WO2013127268A1 - Amido-benzyl sulfone and sulfonamide derivatives - Google Patents

Abstract

Disclosed are certain amido-benzyl sulfone and sulfonamide compounds, pharmaceutical compositions comprising such compounds, land methods of treatment using such compounds.

Description

AMIDO-BENZYL SULFONE AND SULFONAMIDE DERIVATIVES

Field of the Invention

The present invention relates to certain amido-benzyl sulfone and sulfonamide compounds, pharmaceutical compositions comprising such compounds, and methods of treating cancer, including leukemias and solid tumors, inflammatory diseases, osteoporosis, atherosclerosis, irritable bowel syndrome, and other diseases and medical conditions, with such compounds and pharmaceutical compositions. The present invention also relates to certain amido-benzyl sulfone and sulfonamide compounds for use in inhibiting nicotinamide phosphoribosyltransferase ("NAMPT").

Background of the Invention

Nicotinamide adenine dinucleotide (NAD) plays a fundamental role in both cellular energy metabolism and cellular signaling. NAD plays an important role in energy metabolism, as the pyridine ring in the NAD molecule readily accepts and donates electrons in hydride transfer reactions catalyzed by numerous

dehydrogenases. The enzyme nicotinamide phosphoribosyltransferase (NAMPT, NMPRT, NMPRTase, or NAmPRTase, International nomenclature: E.C. 2.4.2.12), promotes the condensation of nicotinamide with 5-phosphoribosyl-l -pyrophosphate to generate nicotinamide mononucleotide, which is a precursor in the biosynthesis of NAD.

NAMPT is implicated in a variety of functions, including the promotion of vascular smooth muscle cell maturation, inhibition of neutrophil apoptosis, activation of insulin receptors, development of T and B lymphocytes, and reduction of blood glucose. Thus, small molecule NAMPT inhibitors have potential uses as therapies in a variety of diseases or conditions, including cancers involving solid and liquid tumors, non-small cell lung cancer, leukemia, lymphoma, ovarian cancer, glioma, breast cancer, uterine cancer, colon cancer, cervical cancer, lung cancer, prostate cancer, skin cancer, rhino-gastric tumors, colorectal cancer, central nervous system (CNS) cancer, bladder cancer, pancreatic cancer and Hodgkin's disease. NAMPT inhibitors also have potential uses as therapies for diseases or conditions such as cancer, rheumatoid arthritis, diabetes, atherosclerosis, sepsis, or aging.

Rongvaux et al. have demonstrated that NAMPT is implicated in the regulation of cell viability during genotoxic or oxidative stress, and NAMPT inhibitors may therefore be useful as treatments for inflammation. Rongvaux, A., et al. J. Immunol. 2008, 1 81 , 4685-4695. NAMPT may also have effects on the reaction of endothelial cells to high glucose levels, oxidative stress, and aging. Thus, NAMPT inbhitors may enable proliferating endothelial cells to resist the oxidative stress of aging and of high glucose, and to productively use excess glucose to support replicative longevity and angiogenic activity.

In particular, NAMPT inhibitors have been shown to interfere with NAD biosynthesis and to induce apoptotic cell death without any DNA damaging effects or primary effects on cellular energy metabolism, and thus have important anti-tumor effects. For example, the NAMPT inhibitor FK866 has these biochemical effects, and has also been shown to reduce NAD levels, induce a delay in tumor growth and enhance tumor radiosensitivity in a mouse mammary carcinoma model. See, e.g., Hasmann M. and I. Schemainda, "FK866, a Highly Specific Noncompetitive Inhibitor of Nicotinamide Phosphoribosyltransferase, Represents a Novel Mechanism for Induction of Tumor Cell Apoptosis," Cancer Res. 2003, 63, 7436-7442; Drevs, J. et al., "Antiangiogenic potency of FK866 K22.1 75, a new inhibitor of intracellular NAD biosynthesis, in murine renal cell carcinoma," Anticancer Res. 2003, 23, 4853-4858.

More recently, another NAMPT inhibitor, CHS-828, has been shown to potently inhibit cell growth in a broad range of tumor cell lines. See Olesen, U.H. et al., "Anticancer agent CHS-828 inhibits cellular synthesis of NAD," Biochem.

Biophys. Res. Common. 2008, 367, 799-804; Ravaud, A. et al., "Phase I study and guanidine kinetics of CHS-828, a guanidine-containing compound, administered orally as a single dose every 3 weeks in solid tumors: an ECSG EORTC study," Eur. J. Cancer 2005, 41 , 702-707. Both FK866 and CHS-828 are currently in clinical trials as cancer treatments.

There remains a need for potent NAMPT inhibitors with desirable

pharmaceutical properties. Certain amido-benzyl sulfone and sulfonamide derivatives have been found in the context of this invention to have NAMPT- modulating activity.

Summary of the Invention

In one aspect, the invention is directed to compounds selected from the group consisting of:

and stereoisomers thereof, and pharmaceutically acceptable salts of said compounds and stereoisomers.

In another aspect, the invention is directed to compounds selected from the group consisting of:

N-[[4-(8- azabi cy clo [3.2.1 ] octan -3 - ylsulfamoyl)phenyl]meth yl]thieno[2,3-c]pyndine- 2-carboxamide (isomer

1 )

N-[[4-(8- azabicyclo[3.2.1 ]octan-3- ylsulfamoyl)phenyl]meth yl]thieno[2,3-c]pyridine- 2-carboxamide (isomer

2)

N-[[4-(tetrahydropyran- 3- ylsulfamoyl)phenyl]meth yl]imidazo[l ,2- a]pyridine-6- carboxamide (isomer 1 )

N-[[4-(tetrahydropyran- 3- ylsulfamoyl)phenyl]meth yl]imidazo[l ,2- a]pyridine-6- carboxamide (isomer 2) tert-butyl 6-[[4- [(imidazofl ,2-a]pyridine- 6- carbonylamino)methy 1 ]p henyl]sulfonylamino]-3- azabicyclo[3. 1 0]hexane- 3-carboxylate

N-[[4-[(l - methylpyrrolidin-3- yl)sulfamoyl]phenyl]met hyl]imidazo[l ,2- a]pyridine-6- carboxamide

— ^N

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and stereoisomers thereof, and pharmaceutically acceptable salts of said compounds and stereoisomers.

In a further aspect, the invention relates to pharmaceutical compositions each comprising an effective amount of at least one compound listed above or a pharmaceutical ly acceptable salt of such a compound. Pharmaceutical compositions according to the invention may further comprise at least one pharmaceutically acceptable excipient.

In another aspect, the invention is directed to a method of treating a subject suffering from a disease or medical condition mediated by NAMPT activity, comprising administering to the subject in need of such treatment an effective amount of at least one compound listed above or a pharmaceutically acceptable salt of such a compound, or comprising administering to the subject in need of such treatment an effective amount of a pharmaceutical composition comprising an effective amount of at least one compound listed above or a pharmaceutically acceptable salt of such a compound.

An aspect of the present invention concerns the use of compound listed abovev for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of cancer.

An aspect of the present invention concerns the use of a compound listed above for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of cancer, where the cancer is selected from leukemia, lymphoma, ovarian cancer, breast cancer, uterine cancer, colon cancer, cervical cancer, lung cancer, prostate cancer, skin cancer, CNS cancer, bladder cancer, pancreatic cancer and Hodgkin's disease.

An aspect of the present invention concerns the use of a compound listed abocev for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of cancer, where the cancer is selected from cancers with solid and liquid tumors, non-small cell lung cancer, leukemia, lymphoma, ovarian cancer, glioma, breast cancer, uterine cancer, colon cancer, cervical cancer, lung cancer, prostate cancer, skin cancer, rhino-gastric tumors, colorectal cancer, CNS cancer, bladder cancer, pancreatic cancer and Hodgkin's disease.

In another aspect, the compounds listed above and pharmaceutically acceptable salts thereof are useful as NAMPT modulators. Thus, the invention is directed to a method for modulating NAMPT activity, including when NAMPT is in a subject, comprising exposing NAMPT to an effective amount of at least one compound of the invention or a pharmaceutically acceptable salt of a compound listed abovec.

In yet another aspect, the present invention is directed to methods of making compounds as listed above and pharmaceutically acceptable salts thereof.

In certain embodiments of the compounds, pharmaceutical compositions, and methods of the invention, the compound of the invention is a compound selected from those species described or exemplified in the detailed description below, or is a pharmaceutically acceptable salt of such a compound. 0215

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Additional embodiments, features, and advantages of the invention will be apparent from the following detailed description and through practice of the invention.

Detailed Description and Particular Embodiments

For the sake of brevity, the disclosures of the publications cited in this

specification, including patents and patent applications, are herein incorporated by reference in their entirety.

Most chemical names were generated using IUPAC nomenclature herein.

Some chemical names were generated using different nomenclatures or alternative or commercial names known in the art. In the case of conflict between names and structures, the structures prevail.

As used above, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings. If a

definition is missing, the conventional definition as known to one skilled in the art controls. If a definition provided herein conflicts or is different from a definition provided in any cited publication, the definition provided herein controls.

As used herein, the terms "including," "containing," and "comprising" are used in their open, non-limiting sense.

As used herein, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term "about". It is understood that, whether the term "about" is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including equivalents and approximations due to the experimental and/or

measurement conditions for such given value. Whenever a yield is given as a

percentage, such yield refers to a mass of the entity for which the yield is given with respect to the maximum amount of the same entity that could be obtained under the particular stoichiometric conditions. Concentrations that are given as percentages refer to mass ratios, unless indicated differently. As used herein, "alkyl" refers to a saturated, straight- or branched-chain hydrocarbon group having from 1 to 1 0 carbon atoms. Representative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methy 1- 1 -propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3 -methyl- 1 -butyl, 2-methyl-3-butyl, 2,2- dimethy 1-1 -propyl, 2-methyl-l -pentyl, 3-methyl- l -pentyl, 4-methyl- l -pentyl, 2- methyl-2-pentyl, 3 -methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3 ,3 - dimethy 1- 1 -butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and the like, and longer alkyl groups, such as heptyl, octyl, and the like. As used herein, "lower alkyl" means an alkyl having from 1 to 6 carbon atoms.

The term "amino" as used herein refers to an -NH^ group.

Any atom that is represented herein with an unsatisfied valence is assumed to have the sufficient number of hydrogen atoms to satisfy the atom' s valence.

Numerical ranges, as used herein, are intended to include sequential whole numbers. For example, a range expressed as "from 0 to 4" or "0-4" includes 0, 1 , 2, 3, and 4.

When a multifunctional moiety is shown, the point of attachment to the core is indicated by a line or hyphen. For example, arylacyl- refers to a moiety in which an oxygen atom is the point of attachment to the core molecule while aryl is attached to the oxygen atom.

As used herein, the term "subject" encompasses mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans; non-human primates such as chimpanzees, and other apes and monkey species; farm an imals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; and laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish and the like. In one embodiment of the present invention, the mammal is a human.

"Patient" includes both human and animals. The term "inhibitor" refers to a molecule such as a compound, a drug, an enzyme activator, or a hormone that blocks or otherwise interferes with a particular biologic activity.

The term "modulator" refers to a molecule, such as a compound of the present invention, that increases or decreases, or otherwise affects the activity of a given enzyme or protein.

The terms "effective amount" or "therapeutically effective amount" refer to a sufficient amount of the agent to provide the desired biological result. That result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease or medical condition, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a compound, or of a composition comprising the compound, that is required to provide a clinically relevant change in a disease state, symptom, or medical condition. An appropriate "effective" amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation. Thus, the expression "effective amount" generally refers to the quantity for which the active substance has a therapeutically desired effect.

As used herein, the terms "treat" or "treatment" encompass both

"preventative" and "curative" treatment. "Preventative" treatment is meant to indicate a postponement of development of a disease, a symptom of a disease, or medical condition, suppressing symptoms that may appear, or reducing the risk of developing or recurrence of a disease or symptom. "Curative" treatment includes reducing the severity of or suppressing the worsening of an existing disease, symptom, or condition. Thus, treatment includes ameliorating or preventing the worsening of existing disease symptoms, preventing additional symptoms from occurring, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disorder or disease, e.g., arresting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder. Additional Chemical Descriptions

Any formula given herein is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms. For example, compounds of any formula given herein may have asymmetric or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomers, including optical isomers, enantiomers, and diastereomers, of the compounds of the general formula, and mixtures thereof, are considered to fall within the scope of the formula. Furthermore, certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers. All such isomeric forms, and mixtures thereof, are contemplated herein as part of the present invention. Thus, any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more tautomeric or atropisomeric forms, and mixtures thereof.

Diastereomeric mixtures may be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers may be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride, or formation of a mixture of diastereomeric salts), separating the diastereomers and converting (e.g., hydrolyzing or de-salting) the individual diastereomers to the corresponding pure enantiomers. Enantiomers may also be separated by use of chiral HPLC column. The chiral centers of compounds of the present invention may be designated as "R" or "S" as defined by the lUPAC 1974 Recommendations.

The compounds of the invention can form pharmaceutically acceptable salts, which are also within the scope of this invention. A "pharmaceutically acceptable salt" refers to a salt of a free acid or base of a compound of the invention that is nontoxic, is physiologically tolerable, is compatible with the pharmaceutical composition in which it is formulated, and is otherwise suitable for formulation and/or administration to a subject. Reference to a compound herein is understood to include reference to a pharmaceutically acceptable salt of said compound unless otherwise indicated.

Compound salts include acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, where a given compound contains both a basic moiety, such as, but not limited to, a pyridine or imidazole, and an acidic moiety, such as, but not limited to, a carboxylic acid, one of skill in the art will recognize that the compound may exist as a zwitterion ("inner salt"); such salts are included within the term "salt" as used herein. Salts of the compounds of the invention may be prepared, for example, by reacting a compound with an amount of a suitable acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

Exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate ("mesylate"),

ethanesulfonate, benzenesulfonate, / oluenesulfonate, and pamoate (i.e., 1 , 1 '- methylene-bis(2-hydroxy-3-naphthoate)) salts. A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counterion. The countenon may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counterions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion.

Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates,

camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates,

toluenesulfonates (also known as tosylates,) and the like.

Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.

Additionally, acids and bases which are generally considered suitable for the formation of pharmaceutically useful salts from pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of

Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66( 1 ) 1 -19; P. Gould, International J. of Pharmaceutics (1986) 33 201 -2 7; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, MD, available from FDA). These disclosures are incorporated herein by reference thereto.

Additionally, any compound described herein is intended to refer also to any unsolvated form, or a hydrate, solvate, or polymorph of such a compound, and mixtures thereof, even if such forms are not listed explicitly. "Solvate" means a physical association of a compound of the invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Suitable solvates include those formed with pharmaceutically acceptable solvents such as water, ethanol, and the like. In some embodiments, the solvent is water and the solvates are hydrates. One or more compounds of the invention may optionally be converted to a solvate. Methods for the preparation of solvates are generally known. Thus, for example, M. Caira et al., J. Pharmaceutical Sci., 93(3), 601 -61 1 (2004), describes the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water Similar preparations of solvates, hemisolvate, hydrates, and the like are described by E. C. van Tonder et al, A APS PharmSciTech., 5(1 ), article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603 -604 (2001 ). A typical, non-limiting process involves dissolving the compound of the invention in a suitable amounts of the solvent (organic solvent or water or a mixture thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example, infrared spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).

The invention also relates to pharmaceutically acceptable prodrugs of the compounds described herein, and treatment methods employing such

pharmaceutically acceptable prodrugs. The term "prodrug" means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the specific compound described herein). A "pharmaceutically acceptable prodrug" is a prodrug that is non-toxic, biologically tolerable, and otherwise suitable for formulation and/or administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

For example, if a compound as described herein contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (Ci -C₈)alkyl, (C2-Ci 2)alkanoyloxymethyl, 1 -(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl- 1 -(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,

alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1 - (alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1 - (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1 -(N- (alkoxycarbony])amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4- crotonolactonyl, gamma-butyrolacton-4-yi, di-N,N-(Ci-C2)alkylamino(C₂-C3)alkyl (such as β-dimethylaminoethyl), carbamoyl-(G-G)alkyl, N,N-di(G- C₂)alkylcarbamoyl-(Ci-C2)alkyl and piperidino-, pyrrolidino- or morpholine (G- G)alkyl, and the like.

Similarly, if a compound as described herein contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (Ci-C₆)alkanoyloxymethyl, 1 -((G- C6)alkanoyloxy)ethyl, 1 -methyl- l-((G-C6)alkanoyloxy)ethyl, (G- C_f,)alkoxycarbonyloxymethyl, N-(G-G,)alkoxycarbonylaminomethyl, succinoyi, (G - G)alkanoyl, a-amino(G-C4)alkanyl, arylacyl and a-aminoacyl, or a-aminoacyl- a- aminoacyl, where each α-aminoacyl group is independently selected from the naturally occurring L-amino acids, Ρ(0)(ΟΗ)₂, -P(0)(0(Ci-C₆)alkyl)₂ or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.

If a compound as described herein incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (G-Go)alkyl, (G-G) cycloalkyl, benzyl, or R- carbonyl is a natural α-aminoacyl or natural α-aminoacyl, -C(OH)C(0)OY' wherein Y¹ is H, (C-G,)alkyl or benzyl, -C(OY²)Y³ wherein Y² is (C,-C₄) alkyl and Y³ is (G- G)alkyl, carboxy(G-C6)alkyl, amino(G-G)alkyl or mono-N- or di-N,N-(G- G)alkylaminoalkyl, -C(Y⁴)Y⁵ wherein Y^J is H or methyl and Y⁵ is mono-N- or di- N,N-(G-C6)alkylamino mo holino, piperidin-1 -yl or pyrrolidin-1 -yl, and the like.

The present invention also relates to pharmaceutically active metabolites of compounds of the invention, and uses of such metabolites in the methods of the invention. A "pharmaceutically active metabolite" means a pharmacologically active product of metabolism in the body of a compound as described herein or salt thereof. 00215

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Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertohni et al., J. Med. hem.

1997, 40, 201 1 -2016; Shan et al., J. Pharm. Sci. 1997, 86 (7), 765-767; Bagshawe,

Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984, 13, 255-331 ;

Bundgaard, Design of Prodrugs (Elsevier Press, 1 85); and Larsen, Design and

Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991 ).

Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as ²H, ³H, "C, ^{, 3}C, ^, C, ^{, 5}N, ^{, 8}0, ^{, 7}0, ³¹ P, ³²P, ⁵S, ^{, 8}F, ³⁶C1, and ^{, 5}I, respectively.

Such isotopically labelled compounds are useful in metabolic studies (for example with ¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an ^{1 8}F or "C labeled compound may be particularly suitable for PET or SPECT studies. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic

advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the

procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.

The use of the terms "salt," "solvate," "polymorph," "prodrug," and the like, with respect to the compounds described herein is intended to apply equally to the salt, solvate, polymorph, and prodrug forms of enantiomers, stereoisomers, rotamers, tautomers, atropisomers, and racemates of the compounds of the invention. In certain embodiments, the compounds of the present invention are:

or a pharmaceutically acceptable salt thereof.

Pharmaceutical Description The dosage forms of the present invention may contain a mixture of one or more compounds of this invention, and may include additional materials known to those skilled in the art as pharmaceutical excipients. "Excipient" includes any excipient commonly used in pharmaceutics and should be selected on the basis of compatibility and the release profile properties of the desired dosage form.

Exemplary excipients include, e.g., binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like. Exemplary exipients include, e.g., acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lacrylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, and the like. See, e.g., Hoover, John E., Remington 's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975.

Exemplary excipients include: stabilizing additives such as gum acacia, gelatin, methyl cellulose, polyethylene glycol, carboxylic acids and salts thereof, and polylysine; acidifying agents (acetic acid, glacial acetic acid, citric acid, fumaric acid, hydrochloric acid, diluted hydrochloric acid, malic acid, nitric acid, phosphoric acid, diluted phosphoric acid, sulfuric acid, tartaric acid); aerosol propellants (butane, dichlorodifluoro-methane, dichlorotetrafluoroethane, isobutane, propane,

tnchloromonofluoromethane); air displacements (carbon dioxide, nitrogen); alcohol denaturants (denatonium benzoate, methyl isobutyl ketone, sucrose octacetate);

alkalizing agents (strong ammonia solution, ammonium carbonate, diethanolamine, diisopropanolamine, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide, trolamine); anticaking agents (see "glidant" below); antifoaming agents (dimethicone, simethicone); antimicrobial preservatives (benzalkonium chloride, benzalkonium chloride solution, benzelthonium chloride, benzoic acid, benzyl alcohol, butylparaben, cetylpyridinium chloride, chlorobutanol, chlorocresol, cresol, dehydroacetic acid, ethylparaben, methylparaben, methylparaben sodium, phenol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric nitrate, potassium benzoate, potassium sorbate, propylparaben, propylparaben sodium, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid, thimerosal, thymol); antioxidants (ascorbic acid, acorbyl palmitate, butylated hydro xyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium thiosulfate, sulfur dioxide, tocopherol, tocopherols excipient); buffering agents (acetic acid, ammonium carbonate, ammonium phosphate, boric acid, citric acid, lactic acid, phosphoric acid, potassium citrate, potassium metaphosphate, potassium phosphate monobasic, sodium acetate, sodium citrate, sodium lactate solution, dibasic sodium phosphate, monobasic sodium phosphate); capsule lubricants (see "tablet and capsule lubricant" below); chelating agents (edetate disodium, ethylenediaminetetraacetic acid and salts, edetic acid); coating agents (sodium carboxymethylcellulose, cellulose acetate, cellulose acetate phthalate, ethylcellulose, gelatin, pharmaceutical glaze, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, methylcellulose, polyethylene glycol, polyvinyl acetate phthalate, shellac, sucrose, titanium dioxide, carnauba wax, microcystalline wax, zein); colorants (caramel, red, yellow, black or blends, ferric oxide); complexing agents (ethylenediaminetetraacetic acid and salts (EDTA), edetic acid, gentisic acid ethanolmaide, oxyquinoline sulfate); desiccants (calcium chloride, calcium sulfate, silicon dioxide); emulsifying and/or solubilizing agents (acacia, cholesterol, diethanolamine (adjunct), glyceryl monostearate, lanolin alcohols, lecithin, mono- and di-glycerides, monoethanolamine (adjunct), oleic acid (adjunct), oleyl alcohol (stabilizer), poloxamer, polyoxyethylene 50 stearate, polyoxyl 35 caster oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 10 oleyl ether, polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, propylene glycol diacetate, propylene glycol monostearate, sodium lauryl sulfate, sodium stearate, sorbitan monolaurate, soritan monooleate, sorbitan monopalmitate, sorbitan monostearate, stearic acid, trolamine, emulsifying wax); filtering aids (powdered cellulose, purified siliceous earth); flavors and perfumes (anethole, benzaldehyde, ethyl vanillin, menthol, methyl salicylate, monosodium glutamate, orange flower oil, peppermint, peppermint oil, peppermint spirit, rose oil, stronger rose water, thymol, tolu balsam tincture, vanilla, vanilla tincture, vanillin); glidants 15

33

and/or anticaking agents (calcium silicate, magnesium silicate, colloidal silicon dioxide, talc); humectants (glycerin, hexylene glycol, propylene glycol, sorbitol);

plasticizers (castor oil, diacetylated monoglycerides, diethyl phthalate, glycerin, mono- and di-acetylated monoglycerides, polyethylene glycol, propylene glycol, tnacetin, tnethyl citrate); polymers (e.g., cellulose acetate, alkyl celloloses,

hydroxyalkylcelloloses, acrylic polymers and copolymers); solvents (acetone, alcohol, diluted alcohol, amylene hydrate, benzyl benzoate, butyl alcohol, carbon tetrachloride, chloroform, corn oil, cottonseed oil, ethyl acetate, glycerin, hexylene glycol,

isopropyl alcohol, methyl alcohol, methylene chloride, methyl isobutyl ketone, mineral oil, peanut oil, polyethylene glycol, propylene carbonate, propylene glycol, sesame oil, water for injection, sterile water for injection, sterile water for irrigation, purified water); sorbents (powdered cellulose, charcoal, purified siliceous earth);

carbon dioxide sorbents (barium hydroxide lime, soda lime); stiffening agents

(hydrogenated castor oil, cetostearyl alcohol, cetyl alcohol, cetyl esters wax, hard fat, paraffin, polyethylene excipient, stearyl alcohol, emulsifying wax, white wax, yellow wax); suspending and/or viscosity-increasing agents (acacia, agar, alginic acid, aluminum monostearate, bentonite, purified bentonite, magma bentonite, carbomer 934p, carboxymethylcellulose calcium, carboxymethylcellulose sodium,

carboxymethycellulose sodium 12, carrageenan, microcrystalline and

carboxymethylcellulose sodium cellulose, dextrin, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium aluminum silicate, methylcellulose, pectin, polyethylene oxide, polyvinyl alcohol, povidone, propylene glycol alginate, silicon dioxide, colloidal silicon dioxide, sodium alginate, tragacanth, xanthan gum); sweetening agents (aspartame, dextrates, dextrose, excipient dextrose, fructose, mannitol, saccharin, calcium saccharin, sodium

saccharin, sorbitol, solution sorbitol, sucrose, compressible sugar, confectioner's sugar, syrup); tablet binders (acacia, alginic acid, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropyl methylcellulose, methycellulose, polyethylene oxide, povidone, pregelatinized starch, syrup); tablet and/or capsule diluents (calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrates, dextrin, dextrose excipient, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, compressible sugar, confectioner's sugar); tablet disintegrants (alginic acid, microcrystalline cellulose, croscarmellose sodium, corspovidone, polacrilin potassium, sodium starch glycolate, starch, pregelatinized starch); tablet and/or capsule lubricants (calcium stearate, glyceryl behenate, magnesium stearate, light mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, purified stearic acid, talc, hydrogenated vegetable oil, zinc stearate); tonicity agent (dextrose, glycerin, mannitol, potassium chloride, sodium chloride); vehicle: flavored and/or sweetened (aromatic elixir, compound benzaldehyde elixir, iso-alcoholic elixir, peppermint water, sorbitol solution, syrup, tolu balsam syrup); vehicle: oleaginous (almond oil, corn oil, cottonseed oil, ethyl oleate, isopropyl myristate, isopropyl palmitate, mineral oil, light mineral oil, myristyl alcohol, octyldodecanol, olive oil, peanut oil, persic oil, seame oil, soybean oil, squalane); vehicle: solid carrier (sugar spheres); vehicle:

sterile (bacteriostatic water for injection, bacteriostatic sodium chloride injection); viscosity-increasing (see "suspending agent" below); water repelling agent

(cyclomethicone, dimethicone, simethicone), and wetting and/or solubilizing agent (benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, docusate sodium, nonoxynol 9, nonoxynol 10, octoxynol 9, poloxamer, polyoxyl 35 castor oil, polyoxyl 40, hydrogenated castor oil, polyoxyl 50 stearate, polyoxyl 10 oleyl ether, polyoxyl 20, cetostearyl ether, polyoxyl 40 stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, sodium lauryl sulfate, sorbitan monolaureate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, tyloxapol). This list is not meant to be exclusive, but instead merely representative of the classes of excipients and the particular excipients which may be used in dosage forms of the present invention.

