?,47?)-4-hydroxytetrahydro-277-pyran-3-yl)-l,2,3-trimethyl-l / / -indole-7-carboxamide; 4-((S)-3-(2-(l-Naphthamido)-2V-methylacetamido)piperidin-l-yl)-5-fhioro-Af-((3A',4 / )-3-hydroxytetrahydro-27 / -pyran-4-yl)-l,2,3-trimethyl-l / / -indole-7-carboxamide; (S)-4-(3-(2-(l-Naphthamido)-2V-ethylacetamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-177-indole-7-carboxamide; and (S)-4-(3-(2-(l-Naphthamido)-JV-methylacetamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-l / / - indole-7-carboxamide, or a pharmaceutically acceptable salt thereof.In a fourteenth embodiment, the invention is a compound according to any one of the preceding embodiments for use as a medicament.

[0217] In a fifteenth embodiments, the invention is a compound according to any one of the first through thirteenth embodiments, for use in a method of treating cancer, comprising administering to a mammal having cancer a therapeutically effective amount of the compound.

[0218] In a sixteenth embodiment, the invention is the compound for use according to the fifteenth embodiment, additionally comprising determining the cancer responds to UBA5 inhibition.

[0219] In a seventeenth embodiment, the invention is the compound for use according to sixteenth embodiment, wherein the cancer is pancreatic cancer, breast cancer, leukemia, lung cancer or melanoma.

[0220] In an eighteenth embodiment, the invention is the compound for use according to the seventeenth embodiment, wherein the leukemia is acute leukemia, chronic leukemia, lymphocytic leukemia or myelogenous leukemia.

[0221] Also provided herein are isotopically enriched analogs of the compounds provided herein. Isotopic enrichment (for example, deuteration) of pharmaceuticals to improve pharmacokinetics (“PK”), pharmacodynamics (“PD”), and toxicity profiles, has been demonstrated previously with some classes of drugs. See, for example, Lijinsky et. al., Food Cosmet. Toxicol., 20: 393 (1982); Lijinsky et. al., J. Nat. Cancer Inst., 69: 1127 (1982); Mangold et. al., Mutation Res. 308: 33 (1994); Gordon et. al., Drug Metab. Dispos., 15: 589 (1987); Zello et. al., Metabolism, 43: 487 (1994); Gately et. al., J. Nucl. Med., 27: 388 (1986); Wade D, Chem. Biol. Interact. 117: 191 (1999).

[0222] Without being limited by any particular theory, isotopic enrichment of a drug can be used, for example, to (1) reduce or eliminate unwanted metabolites, (2) increase the half-life of the parent drug, (3) decrease the number of doses needed to achieve a desired effect, (4) decrease the amount of a dose necessary to achieve a desired effect, (5) increase the formation of active metabolites, if any are formed, and / or (6) decrease the production of deleterious metabolites in specific tissues and / or create a more effective drug and / or a safer drug for combination therapy, whether the combination therapy is intentional or not.

[0223] Replacement of an atom for one of its isotopes often will result in a change in the reaction rate of a chemical reaction. This phenomenon is known as the Kinetic Isotope Effect (“KIE”). For example, if a C — H bond is broken during a rate-determining step in a chemical reaction (i.e. the step with the highest transition state energy), substitution of a deuterium for that hydrogen will cause a decrease in the reaction rate and the process will slow down. Thisphenomenon is known as the Deuterium Kinetic Isotope Effect (“DKIE”). (See, e.g, Foster et al., Adv. Drug Res., vol. 14, pp. 1-36 (1985); Kushner et al., Can. J. Physiol. Pharmacol., vol. 77, pp. 79-88 (1999)).

[0224] The magnitude of the DKIE can be expressed as the ratio between the rates of a given reaction in which a C — H bond is broken, and the same reaction where deuterium is substituted for hydrogen. The DKIE can range from about 1 (no isotope effect) to very large numbers, such as 50 or more, meaning that the reaction can be fifty, or more, times slower when deuterium is substituted for hydrogen. Without being limited by a particular theory, high DKIE values may be due in part to a phenomenon known as tunneling, which is a consequence of the uncertainty principle. Tunneling is ascribed to the small mass of a hydrogen atom, and occurs because transition states involving a proton can sometimes form in the absence of the required activation energy. Because deuterium has more mass than hydrogen, it statistically has a much lower probability of undergoing this phenomenon.

[0225] Tritium (“T”) is a radioactive isotope of hydrogen, used in research, fusion reactors, neutron generators and radiopharmaceuticals. Tritium is a hydrogen atom that has 2 neutrons in the nucleus and has an atomic weight close to 3. It occurs naturally in the environment in very low concentrations, most commonly found as T2O. Tritium decays slowly (half-life 12.3 years) and emits a low energy beta particle that cannot penetrate the outer layer of human skin. Internal exposure is the main hazard associated with this isotope, yet it must be ingested in large amounts to pose a significant health risk. As compared with deuterium, a lesser amount of tritium must be consumed before it reaches a hazardous level. Substitution of tritium (“T”) for hydrogen results in yet a stronger bond than deuterium and gives numerically larger isotope effects.

[0226] Similarly, substitution of isotopes for other elements, including, but not limited to,13C or14C for carbon,33S,34S, or36S for sulfur,15N for nitrogen, and17O or18O for oxygen, will provide a similar kinetic isotope effects.

[0227] The animal body expresses a variety of enzymes for the purpose of eliminating foreign substances, such as therapeutic agents, from its circulation system. Examples of such enzymes include the cytochrome P450 enzymes (“CYPs”), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases, to react with and convert these foreign substances to more polar intermediates or metabolites for renal excretion. Some of the most common metabolic reactions of pharmaceutical compounds involve the oxidation of a carbon-hydrogen (C — H) bond to either a carbon-oxygen (C — O) or carbon-carbon (C — C) pi-bond. The resultant metabolites may be stable or unstable under physiological conditions, and can have substantiallydifferent pharmacokinetic, pharmacodynamic, and acute and long-term toxicity profiles relative to the parent compounds. For many drugs, such oxidations are rapid. As a result, these drugs often require the administration of multiple or high daily doses.

[0228] Isotopic enrichment at certain positions of a compound provided herein may produce a detectable KIE that affects the pharmacokinetic, pharmacologic, and / or toxicological profiles of a compound provided herein in comparison with a similar compound having a natural isotopic composition. In one embodiment, the deuterium enrichment is performed on the site of C — H bond cleavage during metabolism.

[0229] C. Methods of Treatment and Prevention

[0230] In one embodiment, provided herein is a method of treating and preventing cancer, which comprises administering to a patient a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.

[0231] In another embodiment, provided herein is method of managing cancer, which comprises administering to a patient a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.

[0232] Also provided herein are methods of treating patients who have been previously treated for cancer but are non-responsive to standard therapies, as well as those who have not previously been treated. The invention also encompasses methods of treating patients regardless of patient's age, although some diseases or disorders are more common in certain age groups. The invention further encompasses methods of treating patients who have undergone surgery in an attempt to treat the disease or condition at issue, as well as those who have not. Because patients with cancer have heterogeneous clinical manifestations and varying clinical outcomes, the treatment given to a patient may vary, depending on his / her prognosis. The skilled clinician will be able to readily determine without undue experimentation specific secondary agents, types of surgery, and types of non-drug based standard therapy that can be effectively used to treat an individual patient with cancer.

[0233] As used herein, the term “cancer” includes, but is not limited to, solid tumors and blood borne tumors. The term “cancer” refers to disease of skin tissues, organs, blood, and vessels, including, but not limited to, cancers of the bladder, bone, blood, brain, breast, cervix, chest, colon, endometrium, esophagus, eye, head, kidney, liver, lymph nodes, lung, mouth, neck, ovaries, pancreas, prostate, rectum, stomach, testis, throat, and uterus. Specific cancers include,but are not limited to, advanced malignancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastases, glioblastoma multiforms, glioblastoma, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, recurrent malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C & D colorectal cancer, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma, karotype acute myeloblastic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma, low grade follicular lymphoma, malignant melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressive, hormone refractory prostate cancer, resected high-risk soft tissue sarcoma, unresectable hepatocellular carcinoma, Waldenstrom's macroglobulinemia, smoldering myeloma, indolent myeloma, fallopian tube cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, urachal cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, and leiomyoma

[0234] In certain embodiments, the cancer is a solid tumor. In certain embodiments, the solid tumor is metastatic. In certain embodiments, the solid tumor is drug-resistant. In certain embodiments, the solid tumor is hepatocellular carcinoma, prostate cancer, ovarian cancer, or glioblastoma.

[0235] In certain embodiments, the cancer is a blood borne tumor. In certain embodiments, the blood borne tumor is metastatic. In certain embodiments, the blood borne tumor is drug resistant. In certain embodiments, the cancer is leukemia.

[0236] In one embodiment, methods provided herein encompass treating, preventing or managing various types of leukemias such as chronic lymphocytic leukemia (CLL), chronic myelocytic leukemia (CML), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and acute myeloblastic leukemia (AML) by administering a therapeutically effective amount of a compound of formula I or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.

[0237] In some embodiments, the methods provided herein encompass treating, preventing or managing acute leukemia in a subject. In some embodiments, the acute leukemia is acute myeloid leukemia (AML), which includes, but is not limited to, undifferentiated AML (MO),myeloblastic leukemia (Ml), myeloblastic leukemia (M2), promyelocytic leukemia (M3 or M3 variant [M3V]), myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]), monocytic leukemia (M5), erythroleukemia (M6), and megakaryoblastic leukemia (M7). In one embodiment, the acute myeloid leukemia is undifferentiated AML (MO). In one embodiment, the acute myeloid leukemia is myeloblastic leukemia (Ml). In one embodiment, the acute myeloid leukemia is myeloblastic leukemia (M2). In one embodiment, the acute myeloid leukemia is promyelocytic leukemia (M3 or M3 variant [M3V]). In one embodiment, the acute myeloid leukemia is myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]). In one embodiment, the acute myeloid leukemia is monocytic leukemia (M5). In one embodiment, the acute myeloid leukemia is erythroleukemia (M6). In one embodiment, the acute myeloid leukemia is megakaryoblastic leukemia (M7). Thus, the methods of treating, preventing or managing acute myeloid leukemia in a subject comprise the step of administering to the subject an amount of a compound provided herein or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof effective to treat, prevent or manage acute myeloid leukemia alone or in combination. In some embodiments, the methods comprise the step of administering to the subject a compound provided herein or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof in combination with a second active agent in amounts effective to treat, prevent or manage acute myeloid leukemia.

[0238] In some embodiments, the methods provided herein encompass treating, preventing or managing acute lymphocytic leukemia (ALL) in a subject. In some embodiments, acute lymphocytic leukemia includes leukemia that originates in the blast cells of the bone marrow (B-cells), thymus (T-cells), and lymph nodes. The acute lymphocytic leukemia can be categorized according to the French- American-British (FAB) Morphological Classification Scheme as LI — Mature-appearing lymphoblasts (T-cells or pre-B-cells), L2 — Immature and pleomorphic (variously shaped) lymphoblasts (T-cells or pre-B-cells), and L3 — Lymphoblasts (B-cells;

[0239] Burkitt's cells). In one embodiment, the acute lymphocytic leukemia originates in the blast cells of the bone marrow (B-cells). In one embodiment, the acute lymphocytic leukemia originates in the thymus (T-cells). In one embodiment, the acute lymphocytic leukemia originates in the lymph nodes. In one embodiment, the acute lymphocytic leukemia is LI type characterized by mature-appearing lymphoblasts (T-cells or pre-B-cells). In one embodiment, the acute lymphocytic leukemia is L2 type characterized by immature and pleomorphic (variously shaped) lymphoblasts (T-cells or pre-B-cells). In one embodiment, the acute lymphocytic leukemia is L3type characterized by lymphoblasts (B-cells; Burkitt's cells). In certain embodiments, the acute lymphocytic leukemia is T-cell leukemia. In one embodiment, the T-cell leukemia is peripheral T-cell leukemia. In another embodiment, the T-cell leukemia is T-cell lymphoblastic leukemia. In another embodiment, the T-cell leukemia is cutaneous T-cell leukemia. In another embodiment, the T-cell leukemia is adult T-cell leukemia. Thus, the methods of treating, preventing or managing acute lymphocytic leukemia in a subject comprise the step of administering to the subject an amount of a compound provided herein or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof effective to treat, prevent or manage acute lymphocytic leukemia alone or in combination with a second active agent. In some embodiments, the methods comprise the step of administering to the subject a compound provided herein or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof in combination with a second active agent in amounts effective to treat, prevent or manage acute lymphocytic leukemia.

[0240] In some embodiments, the methods provided herein encompass treating, preventing or managing chronic myelogenous leukemia (CML) in a subject. The methods comprise the step of administering to the subject an amount of a compound provided herein or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof effective to treat, prevent or manage chronic myelogenous leukemia. In some embodiments, the methods comprise the step of administering to the subject a compound provided herein or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof in combination with a second active agent in amounts effective to treat, prevent or manage chronic myelogenous leukemia.

[0241] In some embodiments, the methods provided herein encompass treating, preventing or managing chronic lymphocytic leukemia (CLL) in a subject. The methods comprise the step of administering to the subject an amount of a compound provided herein or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof effective to treat, prevent or manage chronic lymphocytic leukemia. In some embodiments, the methods comprise the step of administering to the subject a compound provided herein or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereofin combination with a second active agent in amounts effective to treat, prevent or manage chronic lymphocytic leukemia.

[0242] In certain embodiments, provided herein are methods of treating, preventing, and / or managing disease in patients with impaired renal function. In certain embodiments, provided herein are method of treating, preventing, and / or managing cancer in patients with impaired renal function. In certain embodiments, provided herein are methods of providing appropriate dose adjustments for patients with impaired renal function due to, but not limited to, disease, aging, or other patient factors.

[0243] In certain embodiments, provided herein are methods of treating, preventing, and / or managing lymphoma, including non-Hodgkin's lymphoma. In some embodiments, provided herein are methods for the treatment or management of non-Hodgkin's lymphoma (NHL), including but not limited to, diffuse large B-cell lymphoma (DLBCL), using prognostic factors.

[0244] In certain embodiments, provided herein are methods of treating, preventing, and / or managing multiple myeloma, including relapsed / refractory multiple myeloma in patients with impaired renal function or a symptom thereof, comprising administering a therapeutically effective amount of the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof to a patient having relapsed / refractory multiple myeloma with impaired renal function.

[0245] In certain embodiments, a therapeutically or prophylactically effective amount of the compound is from about 0.005 to about 1,000 mg per day, from about 0.01 to about 500 mg per day, from about 0.01 to about 250 mg per day, from about 0.01 to about 100 mg per day, from about 0.1 to about 100 mg per day, from about 0.5 to about 100 mg per day, from about 1 to about 100 mg per day, from about 0.01 to about 50 mg per day, from about 0.1 to about 50 mg per day, from about 0.5 to about 50 mg per day, from about 1 to about 50 mg per day, from about 0.02 to about 25 mg per day, from about 0.05 to about 10 mg per day, from about 0.05 to about 5 mg per day, from about 0.1 to about 5 mg per day, or from about 0.5 to about 5 mg per day.

[0246] In certain embodiments, the therapeutically or prophylactically effective amount is about 0.1, about 0.2, about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 30, about 40, about 45, about 50, about 60, about 70, about 80, about 90, about 100, or about 150 mg per day. In some suchembodiments, the therapeutically or prophylactically effective amount is about 2, about 3, about 4, about 5, about 6 or about 7 mg per day.

[0247] In one embodiment, the recommended daily dose range of the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, for the conditions described herein lie within the range of from about 0.5 mg to about 50 mg per day, preferably given as a single once-a-day dose, or in divided doses throughout a day. In some embodiments, the dosage ranges from about 1 mg to about 50 mg per day. In other embodiments, the dosage ranges from about 0.5 to about 5 mg per day. Specific doses per day include 0.1, 0.2, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 mg per day.

[0248] In a specific embodiment, the recommended starting dosage may be 0.5, 1, 2, 3, 4, 5, 10, 15, 20, 25 or 50 mg per day. In another embodiment, the recommended starting dosage may be 0.5, 1, 2, 3, 4, or 5 mg per day. The dose may be escalated to 15, 20, 25, 30, 35, 40, 45 and 50 mg / day. In a specific embodiment, the compound can be administered in an amount of about 25 mg / day to patients with leukemia, including AML. In a particular embodiment, the compound can be administered in an amount of about 10 mg / day to patients with leukemia, including AML. In a particular embodiment, the compound can be administered in an amount of about 5 mg / day to patients with leukemia, including AML. In a particular embodiment, the compound can be administered in an amount of about 4 mg / day to patients with leukemia, including AML. In a particular embodiment, the compound can be administered in an amount of about 3 mg / day to patients with leukemia, including AML.

[0249] In certain embodiments, the therapeutically or prophylactically effective amount is from about 0.001 to about 100 mg / kg / day, from about 0.01 to about 50 mg / kg / day, from about 0.01 to about 25 mg / kg / day, from about 0.01 to about 10 mg / kg / day, from about 0.01 to about 9 mg / kg / day, 0.01 to about 8 mg / kg / day, from about 0.01 to about 7 mg / kg / day, from about 0.01 to about 6 mg / kg / day, from about 0.01 to about 5 mg / kg / day, from about 0.01 to about 4 mg / kg / day, from about 0.01 to about 3 mg / kg / day, from about 0.01 to about 2 mg / kg / day, from about 0.01 to about 1 mg / kg / day, or from about 0.01 to about 0.05 mg / kg / day.

[0250] The administered dose can also be expressed in units other than mg / kg / day. For example, doses for parenteral administration can be expressed as mg / m2 / day. One of ordinary skill in the art would readily know how to convert doses from mg / kg / day to mg / m2 / day given either theheight or weight of a subject or both (see, www.fda.gov / cder / cancer / animalframe.htm). For example, a dose of 1 mg / kg / day for a 65 kg human is approximately equal to 38 mg / m2 / day.

[0251] In certain embodiments, the amount of the compound administered is sufficient to provide a plasma concentration of the compound at steady state, ranging from about 0.001 to about 500 μM, about 0.002 to about 200 μM, about 0.005 to about 100 μM, about 0.01 to about 50 μM, from about 1 to about 50 μM, about 0.02 to about 25 μM, from about 0.05 to about 20 μM, from about 0.1 to about 20 μM, from about 0.5 to about 20 μM, or from about 1 to about 20 μM.

[0252] In other embodiments, the amount of the compound administered is sufficient to provide a plasma concentration of the compound at steady state, ranging from about 5 to about 100 nM, about 5 to about 50 nM, about 10 to about 100 nM, about 10 to about 50 nM or from about 50 to about 100 nM.

[0253] As used herein, the term “plasma concentration at steady state” is the concentration reached after a period of administration of a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. Once steady state is reached, there are minor peaks and troughs on the time dependent curve of the plasma concentration of the compound.

[0254] In certain embodiments, the amount of the compound administered is sufficient to provide a maximum plasma concentration (peak concentration) of the compound, ranging from about 0.001 to about 500 μM, about 0.002 to about 200 μM, about 0.005 to about 100 μM, about 0.01 to about 50 μM, from about 1 to about 50 μM, about 0.02 to about 25 μM, from about 0.05 to about 20 μM, from about 0.1 to about 20 μM, from about 0.5 to about 20 μM, or from about 1 to about 20 μM.

[0255] In certain embodiments, the amount of the compound administered is sufficient to provide a minimum plasma concentration (trough concentration) of the compound, ranging from about 0.001 to about 500 μM, about 0.002 to about 200 μM, about 0.005 to about 100 μM, about 0.01 to about 50 μM, from about 1 to about 50 μM, about 0.01 to about 25 μM, from about 0.01 to about 20 μM, from about 0.02 to about 20 μM, from about 0.02 to about 20 μM, or from about 0.01 to about 20 μM.

[0256] In certain embodiments, the amount of the compound administered is sufficient to provide an area under the curve (AUC) of the compound, ranging from about 100 to about100,000 ng*hr / mL, from about 1,000 to about 50,000 ng*hr / mL, from about 5,000 to about 25,000 ng*hr / mL, or from about 5,000 to about 10,000 ng*hr / mL.

[0257] In certain embodiments, the patient to be treated with one of the methods provided herein has not been treated with anticancer therapy prior to the administration of the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. In certain embodiments, the patient to be treated with one of the methods provided herein has been treated with anticancer therapy prior to the administration of the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. In certain embodiments, the patient to be treated with one of the methods provided herein has developed drug resistance to the anticancer therapy.