In certain aspects, the invention relates to methods of treating diseases or conditions mediated by elevated levels of NAMPT, or which are generally mediated by NAMPT activity. Such disease or condition is one or more selected from the group consisting of cancer, ovarian cancer, breast cancer, uterine cancer, colon cancer, cervical cancer, lung cancer, prostate cancer, skin cancer, bladder cancer, pancreatic 15

35

cancer, leukemia, lymphoma, Hodgkin's disease, viral infections, Human

Immunodeficiency Virus, hepatitis virus, herpes virus, herpes simplex, inflammatory disorders, irritable bowel syndrome, inflammatory bowel disease, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, osteoarthritis, osteoporosis, dermatitis, atoptic dermatitis, psoriasis, systemic lupus erythematosis, multiple sclerosis,

psoriatic arthritis, ankylosing spodylitis, graft-versus-host disease, Alzheimer's disease, cerebrovascular accident, atherosclerosis, diabetes, glomerulonephirihs, metabolic syndrome, non-small cell lung cancer, small cell lung cancer, multiple myeloma, leukemias, lymphomas, squamous cell cancers, kidney cancer, uretral and bladder cancers, cancers of head and neck, and cancers of the brain and central nervous system (CNS).

The compounds of the invention can be useful in the therapy of proliferative diseases such as, but not limited to cancer, autoimmune diseases, viral diseases, fungal diseases, neurological/neurodegenerative disorders, arthritis, inflammation, anti-proliferative (e.g., ocular retinopathy), neuronal, alopecia and cardiovascular disease

More specifically, the compounds can be useful in the treatment of a variety of cancers, including (but not limited to) the following: carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, non- small cell lung cancer, head and neck, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma;

hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma,

Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma, and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic

syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannomas; and other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma. N2013/000215

36

The compounds of the invention may induce or inhibit apoptosis.

The compounds of the invention may also be useful in the chemoprevention of cancer. Chemoprevention is defined as inhibiting the development of invasive cancer by either blocking the initiating mutagenic event or by blocking the progression of pre-malignant cells that have already suffered an insult or inhibiting tumor relapse

A further aspect of the invention is a method of inhibiting a NAMPT pathway in a subject, said method comprising administering to said subject a pharmaceutically acceptable amount of a compound of the invention to a subject in need thereof

Another embodiment of the invention comprises a pharmaceutical formulation of the invention, wherein the pharmaceutical formulation, upon administration to a subject (e.g., a human), results in a decrease in tumor burden.

Still another embodiment of the invention is a pharmaceutical formulation comprising at least one compound of the invention and a pharmaceutically acceptable excipient, and further comprising one or more adjunctive active agent.

The pharmaceutical formulations of the invention may further comprise a therapeutic effective amount of an adjunctive active agent.

The compounds of the present invention are also useful in combination

therapies with at least one adjunctive active agent. Such methods include regimes in which the compound of the invention and the at least one adjunctive active agent are administered simultaneously or sequentially. Also useful are pharmaceutical

compositions in which at least one compound of the present invention and at least one adjunctive active agent are combined in a single formulation.

The expression "adjunctive active agent" generally refers to agents which targets the same or a different disease, symptom, or medical condition as the primary therapeutic agent. Adjunctive active agents may treat, alleviate, relieve, or ameliorate side effects caused by administration of the primary therapeutic agents. Examples of adjunctive active agents include, but are not limited to, antineoplastic agents,

filgrastim, and erythropoietin. Such agents include those which modify blood cell growth and maturation. Non-limiting examples of adjunctive active agent are

filgrastim, pegfilgrastim and erythropoietin. Other such adjunctive active agents include those which inhibit nausea associated with administration of chemotherapeutic agents, such as a 5-HT₃ receptor inhibitor (e.g., dolansetron, granisetron, or ondansetron), with or without dexamethasone. The invention also describes one or more uses of the compounds of the present invention with an adjunctive active agent such as TNF, GCSF, or other chemotherapeutic agents.

Additional adjunctive active agents include those that mediate cytotoxicity of

NAMPT inhibitors, such as nicotinic acid rescue agents, or other compounds that play a role in the NAMPT pathway, such as niacin (nicotinic acid), nicotinamide, or related compounds, or modified release formulations of such compounds, for example, NIASPAN^®.

The terms "chemotherapeutic agent" and "antineoplastic agent" generally refer to agents, which treat, prevent, cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect malignancies and their metastasis. Examples of such agents include, but are not limited to, prednisone, fluorouracil (e.g., 5-fluorouracil (5- FU)), anastrozole, bicalutamide, carboplatin, cisplatin, chlorambucil, cisplatin, carboplatin, docetaxel, doxorubicin, flutamide, interferon-alpha, letrozole, leuprolide, megestrol, mitomycin, oxaliplatin, paclitaxel, plicamycin (Mithracin ^rM), tamoxifen, thiotepa, topotecan, valrubicin, vinblastine, vincristine, and any combination of any of the foregoing.

The invention is also directed to a method of treating or preventing a disorder associated with excessive rate of growth of cells in a subject (e.g., a mammal) comprising administering to the subject an effective amount of the pharmaceutical formulation of the invention. Non-limiting examples of disorder include cancer or metastasis from malignant tumors.

Another aspect of the invention is a method of inhibiting tumor cell growth and rate of division in a subject (e.g., a mammal) with cancer, or other disorder associated with abnormally dividing cells comprising administering to the subject an effective amount of the pharmaceutical formulation of this invention.

Another embodiment of the invention is a method of treating bone pain due to excessive growth of a tumor or metastasis to bone in a subject (e.g., a mammal) in need thereof comprising administering to the subject an effective amount of the pharmaceutical formulation of this invention. 5

38

A further embodiment of the invention is a method of preparing a

pharmaceutical formulation comprising mixing at least one compound of the present invention, and, optionally, one or more pharmaceutically acceptable excipients.

The invention is also directed to methods of synthesizing compounds of the present invention.

Still another aspect of this invention is to provide a method for treating, preventing, inhibiting or eliminating a disease or condition in a patient by inhibiting NAMPT in said patient by administering a therapeutically effective amount of at least one compound of this disclosure, wherein said disease or condition is selected from the group consisting of cancer, ovarian cancer, breast cancer, uterine cancer, colon cancer, cervical cancer, lung cancer, prostate cancer, skin cancer, bladder cancer, pancreatic cancer, leukemia, lymphoma, Hodgkin's disease, viral infections, Human Immunodeficiency Virus, hepatitis virus, herpes virus, herpes simplex, inflammatory disorders, irritable bowel syndrome, inflammatory bowel disease, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, osteoarthritis, osteoporosis, dermatitis, atoptic dermatitis, psoriasis, systemic lupus erythematosis, multiple sclerosis,

psoriatic arthritis, ankylosing spodylitis, graft-versus-host disease, Alzheimer's disease, cerebrovascular accident, atherosclerosis, diabetes, glomerulonephiritis, metabolic syndrome, non-small cell lung cancer, small cell lung cancer, multiple myeloma, leukemias, lymphomas, squamous cell cancers, kidney cancer, uretral and bladder cancers, cancers of head and neck, cancers of the brain and central nervous system.

In a certain embodiment, the compounds of the invention can be used in the treatment of solid and liquid tumors, non-small cell lung cancer, leukemia, lymphoma, ovarian cancer, glioma, breast cancer, uterine cancer, colon cancer, cervical cancer, lung cancer, prostate cancer, skin cancer, rhino-gastric tumors, colorectal cancer,

CNS cancer, bladder cancer, pancreatic cancer and Hodgkin's disease.

In a certain embodiment, the compounds of the invention can be used in the treatment of solid and liquid tumors, non-small cell lung cancer, leukemia, lymphoma, ovarian cancer, breast cancer, uterine cancer, colon cancer, cervical cancer, lung cancer, prostate cancer, skin cancer, rhino-gastric tumors, colorectal cancer, bladder cancer, pancreatic cancer and Hodgkin's disease.

Another embodiment is a pharmaceutical formulation comprising a pharmaceutically acceptable compound of the present invention, which provides, upon administration to a subject (e.g., a human), a decrease in tumor burden and/or metastases. The pharmaceutical formulation can be administered by oral means or other suitable means.

Yet another embodiment is a method of treating ovarian cancer in a subject (e.g., a human) in need thereof by administering to the subject an effective amount of the compound or the pharmaceutical formulation of the present invention.

Yet another embodiment is a method of treating non-small cell lung cancer

(NSCLC) in a subject (e.g., a human) in need thereof by administering to the subject an effective amount of the compound or the pharmaceutical formulation of the present invention.

Yet another embodiment is a method of treating colon cancer in a subject (e.g., a human) in need thereof by administering to the subject an effective amount of the compound or the pharmaceutical formulation of the present invention

Yet another embodiment is a method of treating breast cancer in a subject (e.g., a human) in need thereof by administering to the subject an effective amount of the pharmaceutical formulation of the present invention.

Yet another embodiment is a method of treating leukemia in a subject (e.g., a human) in need thereof by administering to the subject an effective amount of the compound or the pharmaceutical formulation of the present invention.

Yet another embodiment is a method of treating colon cancer before or after surgical resection and/or radiation therapy, in a subject (e.g., a human) in need thereof by administering to the subject an effective amount of the compound or the pharmaceutical formulation of the present invention.

Yet another embodiment is a method of treating cancer before or after surgical resection and/or radiation therapy, in a subject (e.g., a human) in need thereof by administering to the subject an effective amount of the compound or the

pharmaceutical formulation of the present invention, including adjunctive therapy to treat nausea, with or without dexamethasone. Additionally, according to the present invention, the compounds of the invention described herein may be administered and/or formulated in combination with an adjunctive active agent. In certain embodiments, the adjunctive active agent is niacin, nicotinamide, nicotinic acid, nicotinamide mononucleotide (NMN), or variations thereof, including modified release formulations of niacin, such as NIASPAN^®. Niacin, nicotinamide, nicotinic acid, nicotinamide mononucleotide (NMN), or variations thereof have also been described in the literature as "rescue agents" or "rescuing agents" and these terms have been used herein. The role of nicotinamide and/or nicotinic acid as a rescuing or rescue agent has for example been described by Beauparlant et al. in Anti-Cancer Drugs 2009, 20:346-354 and by Rongvaux et al. in The Journal of Immunology, 2008, 1 81 : 4685^69 These two references describe the role of a rescuing or rescue agent with regards to ameliorating possible toxic effects of NAMPT inhibitors.

Yet another embodiment is a method of treating cancer before or after surgical resection and or radiation therapy, in a subject (e.g., a human) in need thereof by administering to the subject an effective amount of the compound or the

pharmaceutical formulation of the present invention, including adjunctive therapy with one or more additional therapeutic agents, or their pharmaceutically acceptable salts. Non-limiting examples of such additional therapeutic agents include cytotoxic agents (such as for example, but not limited to, DNA interactive agents (such as cisplatin or doxorubicin)); taxanes (e.g. taxotere, taxol); topoisomerase Π inhibitors (such as etoposide); topoisomerase I inhibitors (such as irinotecan (or CPT-1 1 ), camptostar, or topotecan); tubulin interacting agents (such as paclitaxel, docetaxel or the epothilones); hormonal agents (such as tamoxifen); thymidilate synthase inhibitors (such as 5-fluorouracil or 5-FU); anti-metabolites (such as methoxtrexate); alkylating agents (such as temozolomide, cyclophosphamide); Farnesyl protein transferase inhibitors (such as, S ARASAR™.(4-[2-[4-[(l 1 R)-3 , 10-dibromo-8-chloro- 6, 1 1 -dihydro-5H-benzo[5,- 6]cyclohepta[ l ,2-b]pyridin-l l -yl-]-l -piperidinyl]-2- oxoehtyl]- l -piperidine- carboxamide, or SCH 66336), tipifarnib (Zarnestra⁸ or Rl 1 5777 from Janssen Pharmaceuticals), L778, l 23 (a farnesyl protein transferase inhibitor from Merck & Company, Whitehouse Station, N.J. ), BMS 214662 (a farnesyl protein transferase inhibitor from Bristol-Myers Squibb Pharmaceuticals, Princeton, N.J.); signal transduction inhibitors (such as, Iressa^® (from Astra Zeneca Pharmaceuticals, England), Tarceva* (EGFR kinase inhibitors), antibodies to EGFR (e.g., C225), GLEEVEC⁸ (C-abl kinase inhibitor from Novartis Pharmaceuticals, East Hanover, N.J.); interferons such as, for example, intron^® (from Merck &

Company), Peg-Intron^® (from Merck & Company); hormonal therapy combinations; aromatase combinations; ara-C, adriamycin, Cytoxan, and gemcitabine.

Other anti-cancer (also known as anti-neoplastic) agents include but are not limited to Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6- Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, oxaliplatin (ELOXATIN^® from Sanofi-Synthelabo Pharmaceuticals, France), Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17a-Ethinylestradiol, Di ethyl stilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate,

Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone,

Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone,

Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide,

Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacnne, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade*, Zevalin, Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole,

Fulvestrant, Exemestane, Ifosfomide, Rituximab, C225, and Campath, 5-fluorouracil and leucovorin, with or without a 5-HT$ receptor inhibitor (e.g., dolansetron, granisetron, ondansetron) with or without dexamethasone.

If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described herein (or as known to those skilled in the art) and the other pharmaceutically active agents or treatments within its dosage range. For example, the CDC2 inhibitor olomucine has been found to act synergistically with known cytotoxic agents in inducing apoptosis (J. Cell Sci., ( 1995) 108, 2897). The compounds of the invention may also be administered sequentially with known anticancer or cytotoxic agents when a combination formulation is inappropriate. In any combination treatment, the invention is not limited in the sequence of administration; compounds of the disclosed Formulas may be administered either prior to or after administration of the known anticancer or cytotoxic agent. For example, the cytotoxic activity of the cyclin-dependent kinase inhibitor flavopiridol is affected by the sequence of administration with anticancer agents. Cancer Research (1997) 57, 3375. Such techniques are within the skills of persons skilled in the art as well as attending physicians.

Any of the aforementioned methods may be augmented by administration of fluids (such as water), loop diuretics, one or more adjunctive active agents, such as a chemotherapeutic or antineoplastic agent, such as leucovorin and fluorouracil, or an adjunctive chemotherapeutic agent (such as filgrastim and erythropoietin), or any combination of the foregoing.

Yet another embodiment is a method for administering a compound of the instant invention to a subject (e.g., a human) in need thereof by administering to the subject the pharmaceutical formulation of the present invention.

Yet another embodiment is a method of preparing a pharmaceutical formulation of the present invention by mixing at least one pharmaceutically acceptable compound of the present invention, and, optionally, one or more pharmaceutically acceptable additives or excipients.

For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral

administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.),

Remington's Pharmaceutical Sciences, 18th Edition, (1 90), Mack Publishing Co., Easton, Pa.

The compositions and formulations of the invention can be administered as sterile compositions and sterile formulations. Sterile pharmaceutical formulations are compounded or manufactured according to pharmaceutical-grade sterilization standards (e.g., United States Pharmacopeia Chapters 797, 1072, and 121 1 , California Business & Professions Code 4127.7; 16 California Code of Regulations 1751 , 21 Code of Federal Regulations 21 , or ex -U. S. counterparts to such regulations) known to those of skill in the art.

Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.

Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

The compounds of this invention may also be delivered subcutaneously. The compound can be administered orally or intravenously.

The pharmaceutical preparation can be in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose. The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 1000 mg, for example from about 1 mg to about 500 mg, in particular from about 1 mg to about 250 mg, or from about 1 mg to about 25 mg, according to the particular application.

The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two to four divided doses.

Schemes and Examples

Exemplary, non-limiting, chemical entities and methods useful in preparing compounds of the invention will now be described by reference to illustrative compounds for their general preparation below and the specific examples that follow. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds according to the invention. Although specific starting materials and reagents are depicted and discussed herein, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the exemplary compounds prepared by the described methods can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Each of the reactions depicted in the reaction schemes is preferably run at a temperature from about 0 °C to the reflux temperature of the solvent used. Unless otherwise specified, the variables shown in the schemes below are as defined above in reference to

Compounds according to the invention may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein, and those for other heterocycles described in: Comprehensive Heterocyclic Chemistry Π, Editors Katritzky and Rees, Elsevier, 1 997, e.g. Volume 3; Liebigs Annalen der Chemie, (9): 1910- 16, ( 1985); Helvetica Chimica Acta, 41 : 1052-60, (1958); Arzneimittel- Forschung, 40( 12): 1328-3 1 , ( 1990), each of which are expressly incorporated by reference. Starting materials are generally available from commercial sources such as Sigma-Aldrich Chemicals (Milwaukee, WT) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1 -23, Wiley, N.Y. (1967-2006 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer- Verlag, Berlin, including supplements (also available via the Beilstein online database).

Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing compounds according to the invention and necessary reagents and intermediates are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection is readily determined by one skilled in the art.

Additional particularly useful reactions in preparing compounds of the present invention include alkylation, reductive amination, oxidation, reduction, and hydrolysis reactions. Such transformations are well within the ordinary skill in the art.

Compounds according to the invention may be prepared singly or as compound libraries comprising, for example, at least two, or 5 to 1 ,000 compounds, or 10 to 100 compounds. Libraries of compounds of the invention may be prepared by a combinatorial "split and mix" approach or by multiple parallel syntheses using either solution phase or solid phase chemistry, by procedures known to those skilled in the art. Thus, according to a further aspect of the invention there is provided a compound library comprising at least two compounds of the invention, or

pharmaceutically acceptable salts thereof.

In the methods of preparing compounds according to the invention, it may be advantageous to separate reaction products from one another and/or from starting materials. The desired products of each step or series of steps is separated and/or purified to the desired degree of homogeneity by the techniques common in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography.

Chromatography can involve any number of methods including, for example: reverse- phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical;

simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.

Another class of separation methods involves treatment of a mixture with a reagent selected to bind to or render otherwise separable a desired product, unreacted starting material, reaction by product, or the like. Such reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, or the like. Alternatively, the reagents can be acids in the case of a basic material, bases in the case of an acidic material, binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid/liquid ion extraction reagents (LIX), N2013/000215

47

or the like. Selection of appropriate methods of separation depends on the nature of the materials involved, such as, boiling point and molecular weight in distillation and sublimation, presence or absence of polar functional groups in chromatography, stability of materials in acidic and basic media in multiphase extraction, and the like.

A single stereoisomer, e.g., an enantiomer, substantially free of its

stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Eliel, E.

and Wilen, S. "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H., (1 975) J. Chromatogr., 1 13(3):283 -302).

Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1 ) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: "Drug Stereochemistry, Analytical Methods and Pharmacology," Irving W. Wainer, Ed., Marcel Dekker, Inc., New York (1993).

Under method (1 ), diastereomeric salts can be formed by reaction of

enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a- methyl-b-phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid. The

diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography. For separation of the optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts.

Alternatively, by method (2), the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S. "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., 1994, p. 322).

Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the pure or enriched enantiomer. A method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g., (-) menthyl chloroformate in the presence of base, or Mosher ester, a-methoxy-a-(trifluoromethyl)phenyl acetate of the racemic mixture and analyzing the Ή NMR spectrum for the presence of the two atropisomeric enantiomers or diastereomers (Jacob ID. J. Org. Chem. ( 1982) 47:4165). Stable diastereomers of atropisomeric compounds can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (WO 96/151 1 1 ). By method (3), a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase ("Chiral Liquid Chromatography" (1989) W. J. Lough, Ed., Chapman and Hall, New York; Okamoto, J Chromatogr., (1990) 513 :375-378). Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.

Abbreviations and acronyms used in the following Schemes and elsewhere herein are defined as follows:

DCM Dichloromethane

DIPEA Diisopropylethylamine

DMF N,N-Dimethylformamide

DMSO Dimethyl sulfoxide

1 -Ethyl-3-(3-dimethylaminopropyl) carbodiimide

EDCI hydrochloride

ELSD Evaporative light scattering detector

equiv Molar equivalent

ESI Electrospray ionization

Et Ethyl

H NMR Proton nuclear magnetic resonance

h Hour(s)

Hydrogen gas

HOBt hydroxybenzotriazole HPLC High performance liquid chromatography

LC MS Liquid chromatography - mass spectrometry

m-CPBA m-Chloroperoxybenzoic acid

MeOH Methanol

min Minute(s)

PDA Photo diode array detector

psi Pounds per square inch

rt Room temperature

Raney Ni Raney Nickel

Re Retention factor

TFA Trifluoroacetic acid

Tf₂0 Trifluoromethanesulfonic anhydride

THF Tetrahydrofuran

TLC Thin layer chromatography

Exemplary reaction schemes that are useful in preparing compounds of the invention are described below. Methods of Chemical Analysis

Unless otherwise indicated,Ή NMR spectra were recorded at ambient temperature using one of the following machines: Varian Unity Inova (400 MHz) spectrometer with a triple resonance 5 mm probe, Bruker Avance DRX400 (400 MHz) spectrometer with a triple resonance 5 mm probe, a Bruker Avance DPX 300 (300 MHz) equipped with a standard 5 mm dual frequency probe for detection ofΉ and '^"'C, a Bruker AVIII (400 MHz) using a BBI Broad Band Inverse 5 mm probe, or a Bruker AVIII (500 MHz) using a QNP (Quad Nucleus detect) 5 mm probe. Chemical shifts are expressed in ppm relative to an internal standard; tetramethylsilane (ppm = 0.00). The following abbreviations have been used: br = broad signal, s = singlet, d = doublet, dd = double doublet, t = triplet, q = quartet, m = multiplet. High Pressure Liquid Chromatography - Mass Spectrometry (LC/MS) experiments to determine retention times (RT) and associated mass ions (e.g.,

[M+H]⁺, [M+Na]⁺, [M-H]^") were performed using one of the following methods:

Method A

Instrument: SHIMADZU LC/MS-2010EV

LC Parameters: Column: Shim-pack XR-ODS, 2.2 urn, 3.0*50mm; Mobile Phase A : Water/0.05% TFA; Mobile Phase B: Acetonitnle; Gradient: 5% to 1 00% B in 2.0 min, 100% B for 1 .1 min, 1 00% to 5% B in 0.2 min, then stop; Flow Rate: l .O mL/min; Column Temperature: 40 °C; Detector: 254 nm and ELSD; Sample Preparation : 1 mg/mL in Methanol; Injection Volume: 1 μί.