[0258] The methods provided herein encompass treating a patient regardless of patient's age, although some diseases or disorders are more common in certain age groups.

[0259] Depending on the disease to be treated and the subject's condition, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracistemal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration. The compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, may be formulated, alone or together, in suitable dosage unit with pharmaceutically acceptable excipients, carriers, adjuvants and vehicles, appropriate for each route of administration.

[0260] In one embodiment, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered orally. In another embodiment, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered parenterally. In yet another embodiment, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered intravenously.The compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, can be delivered as a single dose such as, e.g., a single bolus injection, or oral tablets or pills; or over time, such as, e.g., continuous infusion over time or divided bolus doses over time. The compound can be administered repeatedly if necessary, for example, until the patient experiences stable disease or regression, or until the patient experiences disease progression or unacceptable toxicity. For example, stable disease for solid tumors generally means that the perpendicular diameter of measurable lesions has not increased by 25% or more from the last measurement. Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines, Journal of the National Cancer Institute 92(3): 205-216 (2000). Stable disease or lack thereof is determined by methods known in the art such as evaluation of patient symptoms, physical examination, visualization of the tumor that has been imaged using X-ray, CAT, PET, or MRI scan and other commonly accepted evaluation modalities.

[0261] The compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, can be administered once daily (QD), or divided into multiple daily doses such as twice daily (BID), three times daily (TID), and four times daily (QID). In addition, the administration can be continuous (i.e., daily for consecutive days or every day), intermittent, e.g., in cycles (i.e., including days, weeks, or months of rest without drug). As used herein, the term “daily” is intended to mean that a therapeutic compound, such as the compound of Formula I, is administered once or more than once each day, for example, for a period of time. The term “continuous” is intended to mean that a therapeutic compound, such as the compound of Formula I, is administered daily for an uninterrupted period of at least 10 days to 52 weeks. The term “intermittent” or “intermittently” as used herein is intended to mean stopping and starting at either regular or irregular intervals. For example, intermittent administration of the compound of Formula I is administration for one to six days per week, administration in cycles (e.g., daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week), or administration on alternate days. The term “cycling” as used herein is intended to mean that a therapeutic compound, such as the compound of Formula I, is administered daily or continuously but with a rest period. In some such embodiments, administration is once a day for two to six days, then a rest period with no administration for five to seven days.In some embodiments, the frequency of administration is in the range of about a daily dose to about a monthly dose. In certain embodiments, administration is once a day, twice a day, three times a day, four times a day, once every other day, twice a week, once every week, once every two weeks, once every three weeks, or once every four weeks. In one embodiment, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered once a day. In another embodiment, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered twice a day. In yet another embodiment, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered three times a day. In still another embodiment, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered four times a day.

[0262] In certain embodiments, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered once per day from one day to six months, from one week to three months, from one week to four weeks, from one week to three weeks, or from one week to two weeks. In certain embodiments, the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, is administered once per day for one week, two weeks, three weeks, or four weeks. In one embodiment, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered once per day for 4 days. In one embodiment, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered once per day for 5 days. In one embodiment, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered once per day for 6 days. In one embodiment, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered once per day for one week. In another embodiment, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, isadministered once per day for two weeks. In yet another embodiment, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered once per day for three weeks. In still another embodiment, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered once per day for four weeks.

[0263] C-l. Combination Therapy with a Second Active Agent

[0264] The compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, can also be combined or used in combination with other therapeutic agents useful in the treatment and / or prevention of cancer described herein.

[0265] In one embodiment, provided herein is a method of treating, preventing, or managing cancer, comprising administering to a patient a compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof; in combination with one or more second active agents, and optionally in combination with radiation therapy, blood transfusions, or surgery. Examples of second active agents are disclosed herein (see, e.g., section 5.4).

[0266] As used herein, the term “in combination” includes the use of more than one therapy (e.g., one or more prophylactic and / or therapeutic agents). However, the use of the term “in combination” does not restrict the order in which therapies (e.g., prophylactic and / or therapeutic agents) are administered to a patient with a disease or disorder. A first therapy (e.g., a prophylactic or therapeutic agent such as a compound provided herein, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent) to the subject. Triple therapy is also contemplated herein.

[0267] Administration of the compound of Formula I and one or more second active agents to a patient can occur simultaneously or sequentially by the same or different routes ofadministration. The suitability of a particular route of administration employed for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without decomposing prior to entering the blood stream) and the cancer being treated.

[0268] The route of administration of the compound of Formula I is independent of the route of administration of a second therapy. In one embodiment, the compound of Formula I is administered orally. In another embodiment, the compound of Formula I is administered intravenously. Thus, in accordance with these embodiments, the compound of Formula I is administered orally or intravenously, and the second therapy can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraocularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form. In one embodiment, the compound of Formula I and a second therapy are administered by the same mode of administration, orally or by IV. In another embodiment, the compound of Formula I is administered by one mode of administration, e.g., by IV, whereas the second agent (an anticancer agent) is administered by another mode of administration, e.g., orally.

[0269] In one embodiment, the second active agent is administered intravenously or subcutaneously and once or twice daily in an amount of from about 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50 to about 200 mg. The specific amount of the second active agent will depend on the specific agent used, the type of disease being treated or managed, the severity and stage of disease, and the amount of the compound of Formula I provided herein and any optional additional active agents concurrently administered to the patient.

[0270] One or more second active ingredients or agents can be used together with the compound of formula I in the methods and compositions provided herein. Second active agents can be large molecules (e g., proteins) or small molecules (e.g., synthetic inorganic, organometallic, or organic molecules).

[0271] Examples of large molecule active agents include, but are not limited to, hematopoietic growth factors, cytokines, and monoclonal and polyclonal antibodies, particularly, therapeutic antibodies to cancer antigens. Typical large molecule active agents are biological molecules, such as naturally occurring or synthetic or recombinant proteins. Proteins that are particularly useful in the methods and compositions provided herein include proteins that stimulate the survival and / or proliferation of hematopoietic precursor cells and immunologically active poieticcells in vitro or in vivo. Other useful proteins stimulate the division and differentiation of committed erythroid progenitors in cells in vitro or in vivo. Particular proteins include, but are not limited to: interleukins, such as IL-2 (including recombinant IL-II (“rIL2”) and canarypox IL-2), IL-10, IL-12, and IL-18; interferons, such as interferon alfa-2a, interferon alfa-2b, interferon alfa-nl, interferon alfa-n3, interferon beta-I a, and interferon gamma-I b; GM-CF and GM-CSF; and EPO

[0272] In certain embodiments, GM-CSF, G-CSF, SCF or EPO is administered subcutaneously during about five days in a four or six week cycle in an amount ranging from about 1 to about 750 mg / m2 / day, from about 25 to about 500 mg / m2 / day, from about 50 to about 250 mg / m2 / day, or from about 50 to about 200 mg / m2 / day. In certain embodiments, GM-CSF may be administered in an amount of from about 60 to about 500 mcg / m2intravenously over 2 hours or from about 5 to about 12 mcg / m2 / day subcutaneously. In certain embodiments, G-CSF may be administered subcutaneously in an amount of about 1 mcg / kg / day initially and can be adjusted depending on rise of total granulocyte counts. The maintenance dose of G-CSF may be administered in an amount of about 300 (in smaller patients) or 480 mcg subcutaneously. In certain embodiments, EPO may be administered subcutaneously in an amount of 10,000 Unit 3 times per week.

[0273] Particular proteins that can be used in the methods and compositions include, but are not limited to: filgrastim, which is sold in the United States under the trade name Neupogen® (Amgen, Thousand Oaks, Calif.); sargramostim, which is sold in the United States under the trade name Leukine® (Immunex, Seattle, Wash.); and recombinant EPO, which is sold in the United States under the trade name Epogen® (Amgen, Thousand Oaks, Calif.).

[0274] Recombinant and mutated forms of GM-CSF can be prepared as described in U. S. Pat. Nos. 5,391,485; 5,393,870; and 5,229,496; all of which are incorporated herein by reference. Recombinant and mutated forms of G-CSF can be prepared as described in U. S. Pat. Nos.

[0275] 4,810,643; 4,999,291; 5,528,823; and 5,580,755; the entireties of which are incorporated herein by reference.

[0276] Also provided for use in combination with a compound provided herein or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof are native, naturally occurring, and recombinant proteins. Further encompassed are mutants and derivatives (e.g., modified forms) of naturally occurring proteins that exhibit, in vivo, at least some of the pharmacological activity of the proteins upon which they are based. Examples of mutants include, but are not limited to, proteins that have oneor more amino acid residues that differ from the corresponding residues in the naturally occurring forms of the proteins. Also encompassed by the term “mutants” are proteins that lack carbohydrate moieties normally present in their naturally occurring forms (e.g., nonglycosylated forms). Examples of derivatives include, but are not limited to, pegylated derivatives and fusion proteins, such as proteins formed by fusing IgGl or IgG3 to the protein or active portion of the protein of interest. See, e.g., Penichet, M. L. and Morrison, S. L., J. Immunol. Methods 248:91-101 (2001).

[0277] Second active agents that are small molecules can also be used to alleviate adverse effects associated with the administration of a compound provided herein or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof. However, like some large molecules, many are believed to be capable of providing a synergistic effect when administered with (e.g., before, after or simultaneously) a compound provided herein or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. Examples of small molecule second active agents include, but are not limited to, anti-cancer agents, antibiotics, immunosuppressive agents, and steroids.

[0278] In certain embodiments, the second agent is an HSP inhibitor, a proteasome inhibitor, a FLT3 inhibitor, a TOR kinase inhibitor, an antineoplastic, a tyrosine kinase inhibitor, a hedgehog pathway inhibitor, a Bcl-2 inhibitor, or an isocitrate dehydrogenase (IDH) inhibitor.

[0279] Examples of anti-cancer agents to be used within the methods or compositions described herein include, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; celecoxib (COX-2 inhibitor); cerubidine; chlorambucil; cirolemycin; cisplatin; cladribine; clofarabine; crisnatol mesylate; cytarabine; cyclophosphamide; Ara-C; dacarbazine; dactinomycin; daunorubicin hydrochloride; daunorubicin hydrochloride and cytarabine liposome; daurismo; decitabine; dexormaplatin; dexamethasone; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflomithine hydrochloride; elsamitrucin; enasidenib mesylate; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicinhydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; gemtuzumab ozogamcin; hydroxyurea; ibrutinib; idarubicin hydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; omacetaxine; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; safmgol; safingol hydrochloride; semustine; simtrazene; sorafenib; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; taxotere; tegafur; teloxantrone hydrochloride; temoporfm; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; venetoclax; verteporfm; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicin hydrochloride.

[0280] Other anti-cancer drugs to be included within the methods or compositions include, but are not limited to: 20-epi-l,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; arsenic trioxide; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azacytidine;azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR / ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRestM3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophy cin A derivatives; curacin A; cyclopentanthraquinones; cyclophosphamide; cycloplatam; cypemycin; Ara-C ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemninB; didox; diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflomithine; elemene; emitefur; enasidenib; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; gemtuzumab; gilteritinib; glasdegib; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imatinib (e.g., Gleevec®); imiquimod; immunostimulant peptides; insulin-like growth factor- 1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; ivosidenib; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinaseinhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; midostaurin; MIF inhibitor; mifepristone; miltefosine; mirimostim; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; Mylotarg; Erbitux, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; oblimersen (Genasense®); O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinumtriamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rohitukine; romurtide; roquinimex; rubiginone Bl; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfm; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thioguanine; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyletiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; velaresol; veramine; verdins; verteporfin; vincristine sulfate; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.

[0281] Specific second active agents particularly useful in the methods or compositions include, but are not limited to, rituximab, oblimersen (Genasense®), remicade, docetaxel, celecoxib, melphalan, dexamethasone (Decadron®), steroids, gemcitabine, cisplatinum, temozolomide, etoposide, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate, Arisa®, taxol, taxotere, fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, interferon alpha, pegylated interferon alpha (e.g., PEG INTRON- A), capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin, Ara-C, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulphan, prednisone, bisphosphonate, arsenic trioxide, vincristine, doxorubicin (Doxil®), paclitaxel, ganciclovir, adriamycin, estramustine sodium phosphate (Emcyt®), sulindac, and etoposide.

[0282] In certain embodiments of the methods provided herein, use of a second active agent in combination with a compound provided herein or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof may be modified or delayed during or shortly following administration of a compound provided herein or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof as deemed appropriate by the practitioner of skill in the art. In certain embodiments, subjects being administered a compound provided herein or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof alone or in combination with other therapies may receive supportive care including antiemetics, myeloid growth factors, and transfusions of platelets, when appropriate. In some embodiments, subjects being administered a compound provided herein or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof may be administered a growth factor as a second active agent according to the judgment of the practitioner of skill in the art. In some embodiments, provided is administration of a compound provided herein or an enantiomer or a mixture ofenantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof in combination with erythropoietin or darbepoetin (Aranesp).

[0283] In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered with gemcitabine and cisplatinum to patients with locally advanced or metastatic transitional cell bladder cancer.

[0284] In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with a second active ingredient as follows: temozolomide to pediatric patients with relapsed or progressive brain tumors or recurrent neuroblastoma; celecoxib, etoposide and cyclophosphamide for relapsed or progressive CNS cancer; temodar to patients with recurrent or progressive meningioma, malignant meningioma, hemangiopericytoma, multiple brain metastases, relapased brain tumors, or newly diagnosed glioblastoma multiforms; irinotecan to patients with recurrent glioblastoma; carboplatin to pediatric patients with brain stem glioma; procarbazine to pediatric patients with progressive malignant gliomas; cyclophosphamide to patients with poor prognosis malignant brain tumors, newly diagnosed or recurrent glioblastoma multiforms; Gliadel® for high grade recurrent malignant gliomas; temozolomide and tamoxifen for anaplastic astrocytoma; or topotecan for gliomas, glioblastoma, anaplastic astrocytoma or anaplastic oligodendroglioma.

[0285] In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered with methotrexate, cyclophosphamide, taxane, abraxane, lapatinib, herceptin, aromatase inhibitors, selective estrogen modulators, estrogen receptor antagonists, and / or PLX3397 (Plexxikon) to patients with metastatic breast cancer.

[0286] In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered with temozolomide to patients with neuroendocrine tumors.

[0287] In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt,solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered with gemcitabine to patients with recurrent or metastatic head or neck cancer.

[0288] In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered with gemcitabine to patients with pancreatic cancer.

[0289] In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to patients with colon cancer in combination with ARISA®, avastatin, taxol, and / or taxotere.

[0290] In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered with capecitabine and / or PLX4032 (Plexxikon) to patients with refractory colorectal cancer or patients who fail first line therapy or have poor performance in colon or rectal adenocarcinoma.

[0291] In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with fluorouracil, leucovorin, and irinotecan to patients with Dukes C & D colorectal cancer or to patients who have been previously treated for metastatic colorectal cancer.

[0292] In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to patients with refractory colorectal cancer in combination with capecitabine, xeloda, and / or CPT-11.

[0293] In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered with capecitabine and irinotecan to patients with refractory colorectal cancer or to patients with unresectable or metastatic colorectal carcinoma.

[0294] In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered alone or in combination withinterferon alpha or capecitabine to patients with unresectable or metastatic hepatocellular carcinoma; or with cisplatin and thiotepa to patients with primary or metastatic liver cancer.

[0295] In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with pegylated interferon alpha to patients with Kaposi's sarcoma.

[0296] In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with fludarabine, carboplatin, and / or topotecan to patients with refractory or relapsed or high-risk acute myeloid leukemia.

[0297] In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with liposomal daunorubicin, topotecan and / or cytarabine to patients with unfavorable karotype acute myeloblastic leukemia.

[0298] In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with gemcitabine, abraxane, erlotinib, geftinib, and / or irinotecan to patients with non-small cell lung cancer.

[0299] In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with carboplatin and irinotecan to patients with non-small cell lung cancer.

[0300] In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered with doxetaxol to patients with non-small cell lung cancer who have been previously treated with carbo / VP 16 and radiotherapy.

[0301] In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination withcarboplatin and / or taxotere, or in combination with carboplatin, pacilitaxel and / or thoracic radiotherapy to patients with non-small cell lung cancer.

[0302] In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with taxotere to patients with stage IIIB or IV non-small cell lung cancer.

[0303] In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with oblimersen (Genasense®) to patients with small cell lung cancer.

[0304] In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with ABT-737 (Abbott Laboratories) and / or obatoclax (GX15-070) to patients with lymphoma and other blood cancers.

[0305] In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered alone or in combination with a second active ingredient such as vinblastine or fludarabine to patients with various types of lymphoma, including, but not limited to, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma or relapsed or refractory low grade follicular lymphoma.

[0306] In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with taxotere, IL-2, IFN, GM-CSF, PLX4032 (Plexxikon) and / or dacarbazine to patients with various types or stages of melanoma.

[0307] In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered alone or in combination with vinorelbine to patients with malignant mesothelioma, or stage IIIB non-small cell lung cancer with pleural implants or malignant pleural effusion mesothelioma syndrome.In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to patients with various types or stages of multiple myeloma in combination with dexamethasone, zoledronic acid, palmitronate, GM-CSF, biaxin, vinblastine, melphalan, busulphan, cyclophosphamide, IFN, palmidronate, prednisone, bisphosphonate, celecoxib, arsenic trioxide, PEG INTRON-A, vincristine, or a combination thereof.

[0308] In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to patients with relapsed or refractory multiple myeloma in combination with doxorubicin (Doxil®), vincristine and / or dexamethasone (Decadron®).

[0309] In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to patients with various types or stages of ovarian cancer such as peritoneal carcinoma, papillary serous carcinoma, refractory ovarian cancer or recurrent ovarian cancer, in combination with taxol, carboplatin, doxorubicin, gemcitabine, cisplatin, xeloda, paclitaxel, dexamethasone, or a combination thereof.

[0310] In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to patients with various types or stages of prostate cancer, in combination with xeloda, 5 FU / LV, gemcitabine, irinotecan plus gemcitabine, cyclophosphamide, vincristine, dexamethasone, GM-CSF, celecoxib, taxotere, ganciclovir, paclitaxel, adriamycin, docetaxel, estramustine, Emcyt, denderon or a combination thereof.

[0311] In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to patients with various types or stages of renal cell cancer, in combination with capecitabine, IFN, tamoxifen, IL-2, GM-CSF, Celebrex®, or a combination thereof.

[0312] In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt,solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to patients with various types or stages of gynecologic, uterus or soft tissue sarcoma cancer in combination with IFN, a COX-2 inhibitor such as Celebrex®, and / or sulindac.

[0313] In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to patients with various types or stages of solid tumors in combination with celebrex, etoposide, cyclophosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a combination thereof.

[0314] In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to patients with scleroderma or cutaneous vasculitis in combination with celebrex, etoposide, cyclophosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a combination thereof.

[0315] Also encompassed herein is a method of increasing the dosage of an anti-cancer drug or agent that can be safely and effectively administered to a patient, which comprises administering to the patient (e.g., a human) or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. Patients that can benefit by this method are those likely to suffer from an adverse effect associated with anti-cancer drugs for treating a specific cancer of the skin, subcutaneous tissue, lymph nodes, brain, lung, liver, bone, intestine, colon, heart, pancreas, adrenal, kidney, prostate, breast, colorectal, or combinations thereof. The administration of a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, alleviates or reduces adverse effects which are of such severity that it would otherwise limit the amount of anti -cancer drug.

[0316] In one embodiment, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered orally and daily in an amount ranging from about 0.1 to about 150 mg, from about 1 to about 50 mg, or from about 2 to about 25 mg, prior to, during, or after the occurrence of the adverse effect associated with the administration of an anti-cancer drug to a patient. In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof,or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with specific agents such as heparin, aspirin, coumadin, or G-CSF to avoid adverse effects that are associated with anti-cancer drugs such as but not limited to neutropenia or thrombocytopenia.

[0317] In one embodiment, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to patients with diseases and disorders associated with or characterized by, undesired angiogenesis in combination with additional active ingredients, including, but not limited to, anti-cancer drugs, antiinflammatories, antihistamines, antibiotics, and steroids.

[0318] In another embodiment, encompassed herein is a method of treating, preventing and / or managing cancer, which comprises administering the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, in conjunction with (e.g. before, during, or after) conventional therapy including, but not limited to, surgery, immunotherapy, biological therapy, radiation therapy, or other non-drug based therapy presently used to treat, prevent or manage cancer. The combined use of the compound provided herein and conventional therapy may provide a unique treatment regimen that is unexpectedly effective in certain patients. Without being limited by theory, it is believed that the compound of Formula I may provide additive or synergistic effects when given concurrently with conventional therapy.

[0319] As discussed elsewhere herein, encompassed herein is a method of reducing, treating and / or preventing adverse or undesired effects associated with conventional therapy including, but not limited to, surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy and immunotherapy. A compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, and other active ingredient can be administered to a patient prior to, during, or after the occurrence of the adverse effect associated with conventional therapy.

[0320] In one embodiment, the compound of Formula I can be administered in an amount ranging from about 0.1 to about 150 mg, from about 1 to about 25 mg, or from about 2 to about 10 mg orally and daily alone, or in combination with a second active agent disclosed herein (see, e.g., section 5.4), prior to, during, or after the use of conventional therapy.In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, and doxetaxol are administered to patients with non-small cell lung cancer who were previously treated with carbo / VP 16 and radiotherapy.

[0321] C-2. Use with Transplantation Therapy

[0322] The compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, provided herein can be used to reduce the risk of Graft Versus Host Disease (GVHD). Therefore, encompassed herein is a method of treating, preventing and / or managing cancer, which comprises administering the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, in conjunction with transplantation therapy.

[0323] As those of ordinary skill in the art are aware, the treatment of cancer is often based on the stages and mechanism of the disease. For example, as inevitable leukemic transformation develops in certain stages of cancer, transplantation of peripheral blood stem cells, hematopoietic stem cell preparation or bone marrow may be necessary. The combined use of the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, provided herein and transplantation therapy provides a unique and unexpected synergism. In particular, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, exhibits immunomodulatory activity that may provide additive or synergistic effects when given concurrently with transplantation therapy in patients with cancer.

[0324] The compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, can work in combination with transplantation therapy reducing complications associated with the invasive procedure of transplantation and risk of GVHD. Encompassed herein is a method of treating, preventing and / or managing cancer which comprises administering to a patient (e.g., a human) the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, before, during, or after the transplantation of umbilical cord blood, placental blood, peripheral blood stem cell, hematopoietic stem cell preparation, or bone marrow. Some examples of stemcells suitable for use in the methods provided herein are disclosed in U. S. Pat. No. 7,498,171, the disclosure of which is incorporated herein by reference in its entirety.

[0325] In one embodiment, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to patients with multiple myeloma before, during, or after the transplantation of autologous peripheral blood progenitor cell.

[0326] In one embodiment, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to patients with NHL (e.g., DLBCL) before, during, or after the transplantation of autologous peripheral blood progenitor cell.

[0327] C-3. Cycling Therapy

[0328] In certain embodiments, the prophylactic or therapeutic agents provided herein are cyclically administered to a patient. Cycling therapy involves the administration of an active agent for a period of time, followed by a rest for a period of time, and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid, or reduce the side effects of one of the therapies, and / or improves the efficacy of the treatment.

[0329] Consequently, in certain embodiments, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, provided herein is administered daily in a single or divided doses in a four to six week cycle with a rest period of about a week or two weeks. The cycling method further allows the frequency, number, and length of dosing cycles to be increased. Thus, encompassed herein in certain embodiments is the administration of a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, for more cycles than are typical when it is administered alone. In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, clathrate, or polymorph thereof, is administered for a greater number of cycles that would typically cause dose-limiting toxicity in a patient to whom a second active ingredient is not also being administered.

[0330] In one embodiment, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate,or polymorph thereof, is administered daily and continuously for three or four weeks at a dose of from about 0.1 to about 150 mg / d followed by a break of one or two weeks.

[0331] In another embodiment, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, and a second active ingredient are administered orally, with administration of the compound of Formula I occurring 30 to 60 minutes prior to a second active ingredient, during a cycle of four to six weeks. In certain embodiments, the combination of the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, and a second active ingredient is administered by intravenous infusion over about 90 minutes every cycle. In certain embodiments, one cycle comprises the administration from about 0.1 to about 150 mg / day of the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, and from about 50 to about 200 mg / m2 / day of a second active ingredient daily for three to four weeks and then one or two weeks of rest. In certain embodiments, the number of cycles during which the combinatorial treatment is administered to a patient is ranging from about one to about 24 cycles, from about two to about 16 cycles, or from about four to about three cycles.

[0332] D. Patient Population

[0333] In certain embodiments of the methods provided herein, the subject is an animal, preferably a mammal, more preferably a non-human primate. In particular embodiments, the subject is a human. The subject can be a male or female subject.

[0334] Particularly useful subjects for the methods provided herein include human cancer patients, for example, those who have been diagnosed with leukemia, including acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, and chronic myelogenous leukemia. In certain embodiments, the subject has not been diagnosed with acute promyelocytic leukemia.

[0335] In some embodiments, the subject has a higher than normal blast population. In some embodiments, the subject has a blast population of at least 10%. In some embodiments, the subject has a blast population of between 10 and 15%. In some embodiments, the subject has a blast population of at least 15%. In some embodiments, the subject has a blast population of between 15 and 20%. In some embodiments, the subject has a blast population of at least 20%. In some embodiments, the subject has a blast population of about 10-15%, about 15-20%, orabout 20-25%. In other embodiments, the subject has a blast population of less than 10%. In the context of the methods described herein, useful subjects having a blast population of less than 10% includes those subjects that, for any reason according to the judgment of the skilled practitioner in the art, are in need of treatment with a compound provided herein, alone or in combination with a second active agent.

[0336] In some embodiments, the subject is treated based on the Eastern Cooperative Oncology Group (ECOG) performance status score of the subject for leukemia. ECOG performance status can be scored on a scale of 0 to 5, with 0 denoting asymptomatic; 1 denoting symptomatic but completely ambulant; 2 denoting symptomatic and <50% in bed during the day; 3 denoting symptomatic and >50% in bed, but not bed bound; 4 denoting bed bound; and 5 denoting death. In some embodiments, the subject has an ECOG performance status score of 0 or 1. In some embodiments, the subject has an ECOG performance status score of 0. In some embodiments, the subject has an ECOG performance status score of 1. In other embodiments, the subject has an ECOG performance status score of 2.

[0337] In certain embodiments, the methods provided herein encompass the treatment of subjects who have not been previously treated for leukemia. In some embodiments, the subject has not undergone allogeneic bone marrow transplantation. In some embodiments, the subject has not undergone a stem cell transplantation. In some embodiments, the subject has not received hydroxyurea treatment. In some embodiments, the subject has not been treated with any investigational products for leukemia. In some embodiments, the subject has not been treated with systemic glucocorticoids.

[0338] In other embodiments, the methods encompass treating subjects who have been previously treated or are currently being treated for leukemia. For example, the subject may have been previously treated or are currently being treated with a standard treatment regimen for leukemia. The subject may have been treated with any standard leukemia treatment regimen known to the practitioner of skill in the art. In certain embodiments, the subject has been previously treated with at least one induction / reinduction or consolidation AML regimen. In some embodiments, the subject has undergone autologous bone marrow transplantation or stem cell transplantation as part of a consolidation regimen. In some embodiments, the bone marrow or stem cell transplantation occurred at least 3 months prior to treatment according to the methods provided herein. In some embodiments, the subject has undergone hydroxyurea treatment. In some embodiments, the hydroxyurea treatment occurred no later than 24 hours prior to treatment according to the methods provided herein. In some embodiments, the subjecthas undergone prior induction or consolidation therapy with cytarabine (Ara-C). In some embodiments, the subject has undergone treatment with systemic glucocorticosteroids. In some embodiments, the glucocorticosteroid treatment occurred no later 24 hours prior to treatment according to the methods described herein. In other embodiments, the methods encompass treating subjects who have been previously treated for cancer, but are non-responsive to standard therapies.

[0339] Also encompassed are methods of treating subjects having relapsed or refractory leukemia. In some embodiments, the subject has been diagnosed with a relapsed or refractory AML subtype, as defined by the World Health Organization (WHO). Relapsed or refractory disease may be de novo AML or secondary AML, e.g., therapy -related AML (t-AML).

[0340] In some embodiments, the methods provided herein are used to treat drug resistant leukemias, such as chronic myelogenous leukemia (CML). Thus, treatment with a compound provided herein could provide an alternative for patients who do not respond to other methods of treatment. In some embodiments, such other methods of treatment encompass treatment with Gleevec® (imatinib mesylate). In some embodiments, provided herein are methods of treatment of Philadelphia chromosome positive chronic myelogenous leukemia (Ph+CML). In some embodiments, provided herein are methods of treatment of Gleevec® (imatinib mesylate) resistant Philadelphia chromosome positive chronic myelogenous leukemia (Ph+CML).

[0341] Also encompassed are methods of treating a subject regardless of the subject's age, although some diseases or disorders are more common in certain age groups. In some embodiments, the subject is at least 18 years old. In some embodiments, the subject is more than 18, 25, 35, 40, 45, 50, 55, 60, 65, or 70 years old. In other embodiments, the subject is less than 65 years old. In some embodiments, the subject is less than 18 years old. In some embodiments, the subject is less than 18, 15, 12, 10, 9, 8 or 7 years old.

[0342] In some embodiments, the methods may find use in subjects at least 50 years of age, although younger subjects could benefit from the method as well. In other embodiments, the subjects are at least 55, at least 60, at least 65, and at least 70 years of age. In another embodiment, the subjects have adverse cytogenetics. “Adverse cytogenetics” is defined as any nondiploid karyotype, or greater than or equal to 3 chromosomal abnormalities. In another embodiment, the subjects are at least 60 years of age and have adverse cytogenetics. In another embodiment, the subjects are 60-65 years of age and have adverse cytogenetics. In another embodiment, the subjects are 65-70 years of age and have adverse cytogenetics.In certain embodiments, the subject treated has no history of myocardial infarction within three months of treatment according to the methods provided herein. In some embodiments, the subject has no history of cerebrovascular accident or transient ischemic attack within three months of treatment according to the methods provided herein. In some embodiments, the subject has no suffered no thromboembelic event, including deep vein thrombosis or pulmonary embolus, within 28 days of treatment according to the methods provided herein. In other embodiments, the subject has not experienced or is not experiencing uncontrolled disseminated intravascular coagulation.

[0343] Because subjects with cancer have heterogeneous clinical manifestations and varying clinical outcomes, the treatment given to a patient may vary, depending on his / her prognosis. The skilled clinician will be able to readily determine without undue experimentation specific secondary agents, types of surgery, and types of non-drug based standard therapy that can be effectively used to treat an individual subject with cancer.

[0344] It will be appreciated that every suitable combination of the compounds provided herein with one or more of the aforementioned compounds and optionally one or more further pharmacologically active substances is contemplated herein.

[0345] E. Formulation of Pharmaceutical Compositions

[0346] The pharmaceutical compositions provided herein contain therapeutically effective amounts of one or more of compounds provided herein and a pharmaceutically acceptable carrier, diluent or excipient.

[0347] The compounds can be formulated into suitable pharmaceutical preparations such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs, for oral administration or in sterile solutions or suspensions for ophthalmic or parenteral administration, as well as transdermal patch preparation and dry powder inhalers. Typically the compounds described above are formulated into pharmaceutical compositions using techniques and procedures well known in the art (see, e.g., Ansel Introduction to Pharmaceutical Dosage Forms, Seventh Edition 1999).

[0348] In the compositions, effective concentrations of one or more compounds or pharmaceutically acceptable salts is (are) mixed with a suitable pharmaceutical carrier or vehicle. In certain embodiments, the concentrations of the compounds in the compositions are effective for delivery of an amount, upon administration, that treats, prevents, or ameliorates one or more of the symptoms and / or progression of cancer, including solid tumors and blood borne tumors.Typically, the compositions are formulated for single dosage administration. To formulate a composition, the weight fraction of compound is dissolved, suspended, dispersed or otherwise mixed in a selected vehicle at an effective concentration such that the treated condition is relieved or ameliorated. Pharmaceutical carriers or vehicles suitable for administration of the compounds provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration.

[0349] In addition, the compounds may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients. Liposomal suspensions, including tissue-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. For example, liposome formulations may be prepared as known in the art. Briefly, liposomes such as multilamellar vesicles (MLV's) may be formed by drying down egg phosphatidyl choline and brain phosphatidyl serine (7:3 molar ratio) on the inside of a flask. A solution of a compound provided herein in phosphate buffered saline lacking divalent cations (PBS) is added and the flask shaken until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS.

[0350] The active compound is included in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the patient treated. The therapeutically effective concentration may be determined empirically by testing the compounds in in vitro and in vivo systems described herein and then extrapolated therefrom for dosages for humans.

[0351] The concentration of active compound in the pharmaceutical composition will depend on absorption, tissue distribution, inactivation and excretion rates of the active compound, the physicochemical characteristics of the compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art. For example, the amount that is delivered is sufficient to ameliorate one or more of the symptoms of cancer, including solid tumors and blood borne tumors.

[0352] In certain embodiments, a therapeutically effective dosage should produce a serum concentration of active ingredient of from about 0.1 ng / mL to about 50-100 pg / mL. In one embodiment, the pharmaceutical compositions provide a dosage of from about 0.001 mg to about 2000 mg of compound per kilogram of body weight per day. Pharmaceutical dosage unit forms are prepared to provide from about 1 mg to about 1000 mg and in certain embodiments,from about 10 to about 500 mg of the essential active ingredient or a combination of essential ingredients per dosage unit form.

[0353] The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.

[0354] Thus, effective concentrations or amounts of one or more of the compounds described herein or pharmaceutically acceptable salts thereof are mixed with a suitable pharmaceutical carrier or vehicle for systemic, topical or local administration to form pharmaceutical compositions. Compounds are included in an amount effective for ameliorating one or more symptoms of, or for treating, retarding progression, or preventing. The concentration of active compound in the composition will depend on absorption, tissue distribution, inactivation, excretion rates of the active compound, the dosage schedule, amount administered, particular formulation as well as other factors known to those of skill in the art.

[0355] The compositions are intended to be administered by a suitable route, including but not limited to orally, parenterally, rectally, topically and locally. For oral administration, capsules and tablets can be formulated. The compositions are in liquid, semi-liquid or solid form and are formulated in a manner suitable for each route of administration.

[0356] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include any of the following components: a sterile diluent, such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerine, propylene glycol, dimethyl acetamide or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates, citrates and phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose. Parenteral preparations can be enclosed in ampules, pens, disposable syringes or single or multiple dose vials made of glass, plastic or other suitable material.In instances in which the compounds exhibit insufficient solubility, methods for solubilizing compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants, such as TWEEN®, or dissolution in aqueous sodium bicarbonate.

[0357] Upon mixing or addition of the compound(s), the resulting mixture may be a solution, suspension, emulsion or the like. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the disease, disorder or condition treated and may be empirically determined. The pharmaceutical compositions are provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil water emulsions containing suitable quantities of the compounds or pharmaceutically acceptable salts thereof. The pharmaceutically therapeutically active compounds and salts thereof are formulated and administered in unit dosage forms or multiple dosage forms. Unit dose forms as used herein refer to physically discrete units suitable for human and animal subjects and packaged individually as is known in the art. Each unit dose contains a predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent. Examples of unit dose forms include ampules and syringes and individually packaged tablets or capsules. Unit dose forms may be administered in fractions or multiples thereof. A multiple dose form is a plurality of identical unit dosage forms packaged in a single container to be administered in segregated unit dose form. Examples of multiple dose forms include vials, bottles of tablets or capsules or bottles of pints or gallons. Hence, multiple dose form is a multiple of unit doses which are not segregated in packaging.

[0358] Sustained-release preparations can also be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the compound provided herein, which matrices are in the form of shaped articles, e.g., films, or microcapsule. Examples of sustained-release matrices include iontophoresis patches, polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and ethyl -L-glutamate, non-degradable ethyl ene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3 -hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods. When encapsulated compound remain in the body for a long time, they may denature or aggregate as a result of exposure to moisture at 37° C., resulting in a loss of biological activity and possible changes in their structure. Rational strategies can be devised for stabilization depending on the mechanism of action involved. For example, if the aggregation mechanism is discovered to be intermolecular S — S bond formation through thio-disulfide interchange, stabilization may be achieved by modifying sulfhydryl residues, lyophilizing from acidic solutions, controlling moisture content, using appropriate additives, and developing specific polymer matrix compositions.

[0359] Dosage forms or compositions containing active ingredient in the range of 0.005% to 100% with the balance made up from non toxic carrier may be prepared. For oral administration, a pharmaceutically acceptable non toxic composition is formed by the incorporation of any of the normally employed excipients, such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, cellulose derivatives, sodium crosscarmellose, glucose, sucrose, magnesium carbonate or sodium saccharin. Such compositions include solutions, suspensions, tablets, capsules, powders and sustained release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid and others. Methods for preparation of these compositions are known to those skilled in the art. The contemplated compositions may contain about 0.001% 100% active ingredient, in certain embodiments, about 0.1 85% or about 75-95%.

[0360] The active compounds or pharmaceutically acceptable salts may be prepared with carriers that protect the compound against rapid elimination from the body, such as time release formulations or coatings.

[0361] The compositions may include other active compounds to obtain desired combinations of properties. The compounds provided herein, or pharmaceutically acceptable salts thereof as described herein, may also be advantageously administered for therapeutic or prophylactic purposes together with another pharmacological agent known in the general art to be of value in treating one or more of the diseases or medical conditions referred to hereinabove, such as diseases related to oxidative stress. It is to be understood that such combination therapy constitutes a further aspect of the compositions and methods of treatment provided herein.Lactose-free compositions provided herein can contain excipients that are well known in the art and are listed, for example, in the U. S. Pharmocopia (USP) SP (XXI) / NF (XVI). In general, lactose-free compositions contain an active ingredient, a binder / filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. Exemplary lactose-free dosage forms contain an active ingredient, microcrystalline cellulose, pre-gelatinized starch and magnesium stearate.

[0362] Further encompassed are anhydrous pharmaceutical compositions and dosage forms containing a compound provided herein. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, N. Y., 1995, pp. 379-80. In effect, water and heat accelerate the decomposition of some compounds. Thus, the effect of water on a formulation can be of great significance since moisture and / or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment and use of formulations.

[0363] Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine are anhydrous if substantial contact with moisture and / or humidity during manufacturing, packaging, and / or storage is expected.

[0364] An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs and strip packs.

[0365] E-l. Oral Dosage Forms

[0366] Oral pharmaceutical dosage forms are either solid, gel or liquid. The solid dosage forms are tablets, capsules, granules, and bulk powders. Types of oral tablets include compressed, chewable lozenges and tablets which may be enteric coated, sugar coated or film coated.

[0367] Capsules may be hard or soft gelatin capsules, while granules and powders may be provided in non effervescent or effervescent form with the combination of other ingredients known to those skilled in the art.In certain embodiments, the formulations are solid dosage forms, such as capsules or tablets. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder; a diluent; a disintegrating agent; a lubricant; a glidant; a sweetening agent; and a flavoring agent.

[0368] Examples of binders include microcrystalline cellulose, gum tragacanth, glucose solution, acacia mucilage, gelatin solution, sucrose and starch paste. Lubricants include talc, starch, magnesium or calcium stearate, lycopodium and stearic acid. Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate. Glidants include, but are not limited to, colloidal silicon dioxide. Disintegrating agents include crosscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose. Coloring agents include, for example, any of the approved certified water soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended on alumina hydrate. Sweetening agents include sucrose, lactose, mannitol and artificial sweetening agents such as saccharin, and any number of spray dried flavors. Flavoring agents include natural flavors extracted from plants such as fruits and synthetic blends of compounds which produce a pleasant sensation, such as, but not limited to peppermint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene laural ether. Emetic coatings include fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthalates. Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate.

[0369] If oral administration is desired, the compound could be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition may also be formulated in combination with an antacid or other such ingredient.

[0370] When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents. The compounds can also be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.The active materials can also be mixed with other active materials which do not impair the desired action, or with materials that supplement the desired action, such as antacids, H2 blockers, and diuretics. The active ingredient is a compound or pharmaceutically acceptable salt thereof as described herein. Higher concentrations, up to about 98% by weight of the active ingredient may be included.

[0371] Pharmaceutically acceptable carriers included in tablets are binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, and wetting agents. Enteric coated tablets, because of the enteric coating, resist the action of stomach acid and dissolve or disintegrate in the neutral or alkaline intestines. Sugar coated tablets are compressed tablets to which different layers of pharmaceutically acceptable substances are applied. Film coated tablets are compressed tablets which have been coated with a polymer or other suitable coating.