MS Parameters: Interface: ESI (Positive); Interface Voltage: 4.5 kv; Heat Block: 250 °C; Nebulizing Gas: 1 .50 L/min; Scan Range: 90-900 (m/z); Detector voltage: 1 .7 kv.

Method B

HPLC Waters Acquity UPLC with Sample Organizer

Mobile phase A 95/5/0.1 %: 1 0 mM Ammonium

Formate/Acetonitrile/Formic Acid

Mobile phase B 95/5/0.09%: Acetonitrile/Water/Formic Acid

Column Acquity UPLC BEH C,₈, 1 .7μηι 2.1 x 50 mm

temperature Ambient

LC gradient 1 5 to 1 00% B in 2.5 min, hold 95% B to 2.2 min

LC Flowrate 0.6 mL/min

UV wavelength 220 nm and 254 nm

Mass Spectrometer Waters Micromass ZQ

Ionization ELSD

Method C

Instrument: SHIMADZU LC/MS-2010EV

LC Parameters: Column: Shim-pack XR-ODS, 2.2 urn, 3.0* 50 mm; Mobile Phase A: Water/0.05% TFA; Mobile Phase B: Acetonitri le/0.05% TFA, Gradient: 5% to 100% B in 2.0 min, 100% B for 1 . 1 min, 100% to 5% B in 0.2 min, then stop; Flow Rate: 1.0 mL/min; Column Temperature: 40 °C; Detector: 254 nm and ELSD; Sample Preparation: 1 mg/mL in Methanol, Injection Volume: 1 μί.

MS Parameters: Interface: ESI (Positive); Interface Voltage: 4.5 kv; Heat Block: 250 °C; Nebulizing Gas: 1.50 L/min; Scan Range: 90-900 (m/z); Detector voltage: 1.5 kv.

Method D

Instrument: SHIM ADZ U LC/MS-2010EV

LC Parameters: Column: Waters Xselect C18, 3.0x50 mm, 3.5 μηι; Mobile Phase A: Water/0.1% formic acid; Mobile Phase B: Acetonitrile /0.05% formic acid; Gradient:

5% to 100% B in 2.0 min, 100% B for 1 .2 min, 1 00% to 5% B in 0.1 min, then stop;

Flow Rate: 0.9 mL/min; Column Temperature: 35 °C; Detector: 254 nm and ELSD;

Sample Preparation: 1 mg/mL in Methanol, Injection Volume: 1 μL·.

MS Parameters: Interface: ESI (Positive & Negative); Interface Voltage. 4.5 kv; Heat Block: 250 °C; Nebulizing Gas: 1.50 L/min; Scan Range: 90-900 (m/z); Detector voltage: 1 .5 kv.

Method E

Instrument: SHIMADZU LC/MS-2010EV

LC Parameters: Column: Shim-pack XR-ODS, 3.0x50 mm, 2.2 μιη; Mobile Phase A:

Water/0.05% TFA; Mobile Phase B: Acetonitrile; Gradient: 5% to 100% B in 2.0 min,

100% B for 1 min, 100% to 5% B in 0.3 min, then stop; Flow Rate: 1 .0 mL/min;

Column Temperature: 40 °C; Detector: 254 nm and ELSD; Sample; Preparation: 1 mg/mL in Methanol; Injection Volume: 1 μL·.

MS Parameters: Interface: ESI (Positive); Interface Voltage: 4.5 kv; Heat Block:

250 °C; Nebulizing Gas: 1 .50 L/min; Scan Range: 90-900 (m/z); Detector voltage:

1.3 kv.

Method F

Instrument: SHIMADZU LC/MS-2020 LC Parameters: Column: Shim-pack XR-ODS, 2.2 um, 3.0*50 mm; Mobile Phase A: Water/0.05% TFA; Mobile Phase B: Acetonitrile; Gradient: 5% B tol 00% B for 2.0 min, 100% B for 1.2 min, 100% B to 5% in 0.1 min, then stop; Flow Rate: 1.0 mL/min; Column Temperature: 40 °C; Detector: UV and ELSD; Sample Preparation: 1 mg/mL in Methanol; Injection Volume. 1 ί.

MS Parameters: Interface: ESI (Positive); Interface Voltage: 4.5 kv; Heat Block: 250 °C; Nebulizing Gas: 1.50 L/min; Scan Range: 70-900 (m/z); Detector voltage: 1.1 kv. Method G

Instrument: SHIMADZU LC/MS-2020EV

LC Parameters: Column: Shim-pack XR-ODS, 50 mm*3.0 mm, 2.2 um; Mobile Phase A: Water/0.05% TFA; Mobile Phase B: Acetonitrile; Gradient: 5% to 100% B in 2. 1 min, 100% B for 0.8 min, 100% to 5% B in 0. 1 min, then stop; Flow Rate: 1 .0 mL/min; Column Temperature: 40 °C; Detector: 254 nm and ELSD; Sample

Preparation. 1 mg/mL in Acetonitrile; Injection Volume: 1 μL·.

MS Parameters: Interface: ESI (Positive); Interface Voltage: 4.5 kv; Heat Block: 250 °C; Nebulizing Gas. 1.50 L/min; Scan Range: 90-900 (m/z); Detector voltage. 1.05 kv.

Method H

Instrument: SHIMADZU LC/MS-2020

LC Parameters: Column: Shim-pack XR-ODS, 2.2 um, 3.0*50 mm; Mobile Phase A: Water/0.05% TFA; Mobile Phase B: Acetonitrile/0.05% TFA; Gradient: 5% to 100% B in 2.0 min, 100% B for 1 .2 min, 1 00% to 5% B in 0. 1 min, then stop; Flow Rate: 1.0 mL/min; Column Temperature: 40 °C; Detector: 254 nm and ELSD; Sample Preparation: 1 mg/mL in Methanol; Injection Volume: 1 μί.

MS Parameters: Interface: ESI (Positive); Interface Voltage: 4.5 kv; Heat Block: 250 °C; Nebulizing Gas. 1 .50 L/min; Scan Range: 90-900 (m/z), Detector voltage: 1.1 kv. Method I

Instrument: SHIMADZU LC/MS-2020

LC Parameters: Column: Shim-pack XR-ODS, 50*3.0 nm, 2.2 um; Mobile Phase A: Water/0.05% TFA; Mobile Phase B: Acetonitrile/0.05% TFA; Gradient: 5% B to 100% B for 2.0 min, 100% B for 1 .2 min, 100% B to 5% B in 0.1 min, then stop; Flow Rate: 1 .0 mL/min; Column Temperature: 40 °C; Detector: 254 nm and ELSD; Sample Preparation: 1 mg/mL in Methanol, Injection Volume: 1 μL·.

MS Parameters. Interface: ESI (Positive); Interface Voltage: 4.5 kv; Heat Block: 250 °C; Nebulizing Gas: 1.50 L/min; Scan Range: 70-900 (m/z); Detector voltage: 1 .05 kv.

Method J

HPLC Agilent 1200 Series

Mobile phase A Water with 0. 1 % Formic Acid

Mobile phase B Acetomtrile with 0.1 % Formic Acid

Column Agilent Zorbax SB-Cis, 3.5 μιτι, 2.1 x30 mm

temperature Ambient

LC gradient 15 to 95% B in 2.5 min, hold 95% B to 3.5 min

LC Flowrate 2 mL/min

UV wavelength Signal 254nm; Bandwidth 4 nm. Reference

360 nm, Bandwidth 100 nm

Mass Spectrometer Agilent G1956B, MSD

Ionization Dual Atmospheric Pressure Electrospray

lonisation (APES1) and Chemical Ionization

mode (APCI); Positive and Negative ion

Method K

Instrument: HPLC-Agilent 1 100

LC Parameters: Column: ZORBAX SB-C18, 1 .8 mm, 20 x 2.1 mm; Mobile Phase A. Water/0.05% TFA; Mobile Phase B: Acetonitrile/0.05% TFA; Gradient: 3% to 97% B in 7.0 min, 97% B for 1 .5 min, then stop; Flow Rate: 0.4 mL/min; Column

Temperature: 40 °C; Detector: 220 nm and 254 nm.

MS Parameters: Agilent MSD; Interface: ESI (Positive). Method L

Instrument: SHIMADZU LCMS-2010EV

LC Parameters: Column: Waters XBridge CI 8 3.0 x 50 mm, 3.5 μ, Mobile Phase A. Water/5 mM Ammonium Acetate; Mobile Phase B: Methanol; Gradient: 1 0% to 100% B in 1 .8 minutes, 100% B for 1 .3 minutes, 100% to 10% B in 0.1 minutes, then stop; Flow Rate: 0.9 mL/min; Column Temperature: 40 °C; Detector: PDA and ELSD; Sample Preparation: 1 mg/mL in Methanol; Injection Volume: 1 μί; Report: Area Normalized Purity

MS Parameters: Interface: ESI (Positive & Negative); Interface Voltage: 4.0 kv; Heat Block: 250 °C; Nebulizing Gas: 1.50 L/min; Scan Range: 90-900 (m/z); Detector voltage: 1.5 kv

Method M

Instrument. SHIMADZU LCMS-2020

LC Parameters: Column: Shim-pack XR-ODS 3.0 x 50 mm, 2.2 μ; Mobile Phase A: Water/0.05% TFA; Mobile Phase B: Acetonitrile; Gradient: 5% to 100% B in 2.0 minutes, 100% B for 1.2 minutes, 100% to 5% B in 0.2 minutes, then stop; Flow Rate: 1.0 mL/min; Column Temperature: 40 °C; Detector: 254 nm and ELSD; Sample Preparation. 1 mg/mL in Acetonitrile; Injection Volume: 1 μί; Report: Area

Normalized Purity

MS Parameters: Interface: ESI (Positive); Interface Voltage: 4.5 kv; Heat Block: 200 °C; Nebulizing Gas: 1.50 L/min; Scan Range: 90-900 (m/z); Detector voltage: 1 05 kv

Method N

Instrument: SHIMADZU LCMS-2020 LC Parameters: Column: Shim-pack XR-ODS 3.0 x5 0 mm, 2.2 μ; Mobile Phase A: Water/0.1% formic acid; Mobile Phase B: Acetonitrile/0.05% formic acid; Gradient: 5% to 100% B in 2.0 minutes, 100% B for 1 .2 minutes, 100% to 5% B in 0.2 minutes, then stop; Flow Rate: 1 .0 mL/min; Column Temperature: 40 °C; Detector: 254 nm and ELSD; Sample Preparation: 1 mg/mL in Acetonitrile; Injection Volume 1 μί; Report: Area Normalized Purity

MS Parameters: Interface: ESI (Positive); Interface Voltage. 4.5kv; Heat Block.

200 °C; Nebulizing Gas: 1.50 L/min; Scan Range: 90-900 (m/z); Detector voltage: 0.95 kv

Method O

Instrument: SHIMADZU LCMS-2020

LC Parameters: Column: Gemini-NX 3u C I 8 1 10A; Mobile Phase A: Water/ 0.04% Ammonia; Mobile Phase B: Acetonitrile; Gradient: 5% to 100% B in 2.0 minutes, 100% B for 1.1 minutes, 100% to 5% B in 0.1 minutes, then stop; Flow Rate: 1 .0 mL/min; Column Temperature: 35 °C; Detector: 254 nm and ELSD; Sample

Preparation: 1 mg/mL in Methanol; Injection Volume: 1 μί; Report: Area

Normalized Purity

MS Parameters: Interface: ESI (Positive & Negative); Interface Voltage: 4.5 kv Heat Block: 200 °C; Nebulizing Gas: 1 .50 L/min; Scan Range: 90-900 (m/z);

Detector voltage: 0.75 kv

Method P

Instrument: SHIMADZU LCMS-2020EV

LC Parameters: Column: Shim-pack XR-ODS 50 mm*3.0 mm, 2.2 um; Mobile Phase A: Water /0.05% TFA; Mobile Phase B: Acetonitrile /0.05% TFA; Gradient: 5% to 100% B in 1 .2 minutes, 100% B for 0.9 minutes, 100% to 5% B in 0.2 minutes, then stop; Flow Rate: 1.0 mL/min; Column Temperature: 40 °C; Detector: PDA and ELSD; Sample Preparation: 1 mg/mL in Acetonitrile; Injection Volume: 1 μί; Report. Area Normalized Purity MS Parameters: Interface: ESI (Positive); Interface Voltage: Tuning File; Heat Block: 250 °C; Nebulizing Gas: 1.50 L/min; Scan Range: 90-900(m/z), Detector voltage: 1 . 10 kv Method Q

Instrument: SHIMADZU UPLCMS-2020EV

LC Parameters: Column: Shim-pack XR-ODS 50 mm*2.0 mm, 1 .6 um; Mobile Phase A: Water /0.1 % formic acid; Mobile Phase B: Acetonitnle /0.05% formic acid;

Gradient: 5% to 100% B in 2.0 minutes, 1 00% B for 1 . 1 minutes, 100% to 5% B in 0.1 minutes, then stop; Flow Rate: 0.7 mL/min; Column Temperature. 40 °C;

Detector: PDA and ELSD; Sample Preparation: 1 mg/mL in Acetonitrile; Injection Volume: 1 μΕ; Report: Area Normalized Purity

MS Parameters: Interface: ESI (Positive); Interface Voltage: Tuning File; Heat Block: 250 °C; Nebulizing Gas: 1 .50 L/min; Scan Range: 90-900(m/z); Detector voltage: 0.85 kv

Method R

Instrument: SHIMADZU LCMS-2020EV

LC Parameters: Column: Shim-pack XR-ODS 50 mm*3.0 mm, 2.2um; Mobile Phase A: Water 10.1 % formic acid; Mobile Phase B: Acetonitrile /0.05% formic acid;

Gradient: 5% to 100% B in 2.0 minutes, 100% B for 1 . 1 minutes, 100% to 5% B in

0.1 minutes, then stop; Flow Rate: 1 .0 mL/min; Column Temperature: 40 °C;

Detector: PDA and ELSD; Sample Preparation: 1 mg/mL in Acetonitnle; Injection

Volume: 1 μί; Report: Area Normalized Purity

MS Parameters : Interface: ESI (Positive); Interface Voltage: Tuning File, Heat Block:

250 °C; Nebulizing Gas : 1 .50 L/min; Scan Range: 90-900(m/z); Detector vohage: 0 9 kv

Method S

Instrument: Waters Acquity UPLC LC Parameters: Column: Acquity UPLC BEH CI 8, 1.7 mm, 2.1 *50 mm; Mobile Phase A: Water /0.05% TFA; Mobile Phase B: Acetonitrile /0.05% ; Gradient: 2% to 98% B in 17.5 min, 98% B for 1 .5 min, equilibration for 1 .5 min, then stop; Flow Rate: 0.6 mL/min; Column Temperature: 40 °C; Detector: 254 and 220 nm

MS Parameters (Waters LCT Premier XE): Interface: ESI (Positive); Scan Range: 80- 1300 amu; Detector, time of flight

Method T

Instrument: HPLC Agilent 1200

LC Parameters: Column: Agilent ZORBAX SB-C18, 1 .8 mm, 30 x 2. 1 mm; Mobile Phase A: Water /0.05% TFA; Mobile Phase B: Acetonitrile /0.05% TFA; Gradient: 3% to 95% B in 7.0 minutes, 95% B for 1 5 minutes, equilibration for 1 .5 min, then stop; Flow Rate: 0.4 mL/min; Column Temperature: 35 °C; Detector: 254 and 220 nm; Sample Preparation: 1 mg/mL in MeOH; Injection Volume: 1 μί; Report: Area Normalized Purity

MS Parameters: Interface: ESI (Positive); Scan Range: 1 10-800 amu; Detector: single quadrupole

The following examples illustrate the preparation of representative compounds of the invention. Unless otherwise specified, all reagents and solvents were of standard commercial grade and were used without further purification.

I. Preparation of Intermediates

Intermediate 1 : Furo[2,3-c]pyridi -2-carboxylic acid

Step 1 . Ethyl 3-hydroxyisonicotinate. A solution of 3-hydroxyisonicotinic acid (495 g, 3.56 mol) in ethanol (7 L) and concentrated H2SO4 (250 mL) was heated under reflux for 72 h and then cooled to rt and concentrated under reduced pressure to remove the solvent. The residue was dissolved in water (3 L) and the pH was adjusted to 4 by addition of saturated aqueous NaHCOj solution. The resulting precipitate was removed by filtration and the filtrate was extracted with DCM (2 L><3). The combined organic phase was washed with brine, dried over anhydrous Na2SO and then concentrated under reduced pressure to give ethyl 3-hydroxyisonicotinate (414 g, 70%) as yellow oil.

Step 2. Ethyl 3-(2-ethoxy-2-oxoethoxy)isonicotinate. To a solution of triphenylphosphine (780 g, 2.97 mol) in THF (6 L) at -10 °C was added dropwise diisopropyl azodicarboxylate (600 mL, 2.97 mol). The reaction mixture was stirred at -10 °C for 30 min and then ethyl 3-hydroxyisonicotinate (414 g, 2.48 mol) in THF (1 L) solution was added dropwise. The resulting mixture was stirred at it for 16 h and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate (4 L) and 1 N HC1 (2 L). The aqueous layer was separated and the organic phase was extracted by 1 N HC1 (1 L^x2). The combined aqueous layers were slowly adjusted to pH 8 by addition of solid NaHCO;, and then extracted with ethyl acetate (2 Lx2). The combined organic layers were dried over anhydrous Na2SC>4 and then concentrated under reduced pressure to give the title compound (380 g, 61 %) as a brown oil.

Step 3. Ethyl 3-hydroxyfuro[2.3-c]pyridine-2-carboxylate. To a suspension of NaH (72 g, 1 .8 mol, 60% suspension in mineral oil) in anhydrous THF (2 L) at 0 °C was added dropwise a solution of ethyl 3-(2-ethoxy-2-oxoethoxy)isonicotinate (380 g, 1.5 mol) in THF (1 L) under argon. The reaction mixture was stirred at rt for 16 h and then carefully quenched with ice water (1 L). The resulting mixture was concentrated to a volume of 1 .2 L and then diluted with saturated aqueous NaHCO? solution (2.5 L), and stirred for an additional 30 min. The precipitated solid was collected by filtration and washed with ethyl acetate (1 L). The filtrate was washed with ethyl acetate ( 1 L><2) and the aqueous layer was combined with the solid and carefully acidified to a pH of 5 with acetic acid. The resulting solid was collected by filtration and dried under vacuum to give the title compound (21 0 g, 68%) as a yel low solid.

Step 4. Ethyl 3-(((trifluoromethyl)sulfonynoxy)furo[2.3-c]pyridine-2- carboxylate. To a solution of ethyl 3-hydroxyfuro[2,3-c]pyridine-2-carboxylate (210 g, 1.01 mol) and pyridine (107 mL, 1 .3 mol) in anhydrous DCM (3 L) at 0 °C was added dropwise TfiO (203 g, 1.2 mol). The reaction mixture was stirred at rt for 16 h and then quenched with ice water (1 L). The aqueous layer was extracted with DCM ( 1 Lx2) and the combined organic layer was dried over anhydrous Na2SC>4 and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 10% ethyl acetate/petroleum ether to give the title compound (298 g, 87%) as a white solid.

Step 5. Ethyl furo[2.3-c|pyridine-2-carboxylate. To a solution of ethyl 3- (((trifluoromethyl)sulfonyl)oxy)furo[2,3-c]pyridine-2-carboxylate (298 g, 0.88 mol) in ethanol (3 L) was added 10% Pd/C (30 g) and tnethylamine (281 mL, 2.02 mol). The reaction mixture was stirred under an atmosphere of hydrogen for 1 6 h and then filtered through a pad of diatomaceous earth. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with 20% ethyl acetate/petroleum ether to givethe title compound (158 g, 94%) as a pale yellow solid.

Step 6. To a solution of ethyl furo[2,3-c]pyridine-2-carboxylate ( 158 g, 0.83 mol) in water:THF:MeOH (1 : 1 : 1 , 2.4 L) was added KOH (1 39 g, 2.49 mol). The reaction mixture was stirred at rt for 16 h and then concentrated to a volume of 750 mL. To this residue was added acetic acid until pH ~ 4. The resulting solids were collected by filtration, washed with water (300 mL><2) and dried in a vacuum oven overnight to give the title compound ( 101 g, 75%) as a pale yellow solid. Ή NMR (400 MHz, DMSO-i/₆) δ 9.07 (s, 1 H), 8.47 (d, .7 = 5.6 Hz, 1 H), 7.80 (d, J = 5.2 Hz, 1 H), 7.61 (s, 1 H). MS (ESI+) m z: 164 [M + H]\

Intermediate 2: lmidazo[ l .2-a]pyridine-6-carboxylic acid

Step 1 . Imidazo[l ,2-a]pyridine-6-carboxylic acid hydrochloride salt. A mixture of 2-chloroacetaldehyde (277 g, 40%) and 6-aminonicotinic acid (1 50 g) in ethanol (330 mL) was heated to reflux and stirred for 8 h. After cooling, a solid precipitated and was isolated by vacuum filtration, then washed with ethanol and dried under vacuum to give the title compound as a light yellow solid (1 .78 g, 82%).

Step 2. Irnidazo[ l ,2-a]pyridine-6-carboxylic acid hydrochloride salt ( 1 70 g) was diluted with water (600 mL) and heated until a clear solution resulted, then an aqueous solution of NaOH (2 M) was added slowly to adjust the pH = 5-6. The reaction mixture was cooled to 0 °C using an ice-H₂0 bath. The resulting precipitate was collected by vacuum filtration, then washed with ethanol and dried under vacuum to give the title product (107.2 g, 77%) as a light yellow powder. Ή NMR (400 MHz, DMSO-i _ft) 6 13.76-12.82 (br, 1 H), 9.28 (s, 1 H), 8. 10 (s, 1 H), 7.68 (s, 1 H), 7.64-7.56 (m, 2H). MS (ESI+) m z: 163 [M + Hf .

Intermediate 3: Imidazo[1.2-a]pyrimidine-6-carboxylic acid

Step 1. Sodium (Z)-2-(dimethoxymethyl)-3-methoxy-3-oxoprop-l -en-l -olate. Methyl 3,3-dimethoxypropanoate ( 100 g, 675 mmol) and methyl formate (81 g, 1350 mmol) were dissolved in anhydrous THF (450 mL). Sodium hydride (60% dispersion; 32.4 g, 810 mmol, 1 .2 eq.) was then added slowly in portions at 0 °C. The reaction mixture was stirred at rt for 1 h, then was heated at 50 °C for 3 h. During this period, ¾ evolution was observed. After cooling to rt, the solvent was then removed under reduced pressure to give the crude product which was directly used in the next step without further purification.

Step 2. Methyl 2-aminopyrimidine-5-carboxylate. The crude enolate from step 1 was dissolved in DMF (200 mL), and guanidine hydrochloride (64 g, 670 mmol) was added. The mixture was heated at 100 °C under N2 for 3 h. After cooling to rt, water was added and the mixture was cooled with an ice-water bath. The resulting precipitate was collected by vacuum filtration and dried under vacuum to give the desired product (63 g, 61 % yield for 2 steps).

Step 3. Methyl imidazo[l ,2-a]pyrimidine-6-carboxylate. To a mixture of 2- bromo-1 ,1 -diethoxyethane (100 6 g, 0.51 mol) and methyl 2-aminopyrimidine-5- carboxylate (63 g, 0.41 mol) in ethanol (300 mL) was added concentrated HBr (40%) (55 g). The reaction mixture was heated to reflux for 3 h under N₂. After cooling to rt, the mixture was further cooled with an ice-water bath. The resulting precipitate was collected by vacuum filtration and dried under vacuum overnight to give the desired product (92 g, 87%)

Step 4. Into a round bottom flask containing methyl imidazo[l ,2- a]pyrimidine-6-carboxylate (92 g, 356.5 mmol), was added water (200 mL). NaOH (6 N in H2O, 2.5 eq.) was then added dropwise with stirring at rt. After stirring at rt for 1 h, the mixture was cooled with an ice- water bath and concentrated HCI was added (pH = 5-6). The resulting mixture was concentrated under reduced pressure to approximately 150 mL (3/4 volume) and cooled with an ice-water bath The resulting precipitate was collected by vacuum filtration, washed with cold water (50 mL) and dried to give the title compound as an off-white solid (46 g, 79%). Ή NMR (DMSO- d₆, 400 MHz) δ 9.29 (d, J = 2.0 Hz, 1 H), 8.89 (d, J= 2.0 Hz, 1 H), 7.94 (s, 1 H), 7.70 (s, 1 H). LC-MS (mix, ES⁺): 164.1 [M + H]⁺, 186.1 [M + Naf.