[0372] Multiple compressed tablets are compressed tablets made by more than one compression cycle utilizing the pharmaceutically acceptable substances previously mentioned. Coloring agents may also be used in the above dosage forms. Flavoring and sweetening agents are used in compressed tablets, sugar coated, multiple compressed and chewable tablets. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.

[0373] Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non effervescent granules and effervescent preparations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Emulsions are either oil in-water or water in oil.

[0374] Elixirs are clear, sweetened, hydroalcoholic preparations. Pharmaceutically acceptable carriers used in elixirs include solvents. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may contain a preservative. An emulsion is a two phase system in which one liquid is dispersed in the form of small globules throughout another liquid.

[0375] Pharmaceutically acceptable carriers used in emulsions are non aqueous liquids, emulsifying agents and preservatives. Suspensions use pharmaceutically acceptable suspending agents and preservatives. Pharmaceutically acceptable substances used in non effervescent granules, to be reconstituted into a liquid oral dosage form, include diluents, sweeteners and wetting agents. Pharmaceutically acceptable substances used in effervescent granules, to be reconstituted into a liquid oral dosage form, include organic acids and a source of carbon dioxide. Coloring and flavoring agents are used in all of the above dosage forms.

[0376] Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examples of preservatives include glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol.Examples of non aqueous liquids utilized in emulsions include mineral oil and cottonseed oil. Examples of emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum and acacia. Diluents include lactose and sucrose. Sweetening agents include sucrose, syrups, glycerin and artificial sweetening agents such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Organic adds include citric and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate. Coloring agents include any of the approved certified water soluble FD and C dyes, and mixtures thereof. Flavoring agents include natural flavors extracted from plants such fruits, and synthetic blends of compounds which produce a pleasant taste sensation.

[0377] For a solid dosage form, the solution or suspension, in for example propylene carbonate, vegetable oils or triglycerides, is encapsulated in a gelatin capsule. Such solutions, and the preparation and encapsulation thereof, are disclosed in U. S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. For a liquid dosage form, the solution, e.g., for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be easily measured for administration.

[0378] Alternatively, liquid or semi solid oral formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g., propylene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells. Other useful formulations include, but are not limited to, those containing a compound provided herein, a dialkylated mono- or poly-alkylene glycol, including, but not limited to, 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether wherein 350, 550 and 750 refer to the approximate average molecular weight of the polyethylene glycol, and one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates.

[0379] Other formulations include, but are not limited to, aqueous alcoholic solutions including a pharmaceutically acceptable acetal. Alcohols used in these formulations are any pharmaceutically acceptable water-miscible solvents having one or more hydroxyl groups,including, but not limited to, propylene glycol and ethanol. Acetals include, but are not limited to, di (lower alkyl) acetals of lower alkyl aldehydes such as acetaldehyde diethyl acetal.

[0380] In all embodiments, tablets and capsules formulations may be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient. Thus, for example, they may be coated with a conventional enterically digestible coating, such as phenylsalicylate, waxes and cellulose acetate phthalate.

[0381] E-2. Injectables, Solutions and Emulsions

[0382] Parenteral administration, generally characterized by injection, either subcutaneously, intramuscularly or intravenously is also contemplated herein. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol or ethanol. In addition, if desired, the pharmaceutical compositions to be administered may also contain minor amounts of non toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins. Implantation of a slow release or sustained release system, such that a constant level of dosage is maintained is also contemplated herein. Briefly, a compound provided herein is dispersed in a solid inner matrix, e.g., polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol and crosslinked partially hydrolyzed polyvinyl acetate, that is surrounded by an outer polymeric membrane, e.g., polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinylacetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer, that is insoluble in body fluids. The compound diffuses through the outer polymeric membrane in a release rate controlling step. The percentage of active compound contained insuch parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject.

[0383] Parenteral administration of the compositions includes intravenous, subcutaneous and intramuscular administrations. Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products, such as lyophilized powders, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions. The solutions may be either aqueous or nonaqueous.

[0384] If administered intravenously, suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.

[0385] Pharmaceutically acceptable carriers used in parenteral preparations include aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances.

[0386] Examples of aqueous vehicles include Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil. Antimicrobial agents in bacteriostatic or fungistatic concentrations must be added to parenteral preparations packaged in multiple dose containers which include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride. Isotonic agents include sodium chloride and dextrose. Buffers include phosphate and citrate. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride.

[0387] Suspending and dispersing agents include sodium carboxymethylcellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifying agents include Polysorbate 80 (TWEEN® 80). A sequestering or chelating agent of metal ions include EDTA. Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.

[0388] The concentration of the pharmaceutically active compound is adjusted so that an injection provides an effective amount to produce the desired pharmacological effect. The exact dose depends on the age, weight and condition of the patient or animal as is known in the art.The unit dose parenteral preparations are packaged in an ampule, a vial or a syringe with a needle. All preparations for parenteral administration must be sterile, as is known and practiced in the art.

[0389] Illustratively, intravenous or intraarterial infusion of a sterile aqueous solution containing an active compound is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing an active material injected as necessary to produce the desired pharmacological effect.

[0390] Injectables are designed for local and systemic administration. Typically a therapeutically effective dosage is formulated to contain a concentration of at least about 0.1% w / w up to about 90% w / w or more, such as more than 1% w / w of the active compound to the treated tissue(s). The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the tissue being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the age of the individual treated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed formulations.

[0391] The compound may be suspended in micronized or other suitable form or may be derivatized to produce a more soluble active product or to produce a prodrug. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the condition and may be empirically determined.

[0392] E-3. Lyophilized Powders

[0393] Of interest herein are also lyophilized powders, which can be reconstituted for administration as solutions, emulsions and other mixtures. They may also be reconstituted and formulated as solids or gels.

[0394] The sterile, lyophilized powder is prepared by dissolving a compound provided herein, or a pharmaceutically acceptable salt thereof, in a suitable solvent. The solvent may contain an excipient which improves the stability or other pharmacological component of the powder orreconstituted solution, prepared from the powder. Excipients that may be used include, but are not limited to, dextrose, sorbital, fructose, corn syrup, xylitol, glycerin, glucose, sucrose or other suitable agent. The solvent may also contain a buffer, such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, in one embodiment, about neutral pH. Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides the desired formulation. Generally, the resulting solution will be apportioned into vials for lyophilization. Each vial will contain a single dosage (including but not limited to 10-1000 mg or 100-500 mg) or multiple dosages of the compound. The lyophilized powder can be stored under appropriate conditions, such as at about 4° C. to room temperature.

[0395] Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration. For reconstitution, about 1-50 mg, about 5-35 mg, or about 9-30 mg of lyophilized powder, is added per mL of sterile water or other suitable carrier. The precise amount depends upon the selected compound. Such amount can be empirically determined.

[0396] E-4. Topical Administration

[0397] Topical mixtures are prepared as described for the local and systemic administration. The resulting mixture may be a solution, suspension, emulsion or the like and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories, bandages, dermal patches or any other formulations suitable for topical administration.

[0398] The compounds or pharmaceutically acceptable salts thereof may be formulated as aerosols for topical application, such as by inhalation (see, e.g., U. S. Pat. Nos. 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for delivery of a steroid useful for treatment of inflammatory diseases, particularly asthma). These formulations for administration to the respiratory tract can be in the form of an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the formulation will have diameters of less than 50 microns or less than 10 microns.

[0399] The compounds may be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intracistemal or intraspinal application. Topical administration is contemplated for transdermal delivery and also for administration to the eyes ormucosa, or for inhalation therapies. Nasal solutions of the active compound alone or in combination with other pharmaceutically acceptable excipients can also be administered.

[0400] These solutions, particularly those intended for ophthalmic use, may be formulated as 0.01%-10% isotonic solutions, pH about 5-7, with appropriate salts.

[0401] E-5. Compositions for Other Routes of Administration

[0402] Other routes of administration, such as topical application, transdermal patches, and rectal administration are also contemplated herein.

[0403] For example, pharmaceutical dosage forms for rectal administration are rectal suppositories, capsules and tablets for systemic effect. Rectal suppositories are used herein mean solid bodies for insertion into the rectum which melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients. Pharmaceutically acceptable substances utilized in rectal suppositories are bases or vehicles and agents to raise the melting point. Examples of bases include cocoa butter (theobroma oil), glycerin gelatin, carbowax (polyoxyethylene glycol) and appropriate mixtures of mono, di and triglycerides of fatty acids. Combinations of the various bases may be used. Agents to raise the melting point of suppositories include spermaceti and wax. Rectal suppositories may be prepared either by the compressed method or by molding. An exemplary weight of a rectal suppository is about 2 to 3 grams.

[0404] Tablets and capsules for rectal administration are manufactured using the same pharmaceutically acceptable substance and by the same methods as for formulations for oral administration.

[0405] E-6. Sustained Release Compositions

[0406] Active ingredients provided herein can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U. S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, 5,639,480, 5,733,566, 5,739,108, 5,891,474, 5,922,356, 5,972,891, 5,980,945, 5,993,855, 6,045,830, 6,087,324, 6,113,943, 6,197,350, 6,248,363, 6,264,970, 6,267,981, 6,376,461, 6,419,961, 6,589,548, 6,613,358, 6,699,500 and 6,740,634, each of which is incorporated herein by reference. Such dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile invarying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients provided herein.

[0407] All controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. In one embodiment, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. In certain embodiments, advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.

[0408] Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.

[0409] In certain embodiments, the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration. In one embodiment, a pump may be used (see, Sefton, CRC Crit. Ref Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989). In another embodiment, polymeric materials can be used. In yet another embodiment, a controlled release system can be placed in proximity of the therapeutic target, i.e., thus requiring only a fraction of the systemic dose (see, e.g., Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-138 (1984).

[0410] In some embodiments, a controlled release device is introduced into a subject in proximity of the site of inappropriate immune activation or a tumor. Other controlled release systems are discussed in the review by Langer (Science 249: 1527-1533 (1990). The active ingredient can be dispersed in a solid inner matrix, e.g., polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon,plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol and crosslinked partially hydrolyzed polyvinyl acetate, that is surrounded by an outer polymeric membrane, e.g., polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinylacetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer, that is insoluble in body fluids. The active ingredient then diffuses through the outer polymeric membrane in a release rate controlling step. The percentage of active ingredient contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the needs of the subject.

[0411] E-7. Targeted Formulations

[0412] The compounds provided herein, or pharmaceutically acceptable salts thereof, may also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated. Many such targeting methods are well known to those of skill in the art. All such targeting methods are contemplated herein for use in the instant compositions. For nonlimiting examples of targeting methods, see, e.g., U. S. Pat. Nos. 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542 and 5,709,874.

[0413] In one embodiment, liposomal suspensions, including tissue-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. For example, liposome formulations may be prepared as described in U. S. Pat. No. 4,522,811. Briefly, liposomes such as multilamellar vesicles (MLV's) may be formed by drying down egg phosphatidyl choline and brain phosphatidyl serine (7:3 molar ratio) on the inside of a flask. A solution of a compound provided herein in phosphate buffered saline lacking divalent cations (PBS) is added and the flask shaken until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS.

[0414] E-8. Articles of ManufactureThe compounds or pharmaceutically acceptable salts can be packaged as articles of manufacture containing packaging material, a compound or pharmaceutically acceptable salt thereof provided herein, which is used for treatment, prevention or amelioration of one or more symptoms or progression of cancer, including solid tumors and blood borne tumors, and a label that indicates that the compound or pharmaceutically acceptable salt thereof is used for treatment, prevention or amelioration of one or more symptoms or progression of cancer, including solid tumors and blood borne tumors.

[0415] The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products are well known to those of skill in the art. See, e.g., U. S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, pens, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. A wide array of formulations of the compounds and compositions provided herein are contemplated.

[0416] F. Preparation of Compounds

[0417] The compounds provided herein can be prepared by methods known to one of skill in the art and following procedures similar to those described in the Examples section herein and routine modifications thereof. Exemplary reaction schemes for the preparation of compounds are illustrated below.

[0418] GENERAL SYNTHESIS INCLUDING SCHEMES

[0419] The compounds of Formula (I), Formula (II), and Formula (III) may be prepared by the exemplary processes described in the following schemes and working examples, as well as relevant published literature procedures that are used by one skilled in the art. Exemplary reagents and procedures for these reactions appear hereinafter and in the working examples. Protection and de-protection in the processes below may be carried out by procedures generally known in the art (see, for example, Wuts, P. G. M. et al., Protecting Groups in Organic Synthesis, 4th Edition, Wiley (2007)). General methods of organic synthesis and functional group transformations are found in: Trost, B. M. et al., eds., Comprehensive Organic Synthesis:

[0420] Selectivity, Strategy & Efficiency in Modern Organic Chemistry, Pergam on Press, New York, NY (1991); Smith, MB. et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure. 6th Edition, Wiley & Sons, New York, NY (2007); Katritzky, A. R. et al., eds., Comprehensive Organic Functional Groups Transformations II, 2nd Edition, Elsevier ScienceInc., Tarrytown, NY (2004); Larock, R. C., Comprehensive Organic Transformations, VCH Publishers, Inc., New York, NY (1999), and references therein.

[0421] Buchwald-Hartwig coupling in the processes below may be carried out by procedures generally known in the art (see, for example, Ruiz-Castillo, P.; Buchwald, S. L. Chem. Rev.

[0422] 2016, 116 (19), 12564-12649). Amide coupling in the processes below may be carried out by procedures generally known in the art (see, for example, Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 6 / (46), 10827- 10852). Suzuki-Miyaura coupling in the processes below may be carried out by procedures generally known in the art (see, for example, Beletskaya, I. P.; Alonso, F.; Tyurin, V. Coord. Chem. Rev. 2019, 385, 137-173).

[0423] Compounds of Formula (I) may be synthesized starting with indoles A via coupling to intermediate B using, for example, Buchwald-Hartwig coupling conditions, such as Pd2(dba)s, BINAP and CS2CO3, to give intermediate C as depicted in Scheme 1. Reduction of intermediate C, using a reagent such a H2SO4, and removal of the P. G. on intermediate C, using a reagent such as TFA (when P. G. is a Zc / Z-butoxycarbonyl), gives indole D. The intermediate D can be converted to compounds of Formula (I) through an amide coupling with carboxylic acids E using an amide coupling reagent, such as HATU and base, such as DIPEA.

[0424] Scheme 1

[0425]

[0426]

[0427] Alternatively, compounds of Formula (I) can be synthesized via reaction of intermediate D with carboxylic acids F though an amide coupling using an amide coupling reagent, such as HATU and base, such as DIPEA, as depicted in Scheme 2. Removal of the P. G. on intermediate G, using a reagent such as TFA (when P. G. is a tert-butoxy carbonyl), gives amine H. The intermediate H can be converted to compounds of Formula (I) through an amide coupling with carboxylic acids I using an amide coupling reagent, such as HATU and base, such as DIPEA.

[0428] Scheme 2

[0429]

[0430] Compounds of Formula (I) may be synthesized via reaction of indole J with R2-L. G., such as Mel, as in intermediate K, using a base, such as NaH, as depicted in Scheme 3. The resulting intermediate A can be converted to compounds of Formula (I) via an analogous sequence to that shown in Scheme 1 or Scheme 2.Scheme 3

[0431]

[0432] Compounds of Formula (I) can be synthesized starting from indoles L, which can react with a carboxylic acid protecting group, such as EtI, to provide intermediate M as depicted in Scheme 4. The intermediate M can be coupled to intermediate N using, for example Buchwald-Hartwig coupling conditions, such as Pd2(dba)a, BINAP and CS2CO3, to give intermediate O. Removal of the P. G.2 on intermediate O, using a reagent such as TFA (when P. G. is a tert-butoxycarbonyl), gives intermediate P. The resulting intermediate P can be converted to intermediate Q via an analogous sequence to that shown in Scheme 1 or Scheme 2. P. G.i can be removed using a reagent, such as NaOH, and the resultant carboxylic acid can be converted to compounds of Formula (I) through an amide coupling with amines R using an amide coupling reagent, such as HATU and base, such as DIPEA.Scheme 4

[0433]

[0434] Alternatively, compounds of Formula (I) can be prepared via conversion of intermediate S to intermediate T under acidic conditions in an alcoholic solvent, using an acid such as H2SO4 and solvent such as EtOH, as depicted in Scheme 5. The amine can be protected using an amine protecting group, such as (Boc)2O, to provide intermediate U. Intermediate U can react with R2-L. G., such as Mel, as depicted in intermediate K, and a base, such as NaH, to provide intermediate O. Removal of the P. G 2 on intermediate O, using a reagent such as TFA, (when P. G. is a terAbutoxy carbonyl), gives intermediate P, which can be converted to intermediate Q through an amide coupling with carboxylic acids E using an amide coupling reagent, such as TCFH and base, such as NMI. The intermediate Q can be converted to compounds of Formula (I) via an analogous sequence to that shown in Scheme 4.

[0435] Scheme 5

[0436]

[0437] Compounds of Formula (II) may be synthesized starting with indoles A via coupling to intermediate V using, for example Buchwald-Hartwig coupling conditions, such as Pd2(dba)a, BINAP and CS2CO3, to give intermediate W as depicted in Scheme 6. Intermediate W can react with R3-L. G., such as Mel, as depicted in intermediate X, and a base, such as NaH, to provide intermediate C. The intermediate C can be converted to compounds of Formula (II) via an analogous sequence to that shown in Scheme 1 or Scheme 2.Scheme 6

[0438]

[0439]

[0440] When A = heterocyclyl

[0441]

[0442] Compounds of Formula (III) may be synthesized starting with indoles A via coupling to boronic acids or boronic esters, such as those depicted by intermediate Y, using, for example Suzuki-Miyaura coupling conditions, such as C12Pd(dtbpf)2, and a base, such as K3PO3, to give intermediate C as depicted in Scheme 7. The intermediate C can be converted to compounds of Formula (III) via an analogous sequence to that shown in Scheme 1 or Scheme 2.Scheme 7

[0443]

[0444] The compounds of the present invention may be synthesized by many methods available to those skilled in the art of organic chemistry (Maffrand, J. P. et al., Heterocycles, 16(1 ): 35-37 (1981)). General synthetic schemes for preparing compounds of the present invention are described below. These schemes are illustrative and are not meant to limit the possible techniques one skilled in the art may use to prepare the compounds disclosed herein. Different methods to prepare the compounds of the present invention will be evident to those skilled in the art Additionally, the various steps in the synthesis may be performed in an alternate sequence in order to give the desired compound or compounds.

[0445] Examples of compounds of the present invention prepared by methods described in the general schemes are given in the intermediates and examples section set out hereinafter.

[0446] Preparation of homochiral examples may be carried out by techniques known to one skilled in the art. For example, homochiral compounds may be prepared by separation of racemic products by chiral phase preparative HPLC. Alternatively, the example compounds may be prepared by methods known to give enantiomerically enriched products. These include, but are not limited to, the incorporation of chiral auxiliary functionalities into racemic intermediates which serve to control the diastereoselectivity of transformations, providing enantio-enriched products upon cleavage of the chiral auxiliary.The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in a solvent or solvent mixture appropriate to the reagents and materials employed and suitable for the transformations being affected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention.

[0447] It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene et al. (Protective Groups in Organic Synthesis, 4th Edition, Wiley-Interscience (2006)).

[0448] Examples:

[0449] All reactions were carried out under a static atmosphere of nitrogen and stirred magnetically unless otherwise stated. All reagents used were of commercial quality.JH NMR spectra were obtained with Bruker or JEOL FOURIER® transform spectrometers operating at frequencies as follows:rH NMR: 400 MHz (Bruker or JEOL), 500MHz (Bruker or JEOL), and 600 MHz (Bruker). Spectral data are reported in the format: chemical shift (multiplicity, coupling constants, and number of hydrogens). Chemical shifts are specified in ppm downfield of a tetramethylsilane internal standard (5 units, tetramethylsilane = 0 ppm) and / or referenced to solvent peaks, which in 1H NMR spectra appear at 2.49 ppm for CD2HSOCD3, 3.30 ppm for CD2HOD, and 7.24 ppm for CHCI3. 'H NMR spectra collected in cL-DMSO using a watersuppression sequence, effectively suppresses the water signal and any proton peaks in the same region usually between 3.30-3.65 ppm. This experiment is denoted with the NMR solvent (DMSO-rfc, WS) in the solvent comment.

[0450] HPLC methods used for the experiments are listed below (Methods A-B). Method A;

[0451] Xbridge C18 1.7 p 2.1 x 50 mm column / water-ACN-TFA 95: 5:0.05% to 5:95:0.05% gradient over 3 min at 1 mL / min with 1 min hold at the end of the gradient, UV (220 nm). Method B;Xbridge C18 1.7 p.2.1 x 50 mm column / water-ACN-NH4OAc 95:5:10 mMNE OAc to 5:95:10 mM NH4OAC gradient over 3 min at 1 mL / min with 1 min hold at the end of the gradient, UV (220 nm).

[0452] Intermediate 1

[0453] (S)-5-Fluoro-2,3-dimethyl-4-(3-(methylamino)piperidin-l-yl)-l / / -indole-7-carboxamide

[0454]

[0455] Int-IA: 4-Bromo-5-fluoro-2,3-dimethyl-l / / -indole-7-carbonitrile

[0456]

[0457] Int-IA was prepared according to the procedure described in patent: WO 2016 / 065226. 'HNMR (300 MHz, DMSO- r.) 5 11.95 (br s, 1H), 7.57 (d, J= 9.3 Hz, 1H), 2.42 - 2.29 (m, 6H). MS (ESI) calculated for C11H8BrFN2: 265.99; found: m / z 266.9 [M+H]+.

[0458] Int-IB: / <? / 7-Butyl (S)-(l-(7-cyano-5-fluoro-2,3-dimethyl-l / / -indol-4-yl)piperidin-3-yl)(methyl)carbamate

[0459]

[0460] A mixture of Int-IA (2.0 g, 7.5 mmol), tert-butyl (S)-methyl(piperidin-3-yl)carbamate (1.8 g, 8.2 mmol), CS2CO3 (5.9 g, 18 mmol), BINAP (0.47 g, 0.75 mmol), and Pd2(dba)3 (0.34 g, 0.37 mmol) was degassed with vacuum and nitrogen (3x). 1,4-Dioxane (30 mL) was added, and the mixture was degassed with vacuum and nitrogen (3x). After stirring at 100 °C overnight, the reaction was cooled to room temperature, diluted with EtOAc and washed with water. The organic phase was washed with a saturated brine solution, dried over anhydrous Na2SO4, fdtered and concentrated in vacuo. The residue was triturated using DCM and fdtered to remove unreacted starting material. The fdtrate was concentrated in vacuo and the crude product was purified by flash chromatography (silica gel, 0-20% EtOAc:hexanes) to yield Int-IB (1.6 g, 53%) as an off-white solid. 'HNMR (500 MHz, DMSO- s) 8 11.56 (s, 1H), 7.36 (d, J= 12.8 Hz, 1H), 4.26 - 3.96 (m, 1H), 3.13 - 3.05 (m, 1H), 3.04 - 2.93 (m, 3H), 2.73 (s, 3H), 2.41 - 2.34 (m, 3H), 2.31 (s, 3H), 1.77 (br s, 3H), 1.69 - 1.60 (m, 1H), 1.37 (s, 9H). MS (ESI) calculated for C22H29FN4O2: 400.23; found: m / z 401.1 [M+H]+.

[0461] Intermediate 1. (S)-5-Fluoro-2,3-dimethyl-4-(3-(methylamino)piperidin-l-yl)-177-indole-7-carboxamide

[0462]

[0463] A mixture of Int-IB (1.3 g, 3.1 mmol) and 90% aqueous sulfuric acid (18.5 mL, 312 mmol) (gas evolution observed for ~5 minutes after the addition of acid) was heated at 60 °C and stirred for 1 h. After cooling to room temperature, the reaction mixture was carefully added dropwise to 10 M aq. NaOH at 0 °C (pH ~6-7) and then adjusted to pH 9 with 1 M aq. NaOH. The crude product was extracted with EtOAc (3x), and the combined organic phases were washed with a saturated brine solution, dried over anhydrous MgSO4, fdtered, and concentrated in vacuo to yield Intermediate 1 (0.94 g, 94%) as a tan solid, which was used in the next stepwithout further purification. 'HNMR (500 MHz, DMSO-d6) 5 10.64 (s, 1H), 7.91 (br s, 1H), 7.42 (d, J= 14.1 Hz, 1H), 7.33 (br s, 1H), 3.34 (br s, 2H), 3.04 - 2.89 (m, 3H), 2.46 (s, 3H), 2.34 (s, 3H), 2.31 (s, 3H), 2.11 (br d, J= 8.6 Hz, 1H), 1.80 - 1.63 (m, 2H), 1.29 - 1.15 (m, 1H). MS (ESI) calculated for C17H23FN4O: 318.19; found: m / z 319.0 [M+H]+.

[0464] Intermediate 2

[0465] (S)-5-Fluoro-2,3-dimethyl-4-(3-(methylamino)piperidin-l-yl)-l / 7-indole-7-carboxamide, 2 TFA

[0466]

[0467] Intermediate 2

[0468]

[0469] Int-2A. tert-Butyl (S)-(2-((l-(7-carbamoyl-5-fluoro-2,3-dimethyl-l / 7-indol-4-yl)piperidin-3-yl)(methyl)amino)-2-oxoethyl)carbamate

[0470]

[0471] To a solution of Intermediate 1 (2.00 g, 6.28 mmol) and ( / e / 7-butoxycarbonyl)glycine (1.21 g, 6.91 mmol) in DMF (62.8 mL) was added HATU (3.58 g, 9.42 mmol) and DIPEA (3.28 mL, 18.8 mmol). After stirring at room temperature for 1 h, the reaction mixture was diluted with water. The precipitate was filtered, washed well with water, and dried under vacuum to yield Int-2A (2.56 g, 86 %) as an off-white solid, which was used in the next step without furtherpurification.

[0472]

[0473] NMR (500 MHz, DMSO-d6) 5 10.70 - 10.45 (m, 1H), 8.02 - 7.82 (m, 1H), 7.48 - 7.35 (m, 1H), 7.33 - 7.18 (m, 1H), 6.71 - 6.54 (m, 1H), 4.74 - 4.39 (m, 1H), 4.05 - 3.59 (m, 2H), 3.50 - 3.38 (m, 1H), 3.35 - 3.20 (m, 1H), 2.94 - 2.70 (m, 5H), 2.39 (br s, 3H), 2.30 (br s, 3H), 1.80 - 1.62 (m, 3H), 1.43 - 1.17 (m, 10H). MS (ESI) calculated for C24H34FN5O4: 475.26; found: m / z 476.1 [M+H]+.

[0474] Intermediate 2. (S)-4-(3-(2-Amino-A-methylacetamido)piperidin-l-yl)-5-fluoro-2,3- dimethyl-l / f-indole-7-carboxamide, 2 TFA

[0475]

[0476] To a solution of Int-2A (2.56 g, 5.38 mmol) in DCM (53.8 mL) was added TFA (8.29 mL, 108 mmol). After stirring at room temperature for 2 h, the reaction mixture was concentrated in vacuo to provide a purple oil, the residue was dissolved in DCM and reconcentrated in vacuo (process repeated x2). The residue was then triturated with diethyl ether and the solid was dried under vacuum to yield Intermediate 2 (3.24 g, 100 %) as a yellow solid as the bis-TFA salt, which was used in the next step without further purification.1H NMR (500 MHz, DMSO-tfe) 5 10.69 - 10.42 (m, 1H), 8.02 - 7.80 (m, 1H), 7.51 - 7.34 (m, 1H), 7.33 - 7.01 (m, 1H), 4.55 (d, J= 7.9 Hz, 1H), 3.60 - 3.38 (m, 2H), 3.11 - 2.89 (m, 4H), 2.80 (s, 3H), 2.39 (br s, 3H), 2.30 (br s, 3H), 1.82 - 1.65 (m, 4H). MS (ESI) calculated for C19H26FN5O2: 375.21; found: m / z 376.2 [M+H]+.

[0477] Intermediate 3

[0478] Ethyl (S)-5-fluoro-2,3-dimethyl-4-(3-(methylamino)piperidin-l-yl)-l / / -indole-7-carboxylate, 2 TFA

[0479]

[0480]

[0481] To a solution of 4-bromo-5-fluoro-2,3-dimethyl-177-indole-7-carboxylic acid (see WO 2016 / 065226 for preparation) (2.00 g, 6.99 mmol) in DMF (28.1 mL) was added K2CO3 (1.16 g, 8.39 mmol) and the reaction mixture was stirred for 5 min. Ethyl iodide (0.62 mL, 7.7 mmol) was then added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water, the precipitate was filtered, washed with water, and dried under vacuum to yield Int-3A (1.76 g, 80 %) as a light yellow solid, which was used in the next step without further purification.JH NMR (500 MHz, DMSO-d6) 5 11.02 (br s, 1H), 7.47 (d, = 9.7 Hz, 1H), 4.41 (q, J= 7.1 Hz, 2H), 2.40 (s, 3H), 2.38 (s, 3H), 1.37 (t, J= 7.1 Hz, 3H). MS (ESI) calculated for C13H13BrFNO2: 313.01; found: m / z 313.8 [M+H]+.Int-3B. Ethyl (S)-4-(3-(( / er / -butoxycarbonyl)(methyl)amino)piperidin-l-yl)-5-fluoro-2,3-dimethyl-17 / -indole-7-carboxylate

[0482]

[0483] A mixture of Int-3A (1.76 g, 5.60 mmol), Zc / 7-butyl (5)-methyl(piperidin-3-yl)carbamate (1.31 mL, 6.16 mmol), cesium carbonate (4.38 g, 13.5 mmol), BINAP (0.349 g, 0.560 mmol), and Pd2(dba)3 (0.257 g, 0.280 mmol) was degassed with vacuum and nitrogen (3x). 1,4-Dioxane (22.4 mL) was added, the mixture was degassed (3x) and the reaction mixture was stirred at 100 °C overnight. After cooling to room temperature, the reaction was diluted with EtOAc and filtered through Celite®. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 0-40% EtOAc:hexanes) to yield Int-3B (2.01 g, 80 %) as a pale yellow solid.

[0484]

[0485] NMR (500 MHz, DMSO-cL) 8 10.64 (s, 1H), 7.34 (d, J= 13.6 Hz, 1H), 4.38 (q, J= 7.1 Hz, 2H), 3.31 (br s, 2H), 3.10 (br d, J= 9.3 Hz, 1H), 3.01 (br s, 2H), 2.96 (br d, J= 6.9 Hz, 1H), 2.73 (s, 3H), 2.39 (s, 3H), 2.34 (s, 3H), 1.77 (br s, 3H), 1.38 (s, 9H), 1.35 (t, J= 7.1 Hz, 3H). MS (ESI) calculated for C24H34FN3O4: 447.25; found: m / z 448.2 [M+H]+.

[0486] Intermediate 3. Ethyl (S)-5-fluoro-2,3-dimethyl-4-(3-(methylamino)piperidin-l-yl)-lZ7-indole-7-carboxylate, 2 TFA

[0487]

[0488] To a solution of Int-3B (150 mg, 0.335 mmol) in DCM (3.35 mL) was added TFA (0.52 mL, 6.7 mmol). After stirring at room temperature overnight, the solvent was removed in vacuo, the residue was dissolved in DCM and reconcentrated in vacuo (process repeated x2), to yield Intermediate 3 (195 mg, 100 %) as a brown sticky foam, as the bis-TFA salt, which was used in the next step without further purification. 10 mg of crude material was purified by preparative HPLC (Column: XBridge C18, 19 mm x 200 mm, 5 pm particles; Flow Rate: 20 mL / min;Column Temperature: 25 °C; Mobile Phase A: ACN / H2O (5:95:10 mMNELOAc), Mobile Phase B: ACN / H2O (95:5:10 mM NbLOAc); Gradient: 20 minutes with a 4 minute hold of 100% Mobile Phase B) to yield Intermediate 3, as the neutral form, (4.8 mg). Neutral form data:1H NMR (500 MHz, DMSO-d6) 5 10.59 (s, 1H), 7.33 (d, J= 13.7 Hz, 1H), 4.36 (q, J= 7.0 Hz, 2H), 3.36 - 3.23 (m, 1H), 3.10 - 2.92 (m, 2H), 2.81 - 2.63 (m, 2H), 2.33 (brd, J= 11.0 Hz, 9H), 1.81 (br s, 2H), 1.77 - 1.60 (m, 2H), 1.32 (t, J= 7.0 Hz, 3H). MS (ESI) calculated for C19H26FN3O2: 347.20; found: m / z 348.0 [M+H]+.

[0489] Intermediate 4

[0490] ( 1 -Naphthoyl)gly cine

[0491]

[0492] lnt-4A

[0493] Int-4A. Methyl (l-naphthoyl)glycinate

[0494]

[0495] To a solution of methyl glycinate, HC1 (3.05 g, 24.3 mmol) and 1-naphthoic acid (3.80 g, 22.1 mmol) in DMF (44.1 mL) was added HATU (10.1 g, 26.5 mmol) and DIPEA (15 mL, 88 mmol). After stirring at room temperature for 2 h, the reaction mixture was diluted with water and extracted with EtOAc (x3). The combined organic phases were washed with 10% aq. LiCl (x4), water and sat. brine solution, dried over anhydrous MgSCh, filtered, and concentrated in vacuo to yield Int-4A (6.04 g, 100 %, 89% pure) as a brown solid, which was used in the next step without further purification. 1H NMR (400 MHz, CDCh) 88.38 (dd, J= 8.3, 0.9 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.89 (dd, J= 8.3, 1.1 Hz, 1H), 7.70 (dd, J= 7.0, 1.2 Hz, 1H), 7.62 -7.52 (m, 2H), 7.49 (dd, J= 8.2, 7.0 Hz, 1H), 6.52 (br s, 1H), 4.36 (d, J= 5.5 Hz, 2H), 3.84 (s, 3H). MS (ESI) calculated for C14H13NO3: 243.09; found: m / z 243.9 [M+H]+.

[0496] Intermediate 4. (1 -Naphthoyl )gly cine

[0497]

[0498] To a solution of Int-4A (6.04 g, 22.1 mmol) in MeOH (55 mL) and THF (166 mL) was added IM aq. NaOH (66 mL, 66 mmol). After stirring at room temperature for 2 h, the volatiles were removed in vacuo and the residue was diluted with water. The reaction mixture was acidified to pH ~2 with 1 M aq. HC1. The precipitate was filtered, washed with water, and dried under vacuum to afford Intermediate 4 (2.63 g, 52 %) as an off-white solid, which was used in the next step without further purification.1H NMR (400 MHz, DMSO-cL) 8 12.67 (br s, 1H), 8.87 (t, J= 5.9 Hz, 1H), 8.35 - 8.27 (m, 1H), 8.03 (d, J= 8.2 Hz, 1H), 8.00 - 7.94 (m, 1H), 7.65 -7.60 (m, 1H), 7.59 - 7.52 (m, 3H), 3.98 (d, J= 6.0 Hz, 2H). MS (ESI) calculated for C13H11NO3: 229.07; found: m / z 229.8 [M+H]+.

[0499] Intermediate 5

[0500] (quinoline-5-carbonyl)glycine

[0501]

[0502] Intermediate 5 was prepared according to the procedure described for Intermediate 4 starting from quinoline-5-carboxylic acid. 'H NMR (400 MHz, DMSO-c / r,) 8 12.68 (br s, 1H), 9.01 - 8.93 (m, 2H), 8.77 - 8.69 (m, 1H), 8.18 - 8.09 (m, 1H), 7.84 - 7.74 (m, 2H), 7.60 (dd, J = 8.6, 4.3 Hz, 1H), 4.00 (d, J= 6.0 Hz, 2H). MS (ESI) calculated for C12H10N2O3: 230.07; found: m / z 231.0 [M+H]+.Example 1

[0503] (S)-4-(3-(2-(2,4-Dichlorobenzamido)-A-methylacetamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl- l / / -indole-7-carboxamide

[0504]

[0505] Intermediate 1

[0506] To a solution of Intermediate 1 (13.0 mg, 0.041 mmol), (2,4-dichlorobenzoyl)glycine (12mg, 0.049 mmol), and HATU (23 mg, 0.061 mmol) in DMF (0.408 mL) was added DIPEA (21 μL, 0.12 mmol). After stirring at room temperature overnight, the reaction mixture was purified by preparative HPLC (Column: XBridge Cl 8, 19 mm x 200 mm, 5 pm particles; Flow Rate: 20 mL / min; Column Temperature: 25 °C; Mobile Phase A: ACN / H2O (5:95:10 mM NEUOAc), Mobile Phase B: ACN / H2O (95:5: 10 mM NFUOAc); Gradient: 20 minutes with a 4 minute hold of 100% Mobile Phase B) to yield Example 1 (18.5 mg, 83%). 'H NMR (500 MHz, DMSO- e, WS) 8 10.67 - 10.49 (m, 1H), 8.63 - 8.39 (m, 1H), 7.92 (br dd, J= 4.0, 2.7 Hz, 1H), 7.66 (s, 1H), 7.55 - 7.36 (m, 3H), 7.30 (br d, J= 2.9 Hz, 1H), 4.71 - 4.51 (m, 1H), 4.34 - 3.88 (m, 2H), 3.45 - 2.77 (m, 7H), 2.44 - 2.35 (m, 3H), 2.33 - 2.23 (m, 3H), 1.95 - 1.57 (m, 4H). MS (ESI) calculated for C26H28CI2FN5O3: 547.16; found: m / z 548.1 [M+H]+. Analytical HPLC Retention times: 2.00 min (Method A), 2.06 min (Method B)The Examples in the following Table (Table 1) were prepared in a similar manner as the preparation of Example 1.

[0507]

[0508] NMR was measured at 500 MHz, DMSO-c / z, WS unless otherwise indicated.

[0509] Table 1

[0510]

[0511]

[0512]

[0513]

[0514] Example 5

[0515] (S)-4-(3-(2-(1-Naphthamido)-N-methylacetamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

[0516]

[0517] Intermediate 2

[0518] To a solution of Intermediate 2 (25 mg, 0.041 mmol) and 1-naphthoic acid (7.9 mg, 0.046 mmol) in DMF (0.41 m ) was added TCFH (17.4 mg, 0.062 mmol) and NMI (20 pL, 0.25 mmol). After stirring at room temperature for 1 h, the reaction mixture was purified by preparative HPLC (Column: XBridge C18, 19 mm x 200 mm, 5 pm particles; Flow Rate: 20 mL / min; Column Temperature: 25 °C; Mobile Phase A: ACN / H₂O (5:95:10 mM NH₄OAc), Mobile Phase B: ACN / H₂O (95:5:10 mM NH₄OAc); Gradient: 20 minutes with a 4 minute hold of 100% Mobile Phase B) to yield Example 5 (14 mg, 60%).JH NMR (500 MHz, DMSO- e, WS) 8 10.65 - 10.50 (m, 1H), 8.57 - 8.44 (m, 1H), 8.34 (br dd, J= 3.5, 2.5 Hz, 1H), 8.04 - 7.87 (m, 3H), 7.69 - 7.59 (m, 1H), 7.56 - 7.38 (m, 4H), 7.35 - 7.22 (m, 1H), 4.72 -3.93 (m, 3H), 3.42 - 3.24 (m, 1H), 3.20 - 3.09 (m, 1H), 3.04 (br s, 2H), 3.00 - 2.84 (m, 3H), 2.47 - 2.38 (m, 3H), 2.34 - 2.23 (m, 3H), 1.98 - 1.66 (m, 4H). MS (ESI) calculated for C30H32FN5O3: 529.25; found: m / z 530.2 [M+H]+. Analytical HPLC Retention times: 1.93 min (Method A), 1.92 min (Method B).The Examples in the following Table (Table 2) were prepared in a similar manner as the preparation of Example 5. 'H NMR was measured at 500 MHz, DMSO-de, WS unless otherwise indicated.

[0519] Table 2

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527] Example 13

[0528] (S)-5-Fluoro-jV,2,3-trimethyl-4-(3-(A-methylbut-2-ynamido)piperidin-l-yl)-l / / -indole-7-carb oxami de

[0529]

[0530] 13 A. Ethyl (S)-5-fluoro-2,3-dimethyl-4-(3-(A-methylbut-2-ynamido)piperidin-l-yl)-l / / -indole-7-carboxylate

[0531]

[0532] To a solution of Intermediate 3 (0.230 g, 0.662 mmol), but-2-ynoic acid (0.067 g, 0.79 mmol), and HATU (0.378 g, 0.993 mmol) in DMF (2.2 mL) was added DIPEA (0.58 mL, 3.3 mmol). After stirring at room temperature for 15 min, the reaction mixture was diluted with water. The precipitate was filtered, washed well with water, and dried under vacuum to provide 13 A (0.237 g, 87 %) as a beige solid, which was used in the next step without further purification.1H NMR (500 MHz, DMSO-t / e) 5 10.66 (br d, J= 14.8 Hz, 1H), 7.34 (dd, J= 13.6, 9.2 Hz, 1H), 4.62 - 4.46 (m, 1H), 4.38 (qd, J= 7.1, 3.0 Hz, 2H), 3.37 - 3.32 (m, 1H), 3.21 (br d, J= 1.8 Hz, 1H), 3.15 - 2.90 (m, 5H), 2.40 (d, J= 16.6 Hz, 3H), 2.35 (d, J= 6.8 Hz, 3H), 2.01 (d, J= 9.6 Hz, 3H), 1.87 - 1.65 (m, 4H), 1.35 (t, J= 7.1 Hz, 3H). MS (ESI) calculated for C23H28FN3O3: 413.21; found: m / z 414.0 [M+H]+.