Intermediate 4: 1 H-Pyrazolo[3.4-b]pyridine-5-carboxylic acid

Step 1 . I -(4-Methoxybenzyl)- l H-pyrazol-5-amine. To a solution of acrylonitrile (30 ml, 455 mmol) in THF (250 mL), NH₂NH₂ H₂0 (23.19 mL, 478 mmol) was added drop-wise at 0 °C. After addition was complete, the mixture was stirred at rt for 2 h, then 4-methoxybenzaldehyde (55.4 mL, 455 mmol) was added drop-wise. The mixture was stirred at rt overnight, then at reflux for 2 h. After cooling to rt the mixture was quenched by addition of 300 mL of ice water. The mixture was extracted with ethyl acetate (3 x), then the combined organic layers were extracted with 1 N HCI. The aqueous layer was neutralized with aqueous 10 N NaOH solution, then extracted with ethyl acetate. The organic layer was washed with H2O and brine, then dried over Na₂S0₄. Filtration, concentration, and recrystrallization with diethyl ether gave the target compound as a white solid (50 g, 60%).

Step 2. Ethyl 4-hvdroxy- l -(4-methoxybenzvD- l H-pyrazolo[ ,4-b1pyridine-5- carboxylate. 1 -(4-Methoxybenzyl)-l H-pyrazol-5-amine (3.94 g, 1 9.39 mmol), followed by diethyl 2-(ethoxymethylene)malonate (4 mL, 20 mmol) was added to a 200 mL round bottom flask fitted with a distillation head to remove ethanol. The mixture was heated to 130 °C for 45 min, then 10 mL of diphenyl ether was added and the temperature was raised to 240 °C for 2 h. The reaction mixture was then cooled to rt and diethyl ether (100 mL) was added. The resulting precipitate was collected by vacuum filtration and dried under vacuum to afford the target compound as a white solid (4 g, 62%).

Step 3. Ethyl 4-chloro-l -(4-methoxybenzylVl H-pyrazolo[3.4-b]pyridine-5- carboxylate. POCI3 (10 mL) was added to ethyl 4-hydroxy-l -(4-methoxybenzyl)-l H- pyrazolo[3,4-b]pyridine-5-carboxylate (7.5 g, 19.39 mmol). The mixture was stirred at 60 °C for 3 h. The mixture was poured into ice water and the resulting precipitate was collected by vacuum filtration and dried under vacuum to afford the target compound a light yellow solid (6.4 g, 80%).

Step 4. Ethyl l -(4-methoxybenzyn-l H-pyrazolo[3,4-b]pyridine-5-carboxylate. To a solution of ethyl 4-chloro- l -(4-methoxybenzyl)- 1 H-pyrazolo[3,4-b]pyridine-5- carboxylate (5.9 g, 17 mmol) in THF (50 mL), triethylamine (1.7 g, 17 mmol), followed by Pd(OH)₂/C (300 mg) was added. The mixture was stirred at rt for 3 h under ¾. The mixture was filtered and concentrated. The residue was dissolved in ethyl acetate and washed with saturated aqueous NaHCC solution and brine, then dried over Na_^SO,*. Filtration and concentration gave target compound as a light gray solid (5.3 g, 100%).

Step 5. Ethyl 1 -(4-methoxybenzyl)-l H-pyrazolo[3,4-b]pyridine-5-carboxylate (4.4 g, 14 mmol) was dissolved in TFA (1 58 mL) and heated to 80 °C. The mixture was stirred at 80 °C for 4 h, then was concentrated to dryness. The residue was poured into ice water, then aqueous NaOH solution (2 M) was added until the pH was approximately 14. The solid formed was removed by filtration, and the aqueous layer was washed with ethyl acetate. To the aqueous layer was added concentrated HC1 was added until the pH was approximately 7. The resulting precipitate was collected by vacuum filtration and dried under vacuum to afford the title compound as a white solid (2. 1 g, 80%). Ή NMR (400 MHz, OMSO-d₆) δ 14.38- 13.62 (br, 1 H), 9.07 (d, .7 = 1.6 Hz, 1 H), 8.81 (d, J = 1.6 Hz, 1 H), 8.32 (s, 1 H). MS (ESI+) m z: 164 [M + H]⁺.

Intermediate 5: l H-Pyrrolo[3.2-c]pyridine-2-carboxylic acid

Step l . 3-Iodopyridin-4-amine. To a 2 L 3-necked flask was added a solution of 38 mL of concentrated sulfuric acid in 200 mL water. The solution was cooled with an ice-water bath, then 4-aminopyridine (200 g, 2.12 mol) and acetic acid (700 mL) were added in batches. The mixture was then heated to reflux. Iodine (1 89 g, 0.745 mol) and periodic acid dihydrate (97 g, 0.424 mol) were both equally divided into four parts. One batch of iodine was added and then one batch of periodic acid dihydrate was added 1 5 min later. After 30 min, a new batch of iodine and periodic acid dihydrate were added in the same way. When all four batches of iodine and periodic acid dehydrate were added, the mixture was kept refluxing for an additional 3 h. After cooling to rt the reaction mixture was slowly poured into water while stirring, then a 40% solution of NaOH in water was added until pH > 9. Na2SOj was added to destroy the unreacted iodine. After cooling to rt, a filtration was performed. The collected solid was further purified by recrystallization in chloroform to give the desired product (184 g, 39%).

Step 2. To a 2 L 3-necked flask was added DMF (700 mL), triethylene diamine ( 168 g, 1 .5 mol), and 4-amino-3-iodopyridine (24, 1 10 g, 0.5 mol). The mixture was cooled with an ice-water bath and pyruvic acid (1 32 g, 1 .5 mol) was slowly added, followed by palladium acetate (4.49 g, 0.02 mol). Under nitrogen atmosphere, the mixture was heated to 1 15 °C. The reaction generated effervescence. The reaction mixture was kept at 1 15-120 °C for 1 1 h. The mixture was concentrated under reduced pressure. The residue was poured into water (500 mL), and concentrated HC1 was added to adjust pH to <1 . The mixture was cooled by adding ice and a filtration was performed. The cake thus obtained was a brownish black solid.

The above cake was added into 500 mL of water. Concentrated HC1 was added (to ensure complete protonation) followed by 5 g of active carbon. The mixture was heated to reflux for 20 min and then filtration was performed while hot. The solid was discarded and the hot filtrate was placed in a refrigerator to allow the HC1 salt of the desired product to precipitate. Upon cooling, filtration was performed which afforded a dark brown solid with a wet weight of 48 g as the HC1 salt of the desired product.

The solid was then added to 250 mL of water and the mixture was heated until a clear solution resulted. Solid NaOH was slowly added to adjust pH to 5-6, then active carbon and an addtional 500 mL of water was added. The mixture was heated to reflux for 30 min, then filtration was performed while hot. The resulting cake was added to 750 mL of water, heated to reflux, and filtered again. The cake thus obtained was discarded. The two batches of filtrate were combined and cooled in a refrigerator. The resulting precipitate was collected by vacuum filtration, then washed with ethanol to give the title compound as a slightly yellow solid (25 g, 3 1 %). MS (OT^.'Z, ES^'): 161 .1 [M-l ], 323.1 [2M-1 ]. Ή NMR (DMSO-c/₆, 400 MHz) δ 12.20 (br s, 1H), 8.97 (s, 1 H), 8.27 (d, J = 5.6 Hz, 1 H), 7.41 (d, J = 6.0 Hz, 1 H), 7.23 (s, 1 H).

Intermediate 6: Thieno[2.3-c]pyridine-2-carboxylic acid

Step 1 . 3.5-Dibromoisonicotinaldehyde. Lithium diisopropylamide (507 mmol, 1 .2 eq.) was added to 200 mL of dry THF at -78 °C under N₂. A solution of 3,5-dibromopyridine (100 g, 424 mmol) in 537 mL of dry THF was then added drop- wise over 30 min. The reaction mixture was stirred at -78 °C for 1 h. Ethyl formate (34.4 g, 465 mmol) was added drop-wise and stirred at -78 °C for 30 min, then the reaction mixture was poured into ice-cold saturated aqueous NaHCO_? solution. The mixture was extracted with 3 x 500 mL of ethyl acetate. The organic layer was concentrated to provide a brown solid, which was filtered through a pad of silica gel (eluted with DCM) to give the title compound as a yellow powder (70 g, 63%).

Step 2: Methyl 4-bromothieno[2,3-c|pyridine-2-carboxylate. 3,5- Dibromoisonicotinaldehyde (80 g, 303 mmol), followed by cesium carbonate (98 g, 302 mmol) was added to a 2 L round bottom flask containing THF (1 .3 L) under N₂. Methyl mercaptoacetate (32 g, 302 mmol) was added and the mixture was heated at 60 °C overnight. After cooling to rt, ethyl acetate was added and the organic layer was washed with water, aqueous saturated NaHC(¾ solution, and brine, then dried over NazS0₄ and filtered to give a white solid. The crude product was purified by recrystallization from ethyl acetate to give the desired product (60 g, 73%).

Step 3. Methyl thieno[2.3-c]pyridine-2-carboxylate. Methyl 4- bromothieno[2,3-c]pyridine-2-carboxylate ( 1 1 5 g, 423 mmol), triethylamine (42.7 g, 423 mmol), THF (1 .5 L), and MeOH (500 mL) were mixed and degassed. Under nitrogen, palladium on carbon (1 0%, 14.7 g, 1 3.9 mmol) was added. The mixture was hydrogenated with a Parr apparatus at 45 psi H₂ for 3 days. The catalyst was filtered off and the filtrate was concentrated to give the desired compound as a white solid (65 g, 80%).

Step 4. A three necked 2 L round bottom flask equipped with an overhead stirrer and thermocouple was charged with methyl thieno[2,3-c]pyridine-2- carboxylate (130 g, 674 mmol) and water (650 mL). Aqueous sodium hydroxide solution (1 0 N) was added with stirring at 20 °C. Over the next 20 min, the temperature rose to 25 °C and the solid dissolved. After 1 h, concentrated HC1 (1 .5 eq.) was slowly added to the reaction mixture with rapid stirring, generating a thick slurry. After stirring for 1 h, the slurry was filtered and the solid was dried under vacuum to give the title compound as a white solid ( 1 05.5 g, 88%). MS (ni z, ES ): 178.0 [M-l ]. 'H-NMR (DMSO-dtf, 400 MHz) δ 1 2.24 (br s, 1 H), 8.97 (s, 1 H), 8 27 (d, J = 6.0 Hz, 1 H), 7.40 (d, J = 5.6 Hz, 1 H), 7.23 (s, 1 H).

Intermediate 7: Imidazo[l .2-b]pyridazine-6-carboxylic acid 5

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Step 1 . 6-Chloro-imidazo[l ,2-b]pyridazine. A solution of 6-chloro-l ,2- diazinan-3-amine (10 g, 73.75 mmol, 1 .00 equiv), 2-bromo-l ,l -dimethoxyethane (50 g, 295.83 mmol, 4.01 equiv), and HBr (40%, 45 mL) in ethanol (100 mL) was stirred overnight at 90 °C. The majority of the ethanol was removed under reduced pressure then the pH value of the solution was adjusted to 10 with 5% aqueous potassium carbonate solution. The resulting mixture was extracted with 6x500 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1 /2 to 1 /1 ) to give 6.5 g (57%) of the title

compound as a yellow solid. Ή NMR (300 MHz, CDCb) δ 7.95 (s, 1 H), 7.91 (s, 1 H), 7.80 (s, 1 H), 7.05 (d, J = 9.3 Hz, 1 H).

Step 2. midazof 1 ,2-b1pyridazine-6-carboxylic acid methyl ester. A mixture of 6-chloro-imidazo[l ,2-b]pyridazine (200 mg, 1 .30 mmol, 1 .00 equiv),

bis(triphenylphosphine)palladium(II) dichloride (200 mg, 0.28 mmol, 0.22 equiv), and triethylamine (0.5 mL) in MeOH (4 mL) was stirred under carbon monoxide (10 atm) in a 50-mL pressure reactor overnight at 1 10 °C. The solid material was

removed by filtration. The filtrate was concentrated under vacuum and the residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1 /l ) to give 1 00 mg (43%) of the title compound as a yellow solid Ή NMR (300 MHz,

CDC1₃) δ 8.16 (s, 1 H), 8.08 (d, = 9.6 Hz, 1 H), 7.94 (s, 1 H), 7.77 (d, J = 9.6 Hz, 1 H), 4.09 (s, 3H).

Step 3. A mixture of imidazof 1 ,2-b]pyridazine-6-carboxylic acid methyl ester (900 mg, 5.08 mmol, 1 .00 equiv) and 5% aqueous sodium hydroxide solution ( 1 5 mL, 3.75 equiv) in THF (3 mL) was stirred overnight at rt. The pH value of the solution was adjusted to 2 with 1 M HC1. The resulting mixture was concentrated under vacuum to give 3 g of crude title product as a yellow solid. The crude product was used without further purification. LC/MS (Method A, ESI): RT= 0.43 min, m z =

164.0 [M+H]⁺. P T/CN2013/000215

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Intermediate 8: [1.2.4]Triazolo[ 1.5-a]pyridine-6-carboxylic acid

Step 1 . N'-(5-Bromo-pyridin-2-yl)-N,N-dimethyl-formamidine. A solution of 5-bromopyridin-2-amine (4 g, 23.12 mmol, 1 .00 equiv) and Ν,Ν-dimethylformamide dimethyl acetal (9.6 mL, 3.00 equiv) in DMF (30 mL) was stirred under nitrogen for 12 h at 130 °C. The reaction mixture was cooled to rt and then concentrated under vacuum to give 4 g (76%) of the title compound as an oil. TLC: 1 :5 MeOH/DCM, Rf = 0.6.

Step 2. 6-Bromo-[1 ,2.4]triazolo[1 ,5-a]pyridine. To a solution of N'-(5- bromo-pyridin-2-yl)-N,N-dimethyl-formamidine (4 g, 17.54 mmol, 1.00 equiv) in

MeOH (40 mL) maintained under nitrogen at 0 °C was added pyridine (4 mL, 2.00 equiv) and (aminooxy)sulfonic acid (3.6 g, 31 .83 mmol, 1 .30 equiv). The resulting solution was stirred for 12 h at rt. After the reaction completed, the mixture was concentrated under vacuum. The residue was diluted with 150 mL of ethyl acetate then washed with 1 x50 mL of saturated aqeous sodium carbonate solution and 2x50 mL of water. The organic layer was dried over anhydrous sodium sulfate then

concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/hexane (1 : 1 ) to give 2.5 g (72%) title compound as a solid. LC/MS (Method D, ESI): RT= 1 . 15 min, m z = 198.0 [M+H] ^~.

Step 3. [1 ,2 41Triazolo[1 ,5-a]pyridine-6-carboxylic acid methyl ester. A mixture of 6-bromo-[l ,2,4]triazolo[l ,5-a]pyridine (2.4 g, 1 2 12 mmol, 1 .00 equiv), bis(triphenylphosphine)palladium(II) dichloride (800 mg, 1 .14 mmol, 0.10 equiv) and triethylamine (4 g, 39.53 mmol, 3.00 equiv) in DMSO (1 .6 g, 20.48 mmol, 1 .67 equiv) and MeOH (50 mL) was stirred under carbon monoxide (10 atm) for 20 h at 100 °C.

The reaction mixture was cooled to rt and quenched with brine (50 mL). The resulting solution was extracted with ethyl acetate (3x40 mL). The combined organic layers were dried over anhydrous sodium sulfate then concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/hexane ( 1 : 1 ) to give 0.98 g (46%) of the title compound as a crude solid. LC/MS (Method C, ESI): RT= 1 .04 mm, m 'z = 178.0 [M+H]⁺.

Step 4. A solution of [ l ,2,4]triazolo[l ,5-a]pyridine-6-carboxylic acid methyl ester (200 mg, 1 .13 mmol, 1 .00 equiv) in tetrahydrofuran (2 mL) was added to a solution of potassium hydroxide (1 g, 17.82 mmol, 1 5.79 equiv) in water (10 mL). The resulting mixture was stirred for 10 h at rt. After the reaction completed, the pH value of the solution was adjusted to 5-6 with 1 N HCl. The mixture was extracted with 3x50 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give 1 12 mg (61 %) of the title compound as a solid. LC MS (Method C, ESI): RT= 0.9 min, m z = 164.0 [M+Hf.

Intermediate 9: Pyrazolo[L5-a]pyrimidine-5-carboxylic acid

Step 1 . 4H-Pyrazolo[L5-a]pyrimidin-5-one. A solution of 1 H-pyrazol-3- ylamine (7 g, 84.24 mmol, 1.00 equiv) and ethyl prop-2-ynoate (50 mL) in dioxane (10 g, 1.21 equiv) was stirred under nitrogen overnight at 1 10 °C. The reaction mixture was cooled to rt and the precipitated product was collected by filtration to give 4 g (36%) of the title compound as a light brown solid. Ή NMR (300 MHz, DMSO-c ₆) 5 12.04 (s, 1 H), 8.41 -8 44 (m, 1 H), 7.71 (d, J = 1 .8 Hz, 1 H), 5.88 (d, J = 8.1 Hz, 1 H), 5 77 (m, 1 H).

Step 2. 5-Chloro-pyrazolo[l .5-a]pyrimidine. A solution of 4H-pyrazolo[ 1 ,5- a]pynmidin-5-one (1 g, 7.40 mmol, 1.00 equiv) in phosphorus oxychloride (15 mL) was stirred under nitrogen for 2 h at 120 °C. The reaction mixture was cooled to rt then concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1 :2) to give 0.6 g (53%) of the title compound as a light yellow solid. LC MS (Method I, ESI): RT = 1.21 min, m z = 154.0 [M+H] \ 00215

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Step 3. Pyrazolo[1.5-a]pyrimidine-5-carboxylic acid methyl ester. A mixture of 5-chloro-pyrazolo[ l ,5-a]pyrimidine (2 g, 1 3.02 mmol, 1 .00 equiv), tnethylamine (4 mL), MeOH (80 mL), and bis(triphenylphosphine)pa!ladium(II) dichloride ( 1 g, 1 .42 mmol, 0.1 1 equiv) was stirred in a 100-mL pressure reactor overnight at 100 °C under 10 atmospheres of carbon monoxide. The reaction mixture was cooled to rt then concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1 :5) to yield 1 .2 g (52%) of the title

compound as a light yellow solid. LC/MS (Method I, ESI): RT= 1 .09 min, z =

178.0 [M+H]⁺.

Step 4. To a solution of methyl pyrazolo[l ,5-a]pyrimidine-5-carboxylic acid methyl ester (100 mg, 0.56 mmol, 1.00 equiv) in acetic acid (5 mL) was added

concentrated HC1 (37%, 5 mL). The resulting solution was stirred for 3 h at 120 °C, then concentrated under vacuum. The residue was dissolved in 3 mL of water and then adjusted to pH 5 with saturated aqueous sodium carbonate solution. The

precipitated product was collected by filtration then air-dried to give 0.08 g (87%) of pyrazolo[l ,5-a]pyrimidine-5-carboxylic acid as a light yellow solid. LC/MS (Method I, ESI): RT= 0.95 min, m z = 164.0 [M+Hf.

Intermediate 10: 2,3-Dihydro-l H-pyrrolo[3,4-c]pyridine.

Step 1 . Ethyl N-(prop-2-yn- 1 -yl Carbamate. To a solution of prop-2-yn- l - amine (1 1 .5 g, 208.79 mmol, 1 .00 equiv) and sodium hydroxide (9.1 g, 227.50 mmol, 1 .09 equiv) in water (40 mL) and toluene (1 10 mL) maintained under nitrogen was added ethyl chloroformate (23.9 g, 220.23 mmol, 1 .05 equiv) dropwise in 20 min with stirring at 10 °C. The resulting solution was stirred overnight at rt then extracted with 3x100 mL of toluene. The combined organic layers were dried over anhydrous sodium sulfate then concentrated under vacuum to give 1 5 g (57%) of ethyl N-(prop- 2-yn-l -yl)carbamate as a light yellow oil. TLC: ethyl acetate/petroleum ether ( 1 :2), R_f = 0.5. Step 2. Pyrimidine-5-carboxaldehvde. To a solution of 5-bromopyrimidine (2 g, 12.58 mmol, 1.00 equiv) in THF (20 mL) placed in a 50-mL 3-necked round- bottom flask purged and maintained with an inert atmosphere of nitrogen was added n-butyllithium ( 1 . 1 mL) at -78 °C. The reaction mixture was stirred at -78 °C for another 2 h. Ethyl formate (5.2 mL) was then added and the resulting solution was stirred for 2 h at -78 °C. The resulting mixture was warmed to 0 °C and washed with 50 mL of brine. The organic layer was dried with anhydrous sodium carbonate and concentrated. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1 :1 ) to give 1 1 g of crude pyrimidine-5-carboxaldehyde as a yellow oil. TLC: ethyl acetate/petroleum ether (1/1 ), R_f = 0.2.

Step 3. Pyrimidin-5-ylmethanol. A mixture of pyrimidine-5-carboxaldehyde (2 g, 1 8.50 mmol, 1 .00 equiv) and sodium borohydride (2 g) in MeOH (100 mL) was stirred at 0 - 10°C for 30 min. The reaction mixture was concentrated under vacuum and the residue was purified on a silica gel column eluted with DCM/MeOH (50: 1 ) to yield 1 .2 g (59%) of pyrimidin-5-ylmethanol as a light yellow solid. LC/MS (Method K, ESI): RT= 0.74 min, m z = 1 1 1 0 [M+H]⁺.

Step 4. 5-(Chloromethyl)pyrimidine. To a solution of pyrimidin-5- ylmethanol (l . l g, 10 mmol, 1 .00 equiv) in DCM (30 mL) was added thionyl chloride (2 mL) dropwise with stirring. The resulting solution was stirred at rt for 2 h then concentrated in vacuum to give 1 .1 g of crude 5-(chloromethyl)pyrimidine as a yellow oil. TLC: ethyl acetate/petroleum ether (1 : 1 ), R_f = 0.4.

Step 5. Ethyl N-(prop-2-yn-l -yl)-N-(pyrimidin-5-ylmethyl)carbamate. A mixture of ethyl N-(prop-2-yn-l -yl)carbamate (1 .27 g, 9.99 mmol, 1 .00 equiv) benzyltriethylammonium chloride (500 mg, 2.60 mmol, 0.26 equiv), 5- (chloromethyl)pyrimidine (1 .28 g, 9.96 mmol, 1 .00 equiv) and potassium hydroxide (3 g, 53.47 mmol, 5.37 equiv) in toluene (30 mL) was stirred overnight under nitrogen at rt. The resulting mixture was concentrated under vacuum and the residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1 : 1 ) to afford 0.3 g (14%) of ethyl N-(prop-2-yn-l -yl)-N-(pyrimidin-5-ylmethyl)carbamate as a light yellow oil. Ή NMR (300 MHz, CDC1 ) δ 9. 16 (s, 1 H), 8.73 (s, 2H), 4.59 (s, 2H), 4.1 1 -4.26 (m, 4H), 2.28 (t, J = 2.4 Hz, 1 H), 1 .30 (t, J = 7.2 Hz, 3H). Step 6. Ethyl l H,2H.3H-Pyrrolo[3,4-c1pyridine-2-carboxylate. A mixture of ethyl N-(prop-2-yn-l -yl)-N-(pynmidin-5-ylmethyl)carbamate (1 g, 4.56 mmol, 1 .00 equiv) in xylene (30 mL) was stirred under nitrogen at 150 °C for 2 days. The resulting mixture was concentrated under vacuum and the residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1 /2) to give 0.4 g (46%) of ethyl l H,2H,3H-pyrrolo[3,4-c]pyridine-2-carboxylate as a light brown crude solid. 'H NMR (300 MHZ, CDCh) δ 8.53-8.93 (m, 2H), 7.24 (d, ./ = 5.1 Hz, 1 H), 4.73-4.80 (m, 4H), 4.22-4.33 (m, 2H), 1 .33-1 .49 (m, 3 H).

Step 7. 2,3-Dihydro-l H-pyrrolo[3,4-clpyridine. A mixture of ethyl lH,2H,3H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (400 mg, 2.4 mmol, 1 .00 equiv) and barium hydroxide (0.8 g) in water (100 mL) was stirred overnight at 120 °C. The reaction mixture was cooled to rt and the solid material was collected by filtration. The residue was stirred in hot ethyl acetate (1 50 mL) and then filtered to remove solid material. The filtrate was concentrated under vacuum to give 0. 18 g (72%) of 2,3- dihydro-l H-pyrrolo[3,4-c]pyndine as a light yellow oil. Ή MR (300 MHz, CDC1,) δ 8.51 (s, 1 H), 8.41 -8.45 (t, J = 4.8 Hz, 1 H), 7.13-7.20 (m, 1 H), 4.25 (s, 2H), 4.22 (s, 2H).