[0533] 13B. (S)-5-Fluoro-2,3-dimethyl-4-(3-(A-methylbut-2-ynamido)piperidin-l-yl)-177-indole-7-carboxylic acid

[0534]

[0535] To a solution of 13A (0.230 g, 0.556 mmol) in MeOH (2.23 mL), THF (2.23 mL) and H2O (1.11 mL) was added IM aq. NaOH (1.67 mL, 1.67 mmol). After stirring at 50 °C for 4h, the volatiles were removed in vacuo and the residue was diluted with water. The reaction mixture was acidified to pH ~2 with IM aq. HC1 and the precipitate was filtered, washed well with water, and dried under vacuum to afford 13B (0.145 g, 65 %) as a beige solid, which was used in the next step without further purification.1H NMR (500 MHz, DMSO-d6) 5 10.57 (br d, J= 12.4 Hz, 1H), 7.27 (dd, J= 13.6, 7.0 Hz, 1H), 4.64 - 4.41 (m, 1H), 3.56 (s, 1H), 3.48 - 3.31 (m, 1H), 3.23 - 2.82 (m, 5H), 2.39 (d, J= 17.2 Hz, 3H), 2.32 (d, J= 6.1 Hz, 3H), 2.01 (d, J= 9.9 Hz, 3H), 1.87 - 1.61 (m, 4H). MS (ESI) calculated for C21H24FN3O3: 385.18; found: m / z 386.0 [M+H]+.

[0536] Example 13. (S)-5-Fluoro-A,2,3-trimethyl-4-(3-(A-methylbut-2-ynamido)piperidin-l-yl)-l / / -indole-7-carboxamide

[0537]

[0538] To a solution of 13B (0.015 g, 0.039 mmol), methylamine hydrochloride (3.4 mg, 0.051 mmol), and HATU (0.022 g, 0.058 mmol) in DMF (0.39 mL) was added DIPEA (0.027 mL, 0.16 mmol). After stirring at room temperature for 15 min, the reaction mixture was purified by preparative HPLC (Column: XBridge Cl 8, 19 mm x 200 mm, 5 pm particles; Flow Rate: 20 mL / min; Column Temperature: 25 °C; Mobile Phase A: ACN / H2O (5:95:10 mM NH4OAc), Mobile Phase B: ACN / H2O (95:5:10 mM NH4OAc); Gradient: 20 minutes with a 4 minute hold of 100% Mobile Phase B) to yield Example 13 (6.0 mg, 38%). 'H NMR (500 MHz, DMSO-tfe, WS) 58.38 (br dd, J= 8.0, 4.5 Hz, 1H), 7.32 (dd, J= 14.0, 9.2 Hz, 1H), 4.63 - 4.45 (m, 1H), 3.25 - 2.90 (m, 5H), 2.83 - 2.76 (m, 5H), 2.38 (br d, J= 17.5 Hz, 3H), 2.31 (br d, J= 6.6 Hz, 3H), 2.01 (d, J= 8.7 Hz, 3H), 1.85 - 1.69 (m, 4H). MS (ESI) calculated for C22H27FN4O2: 398.21; found: m / z 399.2 [M+H]+. Analytical HPLC Retention times: 1.95 min (Method A), 1.79 min (Method B).

[0539] Example 14

[0540] (5)-5-Fluoro-l,2,3-trimethyl-4-(3-(A-methylbut-2-ynamido)piperidin-l-yl)-l / / -indole-7- carboxamide

[0541]

[0542] 14A. 4-Bromo-5-fluoro-l,2,3-trimethyl-l / / -indole-7-carbonitrile

[0543]

[0544] To a room temperature solution of Int-IA (0.076 g, 0.29 mmol) in DMF (1.14 mL) was added 60% NaH in mineral oil (0.017 g, 0.43 mmol). After stirring at room temperature for 15 minutes, iodomethane (0.023 mL, 0.37 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 1 h, forming a thick white precipitate. The reaction mixture was diluted with water and the precipitate was filtered, washed well with water, and dried under vacuum to yield 14A (0.071 g, 89%) as a white solid, which was used in the next step without further purification.1H NMR (500 MHz, methanol-d4) 87.32 (d, J= 8.7 Hz, 1H), 4.01 (s, 3H), 2.50 (s, 3H), 2.38 (s, 3H). MS (ESI) calculated for Ci2HioBrFN2: 280.00; found: m / z 281.1 [M+H]+.14B. Zc / 7-Butyl (5)-(l-(7-cyano-5-fluoro-l,2,3-trimethyl-l / / -indol-4-yl)piperidin-3-yl)(methyl)carbamate

[0545]

[0546] 14B was prepared according to the procedure described for Int-IB. (65 mg, 63%).1H NMR (500 MHz, CDCl3) 57.13 (d, J= 12.3 Hz, 1H), 4.48 - 4.10 (m, 1H), 3.96 (s, 3H), 3.21 - 3.13 (m, 1H), 3.13 - 3.00 (m, 3H), 2.81 (s, 3H), 2.49 (s, 3H), 2.33 (s, 3H), 1.93 - 1.83 (m, 2H), 1.84 -1.77 (m, 1H), 1.71 - 1.58 (m, 1H), 1.45 (s, 9H). MS (ESI) calculated for C23H31FN4O2: 414.24; found: m / z 415.2 [M+H]+.

[0547] 14C. (5)-5-Fluoro-l,2,3-trimethyl-4-(3-(methylamino)piperidin-l-yl)-l / f-indole-7-carb oxami de

[0548]

[0549] 14C was prepared according to the procedure described for Intermediate 1. (35 mg, 70%).1H NMR (500 MHz, DMSO-d6) 57.95 (br s, 1H), 7.53 (br s, 1H), 6.82 (d, J= 13.1 Hz, 1H), 3.57 (s, 3H), 3.22 (br dd, J= 5.8, 3.5 Hz, 2H), 2.97 (br s, 2H), 2.81 - 2.70 (m, 1H), 2.44 - 2.23 (m, 9H), 1.95 - 1.64 (m, 4H). MS (ESI) calculated for C18H25FN4O2: 332.20; found: m / z 333.2 [M+H]+.

[0550] Example 14. (S)-5-Fluoro-l,2,3-trimethyl-4-(3-(jV-methylbut-2-ynamido)piperidin-l-yl)-l / / -indole-7-carboxamide

[0551]

[0552] Example 14 was prepared according to the procedure described for Example 1. (26.6 mg, 63%).1H NMR (500 MHz, DMSO-d6, WS) 87.98 (br s, 1H), 7.60 - 7.51 (m, 1H), 6.88 - 6.79 (m, 1H), 4.64 - 4.44 (m, 1H), 3.60 - 3.56 (m, 2H), 3.46 - 3.34 (m, 1H), 3.23 - 3.16 (m, 1H), 3.14 - 3.00 (m, 2H), 3.00 - 2.84 (m, 2H), 2.79 (s, 2H), 2.48 - 2.40 (m, 3H), 2.31 - 2.25 (m, 3H), 2.01 (d, J = 8.8 Hz, 3H), 1.87 - 1.64 (m, 4H). MS (ESI) calculated for C22H27FN4O2: 398.21; found: m / z 399.2 [M+H]+. Analytical HPLC Retention times: 1.90 min (Method A), 1.79 min (Method B).

[0553] Example 15

[0554] (S)-1-Ethyl-5-fluoro-2,3-dimethyl-4-(3-(N-methylbut-2-ynamido)piperidin-1-yl)-1H-indole-7- carboxamide

[0555]

[0556] Example 15 was prepared according to the procedure described for Example 14. Ethyl iodide was used in-place of methyl iodide (7.1 mg, 25%).1H NMR (500 MHz, DMSO-d6, WS) δ 8.01 (br s, 1H), 7.65 - 7.47 (m, 1H), 6.87 - 6.76 (m, 1H), 4.61 - 4.40 (m, 1H), 4.31 - 4.10 (m, 2H), 3.47 - 2.77 (m, 5H), 2.48 - 2.40 (m, 3H), 2.30 (br d, J= 6.7 Hz, 3H), 2.02 (d, J= 11.7 Hz, 3H), 1.85 - 1.64 (m, 4H), 1.10 (q, J= 7.1 Hz, 3H). MS (ESI) calculated for C23H29FN4O2: 412.23; found: m / z 413.0 [M+H]+. Analytical HPLC Retention times: 1.73 min (Method A), 1.73 min (Method B).

[0557] Example 16

[0558] (S)-4-(3-(3-Cyclopropyl-A-methylpropiolamido)piperidin-l-yl)-5-fluoro-l,2,3-trimethyl-177- indole-7-carboxamide

[0559]

[0560] Example 16 was prepared according to the procedure described for Example 14. 3- Cyclopropylprop-2-ynoic acid was used in place of but-2-ynoic acid (9.9 mg, 76%).1H NMR (500 MHz, DMSO-d6, WS) δ 8.09 - 7.86 (m, 1H), 7.64 - 7.46 (m, 1H), 6.85 - 6.75 (m, 1H), 4.56 - 4.33 (m, 1H), 3.63 - 3.45 (m, 1H), 3.23 - 3.05 (m, 1H), 3.04 - 2.83 (m, 4H), 2.48 - 2.38 (m, 4H), 2.29 - 2.21 (m, 3H), 1.91 - 1.57 (m, 4H), 1.50 (tt, J= 8.2, 5.0 Hz, 1H), 0.99 - 0.87 (m, 2H), 0.80 -0.68 (m, 2H). MS (ESI) calculated for C24H29FN4O2: 424.23; found: m / z 425.0 [M+H]+. Analytical HPLC Retention times: 1.89 min (Method A), 1.75 min (Method B).Example 17

[0561] (S)-5-Fluoro- 1,2, 3 -trimethyl -4-(3-(JV-methylbut-2-ynamido)azepan-l-yl)-l#-indole-7-

[0562]

[0563] 17A. tert-Butyl (*$')- (I - ( 7 -cy ano-5-fluoro- 1,2,3 -trimethyl- 17 / -indol-4-yl)azepan-3 -yl)carbamate

[0564]

[0565] A mixture of 14A (75 mg, 0.27 mmol), te / 7-butyl (S)-azepan-3-ylcarbamate (63 mg, 0.29 mmol), CS2CO3 (210 mg, 0.64 mmol), BINAP (17 mg, 0.027 mmol), and Pd2(dba)s (12 mg, 0.013 mmol) was degassed with vacuum and nitrogen (3x). 1,4-Dioxane (1.07 mL) was added, and the mixture was degassed with vacuum and nitrogen (3x). After stirring at 100 °C overnight, the reaction was cooled to room temperature, diluted with EtOAc and washed with water. The organic phase was washed with a saturated brine solution, dried over anhydrous Na2SO4, filtered andconcentrated in vacuo. The residue was triturated using DCM and filtered to remove unreacted starting material. The filtrate was concentrated in vacuo and the crude product was purified by flash chromatography (silica gel, 0-35% EtOAc:hexanes) to yield 17A (35 mg, 19%) as a yellow solid.1H NMR (500 MHz, CDCl3) δ 7.17 (d, J= 11.5 Hz, 1H), 3.97 (s, 3H), 3.95 (s, 2H), 3.17 (br s, 2H), 2.58 - 2.43 (m, 3H), 2.41 (s, 2H), 2.35 - 2.32 (m, 3H), 2.31 (s, 2H), 1.81 (br s, 4H), 1.36 (s, 9H). MS (ESI) calculated for C23H31FN4O2: 414.24; found: m / z 415.1 [M+H]+.

[0566] 17B. tert-Butyl (S)-(l-(7-cyano-5-fluoro-l,2,3-trimethyl-17 / -indol-4-yl)azepan-3-yl)(methyl)carbamate

[0567]

[0568] To a room temperature solution of 17A (28 mg, 0.041 mmol) in DMF (0.16 mL) was added 60% NaH in mineral oil (2.4 mg, 0.061 mmol). After stirring at room temperature for 15 minutes, iodomethane (3.3 pL, 0.053 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 1 h. Additional 60% NaH in mineral oil (2.4 mg, 0.061 mmol) and iodomethane (3.3 pL, 0.053 mmol) was added and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with water and extracted with EtOAc (x3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 0-50% EtOAc: hexanes) to yield 17B (20 mg, >100% contained inseparable unreacted starting material) as a yellow oil, which was not purified further.1H NMR (500 MHz, CDCl3) δ 7.17 (d, J = 11.7 Hz, 1H), 3.97 (s, 3H), 3.35 - 3.02 (m, 4H), 2.74 (s, 3H), 2.50 (s, 3H), 2.33 (s, 3H), 1.98 - 1.68 (m, 7H), 1.40 (s, 9H). MS (ESI) calculated for C24H33FN4O2: 428.26; found: m / z 429.5 [M+H]+.

[0569] 17C. (5)-5-Fluoro-l,2,3-trimethyl-4-(3-(methylamino)azepan-l-yl)-177-indole-7-carb oxami de

[0570]

[0571] A mixture of 17B (15.6 mg, 0.036 mmol) and 90% aqueous sulfuric acid (0.22 mL, 3.7 mmol) (gas evolution observed for ~ 5 minutes after the addition of acid) was heated at 60 °C and stirred for 1 h. After cooling to room temperature, the reaction mixture was carefully added dropwise to 10 M aq. NaOH at 0 °C (pH —6-7) and then adjusted to pH 9 with 1 M aq. NaOH. The crude product was extracted with EtOAc (3x), and the combined organic phases were washed with saturated brine solution, dried over anhydrous MgSCh, filtered, and concentrated in vacuo to yield 17C (9.8 mg, 78%) as a tan solid, which was used in the next step without further purification.

[0572] 1H NMR (400 MHz, CDCl3) δ 6.92 (brd, J= 11.8 Hz, 1H), 6.63 - 6.19 (m, 2H), 3.48 (s, 3H), 3.41 (br s, 1H), 3.23 - 3.14 (m, 3H), 2.60 - 2.34 (m, 7H), 1.98 - 1.67 (m, 7H), 0.88 (br s, 2H). MS (ESI) calculated for C19H27FN4O: 346.22; found: m / z 347.0 [M+H]+.

[0573] Example 17. (5)-5-Fluoro-l,2,3-trimethyl-4-(3-(A-methylbut-2-ynamido)azepan-l-yl)-l / / -indole-7-carboxamide

[0574]

[0575] Example 17 was prepared according to the procedure described for Example 1. (4.1 mg,

[0576]

[0577] 8.03 - 7.85 (m, 1H), 7.54 (br d, J= 5.4 Hz, 1H), 6.92 - 6.80 (m, 1H), 4.76 - 4.45 (m, 1H), 3.98 - 3.50 (m, 3H), 3.43 - 3.35 (m, 2H), 3.25 - 2.95 (m, 3H), 2.84 - 2.63 (m, 3H), 2.47 - 2.38 (m, 2H), 2.29 (d, J= 2.1 Hz, 3H), 2.03 - 1.64 (m, 9H). MS (ESI) calculated for C23H29FN4O2: 412.23; found: m / z413.2 [M+H]+. Analytical HPLC Retention times: 1.74 min (Method A), 1.77 min (Method B).

[0578] Example 18

[0579] (5)-4-(3-(5-(ter / -butyl)-A-methyl-177-pyrazole-3-carboxamido)piperidin-l-yl)-A-(cy anomethyl)- 5-fluoro-2,3-dimethyl-17 / -indole-7-carboxamide

[0580]

[0581]

[0582] 18A. Ethyl (S)-4-(3-(5-(tert-butyl)-N-methyl-1H-pyrazole-3-carboxamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylate

[0583]

[0584] To a solution of Intermediate 3 (185 mg, 0.321 mmol) and 5-(terLbutyl)-l / / -pyrazole-3-carboxylic acid (59.5 mg, 0.354 mmol) in DMF (3.22 mL) was added HATU (183 mg, 0.482 mmol) and DIPEA (0.280 mL, 1.61 mmol). After stirring at room temperature overnight, the reaction was diluted with water and the precipitate was filtered, washed well with water and dried under vacuum to yield 18A (167 mg, 100 % yield) as a pale yellow solid, which was used in the next step without further purification.1H NMR (500 MHz, DMSO-d6) 5 10.57 (br s, 1H), 7.32 (br d,. / 13.5 Hz, 1H), 6.33 - 6.08 (m, 1H), 4.74 - 4.51 (m, 1H), 4.35 (q, J= 7.0 Hz, 2H), 3.30 -2.80 (m, 7H), 2.45 - 2.28 (m, 3H), 2.29 - 2.01 (m, 3H), 1.93 - 1.57 (m, 4H), 1.32 (br t, J= 7.0 Hz, 3H), 1.25 (br s, 9H). MS (ESI) calculated for C27H36FN5O3: 497.28; found: m / z 498.3 [M+H]+.

[0585] 18B. (S)-4-(3-(5-(tert-Butyl)-N-methyl-1H-pyrazole-3-carboxamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylic acid, HCl

[0586]

[0587] 1M aqueous NaOH (1.19 mL, 1.19 mmol) was added to a solution of 18A(215 mg, 0.397 mmol) in THF (2.98 mL) and EtOH (0.99 mL) and stirred at 50 °C in a sealed reaction vial for 4 h. After cooling to room temperature, the solvent was removed in vacuo and the residue briefly dried under vacuum to remove trace EtOH. The residue was dissolved in water, followed by acidification with 1 M aq. HC1 to pH ~2. The precipitate was filtered, washed well with water and dried under vacuum to yield 18B (176 mg, 83 %) as an off-white solid as the HC1 salt, which was used in the next step without further purification.1H NMR (500 MHz, DMSO-d6) 5 12.85 (br s, 1H), 10.58 (br s, 1H), 7.16 (br d, J= 13.5 Hz, 1H), 6.39 - 6.21 (m, 1H), 6.17 (br s, 1H), 4.77 - 4.48 (m, 1H), 3.19 -2.87 (m, 7H), 2.47 -2.39 (m, 1H), 2.35 -2.23 (m, 3H), 2.04 (br s, 2H), 1.91 - 1.69 (m, 4H), 1.27 (br s, 9H). MS (ESI) calculated for C25H32FN5O3: 469.25; found: m / z 470.2 [M+H]+.

[0588] Example 18. (S)-4-(3-(5-(tert-Butyl)-N-methyl-1H-pyrazole-3-carboxamido)piperidin-1-yl)-N-(cyanomethyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

[0589]

[0590] To a solution of 18B (15 mg, 0.030 mmol) and 2-aminoacetonitrile (1.8 mg, 0.033 mmol) in DMF (0.30 mL) was added TCFH (13 mg, 0.044 mmol) and NMI (0.014 mL, 0.18 mmol). After stirring at room temperature for 2 h, the reaction mixture was purified by preparative HPLC (Column: XBridge Cl 8, 19 mm x 200 mm, 5 pm particles; Flow Rate: 20 mL / min; Column Temperature: 25 °C; Mobile Phase A: ACN / H2O (5:95:10 mM NH4OAC), Mobile Phase B: ACN / H2O (95:5:10 mM NH4OAC); Gradient: 20 minutes with a 4 minute hold of 100% Mobile Phase B) to yield Example 18 (15 mg, 100%). 'H NMR (500 MHz, DMSO-d6, WS) δ 10.76 - 10.62 (m, 1H), 9.16 - 9.05 (m, 1H), 7.36 (br d, J = 13.9 Hz, 1H), 6.36 - 6.23 (m, 1H), 6.22 - 6.09 (m, 1H), 4.76 - 4.50 (m, 1H), 4.30 (br d, J = 4.8 Hz, 2H), 3.53 - 2.74 (m, 7H), 2.48 - 2.38 (m, 1H), 2.35 - 2.20 (m, 3H), 2.08 - 1.99 (m, 2H), 1.94 - 1.56 (m, 4H), 1.25 (br s, 9H). MS (ESI) calculated for C27H34FN7O2: 507.28; found: m / z 508.3 [M+H]+. Analytical HPLC Retention times: 1.99 min (Method A), 2.01 min (Method B).

[0591] The Examples in the following Table (Table 3) were prepared in a similar manner as the preparation of Example 18. ^HNMR was measured at 500 MHz, DMSO-d6, WS unless otherwise indicated.Table 3

[0592]

[0593]

[0594]

[0595]

[0596] Example 23

[0597] 4-((5-3-(2-(l-Naphthamido)-A-methylacetamido)piperidin-l-yl)-5-fluoro-A-((3A,47?)-4- hydroxytetrahydro-2 / / -pyran-3-yl)-2,3-dimethyl-l / / -indole-7-carboxamide

[0598]

[0599] 23 A. Ethyl (5)-4-(3-(2-((fert-butoxycarbonyl)amino)-A-methylacetamido)pi peri din-l-yl)-5-fluoro-2,3-dimethyl-177-indole-7-carboxylate

[0600]

[0601] To a solution of Intermediate 3 (250 mg, 0.434 mmol) and (tert-butoxycarbonyl)glycine (84.0 mg, 0.478 mmol) in DMF (4.34 mL) was added HATU (248 mg, 0.652 mmol) and DIPEA (0.23 mL, 1.3 mmol). After stirring at room temperature for 1 h, the reaction was diluted with water. The precipitate was filtered, washed well with water and dried under vacuum to yield 23A (179 mg, 78 %) as a white solid, which was used in the next step without further purification. 'H NMR (500 MHz, DMSO-ofc) 5 10.70 - 10.58 (m, 1H), 7.37 - 7.29 (m, 1H), 6.61 (br t, J= 5.2 Hz, 1H), 4.59 (br d, J= 2.6 Hz, 1H), 4.37 (q, J= 7.1 Hz, 2H), 4.06 - 3.60 (m, 3H), 3.12 - 3.01 (m, 3H), 2.97 - 2.90 (m, 1H), 2.84 (s, 2H), 2.41 (s, 3H), 2.34 (s, 3H), 1.87 -1.64 (m, 4H), 1.39 - 1.32 (m, 12H). MS (ESI) calculated for C26H37FN4O5: 504.27; found: m / z 505.2 [M+H]+.

[0602] 23B. Ethyl (5)-4-(3-(2-Amino-A-methylacetamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl- l / / -indole-7-carboxylate, 2 TFA

[0603]

[0604] To a solution of 23 A (175 mg, 0.347 mmol) in DCM (3.47 mL) was added TFA (0.53 mL, 6.9 mmol). After stirring at room temperature overnight, the reaction mixture was concentrated in vacuo, the residue was dissolved in DCM and reconcentrated in vacuo (process repeated x2). The residue was then triturated with diethyl ether and the solid was dried under vacuum to yield 23B (189 mg, 86 %) as a tan solid as the bis-TFA salt, which was used in the next step without further purification. 20 mg of crude material was purified by preparative HPLC (Column: XBridge C18, 19 mm x 200 mm, 5 pm particles; Flow Rate: 20 mL / min; Column Temperature: 25 °C; Mobile Phase A: ACN / H2O (5:95:10 mM NH4OAc), Mobile Phase B: ACN / H2O (95:5:10 mM NH4OAC); Gradient: 20 minutes with a 4 minute hold of100% Mobile Phase B) to yield 23B, as the neutral form, (8.5 mg). Neutral form data: 'H NMR(500MHz, DMSO-cL) 8 10.70 - 10.55 (m, 1H), 7.40 - 7.25 (m, 1H), 4.69 - 4.54 (m, 1H), 4.37 (q, J= 7.2 Hz, 2H), 3.52 - 3.38 (m, 1H), 3.32 - 3.21 (m, 1H), 3.18 - 2.87 (m, 4H), 2.79 (s, 3H), 2.41 (br s, 3H), 2.33 (s, 3H), 1.82 - 1.65 (m, 4H), 1.34 (t, J = 7.1 Hz, 3H). MS (ESI) calculated for C21H29FN4O3: 404.22; found: m / z 405.2 [M+H]+.

[0605] 23C. Ethyl (5)-4-(3-(2-(l-naphthamido)-A-methylacetamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-12 / -indole-7-carboxylate

[0606]

[0607] To a solution of 23B (bis-TFA salt) (179 mg, 0.283 mmol) and 1-naphthoic acid (53.6 mg, 0.311 mmol) in DMF (2.8 mL) was added TCFH (119 mg, 0.424 mmol) and NMI (0.14 mL, 1.7 mmol). After stirring at room temperature for 2 h, the reaction mixture was diluted with water. The precipitate was filtered, washed well with water, and dried under vacuum to yield 23C (152 mg, 92 %) as light tan solid, which was used in the next step without further purification. 'H NMR (500 MHz, DMSO-c / r,) 8 10.73 - 10.55 (m, 1H), 8.49 (br t, J= 5.7 Hz, 1H), 8.39 - 8.33 (m, 1H), 8.03 - 7.93 (m, 2H), 7.67 - 7.60 (m, 1H), 7.58 - 7.46 (m, 3H), 7.34 (d, J= 13.6 Hz, 1H), 4.72 - 4.59 (m, 1H), 4.37 (q, J= 7.0 Hz, 2H), 4.30 - 4.29 (m, 1H), 4.26 -4.07 (m, 2H), 3.19 - 2.93 (m, 6H), 2.47 - 2.31 (m, 6H), 1.87 - 1.68 (m, 4H), 1.35 (t, J= 7.1 Hz, 3H). MS (ESI) calculated for C32H35FN4O4: 558.26; found: m / z 559.3 [M+H]+.

[0608] 23D. (5)-4-(3-(2-(l-Naphthamido)-A-methylacetamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-l / / -indole-7-carboxylic acid, HC1

[0609]

[0610] IM aqueous NaOH (0.806 mL, 0.806 mmol) was added to a solution of 23C (150 mg, 0.269 mmol) in THF (2.01 mL) and EtOH (0.671 mL). After stirring at 50 °C overnight, thereaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in water followed by acidification to pH ~2 using IM aqueous HC1. The solid was filtered, washed well with water, and dried under vacuum to yield 23D (109 mg, 68%) as an off-white solid as the HC1 salt, which was used in the next step without further purification.

[0611] 'HNMR (500MHz, DMSO-d6) 5 12.95 (br s, 1H), 10.69 - 10.42 (m, 1H), 8.60 - 8.47 (m, 1H), 8.36 (br dd, J= 5.8, 3.6 Hz, 1H), 8.04 - 7.93 (m, 3H), 7.64 (br d, J= 6.9 Hz, 1H), 7.57 - 7.54 (m, 2H), 7.31 (d, J= 13.6 Hz, 1H), 4.50 - 3.98 (m, 3H), 3.39 - 3.31 (m, 1H), 3.20 - 3.11 (m, 1H), 3.10 - 2.97 (m, 5H), 2.46 - 2.41 (m, 3H), 2.37 - 2.33 (m, 3H), 1.86 - 1.73 (m, 4H). MS (ESI) calculated for C30H31FN4O4: 530.23; found: m / z 531.5 [M+H]+.

[0612] Example 23. 4-((5)-3-(2-(l-Naphthamido)-A-methylacetamido)piperidin-l-yl)-5-fluoro- / ' / -((3 / ,4 / )-4-hydroxytetrahydro-27 / -pyran-3-yl)-2,3-dimethyl-17 / -indole-7-carboxamide

[0613]

[0614] To a solution of 23D (15 mg, 0.026 mmol) and (3A,47?)-3-aminotetrahydro-2 / 7-pyran-4-ol (3.4 mg, 0.029 mmol) in DMF (0.27 mL) was added TCFH (11 mg, 0.040 mmol) and NMI (13 pL, 0.16 mmol). After stirring at room temperature for 1 h, the reaction mixture was purified by preparative HPLC (Column: XBridge C18, 19 mm x 200 mm, 5 pm particles; Flow Rate: 20 mL / min; Column Temperature: 25 °C; Mobile Phase A: ACN / H2O (5:95:10 mM NH4OAC), Mobile Phase B: ACN / H2O (95:5: 10 mM NH4OAc); Gradient: 20 minutes with a 4 minute hold of 100% Mobile Phase B) to yield Example 23 (12 mg, 73%).1HNMR(500MHz, DMSO-d6, WS) 8 10.72 - 10.49 (m, 1H), 8.59 - 8.45 (m, 1H), 8.40 - 8.30 (m, 1H), 8.15 - 8.07 (m, 1H), 8.02 - 7.94 (m, 2H), 7.67 - 7.58 (m, 1H), 7.58 - 7.42 (m, 4H), 4.73 - 4.57 (m, 1H), 4.39 - 4.29 (m, 1H), 4.25 - 4.09 (m, 2H), 4.06 - 3.95 (m, 1H), 3.83 (br dd, J= 6.4, 3.9 Hz, 2H), 3.79 - 3.65 (m, 2H), 3.35 - 3.24 (m, 1H), 3.19 - 3.10 (m, 1H), 3.05 (br t, J= 10.1 Hz, 3H), 3.00 - 2.94 (m, 3H), 2.46 - 2.38 (m, 3H), 2.35 - 2.28 (m, 3H), 1.98 - 1.87 (m, 2H), 1.84 - 1.73 (m,3H), 1.56 - 1.43 (m, 1H). MS (ESI) calculated for C35H40FN5O5: 629.30; found: m / z 630.3 [M+H]+. Analytical HPLC Retention times: 1.91 min (Method A), 1.90 min (Method B).The Examples in the following Table (Table 4) were prepared in a similar manner as the preparation of Example 23.

[0615]

[0616] NMR was measured at 500 MHz, DMSO-tfe, WS unless otherwise indicated.

[0617] Table 4

[0618]

[0619]

[0620]

[0621]

[0622] Example 28

[0623] 7V-(2-(((S)-l-(5-Fluoro-7-(((37?,4^)-4-hydroxytetrahydro-2 / -pyran-3-yl)carbamoyl)-l,2,3- trimethyl- l / 7-indol-4-yl)piperidin-3-yl)(methyl)amino)-2-oxoethyl)quinoline-5-carboxamide

[0624]

[0625] 28A. Ethyl (A')-5-fluoro-2, 3 -di ethyl -4-(3-(methylami no)piperi di n-l-yl)-l / / -indole-7-carboxylate

[0626]

[0627] To a solution of Intermediate 1 (2.00 g, 6.28 mmol) in EtOH (31.4 mL) was carefully added concentrated H2SO4 (9.37 mL, 176 mmol). After stirring at reflux overnight, the reaction mixture was cooled to 0 °C and 1 M aqueous NaOH (176 mL, 176 mmol) was added carefully and then the pH was adjusted to ~6 with IM aqueous NaOH. The reaction mixture was extracted with CHCh / iPrOH (3:1) (3x), and the combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to yield 28A (1.97 g, 90 %) as a light tan solid, which was used in the next step without further purification.1H NMR (500 MHz, DMSO-d6) 8 10.71 (s, 1H), 8.23 - 7.88 (m, 1H), 7.41 - 7.27 (m, 1H), 4.38 (q, J= 7.1 Hz, 2H), 3.42 (br d, J= 9.0 Hz, 1H), 3.19 (br s, 1H), 3.10 - 2.90 (m, 3H), 2.58 (s, 3H), 2.35 (s, 6H), 2.24 - 2.12 (m, 1H), 1.80 (br s, 2H), 1.35 (t, J= 7.1 Hz, 4H). MS (ESI) calculated for C19H26FN3O2: 347.2; found: m / z 348.3 [M+H]+.

[0628] 28B. Ethyl (5)-4-(3-((tert-butoxycarbonyl)(methyl)amino)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lZf-indole-7-carboxylate

[0629]

[0630] To a solution of 28A (1.50 g, 4.32 mmol) and NEts (2.41 mL, 17.3 mmol) in DCM (28.8 mL) was added (Boc)2O (1.10 mL, 4.75 mmol). After stirring at room temperature for 1 h, the reaction mixture was diluted with DCM, washed with sat. aq. NH4CI, water, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 0-25% EtOAc:hexanes) to yield 28B (1.34 g, 71%) as a pale yellow solid. 'HNMR (500 MHz, DMSO-d6) 8 10.64 (s, 1H), 7.34 (d, J= 13.6 Hz, 1H), 4.38 (q, J= 7.1 Hz, 2H), 3.31 (br s, 2H), 3.10 (br d, J= 9.3 Hz, 1H), 3.01 (br s, 2H), 2.96 (br d, J = 6.9 Hz, 1H), 2.73 (s, 3H), 2.39 (s, 3H), 2.34 (s, 3H), 1.77 (br s, 3H), 1.38 (s, 9H), 1.35 (t, J = 7.1 Hz, 3H). MS (ESI) calculated for C24H34FN3O4: 447.3; found: m / z 448.2 [M+H]+.28C. Ethyl (S)-4-(3-(( / erLbutoxycarbonyl)(methyl)amino)piperidin-l-yl)-5-fluoro-l,2,3-trimethyl-l / / -indole-7-carboxylate

[0631]

[0632] To a room temperature solution of 28B (1.37 g, 3.06 mmol) in DMF (12.2 mL) was added 60% NaH in mineral oil (0.184 g, 4.59 mmol). After stirring at room temperature for 15 minutes, iodomethane (0.25 mL, 4.0 mmol) was added to the reaction mixture and stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with EtOAc (x3). The combined organic phases were washed with 10% aqueous LiCl, water, sat. brine solution, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield 28C as a brown oil (1.30 g, 92%), which was used in the next step without further purification. 'H NMR(500MHz, DMSO-d6) δ 7.14 (d, J= 13.3 Hz, 1H), 4.34 (q, J= 7.2 Hz, 2H), 3.53 (s, 3H), 3.14 - 2.89 (m, 5H), 2.73 (s, 3H), 2.44 (s, 3H), 2.30 (s, 3H), 1.76 (br s, 3H), 1.64 (br d, J= 11.4 Hz, 1H), 1.37 (s, 9H), 1.33 (t, J= 7.1 Hz, 3H). MS (ESI) calculated for C25H36FN3O4: 461.27; found: m / z 462.3 [M+H]+.

[0633] 28D. Ethyl (5)-5-fluoro-l,2,3-trimethyl-4-(3-(methylamino)piperidin-l-yl)-lZ / -indole-7-carboxylate, 2 TFA

[0634]

[0635] To a solution of 28C (1.40 g, 3.03 mmol) in DCM (30.3 mL) was added TFA (4.67 mL, 60.7 mmol). After stirring at room temperature for 5 h, the solvent was concentrated in vacuo, the residue was dissolved in DCM and reconcentrated in vacuo (process repeated x2) and triturated with diethyl ether to yield 28D (1.52 g, 85 % yield) as a dark brown oil, as the bis-TFA salt, which was used in the next step without further purification. 1H NMR (500 MHz, DMSO-d6) δ 8.72 - 8.57 (m, 1H), 7.17 (d, J= 13.2 Hz, 1H), 4.35 (q, J= 7.2 Hz, 2H), 3.54 (s,3H), 3.42 - 3.37 (m, 2H), 3.25 (br d, J= 5.1 Hz, 1H), 3.13 - 2.91 (m, 3H), 2.65 - 2.59 (m, 3H), 2.40 (s, 3H), 2.31 (s, 3H), 2.21 (brd, J = 11.2 Hz, 1H), 1.86 - 1.70 (m, 2H), 1.33 (t, = 7.1 Hz, 3H). MS (ESI) calculated for C20H28FN3O2: 361.22; found: m / z 362.1 [M+H]+.

[0636] 28E. Ethyl (5)-5-fluoro-l,2,3-trimethyl-4-(3-(A-methyl-2-(quinoline-5-carboxamido)acetami do) piperidin-1-yl)-1H-indole-7-carboxylate

[0637]

[0638] To a solution of 28D (0.500 g, 0.848 mmol), Intermediate 5 (0.215 g, 0.933 mmol), and HATU (0.484 g, 1.27 mmol) in DMF (8.48 mL) was added DIPEA (0.739 mL, 4.24 mmol). After stirring at room temperature for 2 h, the reaction mixture was diluted with water. The precipitate was filtered, washed well with water, and dried under vacuum to provide 28E (0.419 g, 86 %) as a brown solid, which was used in the next step without further purification. 'H NMR (500 MHz, DMSO-d6) δ 8.94 (br d, J= 4.0 Hz, 1H), 8.85 - 8.78 (m, 1H), 8.74 - 8.61 (m, 1H), 8.17 - 8.07 (m, 1H), 7.83 - 7.70 (m, 2H), 7.58 (dd, J = 8.5, 4.2 Hz, 1H), 7.15 (br d, J = 13.3 Hz, 1H), 4.37 - 4.31 (m, 2H), 4.26 - 4.08 (m, 2H), 4.05 - 3.93 (m, 1H), 3.55 - 3.50 (m, 3H), 3.18 - 2.98 (m, 4H), 2.91 - 2.83 (m, 3H), 2.49 - 2.48 (m, 2H), 2.49 - 2.47 (m, 1H), 2.30 (s, 3H), 1.85 - 1.74 (m, 3H), 1.40 - 1.29 (m, 4H). MS (ESI) calculated for C32H36FN5O4: 573.28; found: m / z 574.3 [M+H]+.

[0639] 28F. (S)-5-Fluoro-l,2,3-trimethyl-4-(3-(A-methyl-2-(quinoline-5-carboxamido)acetamido)piperidin-l-yl)-17 / -indole-7-carboxylic acid, 2 HCI

[0640]

[0641] To a solution of 28E (0.415 g, 0.723 mmol) in EtOH (0.904 mL), THF (2.23 mL) and H2O (1.11 mL) was added 1 M aq. NaOH (1.67 mL, 1.67 mmol). After stirring at 50 °C overnight, the solvent was removed in vacuo and the residue was diluted with water. Thereaction mixture was acidified to pH ~2 with IM aq. HC1 and the precipitate was filtered, washed well with water, and dried under vacuum to afford 28F (0.339 g, 75 %) as a tan solid as the bis-HCl salt, which was used in the next step without further purification.1H NMR (500 MHz, DMSO-d6) 58.93 (br d, J= 2.5 Hz, 1H), 8.82 (br s, 1H), 8.72 - 8.60 (m, 1H), 8.11 (br d, J= 8.2 Hz, 1H), 7.84 - 7.70 (m, 2H), 7.58 (br dd, J= 8.5, 3.8 Hz, 1H), 7.04 - 6.93 (m, 1H), 4.75 - 4.31 (m, 1H), 4.26 - 3.94 (m, 2H), 3.57 (br s, 3H), 3.45 - 3.30 (m, 1H), 3.19 - 2.82 (m, 6H), 2.47 (br s, 3H), 2.26 (br s, 3H), 1.91 - 1.90 (m, 1H), 1.84 - 1.69 (m, 3H). MS (ESI) calculated for C30H32FN5O4545.24; found: m / z 546.2 [M+H]+.

[0642] Example 28. A-(2-(((5)-l-(5-Fluoro-7-(((3A,47?)-4-hydroxytetrahydro-2 / / -pyran-3-yl)carbamoyl)-l,2,3-trimethyl-l / / -indol-4-yl)piperidin-3-yl)(methyl)amino)-2-oxoethyl)quinoline-5-carboxamide

[0643]

[0644] To a solution of 28F (15 mg, 0.024 mmol) and (3A,47?)-3-aminotetrahydro-2H-pyran-4-ol (4.10 mg, 0.027 mmol) in DMF (0.172 mL) was added TCFH (10.2 mg, 0.036 mmol) and NMI (9.7 pL, 0.121 mmol). After stirring at room temperature overnight, the reaction mixture was purified by preparative HPLC (Column: XBridge Cl 8, 19 mm x 200 mm, 5 pm particles; Flow Rate: 20 mL / min; Column Temperature: 25 °C; Mobile Phase A: ACN / H2O (5:95:10 mM NH4OAC), Mobile Phase B: ACN / H2O (95:5:10 mM NH4OAC); Gradient: 20 minutes with a 4 minute hold of 100% Mobile Phase B) to yield Example 28 (6.6 mg, 42%).1H NMR (500 MHz, DMSO-d6, WS) 58.96 - 8.84 (m, 1H), 8.77 (br d, J= 8.2 Hz, 1H), 8.70 - 8.57 (m, 1H), 8.37 - 8.24 (m, 1H), 8.11 - 8.02 (m, 1H), 7.80 - 7.66 (m, 2H), 7.54 (br dd, J= 8.1, 4.3 Hz, 1H), 6.88 - 6.75 (m, 1H), 5.03 - 4.87 (m, 1H), 4.74 - 4.52 (m, 1H), 4.40 - 4.25 (m, 1H), 4.24 - 4.06 (m, 2H), 4.02 - 3.86 (m, 1H), 3.86 - 3.75 (m, 1H), 3.74 - 3.63 (m, 1H), 3.55 - 3.44 (m, 2H), 3.41 - 3.17 (m, 1H), 3.14 - 2.79 (m, 7H), 2.45 - 2.42 (m, 3H), 2.23 (s, 3H), 1.93 - 1.63 (m, 5H), 1.51 - 1.38 (m, 1H). MS (ESI) calculated for C35H41FN6O5: 644.31; found: m / z 645.4 [M+H]+. Analytical HPLC Retention times: 1.33 min (Method A), 1.54 min (Method B).The Examples in the following Table (Table 5) were prepared in a similar manner as the preparation of Example 28 using either Intermediate 4 or Intermediate 5. ' H NMR was measured at 500 MHz, DMSO-d6, WS unless otherwise indicated.