Intermediate 1 1 : Imidazo[ 1 .5-a]pyridine-7-carboxylic acid hydrochloride salt

Step 1 . 4-(Methoxycarbonyl)pyridine 1 -oxide. A solution of methyl pyridine- 4-carboxylate (3 g, 21 .88 mmol, 1 .00 equiv) and m-chloroperbenzoic acid (5 g, 28.97 mmol, 1 .32 equiv) in DCM (30 mL) was stirred overnight at ty. The precipitated product was collected by filtration to give 2.6 g (78%) of 4- (methoxycarbonyl)pyridine 1 -oxide as an off-white solid. LC/MS (Method J, ESI): RT= 0.89 min, z = 1 4.0 [M+Hf .

Step 2. Methyl 2-cyanopyridine-4-carboxylate. A mixture of 4- (methoxycarbonyl)pyridine 1 -oxide (2 g, 13.06 mmol, 1.00 equiv), N,N- dimethylcarbamoyl chloride (6 g, 55.79 mmol, 4.27 equiv) and N2013/000215

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trimethylsilanecarbonitrile (6 g, 60.48 mmol, 4.63 equiv) in chloroform (60 g) was stirred overnight under nitrogen at 50 °C. The reaction mixture was concentrated under vacuum and the residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether ( 1 :20) to give 1 .2 g (57%) of methyl 2-cyanopyridine-4- carboxylate as a light yellow solid. LC MS (Method F, ESI): RT= 1.22 min, m z = 163.0 [M+H]⁺.

Step 3. Methyl 2-(aminomethyl)pyridine-4-carboxylate. ethyl 2- cyanopyridine-4-carboxylate (500 mg, 3.08 mmol, 1 .00 equiv) and Raney Ni (1 .5 g) in MeOH (30 mL) was stirred under 1 atmosphere of hydrogen for 30 min at rt. The catalyst was removed by filtration and the filtrate was concentrated under vacuum to give 0.5 g (98%) of methyl 2-(aminomethyl)pyridine-4-carboxylate as a light yellow solid. LC MS (Method F, ESI): RT= 0.82 min, m z = 167.0 [M+H]⁺.

Step 4. Methyl 2-(formamidomethyl)pyridine-4-carboxylate. A solution of methyl 2-(aminomethyl)pyridine-4-carboxylate (2 g, 12.04 mmol, 1 .00 equiv) in formic acid (20 mL) was stirred for 2 h at 100 °C. The resulting mixture was

concentrated under vacuum to afford 0.8 g (34%) of methyl 2-

(formamidomethyl)pyridine-4-carboxylate as a light yellow solid. LC MS (Method F, ESI): RT = 0.91 min, m z = 195.0 [M+H] ¹.

Step 5. Methyl imidazo[ l ,5-a]pyridine-7-carboxylate. A solution of methyl 2- (formamidomethyl)pyridine-4-carboxylate (800 mg, 4.12 mmol, 1 .00 equiv) and phosphorous oxychloride (2 mL) in dichloroethane (30 mL) was stirred for 1 h at 90 °C. The resulting mixture was concentrated under vacuum to give 0.45 g (62%) of methyl imidazo[l ,5-a]pyridine-7-carboxylate as a light yellow solid. LC/MS

(Method F, ESI): RT= 0.88 min, m/z = 177.0 [M+H]⁺.

Step 6. A mixture of methyl lmidazof l ,5-a]pyridine-7-carboxylate (50 mg,

0.28 mmol, 1 .00 equiv) in 37% hydrochloric acid (5 mL) and acetic acid (5 mL) was stirred for 2 h at 12 0°C. The resulting mixture was concentrated under vacuum to yield 0.05 g (89%) of imidazo[l ,5-a]pyridine-7-carboxylic acid hydrochloride as a light yellow solid. LC/MS (Method J, ESI): RT = 0.80 min, m z = 163.0 [M+H] ' .

Intermediate 12: 3-tert-Butylamino-imidazo[l ,2-a]pyridine-6-carboxylic acid

Step 1 . 3-tert-Butylamino-imidazo[l ,2-a]pyridine-6-carboxylic acid methyl ester. To a solution of methyl 6-aminopyridine-3-carboxylate (3.8 g, 24.98 mmol, 1.00 equiv) and 2-oxoacetic acid hydrate (3.9 g, 42.39 mmol, 1 .70 equiv) in MeOH (120 mL) was added perchloric acid (250 mg, 2.50 mmol, 0.10 equiv). The reaction mixture was stirred for 30 min and 2-isocyano-2-methylpropane (2.08 g, 25.02 mmol,

I .00 equiv) was then added. The reaction mixture was stirred for 12 h at rt and then concentrated under vacuum. The residue was purified on a silica gel column eluted with DCM/ethyl acetate (2.1 ) to give 850 mg (14%) of the title compound as a yellow solid. Ή NMR (300 MHz, CDCb) δ 8.97-8.96 (dd, J = 0.9, 1 .5 Hz, 1 H), 7.69-7.65 (dd, J = 4.2, 9.6 Hz, 1 H), 7.53-7.50 (dd, J = 4.2, 9.6 Hz, 1 H), 7.39 (s, 1 H), 3.96 (s, 3H), 1 .23(s, 9H).

Step 2. Sodium 3-tert-Butylamino-imidazo[l ,2-a]pyridine-6-carboxylate. To a solution of 3-tert-butylamino-imidazo[l ,2-a]pyridine-6-carboxylic acid methyl ester (300 mg, 1 .21 mmol, 1 .00 equiv) in MeOH (5 mL) was added a solution of sodium hydroxide (97 mg, 2.42 mmol, 2.00 equiv) in water (5 mL). The resulting solution was stirred for 1 .5 h at 46 °C. The reaction mixture was cooled to rt and then quenched by the addition of 0.15 mL of HCl. The resulting mixture was concentrated under vacuum to give 345.6 mg (crude) of the title product as a yellow solid. LC MS (Method I, ESI): RT = 1 .02 min, m∑ = 234.0 [M+H - 22]^*.

Step 3. Sodium 3-tert-butylamino-imidazo[l ,2-a]pyridine-6-carboxylate (300 mg, 1.17 mmol, 1.00 equiv) was dissolved in acetic acid (10 mL) and then concentrated under vacuum. The residue was purified on a silica gel column eluted with DCM/MeOH (20: 1 ) to give 150 mg (54%) of the title compound as a yellow solid. LC MS (Method F, ESI): RT = 0.94 min, m z = 234.0 [M+H] .

II. Preparation of Example Compounds Example 10: Imida2o[1.2-b]pyridazine-6-carboxylic acid 4-benzenesulfonyl- benzylamide

Step 1 . 4-Benzenesulfonyl-benzonitrile. A mixture of 4-fluorobenzonitrile (5 g, 41 .3 mmol) and sodium benzenesulfinate (7.45 g, 45.4 mmol) in DMSO (30 mL) was heated at 130 °C for 16 h. The mixture was cooled to rt and poured onto 300 g of ice. The precipitate was collected, washed with water, and dried to afford the title compound. ^lR NMR (300 MHz, CDClj) δ 8.03-8.07 (m, 2H), 7.93-7.97 (m, 2H), 7.78-7.82 (m, 2H), 7.60 (m7.65, 1 H), 7.26-7.58 (m, 2H).

Step 2. 4-Benzenesulfonyl-benzylamine. A mixture of 4-benzenesulfonyl- benzonitnle (9.4 g, 38.64 mmol) and Raney Ni (500 mg) in 2 N NHi in MeOH ( 1 50 mL) was hydrogenated for 16 hours at 50 psi. Nitrogen gas was bubbled through the mixture, which was then filtered through a short pad of diatomaceous earth, and washed with MeOH. The filtrate was concentrated and triturated with ether to afford the title compound. Ή NMR (300 MHz, DMSO-^) 5 7.85-7.95 (m, 4H), 7.53-7.68 (m, 5H), 3.74 (s, 2H), 1 .83 (br s, 2H).

Step 3. Imidazo l ,2-b]pyridazine-6-carboxylic acid 4-benzenesulfonyl- benzylamide. A solution of 4-benzenesulfonyl-benzylamine ( 100 mg, 0.40 mmol, 1 .00 equiv), imidazo[l ,2-b]pyridazine-6-carboxylic acid (900 mg crude), HOBt (66 mg, 0.49 mmol, 1 .21 equiv), EDCI (93 mg, 0.48 mmol, 1 .20 equiv), and

diisopropylethylamine (210 mg, 1.62 mmol, 4.02 equiv) in DMF (3 mL) was stirred overnight at rt. The reaction was then quenched by the addition of 20 mL of water and the resulting solution was extracted with 3x60 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1 /1 ) to give 40.5 mg (26%) of the title compound as an off- white solid. LC/MS (Method A, ESI), RT= 1 .57 min, z = 393.0 [M+H] ' . Ή NMR (300 MHz, CDC1₃) δ 8.13 (d, J = 9.6 Hz, 1 H), 7.96 (m, 8H), 7.50 (m, 5H), 4.73 (d, J = 6.0 Hz, 2H). Example 16: [1.2.4]Triazolo[1.5-a]pyridine-6-carboxylic acid 4-benzenesulfonyl- benzylamide

A solution of [1 ,2,4]triazolo[l ,5-a]pyridine-6-carboxylic acid (1 10 mg, 0.67 mmol, 1 .00 equiv), 4-benzenesulfonyl-benzylamine (247 mg, 1 .00 mmol, 1 .50 equiv), EDCI (1 53 mg, 0.80 mmol, 1 .20 equiv), HOBt ( 1 08 mg, 0.80 mmol, 1 .20 equiv), and diisopropylethylamine (258 mg, 3.00 equiv) in DMF (10 mL) was stirred for 10 h at rt. After the reaction completed, the reaction mixture was concentrated under vacuum and the residue was purified on a silica gel column eluted with DCM/MeOH (20: 1 ) to give 50 mg (19%) of the title compound as a white solid. LC MS (Method D, ESI): RT= 1 .52 min, m z = 393.0 [M+Hf. Ή N R (300 MHz, DMSO-^) δ 9.46 (s, 1 H), 9.40 (m, I H), 8.62 (s, I H), 8.07 (d, J = 1 .8 Hz, 1 H), 7.90-8.05 (m, 5H), 7.57-7.68 (m, 5H), 4.57 (d, J = 5.7 Hz, 2H).

Example 17: Furo[2,3-c]pyridine-2-carboxylic acid 4-(tetrahydro-pyran-4- ylsulfamoyO-benzylamide

Step 1. 4-Cyano-N-(tetrahydro-pyran-4-yl)-benzenesulfonamide. A mixture of tetrahydro-pyran-4-ylamine (700 mg, 6.92 mmol, 1.00 equiv), 4-cyanobenzene-l - sulfonyl chloride (1.4 g, 6.94 mmol, 1 .00 equiv) and triethylamine (3 mL) in DCM (50 mL) was stirred for 0.5 h at rt. The resulting mixture was concentrated under vacuum and the residue was purified on a silica gel column eluted with ethyl acetate/hexane (1 :1 ) to yield 0.8 g (43%) of the title compound as a white solid.

LC/MS (Method B, ESI): RT = 1.31 min, m z = 267.0, [M+Hf. 2013/000215

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Step 2. 4-Aminomethyl-N-(tetrahydro-pyran-4-yn-benzenesulfonamide. To a solution of 4-cyano-N-(tetrahydro-pyran-4-yl)-benzenesulfonamide (800 mg, 3.00 mmol, 1 .00 equiv) in MeOH (50 mL) was added Raney Ni (3 g). The reaction

mixture was stirred for 2 h at rt. The nickel catalyst was removed by filtration and the filtrate was concentrated under vacuum to give 0.5 g (62%) of the title compound as a white solid. LC MS (Method H, ESI): RT = 0.93 min, m/z = 271 .0, [M+H]^r.

Step 3. A solution of furo[2,3-c]pyridine-2-carboxylic acid (73 mg, 0.45 mmol, 1 .50 equiv), 4-aminomethyl-N-(tetrahydro-pyran-4-yl)-benzenesulfonamide (80 mg, 0.30 mmol, 1 .00 equiv), EDCI (69 mg, 0.36 mmol, 1 .20 equiv), HOBt (49 mg, 0.36 mmol, 1.20 equiv), and diisopropylethylamine (1 16 mg, 3.00 equiv) in DMF (5 mL) was stirred for 10 h at rt. The resulting mixture was concentrated under vacuum. The residue was purified on a silica gel column eluted with DCM/MeOH (20: 1 to 5: 1 ) to afford 40 mg (33%) of the title compound as a white solid. LC/MS (Method C, ESI): RT = 1 .33 min, m/z = 416.0, [M+H] . Ή NMR (400 MHz,

DMSO-c¾ 5 9.60 (t, J = 6.0 Hz, l H), 9.06 (s, 1 H), 8.48 (d, J = 5.1 Hz, 1 H), 7.75-7 84 (m, 4H), 7.66 (d, ./ = 0.9 Hz, 1 H), 7.52 (d, J = 8.1 Hz, 2H), 4.57 (d, ./ = 6.0 Hz, 2H), 3.67 (m, 2H), 3.1 6-3.31 (m, 3 H), 1 .49 (m, 2H), 1 .31 (m, 2H).

Example 23 : Pyrazolo[l ,5-a]pyrimidine-5-carboxylic acid 4-benzenesulfonyl- benzylamide

A solution of pyrazolo[l ,5-a]pyrimidine-5-carboxylic acid (80 mg, 0.49 mmol, 1.00 equiv), 4-benzenesulfonyl-benzylamine ( 130 mg, 0.53 mmol, 1 .07 equiv), HOBt (90 mg, 0.67 mmol, 1 .44 equiv), EDCI ( 1 10 mg, 0,57 mmol, 1 .44 equiv), and

diisopropylethylamine (0.5 mL) in DMF (4 mL) was stirred for 3 h at rt. The

resulting solution was diluted with 5 mL of water and the resulting solution was extracted with 3x20 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/hexane (3: 1 ) to give 0.08 g 5

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(42%) of the title compound as an off-white solid. LC MS (Method I, ESI): RT=

1 .72 min, m/z = 393.0 [M+H]⁺. Ή NMR (300 MHz, DMSO-c/ή) δ 9.62 (t, J = 6.3 Hz, 1 H), 9.21 (d, J = 6.3 Hz, 1 H), 8.33 (d, J = 2.4 Hz, 1 H), 7.86-7.89 (m, 4H), 7.47-7.66 (m, 6H), 6.84 (dd, = 2.4, 0.9 Ηζ, ΙΗ), 4.49 (d, J = 6.3 Hz, 2H).

Example 24; 3-Amino-imidazo[l .2-a]pyridine-6-carboxylic acid 4-(3.5-difluoro- benzenesulfonyP-benzylamide

Step 1 . 4-(3.5-Difluoro-phenylsulfanyl)-benzonitrile. A mixture of 4- fluorobenzonitrile (1.5 g, 12.39 mmol, 1.00 equiv), 3,5-difluorobenzene-l -thiol (2.17 g, 14.85 mmol, 1.20 equiv), and potassium carbonate (5.13 g, 37.12 mmol, 3.00 equiv) were combined in DMF (50 mL). The reaction mixture was stirred under nitrogen for 5 h at 1 00 °C. The resulting solution was diluted with 150 mL of water and then extracted with 3x50 mL of ethyl acetate. The combined organic layers were washed with 3x100 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl

acetate/petroleum ether (1 :5) to give 2 g (65%) of the title compound as a yellow solid. Ή NMR (300 MHz, CDC1₃) δ 7.60-7.57(d, J = 8.7 Hz, 2H), 7.37-7.34 (d, J = 8.7 Hz, 2H), 7.04-6.89 (m, 2H), 6.84-6.77 (m, 1 H).

Step 2. 4-(3.5-Difluoro-benzenesulfonyl)-benzonitrile. To a solution of 4-

(3,5-difluoro-phenylsulfanyl)-benzonitrile (2 g, 8.09 mmol, 1.00 equiv) in chloroform (20 mL) at 0-5 °C was added m-CPBA (6.96 g, 40.33 mmol, 5.00 equiv) in several portions. The resulting solution was stirred for 2 h at rt. The reaction mixture was diluted with 100 mL of chloroform, then washed with 3x1 50 mL of saturated aqueous sodium bisulfite solution, 3x150 mL of 1 N aqueous sodium hydroxide solution, and 3x150 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give 1.92 g (85%) of the title compound as a yellow solid. TLC: 5 : 1 petroleum ether/ethyl acetate, R_f = 0.3. N2013/000215

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Step 3. 4-(3.5-Difluoro-benzenesulfonyl)-benzylamine. A mixture of 4-(3,5- difluoro-benzenesulfonyl)-benzonitnle (1 .92 g, 6.88 mmol, 1 .00 equiv), Raney-Ni (1 g), and ammonium hydroxide (5 mL) in MeOH ( 1 50 mL) was stirred under I

atmosphere of hydrogen for 3 h at rt. The catalyst was removed by filtration. The filtrate was concentrated under vacuum to give 1 .8 g (92%) of the title product as a yellow solid. LC MS (Method I, ESI): RT = 1 .1 1 min, m z = 325.0 [M+H+C¾CN]⁺.

Step 4. 3-tert-Butylamino-imidazo[l .2-a1pyridine-6-carboxylic acid 4-(3.5- difluoro-benzenesulfonyD-benzylamide. A solution of 3-tert-butylamino- imidazofl ,2-a]pyridine-6-carboxylic acid (1 50 mg, 0.64 mmol, 1 .00 equiv), 4-(3,5- difluoro-benzenesulfonyl)-benzylamine (219 mg, 0 77 mmol, 1 .20 equiv), EDCI (492 mg, 2.57 mmol, 3.99 equiv), HOBt (174 mg, 1 .29 mmol, 2.00 equiv), and

triethylamine (325 mg, 3.21 mmol, 4.99 equiv) in DMF (5 mL) was stirred overnight at rt. The reaction was quenched by the addition of 20 mL of water/ice and the

resulting solution was extracted with 3x50 mL of ethyl acetate. The combined

organic layers were washed with 3x20 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified on a silica gel column eluted with DCM/MeOH (60: 1 ) to give 0.229 g (71%) of the title compound as a yellow solid. LC MS (Method F, ESI): RT = 1.20 min, m z = 499.0 [M + H] .

Step 5. A mixture of 3-tert-butylamino-imidazo[ l ,2-a]pyridine-6-carboxylic acid 4-(3,5-difluoro-benzenesulfonyI)-benzylamide (80 mg, 0.16 mmol, 1 .00 equiv) in 12 N aqueous hydrochloric acid solution (5 mL) was stirred for 2 h at 65°C. The reaction mixture was concentrated under vacuum and the crude product was purified by Preparative HPLC (2#-Waters 2767-2 (HPLC-08); Column, Xbndge; mobile phase, water with 0.1 % NH₄HCO₃ and CH CN (5.0% CH_:,CN up to 30% in 10 min, up to 100.0% in 1 min, down to 5.0% in 2 min); Detector, UV 254 nm) to give 4.5 mg (6%) of the title compound as a light brown solid. LC/MS (Method C, ESI): RT =

2.09 min, m/z = 443.2 [M + H]⁺. Ή NMR (400 MHz, DMSO-£/₆) δ 9.1 9-9.1 7 (m,

1 H), 8.70 (s, 1H), 8.03-8.01 (d, J = 8.6 Hz, 2H), 7.75-7.67 (m, 2H), 7.60-7.58 (m, 1 H), 7.58-7.42 (d, J = 8.6 Hz, 2H), 7.42-7.41 (m, 2H), 6.90 (s, 1 H), 5.1 3 (s, 2H), 4.57-4.56 (d, 2H), 3.38-3.3 1 (m, 1 H), 1 .38 (m, 1 H). Example 27: Imidazo[1.2-b]pyridazine-6-carboxylic acid 4-(3.5-difluoro- benzenesulfonyP-benzylamide

A solution of imidazo[l ,2-b]pyridazine-6-carboxylic acid ( 100 mg, 0 61 mmol, 1.00 equiv), 4-(3,5-difluoro-benzenesulfonyl)-benzylamine (175 mg, 0.62 mmol, 1.00 equiv), diisopropylethylamine (240 mg, 3.00 equiv), EDO (143 mg, 0.75 mmol, 1.20 equiv), and HOBt (101 mg, 0.75 mmol, 1.20 equiv) in DMF (10 mL) was stirred for 12 h at rt. After the reaction completed, the resulting mixture was concentrated under vacuum and the residue was purified on a silica gel column eluted with DCM/MeOH (20: 1 ). The collected fractions were combined and concentrated under vacuum. This resulted in 40 mg (15%) of the title compound as a white solid. LC MS (Method E, ESI), RT = 1.68 min, z = 429.0 [M+H]⁺. Ή NMR (400 MHz, DMSO-i ₆) δ 9.56 (t, J = 6.0 Hz, 1 H), 8.34 (s, 1 H), 8.26 (d, J = 9.2 Hz, 1 H), 8.01 (d, J = 8.4 Hz, 2H), 7.96 (s, 1 H), 7.77-7.60 (m, 6H), 4.58 (d, J = 6.0 Hz, 2H).

Example 31 : Imidazo[l ,5-a]pyridine-7-carboxylic acid 4-benzenesulfonyl- benzylamide

A solution of imidazo[l ,5-a]pyridine-7-carboxylic acid hydrochloride (50 mg, 0.25 mmol, 1.00 equiv), [4-(benzenesulfonyl)phenyl]methanamine (120 mg, 0.49 mmol, 1.57 equiv), HOBt (100 mg, 0.74 mmol, 2.40 equiv), EDC1 (150 mg, 0.78 mmol, 3.13 equiv), and diisopropylethylamine (1 mL) in DMF (3 mL) was stirred overnight at rt. The resulting mixture was concentrated under vacuum and the residue was purified on a silica gel column with ethyl acetate/hexane (4: 1 ) to give 0.03 g (30%) of the title compound as a light yellow solid. LC/MS (Method F, ESI): RT = 1.34 min, m z = 392.1 [M+H]⁺. Ή NMR (400 MHz, DMSO-c/₆) δ 9.1 3 (t, J = 5.6 Hz, 1 H), 8.48 (s, 1 H), 8.36 (d, J = 7.2 Ηζ,Ι Η), 8.1 8 (s, 1 H), 7.95-7.92 (m, 4H), 7.72 -7.54 (m, 6H), 7.05 (dd, J = 7.4 Hz, J = 1.4 Hz, 1 H), 4.53 (d, J = 5.6 Hz, 2H).

Example 33 : Imidazo[ l ,2-a]pyridine-6-carboxylic acid 4-(3-hvdroxy-3-methyl- cyclobutanesulfonyl)-benzylamide

Step 1. l -Bromo-4-(3-methyl-but-3-ene-l -sulfonyl)-benzene. To a solution of diisopropylamine (0 95 g) in THF (20 mL) maintained under nitrogen at -70 to -80 "C was added a solution of n-butyllithium in hexanes (1 .6 M, 5.9 mL) dropwise with stirring. The resulting solution was stirred for 30 min at -50 °C. A solution of 1 - bromo-4-methanesulfonylbenzene (2 g, 8.51 mmol, 1 .00 equiv) in THF (15 mL) was then added dropwise with stirring at -70 to -80 °C. The reaction mixture was stirred for another 20 min at -70 to -80 °C, and then 3-chloro-2-methyI-propene (850 mg, 9.39 mmol, 1 .10 equiv) was added dropwise. The resulting solution was allowed to stir for 1 h at -70 to -80 °C. After the reaction completed, it was quenched by the addition of 50 mL of water. The mixture was extracted with 2x100 mL of ethyl acetate. The combined organic layers were washed with 2x100 mL of water, dried over anhydrous sodium sulfate, and concentrated under vacuum The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether ( 1 : 10) to yield 0.7 g (28%) of the title compound as a white solid. Ή NMR (300 MHz, CDClj) 5 7.72 (m, 4H), 4.74 (s, 1 H), 4.63 (s, 1 H), 3.17 (m, 2H), 2.37 (m, 2H), 1 .66 (s, 3H).

Step 2. 2-[2-(4-Bromo-benzenesulfonyl)-ethyl1-2-methyl-oxirane. A solution of l -bromo-4-(3-methyl-but-3-ene- l -sulfonyl)-benzene (700 mg, 2.42 mmol, 1 .00 equiv) and m-CPBA (850 mg, 4.93 mmol, 2.03 equiv) in DCM (20 mL) was refluxed overnight. After the reaction completed, the resulting solution was diluted with 50 mL of DCM and then washed with 100 mL of 5% aqueous sodium carbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl 2013/000215

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acetate/petroleum ether (1 .5) to give 0.5 g (68%) of the title compound as a white solid. TLC: 5 : 1 petroleum ether/ethyl acetate, Rr = 0.2.