[0645] Table 5

[0646]

[0647]

[0648]

[0649] Example 32

[0650] (S)-4-(3-(2-(l-naphthamido)-7V-ethylacetamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-l / 7-indole-7-carboxamide

[0651]

[0652] 32A. (S)-4-(3-(ethylamino)piperidin-l-yl)-5-fluoro-2,3-dimethyl-l / 7-indole-7-carb oxami de, 2 TFA

[0653]

[0654] To a solution of (5)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-17 / -indole-7-carboxamide (100 mg, 0.329 mmol) (see US2016 / 115126 for preparation) in MeOH (3.29 mL) was added acetaldehyde (0.037 mL, 0.329 mmol) and 3A molecular sieves (350 mg). After stirring at room temperature overnight, NaBH4 (20 mg, 0.53 mmol) was added. After stirring at room temperature for 20 minutes, the reaction mixture was filtered. The filtrate was concentrated in vacuo, the residue was diluted with DCM and washed with 1 M aq. NaOH. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Thecrude material was purified using the Aquity preparative ISCO (ACCQ HP 150 prep (PHC18 AXIS, 30 x 100 mm, 13 min gradient, 20 min run, 10% to 100% Solvent B = 90% ACN / 10%Water / 0.1%TFA, Solvent A = 10%ACN / 90%Water / 0.1% TFA) to 32A (28 mg, 15%) as a yellow gummy solid as the bis-TFA salt. 'H NMR (500 MHz, DMSO-d6) 5 10.68 (s, 1H), 8.52 - 8.27 (m, 2H), 7.93 (br s, 1H), 7.37 (br s, 1H), 3.42 (br d, J= 9.4 Hz, 1H), 3.30 (br d, J= 3.5 Hz, 1H), 3.13 - 2.92 (m, 5H), 2.34 (s, 3H), 2.32 (s, 3H), 2.24 - 2.14 (m, 1H), 1.84 - 1.71 (m, 2H), 1.44 - 1.32 (m, 1H), 1.18 (t, J = 7.2 Hz, 3H). MS (ESI) calculated for C18H25FN4O: 332.20; found: m / z 333.1 [M+H]+.

[0655] Example 32. (5)-4-(3-(2-(l-naphthamido)-A-ethylacetamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-l / / -indole-7-carboxamide

[0656]

[0657] To a solution of 32A (9.0 mg, 0.016 mmol) and Intermediate 4 (4.1 mg, 0.018 mmol) in DMF (0.16 mL) was added HATU (9.2 mg, 0.024 mmol) and DIPEA (14 µL, 0.080 mmol). After stirring at room temperature overnight, the reaction mixture was purified by preparative HPLC (Column: XBridge C18, 19 mm x 200 mm, 5 pm particles; Flow Rate: 20 mL / min; Column Temperature: 25 °C; Mobile Phase A: ACN / H2O (5:95:10 mM NH4OAC), Mobile Phase B: ACN / H2O (95:5:10 mM NH4OAC); Gradient: 20 minutes with a 4 minute hold of 100% Mobile Phase B) to yield Example 32 (13 mg, 75%). 1H NMR (500 MHz, DMSO-d6, WS) 8 10.66 - 10.53 (m, 1H), 8.60 - 8.44 (m, 1H), 8.35 (br d, J= 7.2 Hz, 1H), 8.08 - 7.86 (m, 3H), 7.63 (br t, J= 6.1 Hz, 1H), 7.54 (br dd, J= 6.7, 2.7 Hz, 3H), 7.46 - 7.38 (m, 1H), 7.35 -7.27 (m, 1H), 4.67 - 4.44 (m, 1H), 4.41 - 4.11 (m, 2H), 4.06 - 3.87 (m, 1H), 3.52 - 3.29 (m, 1H), 3.25 - 3.13 (m, 2H), 3.10 - 2.97 (m, 2H), 2.47 - 2.39 (m, 3H), 2.35 - 2.27 (m, 3H), 1.86 -1.70 (m, 3H), 1.22 (br t, J = 7.0 Hz, 2H), 1.14 - 0.98 (m, 2H). MS (ESI) calculated for C31H34FN5O3: 543.26; found: m / z 544.3 [M+H]+. Analytical HPLC Retention times: 2.05 min (Method A), 2.06 min (Method B).

[0658] Example 335-Fluoro- 1,2,3-trimethyl-4-(3-(A-methylbut-2-ynamido)phenyl)- l / 7-indole-7-carboxamide

[0659]

[0660] 33A. tert-Butyl (3-(7-cyano-5-fluoro-l,2,3-trimethyl-177-indol-4-yl)phenyl)(methyl)carbamate

[0661]

[0662] A mixture of 14A (50 mg, 0.18 mmol), (3-((terZ butoxycarbonyl)(methyl)amino)phenyl)boronic acid (53.6 mg, 0.213 mmol), 2 M aq. K3PO4(0.267 mL, 0.534 mmol), and THF (1.02 mL) was degassed with vacuum and purged with nitrogen (3x). l,l'-Bis(di-fer / -butylphosphino)ferrocene palladium dichloride (5.8 mg, 8.9 pmol) was added, and the reaction mixture was degassed (3x). After stirring at room temperature for 1 h, the reaction mixture was diluted with EtOAc and washed with water, sat. aq. brine solution, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc / hexanes) to afford 33A (55 mg, 76 %) as a white solid. 'H NMR (500 MHz, CDCh) 87.46 - 7.37 (m, 2H), 7.33 - 7.29 (m, 1H), 7.21 (d, J= 1.7 Hz, 1H), 7.17 - 7.13 (m, 1H), 4.04 (s, 3H), 3.29 (s, 3H), 2.32 (s, 3H), 1.64 (s, 3H), 1.43 (s, 9H). MS (ESI) calculated for C23H26FN3O2: 407.20; found: m / z 352.3 [M-56+H]+.

[0663] 33B. 5-Fluoro-l,2,3-trimethyl-4-(3-(methylamino)phenyl)-17 / -indole-7-carboxamide

[0664]

[0665] 33B was prepared following the procedure used to prepare Intermediate 1. (34 mg, 79%). ‘HNMR (400 MHz, CDCh) 87.26 - 7.21 (m, 1H), 7.07 (d, J= 9.5 Hz, 1H), 6.78 - 6.70 (m, 2H), 6.64 (d, J = 1.7 Hz, 1H), 6.00 (br s, 1H), 5.83 (br s, 1H), 3.73 (s, 3H), 2.87 (s, 3H), 2.30 (s, 3H), 1.70 (s, 3H). MS (ESI) calculated for C19H20FN3O: 325.15; found: m / z 326.0 [M+H]+.

[0666] Example 33. 5-Fluoro- 1,2,3 -trimethyl-4-(3-(A-methylbut-2-ynamido)phenyl)- 177-indole-7-carboxamide

[0667]

[0668] Example 33 was prepared following the procedure described for Example 1. (4.6 mg, 12%). 1H NMR (500 MHz, DMSO-d6, WS) 88.15 - 8.04 (m, 1H), 7.66 (br s, 1H), 7.58 - 7.49 (m, 1H), 7.42 (br d, J= 7.6 Hz, 1H), 7.34 - 7.25 (m, 2H), 6.95 (d, J= 9.9 Hz, 1H), 3.89 (s, 3H), 3.65 (s, 3H), 2.26 (s, 3H), 1.72 (s, 3H), 1.58 (s, 3H). MS (ESI) calculated for C23H22FN3O2: 391.17; found: m / z 392.4 [M+H]+. Analytical HPLC Retention times: 1.60 min (Method A), 1.88 min (Method B).

[0669] BIOLOGICAL EVALUATION UBA5 biochemical potencies

[0670]

[0671]

[0672] UBA5 biochemical assay protocol details

[0673] For the UBA5 charging HTRF assay, 120 nL of 100X compounds serially diluted in DMSO were added to a 384 well-plate (Coming 3821) using a Beckman Echo 650. The top compound concentration was either 10 pM or 100 pM. Assay buffer was prepared as following: 50 mMHepes pH 7.4 containing 50 mMNaCl, 10 mM MgCl2, 0.1% BSA, 0.01% Brij-35, 0.5 mM TCEP. 2 pL of 6X His-UBA5 prepared in the assay buffer was added to the compound plate to a final concentration of 0.0375 pM. The mixture was then incubated with His-UBA5 at room temperature for 2 hours. After the incubation, 2 pL of 6X TMR labeled UFM1 for a final assay concentration of 0.06 pM and 4 pL of a 3X concentration of Invitrogen’s LanthaScreen™ Elite Tb-anti-HIS Antibody for a final assay concentration of 0.002 pM were added to the plate. 4 pL of assay buffer was then added to column 1 of the assay plate. Columns 2-24 received 4 pL of 3X ATP for a final assay concentration of 0.00625 mM. The reaction was then incubated at room temperature for 10 minutes. After incubation, 2 pL of 140 mM EDTA was added to the entire plate. The reaction was then incubated again at room temperature for 15 minutes. Assay plates were centrifuged at 1000 rpm for 1 minute. HTRF signal of the interaction (Ax 320, Am 595, Am 545) was then read at room temperature using PerkinElmer’sEnvision plate reader. The signal ratio λem595 / λem545 was then calculated and used to determine IC50values.

[0674] The embodiments described above are intended to be merely exemplary, and those skilled in the art will recognize, or will be able to ascertain using no more than routine experimentation, numerous equivalents of specific compounds, materials, and procedures. All such equivalents are considered to be within the scope of the invention and are encompassed by the appended claims.

Claims

CLAIMSWhat is claimed is:

1. A compound having a Formula (I),wherein:A is aryl or heterocyclyl, with the proviso that if A is aryl, then R2 must be alkyl; Ri is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl;R2 is H or alkyl;R3 is alkyl;R4 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted -alkyl-NHC(O)-aryl, substituted or unsubstituted -alkyl-NHC(O)- heteroaryl, or substituted or unsubstituted -alkyl-NHSO2-aryl, with the proviso that if R4 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, then R2 must be alkyl,or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein the compound is of Formula (II),whereinn is 1 or 2,or a pharmaceutically acceptable salt thereof.

3. The compound according to claims 1 or 2, wherein the compound is of Formulaor a pharmaceutically acceptable salt thereof.

4. The compound according to claims 1 or 2, wherein the compound is of Formulaor a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, wherein the compound is of Formula (III),or a pharmaceutically acceptable salt thereof.

6. The compound according to any one of the preceding claims wherein Ri is selectedor a pharmaceutically acceptable salt thereof.

7. The compound according to any one of the preceding claims wherein Ri isor a pharmaceutically acceptable salt thereof.

8. The compound according to any one of claims 1-6 wherein Ri isor a pharmaceutically acceptable salt thereof.

9. The compound according to any one of the preceding claims wherein R2 is Me, or a pharmaceutically acceptable salt thereof.

10. The compound according to any one of the preceding claims wherein R3 is methyl, or a pharmaceutically acceptable salt thereof.

11. The compound according to any one of the preceding claims wherein R4 is selected from:or a pharmaceutically acceptable salt thereof.

12. The compound according to any one of the preceding claims wherein R.4 isor a pharmaceutically acceptable salt thereof.

13. The compound of claim 1, wherein the compound is selected from:(5)-4-(3-(2-(2,4-Dichlorobenzamido)-7V-methylacetamido)piperidin-l-yl)-5-fluoro-2,3- dimethyl- 17 / -indole-7-carboxami de;( )-4-(3-(2-Benzamido-JV-methylacetamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-l / 7- indole-7-carboxamide;CS')-4-(3-(3-( / c77-Butyl)-, V-methyl-l / / -pyrazole-5-carboxarnido)piperidin-l-yl)-5-fluoro- 2,3-dimethyl-l / / -indole-7-carboxamide;(5)-5-Fluoro-4-(3-(2-((3-fluorophenyl)sulfonamido)-JV-methylacetamido)piperidin-l- yl)-2,3-dimethyl-12 / -indole-7-carboxamide;(5)-4-(3-(2-(2,3-Dimethylbenzamido)-jV-methylacetamido)piperidin-l-yl)-5-fluoro-2,3- dimethyl- 17 / -indole-7-carboxami de;(5)-JV-(2-((l-(7-Carbamoyl-5-fluoro-2,3-dimethyl-l / / -indol-4-yl)piperidin-3- yl)(methyl)amino)-2-oxoethyl)quinoline-8-carboxamide;(S)-iV-(2-((l-(7-Carbamoyl-5-fluoro-2,3-dimethyl-l / / -indol-4-yl)piperidin-3- yl)(methyl)amino)-2-oxoethyl)quinoline-4-carboxamide;(5)-JV-(2-((l-(7-Carbamoyl-5-fluoro-2,3-dimethyl-l / / -indol-4-yl)piperidin-3- yl)(methyl)amino)-2-oxoethyl)quinoline-5-carboxamide;(5)-JV-(2-((l-(7-Carbamoyl-5-fluoro-2,3-dimethyl-17 -indol-4-yl)piperidin-3- yl)(methyl)amino)-2-oxoethyl)isoquinoline-8-carboxamide;( )-TV-(2-((l-(7-Carbamoyl-5-fluoro-2,3-dimethyl-l / / -indol-4-yl)piperidin-3- yl)(methyl)amino)-2-oxoethyl)isoquinoline-4-carboxamide;(5)-V-(2-((l-(7-Carbamoyl-5-fluoro-2,3-dimethyl-177-indol-4-yl)piperidin-3- yl)(methyl)amino)-2-oxoethyl)isoquinoline- 1 -carboxamide;(5)-5-Fluoro-V,2,3-trimethyl-4-(3-(jV-methylbut-2-ynamido)piperidin-l-yl)-17 / -indole- 7-carboxamide;(5)-5-Fluoro-l,2,3-trimethyl-4-(3-(jV-methylbut-2-ynamido)piperidin-l-yl)-177-indole- 7-carboxamide;(5)-l-Ethyl-5-fluoro-2,3-dimethyl-4-(3-(7 / -methylbut-2-ynamido)piperidin-l-yl)-l / 7- indole-7-carboxamide;(5)-4-(3-(3-Cyclopropyl-7V-methylpropiolamido)piperidin-l-yl)-5-fluoro-l,2,3- trimethyl-177-indole-7-carboxamide;(5)-5-Fluoro-l,2,3-trimethyl-4-(3-(jV-methylbut-2-ynamido)azepan-l-yl)-l / / -indole-7- carboxamide;5-Fluoro-l,2,3-trimethyl-4-(3-(A-methylbut-2-ynamido)phenyl)-l / 7-indole-7- carboxamide;(5)-4-(3-(5-( / er / -butyl)-jV-methyl-177-pyrazole-3-carboxamido)piperidin-l-yl)-jV- (cyanomethyl)-5-fluoro-2,3-dimethyl-l / 7-indole-7-carboxamide;4-((S)-3-(5-(fert-Butyl)-A methyl-l / / -pyrazole-3-carboxamido)piperidin-l-yl)-5-fluoro- jV-((lS,27?)-2-hydroxycyclohexyl)-2,3-dimethyl-l / / -indole-7-carboxamide;(5)-4-(3-(5-(fert-Butyl)-A methyl-l / / -pyrazole-3-carboxamido)piperidin-l-yl)-7V-(3,3- difluoro-l-(hydroxymethyl)cyclobutyl)-5-fluoro-2,3-dimethyl-17 / -indole-7- carboxamide;(5)-4-(3-(5-(ter?-Butyl)-jV-methyl-l / / -pyrazole-3-carboxamido)piperidin-l-yl)-5-fluoro- JV-((1 -hydroxy cyclobutyl)methyl)-2,3-dimethyl-177-indole-7-carboxamide;(1S')-4-(3-(5-( / c 7-Butyl)-, V-methyl-l / / -pyrazole-3-carboxamido)piperidin-l-yl)-.¥-(l- cyclopropylpiperidin-4-yl)-5-fluoro-2,3-dimethyl-l / 7-indole-7-carboxamide;4-((5)-3-(2-(l-Naphthamido)-JV-methylacetamido)piperidin-l-yl)-5-fluoro-V-((37?,47?)- 4-hydroxytetrahydro-2 / / -pyran-3-yl)-2,3-dimethyl-l / / -indole-7-carboxamide; 4-((S)-3-(2-(l-Naphthamido)-JV-methylacetamido)piperidin-l-yl)-5-fluoro-7V-((35,47?)- 3-hydroxytctrahydro-27 / -pyran-4-yl)-2,3-dimcthyl-17 / -indolc-7-carboxamidc, V-(2-(((1S)-l-(5-Fluoro-7-(((37?,47?)-4-hydroxytetrahydro-2 / / -pyran-3-yl)carbamoyl)- 2.3-dimethyl-l / / -indol-4-yl)piperidin-3-yl)(methyl)amino)-2-oxoethyl)quinoline-5- carboxamide;V-(2-(((1S)-l-(5-Fluoro-7-(((37?,47?)-4-hydroxytetrahydro-2 / / -pyran-3-yl)carbamoyl)- 2.3-dimethyl-l / / -indol-4-yl)piperidin-3-yl)(methyl)amino)-2-oxoethyl)quinoline-4- carboxamide;V-(2-(((5)- 1 -(5 -Fluoro-7-(((3S,47?)-3 -hydroxytetrahydro-2 / / -pyran-4-yl)carbamoyl)- 2.3-dimethyl-l / / -indol-4-yl)piperidin-3-yl)(methyl)amino)-2-oxoethyl)quinoline-4- carboxamide;V-(2-(((5)- 1 -(5 -Fl uoro-7-(((3 / <47?)-4-hydroxytetrahydro-27 / -pyran-3 -yl)carbamoyl)- 1.2.3-trimethyl-l / / -indol-4-yl)piperidin-3-yl)(methyl)amino)-2-oxoethyl)quinoline- 5-carboxamide;7V-(2-(((S)-l-(5-Fluoro-7-(((37?,47?)-4-hydroxytetrahydro-277-pyran-3-yl)carbamoyl)- l,2,3-trimethyl-l / / -indol-4-yl)piperidin-3-yl)(methyl)amino)-2-oxoethyl)quinoline- 4-carboxamide;4-((S)-3-(2-(l-Naphthamido)-V-methylacetamido)piperidin-l-yl)-5-fluoro-7V-((37?,47?)- 4-hydroxytetrahydro-27 / -pyran-3 -yl)- 1,2,3-trimethyl- l / / -indole-7-carboxamide; 4-((5)-3-(2-(l-Naphthamido)-JV-methylacetamido)piperidin-l-yl)-5-fluoro-V-((35,4?)- 3 -hydroxytetrahydro-2 / / -pyran-4-yl)- 1,2,3-trimethyl- l / / -indole-7-carboxamide; (5)-4-(3-(2-(l-Naphthamido)-JV-ethylacetamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl- 17 / -indole-7-carboxamide; and(5)-4-(3-(2-(l-Naphthamido)-jV-methylacetamido)piperidin-l-yl)-5-fluoro-2,3- dimethyl-17 - indole-7-carboxamide,or a pharmaceutically acceptable salt thereof.

14. A compound according to any one of the preceding claims for use as a medicament.

15. A compound according to claims 1-13, for use in a method of treating cancer, comprising administering to a mammal having cancer a therapeutically effective amount of the compound.

16. The compound for use according to claim 15, additionally comprising determining the cancer responds to UBA5 inhibition.

17. The compound for use according to claim 16, wherein the cancer is pancreatic cancer, breast cancer, leukemia, lung cancer or melanoma.

18. The compound for use according to claim 17, wherein the leukemia is acute leukemia, chronic leukemia, lymphocytic leukemia or myelogenous leukemia.

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