Step 3. 3-(4-Bromo-benzenesulfonyl)- l -methyl-cyclobutanol. To a solution of 2-[2-(4-bromo-benzenesulfonyl)-ethyl]-2-methyl-oxirane (500 mg, 1 .64 mmol, 1.00 equiv) in THF (30 mL) maintained under nitrogen at -70 to -80 °C was added a methylmagnesium iodide (2 M, 2.2 mL in ether) dropwise with stirring. The resulting solution was stirred overnight at rt then quenched by the addition of 50 mL of water. The mixture was extracted with 100 mL of ethyl acetate and the organic layer was washed with 100 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1 3) to give 0.4 g (80%) of crude title product as a white solid. TLC: 1 : 1 petroleum ether/ethyl acetate, Rf = 0.3.

Step 4. 4-(3-Hydroxy-3-methyl-cyclobutanesulfonyl)-benzonitrile. A

solution of 3-(4-bromo-benzenesulfonyl)- l -methyl-cyclobutanol (400 mg, 1 .3 1 mmol, 1.00 equiv), zinc cyanide (0.23 g), 1 ,l '-bis(diphenylphosphino)ferrocene (100 mg, 0.1 8 mmol, 0.14 equiv), and tris(dibenzylideneacetone)dipalladium(0) (1 00 mg, 0.1 1 mmol, 0.08 equiv) in DMF (20 mL) was stirred at 100 "C under nitrogen overnight The resulting solution was diluted with 100 mL of ethyl acetate. The insoluble material was removed by filtration then the filtrate was washed with 2x 100 mL of water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1 :2) to give 0.24 g (73%) of the title compound as a yellow solid. TLC: 1 1

petroleum ether/ethyl acetate, Rf = 0.1 .

Step 5. 3-(4-Aminomethyl-benzenesulfonyl)-l -methyl-cyclobutanol. To a solution of 4-(3-hydroxy-3 -methyl-cyclobutanesulfonyl)-benzonitrile (200 mg, 0.80 mmol, 1 .00 equiv) in methanolic ammonia solution (60 mL) was added Raney Ni (2 g). The mixture was stirred under 1 atmosphere of hydrogen for 2 h at rt. After the reaction completed, the catalyst was removed by filtration and the filtrate was

concentrated under vacuum to give 0.18 g (89%) of the title compound as a gray solid. LC/MS (Method C, ESI): RT = 0.84, m/z = 256.0 [M+H]\ Step 6. A solution of imidazo[ l ,2-a]pyridine-6-carboxylic acid (76 mg, 0.47 mmol, 1 .33 equiv), EDCI (90 mg, 0.47 mmol, 1 .33 equiv), HOBt (75 mg, 0.56 mmol, 1.57 equiv), and diisopropylethylamine (500 mg, 3.87 mmol, 10.98 equiv) in DMF (8 mL) was stirred for 10 min at rt. A solution of 3-(4-aminomethyl-benzenesulfonyl)- 1 -methyl-cyclobutanol (90 mg, 0.35 mmol, 1 .00 equiv) in DMF was then added and the resulting solution was stirred overnight at rt. After the reaction completed, the solution was diluted with 100 mL of ethyl acetate and then washed with 100 mL of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Preparative HPLC [Column, Sunfire CI 8, 19*1 5; mobile phase, CH₃CN:NH₄C0₃ (10 mmol/L)/H₂0 = 1 5%-60%, 10 min;

Detector, UV 254 nm] to give 14.5 mg (10%) of the title compound as a white solid. LC/MS (Method C, ESI): RT = 1 .33 min, m z = 399.9 [M+H] \ Ή NMR (300 MHz, DMSO-c ή) δ 9.23 (t, J = 6.0 Hz, 1 H), 9.17 (s, 1 H), 8.08 (s, 1 H), 7.78 (m, 2H), 7.66 (m, 5H), 5.36 (s, 1H), 4.60 (d, J = 5.7 Hz, 2H), 3.66 (m, 1 H), 2.35 (m, 2H), 2.04 (m, 2H), 1 .22 (s, 3H).

Example 36: 1.3-Dihydro-pyrrolo[3,4-c]pyridine-2-carboxylic acid 4-(6-methyl- pyndine-3-sulfonyl)-benzylamide

Step 1. [4-(6-Methyl-pyridine-3-sulfonyl)-benzyll-carbamic acid 4-nitro- phenyl ester. A mixture of 4-nitrophenyl chloroformate (40 mg, 0.20 mmol, 1 .04 equiv) and 4-(6-methyl-pyridine-3-sulfonyl)-benzylamine (50 mg, 0.19 mmol, 1 .00 equiv) in toluene (5 mL) was heated to reflux for 1 h. The progress of reaction was monitored by TLC. After the reaction completed, the resulting mixture was concentrated under vacuum to afford 0 08 g (98%o) of the title compound as a light red solid. The residue was used directly without further purification. TLC: 1 :1 ethyl acetate/petroleum ether, Rr = 0.3. Step 2. A mixture of [4-(6-methyl-pyridine-3-sulfonyl)-benzyl]-carbamic acid 4-nitro-phenyl ester (80 mg, 0.19 mmol, 1 .00 equiv) and 2,3-dihydro-l H-pyrrolo[3,4- cjpyridine (30 mg, 0.25 mmol, 1 .33 equiv) in ethanol ( 10 mL) was heated to reflux for 1 h. After the reaction completed, the resulting mixture was concentrated under vacuum. The residue was purified on a silica gel column eluted with DCM/MeOH (92/8) to give 0.022 g (29%) of the title compound as a light yellow solid. LC/MS (Method C, ESI): RT = 2.77 min, nvz = 408.8 [M+H]⁺ Ή NMR (300 MHz, DMSO- i/i) 5 8.97 (d, = 1 .5 Hz, 1 H), 8.57 (s, 1H), 8.46 (d, J = 5.1 Hz, 1 H), 8.18 (dd, .7 = 8.4 Hz, J = 2.1 Hz, 1 H ), 7.93 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 1 H), 7.39 (d, J = 5.4 Hz, 1 H), 7.1 3 (t, ./ = 5.7 Hz, 1 H), 4.63-4.67 (m, 4H), 4.34 (d, J = 5.4 Hz, 2H), 2.54 (s, 3H).

Example 37: N-(4-(6-Methylpyridin-3-ylsulfonyl)benzyl)furo[2.3-c]pyridine-2- carboxamide

Step 1. Lithium 6-methyl-pyndine-3-sulfinate. To a stirred solution of 5- bromo-2-methylpyridine (17.1 g, 99.41 mmol, 1 .00 equiv) in THF (200 mL) maintained under nitrogen at -90 °C was added a solution of n-butyllithium (50 mL, 2.4 M in hexanes) dropwise. The resulting solution was stirred for 30 min at -90 °C. Sulfur dioxide gas was then bubbled into the reaction mixture at this temperature.

The mixture was then warmed to rt and stirred for another hour. The reaction mixture was concentrated under vacuum and the residue was washed with 2x100 mL of hexane to give 15 g of crude title product as a light brown solid. LC/MS (Method C, ESI): RT= 0.38 min, m z = 1 8.0 [M+Hf.

Step 2. 5-(4-Isocyano-benzenesulfonyl)-2-methyl-pyridine. A solution of lithium 6-methyl-pyridine-3-sulfinate (3.26 g) and 4-bromobenzonitrile (3.64 g) in dimethylsulfoxide (50 mL) was stirred for 1 6 h at 130 °C. After the reaction completed, the mixture was cooled to rt and poured into 500mL of ice/water. The precipitated product was collected by filtration and washed with water. The filtrated was extracted with methylene chloride (3x100 mL). The combined organic layer was and washed with water (2x 100 mL) and brine (2 100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was combined with the previously collected crude product then purified by silica gel flash column chromatography eluted with petroleum ether/ethyl acetate (0 to 3 :2) to give 0.8 g of the title product as a light yellow solid. TLC: 1 : 1 petroleum ether/ethyl acetate, Rf= 0.35.

Step 3. 4-(6-Methyl-pyridine-3-sulfonyl)-benzylamine. To a solution of 5-(4- isocyano-benzenesulfonyl)-2-methyl-pyridine (500 mg, 1 .94 mmol, 1 .00 equiv) in MeOH (50 mL) was added Raney nickel (200 mg, 3.41 mmol, 1 .76 equiv) and a saturated solution of ammonia in MeOH (2 mL). The reaction mixture was stirred under 1 atmosphere of hydrogen for 2 h at rt. After the reaction completed, the catalyst was removed by filtration. The filtrate was concentrated under vacuum and the residue was purified on a silica gel column eluted with DCM/MeOH (9/1 ) to afford 0.35 g (69%) of the title product as a light brown solid. TLC: 1 :5

MeOH/DCM, R, = 0 3.

Step 4. A solution of furo[2,3-c]pyndine-2-carboxylic acid (120 mg, 0.74 mmol, 1 .48 equiv), 4-(6-methyl-pyridine-3-suIfonyl)-benzyIamine ( 130 mg, 0.50 mmol, 1 .00 equiv), EDCI (125 mg, 0.65 mmol, 1 .32 equiv), HOBt (90 mg, 0.67 mmol, 1 .34 equiv), and diisopropylethylamine (0.5 mL) in DMF (5 mL) was stirred overnight at rt. After the reaction completed, the resulting solution was diluted with 100 mL of DCM. The mixture was washed with 2x30 mL of water and 2x30 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was then purified on a silica gel column eluted with DCM/MeOH (93 :7) to give 0.045 g (22%) of the title compound as a white solid. LC/MS (Method C, ESI), RT= 1 .70 min, m z = 407.8 [M+H]⁺. Ή NMR (300 MHz, DMSO-c ₆) 6 9.60 (t, J = 6 0 Hz, 1 H), 9.05 (s, 1 H), 8.97 (d, J = 2.1 Hz, l H), 8.97 (d, J = 5.1 Hz, 1 H), 8.19 (dd, J = 8.1 Hz, J = 2.4 Hz, 1 H), 7.97 (d, J = 8.4 Hz, 2H), 7.81 (d, ,/ = 4.8 Hz, 1 H), 7.64 (s, 1 H), 7.57 (d, ./ = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 1 H), 4.55 (d, J = 6.0 Hz, 2H), 2.54 (s, 3H). Examples 52 and 53. N-[[4-(Tetrahvdropyran-3- ylsulfamoyl phenyl]methyllimidazo[1.2-alpyridine-6-carboxamide (isomers 1 and 2).

The title compounds were prepared as for Example 40. The resulting mixture of isomers was separated by chiral chromatography. The compounds displayed LC MS data comparable to Example 40.

Example 58. tert-Butyl 3-fluoro-4-[[4-[(imidazo[l ,2-a]pyridine-6- carbonylamino)methyl]phenyl]sulfonylamino]piperidine-l -carboxylate.

Step 1. lmidazo[l ,2-alpyridine-6-carboxylic acid benzylamide. To a mixture of benzylamine (2.616 g, 23.93mmol), benzotriazol- l -yl- oxytripyrrolidinophosphonium hexafluorophosphate (6.420 g, 1 1.96 mmol), imidazo[l ,2-a]pyridine-6-carboxylic acid (2.000 g, 1 1 96 mmol) in DCM (100 mL), was added triethylamine (10.50 mL, 59.82 mmol). The reaction mixture was stirred at rt for 24 h and then concentrated to dryness under vacuum. The crude material was washed with aqueous sodium bicarbonate solution twice, and washed with water twice to give a crude solid. The crude solid was washed with ether twice to yield a white solid (2.673 g, 88.90%) as the title compound. This material was used in the next step without further purification. Ή NMR (400 MHz, OMSO-d₆) δ 9.1 5 (s, 1 H), 9.1 1 (t, J = 5.8 Hz, 1 H), 8.06 (s, 1 H), 7.73-7.54 (m, 3H), 7.34 (d, J = 4.7 Hz, 4H), 7.28-7.16 (m, 1 H), 4.51 (d, J = 5.9 Hz, 2H). LCMS (ESI): RT = 0.54 min, m z = 252.2 [M + Hf.

Step 2. 4- {[(Imidazo[l ,2-a]pyridine-6-carbonyl)-amino]-methyl }- benzenesulfonyl chloride. Imidazo[l ,2-a]pyridine-6-carboxylic acid benzylamide (2.000 g, 7.80 mmol) was added slowly to a cooled flask containing chlorosulfonic acid (6.51 mL, 97.49 mmol). The reaction mixture was kept at ice bath for another 30 min, then was wanned to rt, and stirred for 2 h. The reaction mixture was poured slowly into ice water to give a milky suspension. After 30 min, the water layer was separated, washed twice with ether, and dried in vacuo to give title compound as glassy solid ( 1 .928 g, 70.7%). This material was used in the next step without further purification.

Ste 3. teit-Butyl 3-fluoro-4-fj4-[(imidazo[L2-a1pyridine-6- carbonylamino)methyl]phenyl]sulfonylamino]piperidine-l -carboxylate. 4-

{[(Imidazo[l ,2-a]pyridine-6-carbonyl)-amino]-methyl} -benzenesulfonyl chloride ( 160 mg, 0.46 mmol) was added to a mixture of tert-butyl 4-amino-3- fluoropiperidine- l -carboxylate ( 1 57 mg, 0.68 mmol) and triethylamine (0.32 mL, 2.28 mmol) in DCM (2 mL). The reaction mixture was stirred at ty for 24 h and then concentrated to dryness under vacuum to give the crude title product. The compound was purified by chromatography to give a white solid (47.0 mg, 19%). Ή NMR (400

MHz, DMSC δ 9.23 (t, J = 6.2 Hz, 1 H), 9.17 (d, J = 6.2 Hz, 1 H), 8.08 (bs, 2H), 7.79 (d, J = 1.1 Hz, 2H), 7.75-7.55 (m, 3H), 7.53 (d, J = 8.0 Hz, 2H), 4.62-4.55 (m, 2H), 4.34-4.21 (m, 1 H), 4. 19-4.10 (m, 1 H), 3.88-3.63 (m, 1 H), 3.53-3.41 (m, 1 H), 3.23-3.1 1 (m, 1 H), 3.09-2.99 (m, 1 H), 1 .67-1 .55 (m, 1 H), 1.36 (s, 9H), 1 .29-1 .22 (m, 1 H). LCMS (Method T, ESI): RT = 3.91 min, m/z = 532.2 [M + H]⁺ .

Example 64: 7-Amino-N-[[4-(benzenesulfonyl)phenyl]methyl]furo[2.3-c]pyridine-2- carboxamide.

Step 1 . Methyl furo[2.3-c]pyridine-2-carboxylate. A solution of furo[2,3- c]pyridine-2-carboxylic acid (2 g, 12.26 mmol, 1.00 equiv), EDCI (2.8 g, 14.61 mmol, 1.20 equiv), HOBt (2 g, 14.80 mmol, 1.20 equiv) and DIPEA (4.7 g, 3.00 equiv) in MeOH (100 mL) was stirred for 20 h at rt. The resulting mixture was concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1 : 1 ) to give 1 .3 g (60%) of methyl furo[2,3-c]pyndine-2- carboxylate as an off-white solid. TLC: ethyl acetate/petroleum ether = 1 /2, R| = 0.4. Step 2. 2-(Methoxycarbonyl)furo[23-c]pyridin-6-iurn-6-olate. A solution of methyl furo[2,3-c]pyridine-2-carboxylate (500 mg, 2.82 mmol, 1 .00 equiv) and m- CPBA (1 g, 5.79 mmol, 2.00 equiv) in DCM (50 niL) was stirred for 20 h at rt. The reaction was then quenched by the addition of a solution containing 1 g K2CO and 1 g NazS20₃ in 20 mL of water. The organic layer was collected and the aqueous layer was extracted with 2x100 mL of DCM. The combined organic layers were concentrated under vacuum and the residue was purified on a silica gel column eluted first with petroleum ether/ethyl acetate (1 : 1 ) and then with DCM/MeOH (5 : 1 ) to give 0.5 g (92%) of 2-(methoxycarbonyl)furo[2,3-c]pyridin-6-ium-6-olate as an off-white solid_. TLC: DCM MeOH = 5/1 , R, = 0.3_.

Step 3. Methyl 7-(2,2-dimethyl-4-oxo-3.4-dihydro-2H-l ,3-benzoxazin-3- yl)furo[2.3-c] pyridine-2-carboxylate. A solution of 2-(methoxycarbonyl)furo[2,3- c]pyndin-6-ium-6-olate (500 mg, 2.59 mmol, 1 .00 equiv) and 4-chloro-2,2-dimethyl- 2H- l ,3-benzoxazine (500 mg, 2.56 mmol, 1 .00 equiv) (see Ujjainwalla, F.; Walsh, T F Tetrahedron Lett., 2001 , 42, 6441 -6446) in DCM (60 mL) was stirred for 4 h at 50°C The reaction mixture was cooled to rt and concentrated under vacuum. The residue was purified on a silica gel column eluted first with ethyl acetate/petroleum ether ( 1 /1 ) and then with DCM/MeOH (5/1 ) to afford 200 mg (22%) of methyl 7- (2,2-dimethyl-4-oxo-3,4-dihydro-2H- l ,3-benzoxazin-3-yl)furo[2,3-c] pyridine-2- carboxylate as a white solid. TLC: DCM/MeOH = 5/1 , R, = 0.6.

Step 4. 7-Aminofuro[2.3-c]pyridine-2-carboxylic acid. A mixture of methyl 7-(2,2-dimethyl-4-oxo-2H-benzo[e][l ,3]oxazin-3(4H)-yl)furo[2,3-c]pyridine-2- carboxylate (100 mg, 0.28 mmol, 1.00 equiv) in 6 M HC1 (5 mL) was stirred at 100°C for 4 h. The reaction mixture was cooled to rt and then concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1 ): Column, silica gel; mobile phase, 20% to 50% CH₃CN:H₂0 over 20 min; Detector, UV 254 nm to give 20 mg (40%) of 7-aminofuro[2,3-c]pyridine-2- carboxylic acid as a white solid. TLC: DCM MeOH = 5/1 , R_f = 0.2.

Step 5. 7-Amino-N-[[4-(benzenesulfonyl)phenyl]methyl]furo[2.3-c]pyridine- 2-carboxamide. A solution of 7-aminofuro[2,3-c]pyridine-2-carboxylic acid ( 140 mg, 0.79 mmol, 1.00 equiv), EDC1 (282 mg, 1 .47 mmol, 2.00 equiv), HOBt (200 mg, 1 .48 mmol, 2.00 equiv), DIPE A (0.95 g, 1 0.00 equiv) and [4-

(benzenesulfonyl)phenyl]methanamine (500 mg, 2.02 mmol, 3.00 equiv) in D F (10 mL) was stirred for 20 h at rt. The resulting mixture was concentrated under vacuum and the residue was partially purified on a silica gel column eluted with DCM/MeOH (5 : 1 ). The product was further purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1 ): Column, silica gel; mobile phase, 20 to 45% C¾CN:H₂0 over 20 min; Detector, UV 254 nm to yield 4.2 mg (1 %) of 7-amino-N-[[4- (benzenesulfonyl)phenyl]methyl]furo[2,3-c]pyridine-2-carboxamide as an off-white solid. LC/MS (Method O, ESI): RT = 1 .83 min, z = 408.0 [Μ+ΗΓ; 'HNMR (400 MHz, OMSO-d₆, ppm) 5 9.17 (s, 1 H), 7.96-7.94 (m, 4 H), 7.75 (d, ./ = 5.2 Hz, 1 H), 7.69 -7.57 (m, 5 H), 7.45 (s, 1 H), 6.89 (d, J = 5.2 Hz, 1 H), 6.34 (s, 1 H), 4.58 (d, ./ = 5.2 Hz, 2 H).

Example 77. 6-Amino-N-[[4-(benzenesulfonyl)phenyl^"lmethyll- 1 ,3- dihydropyrrolo[3,4-c]pyridine-2-carboxamide.

Step 1 . 4-Nitrophenyl N-|^"[4-(benzenesulfonyl)phenyl]methyl]carbamate. A mixture of [4-(benzenesulfonyl)phenyl]methanamine (500 mg, 2.02 mmol, 1 .00 equiv) and 4-nitrophenyl chloroformate (500 mg, 2.48 mmol, 1 .23 equiv) in toluene (30 mL) was stirred under nitrogen at 120°C for 30 min. The reaction mixture was cooled to rt. The solid was collected by filtration, washed with toluene (5 mL) and then dried in vacuum to give 0.8 g (96%) of 4-nitrophenyl N-[[4- (benzenesulfonyl)phenyl]methyl]carbamate as a light yellow solid.

Step 2. 6-Chloropyridine-3-carbonyl chloride. A mixture of 6- chloropyridine-3-carboxylic acid (20 g, 126.94 mmol, 1 .00 equiv), DMF ( 1 g, 1 3.68 mmol, 0.1 1 equiv) and thionyl chloride (20 mL) in toluene (200 mL) was stirred under nitrogen for 3 h at 80°C. The resulting solution was cooled to rt and

concentrated under vacuum to give 25 g of crude 6-chloropyridine-3-carbonyl chloride as a light yellow solid. Step 3. 6-Chloro-N.N-bis(propan-2-yl)pyridine-3-carboxamide. To a solution of 6-chloropyridine-3-carbonyl chloride (25 g, 142.05 mmol, 1 .00 equiv) in DCM (500 mL) maintained under nitrogen at 0°C was added diisopropylamine (50 g, 494.12 mmol, 3.48 equiv) dropwise with stirring. The reaction mixture was stirred for 50 min at 25°C and then quenched with the addition of H₂0 (300 mL). The organic layer was collected and the aqueous layer was extracted with 2x300 mL of DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give 25 g (73%) of 6-chloro-N,N-bis(propan-2- yl)pyridine-3-carboxamide as a light yellow solid. TLC: ethyl acetate:petroleum ether=l :2, R, = 0.4.

Step 4. 6-Chloro-4-formyl-N,N-bis(propan-2-yl)pyridine-3-carboxamide. To a stirred solution of diisopropylamine (1 g, 9.88 mmol, 4.76 equiv) in ether (30 mL) at -50°C maintained under nitrogen was added a 2.5 M solution of n-BuLi (5 mL) in hexanes dropwise The reaction mixture was stirred for 30 min a -50°C then solid 6- chloro-N,N-bis(propan-2-yl)pyridine-3-carboxamide (500 mg, 2.08 mmol, 1 .00 equiv) was added in a single portion. The resulting solution was stirred for 30 min at -50°C DMF (1 mL) was then added dropwise with stirring. The reaction mixture was stirred at -50°C for 3 h and then warmed to rt and stirred overnight. The reaction was quenched by the addition of 10% aqueous citric acid solution (30 mL) and then extracted with 2x50 mL of ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give 0.5 g of crude 6- chloro-4-formyl-N,N-bis(propan-2-yl)pyridine-3-carboxamide as a yellow solid. LC MS (Method G, ESI): RT= 1 .40 min, m z = 269.0 [M+H]⁺.

Step 5. 6-Chloro-4-(hydroxymethyl)-N,N-bis(propan-2-yl)pyridine-3- carboxamide. A mixture of 6-chloro-4-formyl-N,N-bis(propan-2-yl)pyridine-3- carboxamide (500 mg, 1 .86 mmol, 1 .00 equiv) and NaBH₄ (500 mg, 13.22 mmol, 7.10 equiv) in ethanol (50 mL) was stirred for 50 min at 30°C. The reaction was then quenched by the addition of 1 M HC1. The solid was removed by filtration and the filtrate was concentrated to provide 0.5 g of crude 6-chloro-4-(hydroxymethyl)-N,N- bis(propan-2-yl)pyridine-3 -carboxamide as a light yellow solid. LC MS (Method F, ESI): RT= 1.25 min, m z = 271 .0 [M+Hf. Step 6. 6-Chloro-l H.3H-furo[3.4-c]pyridin-3-one. A mixture of 6-chloro-4- (hydroxymethyl)-N,N-bis(propan-2-yl)pyridine-3-carboxamide (2 g, 7.39 mmol, 1 .00 equiv) in 6M hydrochloric acid (40 mL) was stirred for 30 min at 100°C. The reaction mixture was cooled to rt and the pH value of the solution was adjusted to 8 with sodium carbonate. The mixture was extracted with 200 mL of DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to yield 1 g of crude 6-chloro-l H,3H-furo[3,4-c]pyridin-3-one as a light yellow solid. LC/MS (Method M, ESI): RT= 1 .13 min, m z = 170.0 [M+Hf.

Step 7. [6-Chloro-4-(hvdroxymethyl)pyridin-3-yl]methanol. A mixture of 6- chloro-1 H,3H-furo[3,4-c]pyridin-3-one (1 g, 5.90 mmol, 1 .00 equiv) and NaBR, (0.5 g) in ethanol (50 mL) was stirred for 60 min at 25^UC. The pH value of the solution was adjusted to 1 with 6M hydrochloric acid. The solid was removed by filiation and the filtrate was concentrated under vacuum. The residue was purified on a silica gel column eluted with DCM/MeOH (20: 1 ) to give 0.4 g (39%) of [6-chloro-4- (hydroxymethyl)pyridin-3-yl]methanol as a light yellow solid. LCMS (Method M, ESI): RT= 0.95min, z = 1 74.0 [M+H]⁺.

Step 8. 2-Chloro-4.5-bis(chloromethyl)pyridine hydrochloride. A mixture of [6-chloro-4-(hydroxymethyl)pyridin-3-yl]methanol (100 mg, 0.58 mmol, 1 .00 equiv) and thionyl chloride (2 mL) in DCM (20 mL) was stirred under nitrogen at rt for 1 h. The resulting mixture was concentrated under vacuum to give 0.1 g of crude 2- chloro-4,5-bis(chloromethyl)pyridine hydrochloride as a dark red solid.

Step 9. 6-Chloro-2-[(2.4-dimethoxyphenynmethyl]-l H.2H.3H-pyrrolo[3.4- cjpyridine. A mixture of 2-chloro-4,5-bis(chloromethyl)pyridine hydrochloride (1 g, 4.05 mmol, 1.00 equiv), (2,4-dimethoxyphenyl) methanamine (1 g, 5.98 mmol, 1 .48 equiv) and DIPEA (1 g, 7.74 mmol, 1.91 equiv) in DCM (60 mL) was stirred under nitrogen overnight at rt. The resulting mixture was concentrated under vacuum and the residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (2: 1 ) to give 0.9 g of crude 6-chloro-2-[(2,4-dimethoxyphenyl)methyl]- l H,2H,3H-pyrrolo[3,4-c]pyridine as a reddish oil. LC/MS (Method M, ESI). RT= 0.94min, m z = 305.0 [M+H]⁺. Step 1 0. N.2-bisf(2.4-Dimethoxyphenyl) methyl]- l H.2H.3H-pyrrolo[3.4- c]pyndin-6-amine. A mixture of 6-chloro-2-[(2,4-dimethoxyphenyl)methyl]- l H,2H,3H-pyrrolo[3,4-c]pyridine (200 mg, 0.66 mmol, 1 .00 equiv), Pd₂(dba)₃ ^»CHCl_:, (0. 1 g), t-BuONa (200 mg, 2.08 mmol, 3.17 equiv), BINAP ( 100 mg, 0.16 mmol, 0 24 equiv) and (2,4-dimethoxyphenyl)methanamine (400 mg, 2.39 mmol, 3.65 equiv) in toluene (20 mL) was stirred under nitrogen overnight at 80°C. The resulting solution was diluted with 20 mL of H2O and extracted with 2x50 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1 : 1 ) to give 0.2 g (70%) of N,2-bis[(2,4- dimethoxyphenyl) methyl]-l H,2H,3H-pyrrolo[3,4-c]pyridin-6-amine as a dark red solid. LC/MS (Method M, ESI): RT= 0.92min, m z = 436.0 [M+H]⁺.

Step 1 1 . l H,2H,3H-Pyrrolo[3,4-c1pyridin-6-amine. A solution of N, 2- bis[(2,4-dimethoxyphenyl)methyl]-l H,2H,3H-pyrrolo[3,4-c]pyridin-6-amine (300 mg, 0.69 mmol, 1 .00 equiv) in TFA (20 mL) was stirred under nitrogen overnight at 90°C. The resulting mixture was concentrated under vacuum to remove most of the TFA. The pH value of the residue was adjusted to 8 with saturated sodium carbonate solution. The mixture was concentrated under vacuum and the residue was dissolved in hot ethyl acetate and filtered. The filtrate was concentrated under reduced pressure to provide 0.15 g of crude lH,2H,3H-pyrrolo[3,4-c]pyridin-6-amine as a red oil.

LC MS (Method P, ESI): RT= 0.1 8min, m z = 136.0 [M+Hf.

Step 12. A mixture of 4-nitrophenyl N-[[4- (benzenesulfonyl)phenyl]methyl]carbamate (200 mg, 0.48 mmol, 1 .00 equiv) and l H,2H,3H-pyrrolo[3,4-c]pyridin-6-amine (60 mg, 0.44 mmol, 0.92 equiv) in ethanol (20 mL) was stirred for 1 h at 90°C. The reaction was cooled to it and then concentrated under reduced pressure. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1 0: 1 ) to give 74.1 mg (37%) of 6-amino-N- [[4-(benzenesulfonyl)phenyl]methyl]-l H,2H,3H-pyrrolo[3,4-c]pyridine-2- carboxamide as an off-white solid. LC MS (Method D, ESI): RT= 1 .46 min, m z = 409.0 [M+H] ¹; Ή NMR (300 MHz, DMSO-J₆, ppm): δ 7.95-7.87 (m, 5H), 7.72-7.60 (m, 3H), 7.53 (t, J = 8.4 Hz, 2H), 7.03-7.00 (t, J ^·= 6.0 Hz, 1 H), 6.36 (s, 1 H), 5.84 (s, 1 H), 4.45 (s, 4H), 4.31 (d, J = 5.7 Hz, 2H).

Example 82. 6-Amino-N-[[4-(3,5-difluorophenvnsulfonylphenyllmethyl]-lH- pyrrolo[3.2-c]pyridine- -carboxamide.

Step 1 . 6-Chloro-N.N-bis (4-methoxyphenyl)methyl]pyridin-2-amine. To a solution of 6-chloropyridin-2-amine (20 g, 1 55.57 mmol, 1 .00 equiv) in

dimethylacetamide (200 mL) was added sodium hydride (20 g, 833.33 mmol, 3.00 equiv) at 0°C. The reaction mixture was stirred at 0°C for 20 min and 1 -

(chloromethyl)-4-methoxybenzene (48 g, 306.50 mmol, 2.00 equiv) was then added dropwise with stirring at 0°C. The resulting solution was stirred for 20 h at rt then quenched by the addition of 1 0 mL of water dropwise. The mixture was concentrated under vacuum and then extracted with 400 mL of ethyl acetate. The organic layer was washed with 3x50 mL of H₂0, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give 50 g of crude 6-chloro-N,N-bis[(4- methoxyphenyl)methyl]pyridin-2-amine as a yellow oil. TLC: ethyl acetate/petroleum ether = 1 /2, R_f = 0.5.

Step 2. 6-Chloro-5-iodo-N.N-bis [(4-methoxyphenyl)methyllpyridin-2 -amine. A solution of 6-chloro-N,N-bis[(4-methoxyphenyl)methyl]pyridin-2 -amine (10 g, 27.1 1 mmol, 1 .00 equiv) and N-iodosuccinimide (24 g, 137.94 mmol, 4.00 equiv) in acetonitrile (200 mL) was stirred at 30°C for 20 h. The reaction was then quenched by the addition of a solution of containing K₂CCh (20 g) and Na₂S203 (20 g) in water (30 mL). After stirring for 5 min, the organic layer was collected and the aqueous layer was extracted with 400 mL of ethyl acetate. The combined organic layers were washed with 1 x50 mL of H₂0 and then concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether ( 1 :5) to give 13 g (97%) of 6-chloro-5-iodo-N,N-bis [(4-methoxyphenyl)methyl]pyridin-2-amine as a light yellow solid. TLC: ethyl acetate/petroleum ether = 112, Rr = 0.6.

Step 3. 6-[bis (4-Methoxyphenyl)methyllaminol-2-chloropyridine-3- carbaldehvde. To a solution of 6-chloro-5-iodo-N,N-bis[(4- methoxyphenyl)methyl]pyridin-2-amine (8 g, 1 6. 17 mmol, 1 .00 equiv) in THF (100 mL) maintained under nitrogen at -70°C was added a 2.5 M solution of n-BuLi (8 mL, 1 .20 equiv) in hexanes. The resulting solution was stirred for 5 min at -70°C then ethyl formate (5 mL) was added. The resulting solution was allowed to stir for an additional 1 0 min at -70°C before it was quenched by the addition of 1 0 mL of water. The organic layer was collected and the aqueous layer was extracted with 300 mL of DCM. Thecombined organic layers were washed with 1 x30 mL of H₂O then concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether ( 1 :5) to afford 2 4 g (37%) of 6-[bis[(4- methoxyphenyl)methyl]amino]-2-chloropyridine-3-carbaldehyde as a white solid. TLC : ethyl acetate/petroleum ether = 1 /2, R_t = 0.5.

Step 4. Ethyl 2-azido-3-(6-[bis[(4-methoxyphenyl)methyl]aminol-2- chloropyridin-3-yl)prop-2-enoate. To a solution of 6-[bis[(4- methoxyphenyl)methyl]amino]-2-chloropyridine-3-carbaldehyde (640 mg, 1 .61 mmol, 1.00 equiv) and ethyl 2-azidoacetate (800 mg, 6.20 mmol, 3.00 equiv) in ethanol ( 100 mL) at 0°C was added sodium ethoxide (400 mg, 3.00 equiv) in several portions. The resulting solution was stirred at 0°C for 2 h and then quenched by the addition of 1 0 mL of water. The resulting mixture was concentrated under vacuum and the residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1 /2) to give 320 mg of the crude ethyl 2-azido-3-(6-[bis[(4-methoxyphenyl)methyl]amino]- 2-chloropyridin-3-yl)prop-2-enoate as a light yellow solid. TLC : ethyl

acetate/petroleum ether = 1 /2, Rf = 0.3.

Step 5. Ethyl 6-[bis[(4-methoxyphenyl)methyl]amino]-4-chloro-l H- pyrrolo[3.2-c]pyridine-2-carboxylate. A solution of ethyl 2-azido-3-(6-[bis[(4- methoxyphenyl)methyl]amino]-2-chloropyridin-3-yl)prop-2-enoate (250 mg, 0.49 mmol, 1 .00 equiv) in xylene (20 mL) was stirred for 3 h at 1 30°C The reaction mixture was cooled tort then concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1 :2) to give 100 mg (42%) of ethyl 6-[bis[(4-methoxyphenyl)methyl]amino]-4-chloro-l H-pyrrolo[3,2- c]pyridine-2-carboxylate as a yellow oil. TLC: ethyl acetate/ petroleum ether = 1 /1 , R_f = 0.3.

Step 6. 6-[bis[(4-Methoxyphenyl)methyl] amino]-4-chloro-l H-pyrrolo[3.2- clpyridine-2-carboxylic acid. To a solution of ethyl 6-[bis[(4- methoxyphenyl)methyl]amino]-4-chloro-l H-pyrrolo[3,2-c]pyridine-2-carboxylate (400 mg, 0.83 mmol, 1 .00 equiv) in ethanol (10 mL) was added a solution of potassium hydroxide (400 mg, 7.1 3 mmol, 8.55 equiv) in water (1 0 mL). The reaction mixture was stirred for 20 h at rt. The pH value of the solution was adjusted to 6 with 1M HC1. The mixture was concentrated under vacuum to give 1 g of crude 6-[bis[(4- methoxyphenyl)methyl] amino]-4-chloro-l H-pyrrolo[3,2-c]pyridine-2-carboxylic acid as a yellow solid. TLC: DCM/MeOH=5/l , R_f = 0.3.

Step 7. 6-[^"bisf(4-Methoxyphenyl)methyllamino]-4-chloro-N-([4-[(3,5- difluorobenzene)sulfonyl]phenyl]methyl)-l H-pyrrolo[3.2-c]pyridine-2-carboxamide. A mixture of 6-[bis[(4-methoxyphenyl)methyl]amino]-4-chloro-l H-pyrrolo[3,2- c]pyridine-2-carboxylic acid (300 mg, 0.66 mmol, 1.00 equiv), [4-[(3,5- difluorobenzene)sulfonyl]pheny]]methanamine (400 mg, 1 .41 mmol, 2.00 equiv), EDCI (300 mg, 1.56 mmol, 2.00 equiv), HOBt (200 mg, 1 .48 mmol, 2.00 equiv) and DIPEA (0.6 g, 6.00 equiv) in DMF (20 mL) was stirred for 1 h at 50°C. The resulting mixture was concentrated under vacuum and the residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1 : 1 ) to give 400 mg (84%) of 6- [bis[(4-methoxyphenyl)methyl]amino]-4-chloro-N-([4-[(3,5- difluorobenzene)sulfonyl]phenyl]methyl)-l H-pyrrolo[3,2-c]pyridine-2-carboxamide as a red oil. TLC: ethyl acetate/petroleum ether = 1/1 , R_f = 0.2.

Step 8. 6-Amino-4-chloro-N-(j4-f(3.5- difluorobenzene)sulfonyl]phenyl]methyl)-1 H-pyrro1o[3,2-c]pyridine-2-carboxamide.

A solution of 6-[bis[(4-methoxyphenyl)methyl]amino]-4-chloro-N-([4-[(3,5- difluorobenzene)sulfonyl]phenyl]methyl)-l H-pyrrolo[3,2-c]pyridine-2-carboxamide (200 mg, 0.28 mmol, 1 .00 equiv) and TFA ( 1 mL) in DCM ( 10 mL) was stirred for 2 h at rt. The resulting mixture was concentrated under vacuum and the residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether(l : 1 ) followed by ethyl acetate to give 60 mg (45%) of 6-amino-4-chloro-N-([4-[(3,5- difluorobenzene)sulfonyl]phenyl]methyl)- l H-pyrrolo[3,2-c]pyridine-2-carboxamide as a red oil. TLC: DCM/MeOH=5/l , R_f = 0.6.

Step 9. To a mixture of 6-amino-4-chloro-N-([4-[(3,5- difIuorobenzene)sulfonyl]phenyl]methyl)-l H-pyrrolo[3,2-c]pyridine-2-carboxamide (60 mg, 0.13 mmol, 1.00 equiv) and potassium acetate (0.5 g) in MeOH (20 rtiL) was added 10% palladium on carbon catalyst (60 mg). The mixture was stirred under 1 atmosphere of H₂ for 20 h at rt. The catalyst was removed by filtration. The filtrate was concentrated under vacuum and the residue was purified on a silica gel column eluted with DCM/MeOH (5 : 1 ). The semi pure product was further purified by Prep- HPLC with the following conditions (IntelFlash-1 ): Column, silica gel; mobile phase, 18 to 38 % CH CN:H₂0 within 20 min; Detector, UV 254 nm to give 7.4 mg (13%) of 6-amino-N-([4-[(3 ,5-difluorobenzene)sulfonyl]phenyl] methyl)- 1 H-pyrrolo[3,2- c]pyridine-2-carboxamide as an off-white solid. LC MS (Method N, ESI): RT = 1 .58 min, m z = 443.2 [M+H]^"; Ή NMR (300 MHz, DMSO< ppm) δ 1 1 .26 (s, 1 H), 9.04 (s, 1 H), 8.38 (s, 1 H), 8.02 (d, J = 8.4 Hz, 2H), 7.75-7.55 (m, 5H), 7.08 (s, 1H), 6.37 (s, 1 H), 5.64 (s, 2H), 4.55 (d, J = 5.7 Hz, 2H). Example 83. 5-Amino-N-f[4-(benzenesulfonyl)phenyll methyl]furo 2,3-c]pyridine-

2-carboxamide.

Step 1 . 2-Chloro-5-(methoxymethoxy)pyridine. To a solution of 6- chloropyridin-3-ol ( 10 g, 77. 19 mmol, 1 .00 equiv) in DMF ( 120 mL) maintained under nitrogen at 0°C was added NaH (3.8 g , 60%) in small portions. The resulting solution was stirred at rt for 1 h. 1 -Bromo-2-methoxyethane (1 3 g, 93.53 mmol, 1 .21 equiv) was then added dropwise with stirring to the reaction mixture while maintaining the reaction temperature at < 10°C. The resulting solution was stirred at rt for another 2 h. Water (200 mL) was added to quench the reaction. The resulting solution was extracted with 2x200 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with petroleum ether to give 10 g (75%) of 2-chloro-5-(methoxymethoxy)pyridine as a colorless oil. TLC: petroleum ethenethyl acetate = 5: 1 , R_f = 0.5.

Step 2. 2-Chloro-5-(methoxymethoxy^')pyridine-4-carbaldehvde. To a stirred solution of 2-chloro-5-(methoxymethoxy)pyridine ( 0 g, 57.60 mmol, 1 .00 equiv) in THF (120 mL) maintained under nitrogen at -78°C was added a solution of 1 .3M solution of t-BuLi (66 mL) in pentane dropwise. The reaction mixture was stirred at -78°C for 20 min then DMF (8 g, 109.45 mmol, 1 .90 equiv) was added dropwise at -78°C. The resulting solution was stirred for another 30 min at -70 to -80°C and then poured slowly into a saturated aqueous NH4CI solution. The organic layer was collected and the aqueous layer was extracted with 300 mL of ethyl acetate. The combined organic layers were washed with 200 mL of H2O, dried over anhydrous sodium sulfate and concentrated under vacuum to give 12 g of crude 2-chloro-5- (methoxymethoxy)pyridine-4-carbaldehyde as a brown oil. TLC: petroleum ether/ethyl acetate=2: l , R_f= 0.4.

Step 3. 2-Chloro-5-hvdroxypyridine-4-carbaldehyde. A solution of 2-chloro- 5-(methoxymethoxy)pyridine-4-carbaldehyde ( 12 g, 59.52 mmol, 1.00 equiv) in tetrahydrofuran (80 mL) and 3M HC1 (130 mL) was stirred for 1 h at 60°C. The reaction mixture was cooled to rt and the pH value of the solution was adjusted to 7 with 5% aqueous sodium carbonate solution. The organic layer was collected and the aqueous layer was extracted with 400 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl

acetate/petroleum ether (1 :3) to give 6 g (64%) of 2-chloro-5-hydroxypyridine-4- carbaldehyde as a light yellow solid. TLC: petroleum ethenethyl acetate=2: l , R_t = 0.3.

Step 4. Methyl 2-[(6-chloro-4-forrnylpyridin-3-y0oxy]acetate. A solution of 2-chloro-5-hydroxypyridine-4-carbaldehyde (5.7 g, 36. 18 mmol, 1.00 equiv), methyl 2-bromoacetate (7.8 g, 50.99 mmol, 1 .41 equiv) and potassium carbonate (6.5 g) in DMF (100 mL) was stirred for 2 h at 50°C The resulting solution was diluted with 400 mL of ethyl acetate and washed with 2x200 mL of FL . The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether ( 1 :3) to yield 5.5 g (66%) of methyl 2-[(6-chloro-4-formylpyridin-3-yl)oxy]acetate as a light yellow solid. TLC: petroleum ethe ethyl acetate=2: 1 , R_t = 0.3.

Step 5. Methyl 5-chlorofuro[2.3-c1pyridine-2-carboxylate. To a stirred solution of methyl 2-[(6-chloro-4-formylpyridin-3-yl)oxy]acetate (5.5 g, 23.95 mmol, 1.00 equiv) in tetrahydrofuran ( 20 mL) maintained under nitrogen at 0°C was added a 1 M solution of t-BuOK in THF (29 mL) dropwise. The resulting solution was stirred for 2 h at rt and then quenched by the addition of 10 mL of water. The resulting mixture was concentrated under vacuum to give 7 g of crude methyl 5- chlorofuro[2,3-c]pyridine-2-carboxylate as a light yellow solid. The product was used in the next step directly without further purification. TLC: petroleum ether/ethyl acetate=2: l , R, = 0.5.

Step 6. 5-Chlorofuro[2,3-c]pyridine-2-carboxylic acid. A solution of methyl 5-chlorofuro[2,3-c]pyridine-2-carboxylate (370 mg, 1 .75 mmol, 1 .00 equiv) and 10% aqueous sodium hydroxide solution (4 mL) in THF (5 mL) was stirred for 1 h at 60°C. The reaction mixture was cooled to rt and the pH value of the solution was adjusted to 7 with 5% HC1. The resulting mixture was concentrated under vacuum to give 800 mg of crude 5-chlorofuro[2,3-c]pyridine-2-carboxylic acid as a white solid. The product was used in the next step directly without further purification. LC/MS (Method M, ESI): RT=1.47 min, m/z = 198.0 [M+Hf.

Step 7. N-[[4-(Benzenesulfonyl)phenyl]methyl]-5-chlorofuro[2,3-c]pyridine- 2-carboxamide. A solution of the crude 5-chlorofuro[2,3-c]pyridine-2-carboxylic acid (800 mg, 4.05 mmol, 1 .00 equiv), [4-(benzenesulfonyl)phenyl]methanamine (520 mg, 2.10 mmol, 0.52 equiv), EDCI (400 mg, 2.09 mmol, 0.52 equiv), HOBt (283 mg, 2.09 mmol, 0.52 equiv) and diisopropylamine (2 mL) in DMF (10 mL) was stirred at rt overnight. The reaction mixture was diluted with 200 mL of ethyl acetate and washed with 100 mL of ¾0. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (30: 1 00 to 50: 100) to give 400 mg (23%) of N-[[4-(benzenesulfonyl)phenyl]methyl]-5-chlorofuro[2,3- c]pyridine-2-carboxamide as a white solid. TLC: DCM:MeOH = 10: 1 , R_r= 0.6.

Step 8. N-[[4-(Benzenesulfonyl)phenyl1methyl]-5- [(diphenylmethylidene)amino]furo[2.3-c]pyridine-2-carboxamide. A mixture of N- [[4-(benzenesulfonyl)phenyl]methyl]-5-chlorofuro[2,3-c]pyridine-2-carboxamide (200 mg, 0.47 mmol, 1 .00 equiv), diphenylmethanimine (850 mg, 4.69 mmol, 10.01 equiv), Pd₂(dba)₄ (50 mg), BINAP (50 mg, 0.08 mmol, 0.1 7 equiv) and Cs^CO^ ( 1 85 mg, 0.57 mmol, 1 .21 equiv) in 1 ,4-dioxane (5 mL) placed in a 1 0-mL sealed tube maintained under nitrogen was stirred for 3 h at 1 20°C. The reaction mixture was cooled to rt then diluted with 120 mL of ethyl acetate. The resulting mixture was washed with 1 00 mL of HzO. The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified on an alumina column eluted with petroleum ether/ethyl acetate ( 1 : 1 ) to give 300 mg of crude N-[[4- (benzenesuIfonyl)phenyl]methyI]-5-[(diphenyImethylidene)amino]furo[2,3- c]pyridine-2-carboxamide as a yellow solid. LC/MS (Method L, ESI): RT=1 .80 min, m/z = 572 [M+H]⁺.

Step 9, A solution of N-[[4-(benzenesulfonyl)phenyl]methyl]-5- [(diphenylmethylidene)amino]furo[2,3-c]pyridine-2-carboxamide (300 mg, 0.52 mmol, 1 .00 equiv) in THF (5 mL) and 1 8% HC1 (3 mL) was stirred for 30 min at rt. The pH value of the solution was adjusted to 7 with 5% aqueous sodium carbonate solution. The organic layer was collected and the aqueous layer was extracted with 100 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with DCM/MeOH ( 1 00:4) to give 100 mg (47%) of 5-amino-N- [[4-(benzenesulfonyl)phenyl] methyl]furo[2,3-c]pyridine-2-carboxamide as a light yellow solid. LC MS (Method P, ESI): RT=1 .87 min, m/z = 408.0 [M+H] \ Ή NMR (300 MHz, DMSO-^ ppm) δ 9.41 (t, J = 6.0 Hz, 1 H), 8.36 (s, 1 H), 7 94-7.91 (m ,4H), 7.68-7.53 (m, 5H), 7.32 (s, 1 H), 6.64 (d, ./ = 0.9 Hz, 1 H), 5.68 (s, 2H), 4.50 (d, J = 5.7 Hz, 2H). Example 86. N-[[4-(3.5-Difluorophenynsulfonylphenyl|methyl1pyrazolo[l .5- b]pyridazine-5-carboxamide.

Step 1 . 4-Methoxypyridazine. To a solution of 3 ,6-dichloro-4- methoxypyridazine (30 g, 167.59 mmol, 1 .00 equiv) and ammonium formate (3 1 g, 491.63 mmol, 2.93 equiv) in MeOH (500 mL) was added 10% palladium on carbon (3 g) catalyst. The mixture was stirred under 1 atmosphere of ¾ at rt overnight. The catalyst was removed by filtration and the filtrate was concentrated under vacuum. The residue was triturated in 500 mL of DCM MeOH ( 10: 1 ) and the solid material was filtered out. The filtrate was concentrated under vacuum and the residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (2: 1 to 1 : 1 ) to give 1 5 g (81 %) of 4-methoxypyridazine as a brown oil. TLC: petroleum ether: ethyl acetate=2: 1 , Rf=0.1 .

Step 2. Methyl 5-methoxypyrazolo[1.5-b]pyridazine-3-carboxylate. To a stirred solution of hydroxylamine-O-sulfonic acid (30.8 g, 272.57 mmol, 1 .50 equiv) in water (1 00 mL) maintained under nitrogen at 5°C was added a solution of potassium bicarbonate (29. 1 g, 290.67 mmol, 1 .60 equiv) in water (1 00 mL) dropwise. The resulting mixture was stirred for 10 min then a solution of 4-methoxypyridazine (20 g, 181 .63 mmol, 1 .00 equiv) in water (1 00 mL) was added. The reaction mixture was stirred at 70°C for 5 h and then cooled back to rt. A solution of methyl prop-2- ynoate (16.8 g, 199.83 mmol, 1.10 equiv) in DCM (500 mL) followed by a solution of potassium hydroxide (17.3 g, 308.32 mmol, 1 .70 equiv) in water (1 00 mL) were added to the reaction mixture. The resulting solution was stirred overnight at rt then extracted with 4 L of DCM. The organic layer was washed with 3x500 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (6: 1 to 2: 1 ) to give 1 g (3%) of methyl 5-methoxypyrazolo[l ,5-b]pyridazine-3-carboxylate as a brown solid. TLC: petroleum ether.ethyl acetate=l : 1 , Rf=0.4. Step 3. Pyrazolo[l ,5-blpyridazin-3-oI. A solution of methyl 5- methoxypyrazolo[l ,5-b]pyridazine-3-carboxylate (2 g, 9.65 mmol, 1.00 equiv) in 40% HBr (50 mL) was refluxed overnight. The resulting mixture was cooled to rt then concentrated under vacuum. The residue was dissolved in 50 mL of H2O and the pH value of the solution was adjusted to 6-7 with saturated aqueous KHCO? solution (50mL). The mixture was concentrated and the residue was purified on a silica gel column eluted with DCM:MeOH (10: 1 ) to give 500 mg (38%) of pyrazolo[l ,5- b]pyridazin-3-ol as a brown solid. LC/MS (Method D, ESI): RT = 0.41 min, m z = 136.0 [M + Hf.

Step 4. Pyrazolo[l ,5-b]pyridazin-3-yl trifluoromethanesulfonate. To a solution of pyrazolof l ,5-b]pyridazin-3-ol (450 mg, 3.33 mmol, 1 .00 equiv) and pyridine (1 .1 g, 1 3.91 mmol, 3.00 equiv) in DCM (20 mL) maintained under nitrogen at -5°C was added trifluoromethanesulfonic anhydride (1 .9 g, 6.73 mmol, 2.02 equiv) dropwise with stirring in 20 min. The resulting solution was stirred for another 60 min at 0°C and then diluted with 200 mL of DCM. The mixture was washed with 3x100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1 : 10 to 1 :5) to give 570 mg (64%) of pyrazolo[l ,5- b]pyridazin-3-yl trifluoromethanesulfonate as a white solid. TLC: petroleum ether:ethyl acetate =1 : 1 , R_f=0.2.

Step 5. Methyl pyrazolo[1.5-b]pyridazine-3-carboxylate. A mixture of pyrazolo[l ,5-b]pyridazin-3-yl trifluoromethanesulfonate (600 mg, 2.23 mmol, 1 .00 equiv), Pd(PPh₃)₂Cl₂ (300 mg, 0.43 mmol, 0.19 equiv) and pyridine (530 mg, 6.70 mmol, 3.01 equiv) in DMF (20 mL) and MeOH (5 mL) was stirred under 10 atmosphere of CO in a 50-mL pressure tank reactor overnight at 80°C. The reaction mixture was cooled to rt then diluted with 1 00 mL of H₂0. The resulting solution was extracted with 3x100 mL of ethyl acetate. The combined organic layers were washed with 3x100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether ( 1 :5) to yield 200 mg (51 %) of methyl pyrazolo[ l ,5- b]pyridazine-3-carboxylate as a yellow solid. TLC: petroleum ethenethyl acetate =2: l , Rr=0.4.

Step 6. Lithium pyrazolof 1 ,5-blpyridazine-5-carboxylate. To a solution of methyl pyrazolo[ l ,5-b]pyridazine-3-carboxylate (60 mg, 0.34 mmol, 1 .00 equiv) in THF (5 mL) was added a solution of LiOH (40 mg, 1 667mmol, 1.7 equiv) in water (1 mL). The reaction mixture was stirred overnight at 50°C and then concentrated under vacuum to give 150 mg of crude lithium pyrazolo[l ,5-b]pyridazine-5- carboxylate as a dark red solid.

Step 7. N-([4-[(3,5-Difluorobenzene)sulfonyllphenyl]methyl)pyrazolo[l ,5- b]pyridazine-5-carboxamide. A solution of lithium pyrazolo[l ,5-b]pyridazine-5- carboxylate (100 mg, 0.59 mmol, 1 .00 equiv), 4-[(3,5- difluorobenzene)sulfonyl]phenylmethanamine (194 mg, 0.68 mmol, 1 .1 6 equiv), EDC1 (546 mg, 2.85 mmol, 4.82 equiv), HOBt (1 16 mg, 0.86 mmol, 1 .45 equiv) and triethylamine (404 mg, 3.99 mmol, 6.75 equiv) in DMF (5 mL) was stirred at it for 2 h. The reaction was then quenched by the addition of 1 00 mL of H2O and the resulting solution was extracted with 3x100 mL of ethyl acetate. The combined organic layers were washed with 3x100 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified by Prep-HPLC with the following conditions [(Waters-2; Column, XBridge C 1 8 19* 1 50; mobile phase, mobile phase, phase A: water with 0.2% NH₄HCO₃; phase B: C¾CN ( 10% CH₃CN up to 43% in 10 min, up to 100% in 13 min); Detector, UV 254 nm] to give 6.4 mg (3%) of N-([4-[(3,5-difluorobenzene)sulfonyl]phenyl]methyl)pyrazolo[l ,5- bJpyridazine-5-carboxamide as an off white solid. LC MS (Method Q, ESI): RT = 1.43 min, m/z = 429.2 [M+H]⁺. Ή NMR (300 MHz, DMSO-c/₆, ppm): δ 9.59 (t, J = 6.0 Hz, l H), 8.60 (s, l H), 8.19 (s, 1 H), 8.04 (d, J = 8.4 Hz, 2H), 7.87-7.55 (m, 6H), 7.03 (s, 1 H), 4.62 (d, J = 6.0 Hz, 2H). Example 90. 4-Amino-N-[[4-(benzenesulfonyl)phenyl]methyll-1.3- dihydropyrrolo[3.4-c]pyridine-2-carboxamide.

Step 1 . 3.4-Dimethyl 2-chloropyridine-3.4-dicarboxylate. A mixture of 3,4- bis(methoxycarbonyl)pyridin-l -ium-l -olate (5 g, 23.68 mmol, 1 .00 equiv) (see Hashimoto, K.; Higashibayashi, S.; Shirahama, H. Heterocycles; 1997, 46, 581 -588) in POCb (20 mL) and CHCb (100 mL) was stirred at reflux for 2h. The reaction mixture was concentrated under vacuum and the residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1 /10 to 1 /5) to afford 1 .2 g of crude 3,4-dimethyl 2-chloropyridine-3,4-dicarboxylate as a dark red solid. TLC: ethyl acetate/petroleum ether = 1 :2, R_f = 0.4.

Step 2. [2-Chloro-4-(hydroxymethyl)pyridin-3-yl]methanol. To a solution of 3,4-dimethyl 2-chloropyridine-3 ,4-dicarboxylate (300 mg, 1 .31 mmol, 1 .00 equiv), in ethanol (30 mL) was added NaBH₄ (300 mg, 7.93 mmol, 6.07 equiv). The resulting solution was stirred at rt for 1 h. The pH value of the solution was adjusted to 5 with the addition of formic acid. The solid material was removed by filtration. The filtrate was concentrated under vacuum to give 0.35 g of crude [2-chloro-4- (hydroxymethyl)pyridin-3-yl]methanol as a light yellow solid. TLC: ethyl acetate/petroleum ether = 2: 1 ; R₍- = 0.1 .

Step 3. 2-Chloro-3 ,4-bis(chloromethyl)pyridine. A solution of [2-chloro-4- (hydroxymethyl)pyridin-3-yl]methanol (300 mg, 1.73 mmol, 1 .00 equiv) and thionyl chloride (20 mL) in DCM (20 mL) was stirred under nitrogen at rt for 1 h. The resulting mixture was concentrated under vacuum. Saturated aqueous sodium carbonate solution was added to the residue to adjust the pH value to 8. The resulting solution was extracted with 2x100 mL of DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give 0.32 g of crude 2-chloro-3,4-bis(chloromethyl)pyridine as a dark red oil. TLC: ethyl acetate/petroleum ether = 1 : 1 , R_f = 0.6. Step 4. 4-Chloro-2-[(2^-dimet oxyphenyl)methyl]-l H.2H.3H-pyrrolo[3.4- cjpyndine. A solution of 2-chloro-3 ,4-bis(chloromethyl)pyndine (200 mg, 0.95 mmol, 1 .00 equiv), (2,4-dimethoxyphenyl)methanamine (500 mg, 2.99 mmol, 3. 15 equiv) and DIPEA (500 mg, 3.87 mmol, 4.07 equiv) in DCM (30 mL) was stirred under nitrogen overnight at rt. The reaction mixture was concentrated under vacuum to give 0.28 g of crude 4-chloro-2-[(2,4-dimethoxyphenyl)methyl]-l H,2H,3H- pyrrolo[3,4-c]pyridine as a dark red oil. TLC: ethyl acetate/petroleum ether = 2: 1 , Rf = 0.3.

Step 5. N,2-bis[(2,4-Dimethoxyphenyl)methyll- l H.2H,3H-pyrrolo[3,4- c]pyridin-4-amine. A mixture of 4-chloro-2-[(2,4-dimethoxyphenyl)methyl]- l H,2H,3H-pyrrolo[3,4-c]pyridine (200 mg, 0.66 mmol, 1 .00 equiv), (2,4- dimethoxyphenyl)methanamine (300 mg, 1 .79 mmol, 2.73 equiv), Pd2(dba)i ( 1 00 mg, 0.1 1 mmol, 0. 17 equiv), BINAP ( 100 mg, 0.1 6 mmol, 0.24 equiv) and t-BuONa (0.3 g) in toluene (40 mL) was stirred under nitrogen at 90°C overnight. The reaction mixture was cooled to rt then concentrated under vacuum. The residue was purified on a silica gel column eluted with DCM MeOH (30: 1 ) to give 0. 1 8 g of crude N,2- bis[(2,4-dimethoxyphenyl)methyl]-l H,2H,3H-pyrrolo[3,4-c]pyridin-4-amine as a dark red solid. LC/MS (Method I, ESI): RT= 1 .08 min, m z = 436.0 [M+H] ; TLC: ethyl acetate/petroleum ether = 3 : 1 , R_f = 0.2.

Step 6. l H.2H.3H-Pyrroloi3.4-clpyridin-4-amine. A solution of N,2-bis[(2,4- dimethoxyphenyl)methyl]- l H,2H,3H-pyrrolo[3 ,4-c]pyridin-4-amine (50 mg, 0.1 1 mmol, 1 .00 equiv) in TFA (20 mL) was reflux under nitrogen for 4 h. The reaction mixture was cooled to rt and then concentrated under vacuum. The residue was diluted in 10 mL of H₂0 and the pH value of the solution was adjusted to 8 with potassium carbonate. The resulting solution was washed with 2x60 mL of ether. The aqueous layer was collected and concentrated under vacuum to give 0.1 2 g of crude 1 H,2H,3H-pyrrolo[3,4-c]pyridin-4-amine as a light yellow sol id. TLC: MeOH DCM = l :2, R_f = 0. 1 .

Step 7. A solution of 1 H,2H,3H-pyrrolo[3,4-c]pyridin-4-amine (1 50 mg, 0.37 mmol, 1 .00 equiv) and 4-nitrophenyl N-[[4-

(benzenesulfonyl)phenyl]methyl]carbamate (200 mg, 0.48 mmol, 1 .31 equiv) in ethanol (30 mL) was reflux under nitrogen for 1 h. The resulting mixture was cooled to rt and concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether ( 1 : 1 to 5 : 1 ) to give 12 mg of 4-amino-N-[[4- (benzenesulfonyl)phenyl]methyl]-l H,2H,3H-pyrrolo[3,4-c]pyridine-2-carboxamide as a light yellow solid. LC/MS (Method R, ESI): RT= 2.24 min, z = 409 3 [M+H]⁺. Ή NMR (300 MHz, CD₃OD, /?w): δ 7.97-7.87 (m, 5H), 7.67-7.54 (m, 6H), 6.64 (s, 1H), 4.59 (s, 4H), 4.48 (s, 2H).

Example 94. Methyl 5-[[4-[3- (trifluoromethyl)phenyl]sulfonylphenyl1methylcarbamoyl]pyrazolo[3.4-b]pyridine-l - carboxylate

A solution of N-[(4-[[3-(trifluoromethyl)benzene]sulfonyl]phenyl)methyl]- 1 H-pyrazolo[3,4-b]pyridine-5-carboxamide (1 .5 g, 3.26 mmol, 1 .00 equiv), chloro(methoxy)methanone ( 1 .6 g, 16.93 mmol, 5.20 equiv) and triethylamine (4 mL) in DMF (10 mL) was stirred at 30°C overnight. The reaction was quenched by the addition of 30 mL of water. The resulting solution was extracted with 3x20 mL of ethyl acetate. The combined organic layers were washed with 2x20 mL of brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with DCM/MeOH (10: 1 ) to give 103.1 mg (6.2%) of methyl 5-[[(4-[[3-(trifluoromethyl)benzene]sulfonyl]phenyl)methyl]carbamoyl]-l H- pyrazolo[3,4-b]pyridine-l -carboxylate as a white solid. TLC: DCM MeOH = 10:1 , R,- = 0.6. LC/MS (Method R, ESI): RT= 2.34 min, m z = 519.2 [M+H] \ Ή NMR (400 MHz, DMSO- ₀, ppm). δ 9.43 (t, = 5.0 Hz, 1 H), 9.1 7 (s, 1 H), 9. 1 7 (s, 1 H), 8.81 (s, 1 H), 8.63 (s, 1 H), 8.27 (t, ./ = 9.2 Hz, 2H), 8.10-8.03 (m, 3H), 7.88 (t, ./ = 7.8 Hz, 1 H), 7.62 (d, J = 8.4 Hz, 2H), 4.61 (d, J = 5.2 Hz, 2H), 4.02 (s, 3H). The compounds of Examples 40-51 were prepared according to the method described for Example 17. The compounds of Examples 62, 75, and 79 were prepared according to the methods described for Example 37. The compounds of Examples 66, 68, 80, 87, 88, and 91 were prepared according to the methods described for Example 24. The compounds of Examples 69 and 78 were prepared according to the methods described in Examples 24 and 36. The compounds of Examples 70, 73, 76, and 81 were prepared according to the methods described in Example 36. The compounds of Examples 84 and 85 were prepared according to the methods described for Example 77. The compounds of Examples 92 and 93 were prepared according to the methods described in Examples 10 and 37. Additional examples were prepared using methods analogous to those described above. The structures of all example compounds were confirmed by LC MS and/or H NMR analysis.

Analytical Characterization:

Each of the specifically exemplified compounds described herein was prepared using the methods analogous to those described above, and were analyzed by LC/MS. Data for each compound, along with the LC/MS method used to generate the data, is provided in Table 1 .

Table 1. LC/MS Data for Example Compounds.

15 1.52 393.0 D

16 1.33 416.0 D

17 1.74 415.2 C

18 1.07 510.2 G

19 1.07 511.1 G

20 1.58 431.2 D

21 1.41 471.0 C

22 1.72 393.2 F

23 2.09 443.2 C

24 1.05 438.0 I

25 1.27 416.2 c

26 1.68 429.0 E

27 1.19 457.1 I

28 1.73 415.2 c

29 186 529.0 H

30 1.34 392.1 F

31 2.80 454.1 K

32 1.32 399.9 C

33 1.05 401.1 F

34 2.01 429.9 C

35 2.79 408.8 C

36 1.70 407.8 C

37 1.61 466.2 J

40 1.73 415.2 c

41 1.05 416.0 I

42 1.28 415.0 D

43 1.57 417.1 C

44 1.07 471.0 I

45 1.10 487.0 I

46 1.44 511.1 G

47 1.62 470.3 C

48 1.11 471.0 C

49 1.41 471.0 C

50 1.19 457.1 C

51 1 18 457.2 C

54 3.79 512.2 T

55 2.42 414.1 T

56 2.70 417.1 T

57 4.26 533.2 T

59 3.23 410.1 T

60 2.79 401.1 T

61 2.78 461.1 T

62 1.16 408.9 M

63 1.38 461.2 T

64 1.83 408.1 0

It is understood that the person skilled in the art will be able to prepare the compounds of the present invention using methods known in the art along with the general method of synthesis described herein.

Assay 1 : Biochemical Inhibition Assay

NAMPT protein purification. Recombinant His-tagged NAMPT was produced in E.coli cells, purified over a Ni column, and further purified over a size- exclusion column by XTAL Biostructures. The NAMPT enzymatic reaction. The NAMPT enzymatic reactions were carried out in Buffer A (50mM Hepes pH 7.5, 50 mM NaCl, 5 mM MgCl₂, and 1 mM THP) in 96- well V-bottom plates. The compound titrations were performed in a separate dilution plate by serially diluting the compounds in DMSO to make a 100X stock. Buffer A (89 μί) containing 33 nM of NAMPT protein was added to 1 μί, of 100X compound plate containing controls (e.g. DMSO or blank). The compound and enzyme mixture was incubated for 1 5 min at rt, then 10 μί of 1 OX substrate and co- factors in Buffer A were added to the test well to make a final concentration of 1 μΜ NAM, 1 00 μΜ 5-Phospho-D-ribose 1 -diphosphate (PRPP), and 2.5 mM Adenosine 5'-triphosphate (ATP). The reaction was allowed to proceed for 30 min at rt, then was quenched with the addition of 1 1 μL of a solution of formic acid and L- Cystathionine to make a final concentration of 1 % formic acid and 10 μΜ L- Cystathionine. Background and signal strength was determined by addition (or non- addition) of a serial dilution of NMN to a pre-quenched enzyme and cofactor mix.

Quantification of NMN. A mass spectrometry-based assay was used to measure the NAMPT reaction product, β-nicotinamide mononucleotide (NMN), and the internal control (L-Cystathionine). NMN and L-Cystathionine were detected using the services of Biocius Lifesciences with the RapidFire system. In short, the NMN and L-Cystathionine were bound to a graphitic carbon cartridge in 0. 1 % formic acid, eluted in 30% acetonitrile buffer, and injected into a Sciex 4000 mass spectrometer. The components of the sample were ionized with electrospray ionization and the positive ions were detected. The Ql (parent ion) and Q3 (fragment ion) masses of NMN were 334.2 and 123.2, respectively. The Ql and Q3 for L- Cystathionine were 223.1 and 134.1 , respectively. The fragments are quantified and the analyzed by the following method.

Determination of IC^o Values. First, the NMN signal was normalized to the L-Cystathionine signal by dividing the NMN signal by the L-Cystathionine signal for each well. The signal from the background wells were averaged and subtracted from the test plates. The compound treated cells were then assayed for percent inhibition by using this formula:

% Inh = 100 - 100*x/y wherein x denotes the average signal of the compound treated wells and y denotes the average signal of the DMSO treated wells.

IC50 values were then determined using the following formula:

IC₅₀ =10^A(LOG,o(X) + (((50-% Inh at Cmpd Concentration 1 )/(XX - YY)*(LOG,o(X)-LOGio(Y))))

wherein X denotes the compound concentration 1 , Y denotes the compound concentration 2, XX denotes the % inhibition at compound concentration 1 (X), and YY denotes the % inhibition at compound concentration 2 (Y).

The compounds of this invention have IC50 values that are preferably under Ι μΜ, more preferably under 0.1 μΜ, and most preferably under 0.01 μΜ. Results for the compounds tested in this assay are provided in Table 2 below

Assay 2; ln-Vitro Cell Proliferation Assay

Assay Method. A2780 cells were seeded in 96-well plates at 1 x 10³ cells/well in 180 μΙ_ of culture medium (10% FBS, 1 % Pen/Strep Amphotericin B, RPMT-1 640) with and without the addition of either NMN or nicotinamide (NAM). After overnight incubation at 37 °C and 5% CO₂, the compound titrations were performed in a separate dilution plate by serially diluting the compounds in DMSO to make a 1000X stock. The compounds were then further diluted to 10X final concentration in culture media, whereupon 20 μΙ_ of each dilution was added to the plated cells with controls (e.g. DMSO and blank) to make a final volume of 200 μΙ_. The final DMSO concentration in each well was 0.1 %. The plates were then incubated for 72 hours at 37 °C in a 5% CO₂ incubator. The number of viable cells was then assessed using sulforhodamine B (SRB) assay. Cells were fixed at 4 °C for 1 hour with the addition of 50 μΙ_ 30% trichloroacetic acid (TCA) to make a final concentration of 6 % TCA. The plates were washed four times with ¾0 and allowed to dry for at least 1 hour, whereupon 100 μί of a 4% SRB in 1 % acetic acid solution was added to each well and incubated at rt for at least 30 min. The plates were then washed three times with 1 % acetic acid, dried, and treated with 100 μί of l OmM Tris-Base solution. The plates were then read in a microplate reader at an absorbance of 570 nm. Background was generated on a separate plate with media only. Determination of IC > Values. First, the signals from the background plate were averaged, then the background was subtracted from the test plates. The compound-treated cells were then assayed for % inhibition by using the following formula:

% Inh = 100 - 100*x/y

wherein x denotes the average signal of the compound-treated cells and y denotes the average signal of the DMSO-treated cells.

IC 0 values were then determined using the following formula:

IC₅₀

Inh at Cmpd Concentration 1 )/(XX- YY)*(LOGu>(X)-LOG,o(Y))))

wherein X denotes the compound concentration 1 , Y denotes the compound concentration 2, XX denotes the % inhibition at compound concentration 1 (X), and YY denotes the % inhibition at compound concentration 2 (Y).

Specificity of cytotoxicity. Inhibition of NAMPT could be reversed by the addition of NAM or NMN. The specificity of the compounds were determined via cell viability assay in the presence of the compound and either NAM or NMN. Percent inhibitions were determined using the method given above.

The compounds of this invention have IC50 values that are preferably under 1 μΜ, more preferably under 0.1 μΜ, and most preferably under 0.01 μΜ. Most preferable compounds of this invention are compounds that have IC50 values in the enzymatic assay and the cell proliferation assay that are both under 1 μΜ, more preferably both of the values are under 0.1 uM, and most preferably both of the values are under 0.01 μΜ. Results for the compounds tested in this assay are provided in Table 2 (NT = not tested).

Table 2. Biochemical and Cell Proliferation Assay Results.

While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and other variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

Claims

CLAIMS compound selected from the group consisting of:

1 H-Pyrrolo[3,2-c]pyridine-2- carboxylic acid 4-(2- trifluoromethoxy- phenylsulfamoyl)-benzylamide

Quinoline-6-carboxylic acid 4-(5- fluoro-2-methoxy- phenylsulfamoyl)-benzylamide

1 H-Pyrrolo[3,2-c]pyridine-2- carboxylic acid 4-(2-methoxy-5- methyl-phenylsulfamoyl)- benzylamide

1 H-Pyrrolo[3,2-c]pyridine-2- carboxylic acid 4-(2,4- dimethoxy-phenylsulfamoyl)- benzylamide

1 H-Pyrrolo[3,2-c]pyridine-2- carboxylic acid 4-(2-ethoxy- phenylsulfamoyl)-benzylamide

1 H-Pyrrolo[3,2-c]pyridine-2- carboxylic acid 4-(2-pyrrolidin- l - yl-phenylsulfamoyl)-benzylamide 1 H-Pyrrolo[3,2-c]pyridine-2- carboxylic acid 4-[2-(2-hydroxy- ethyl)-phenylsulfamoyl]- benzylamide

l H-Pyrrolo[3,2-c]pyndine-2- carboxylic acid 4-[2-((S)-2- hydroxy-propoxy)- phenylsulfamoyl]-benzylamide

/ra/7.v-Thieno[2,3-c]pyridine-2- carboxylic acid 4-(4-amino- cyclohexylsulfamoyl)- benzylamide lmidazo[l ,2-b]pyridazine-6- carboxylic acid 4- benzenesulfonyl-benzylamide

Imidazofl ,2-a]pyridine-6- carboxylic acid 4-(tetrahydro- pyran -4 -y 1 s u lfam oy 1 )- benzylamide

Imidazo[l ,2-a]pyrimidine-6- carboxylic acid 4-(tetrahydro- pyran -4 -y 1 s u lfam oy 1 )- benzylamide

1 H-Pyrazolo[3,4-b]pyndine-5- carboxylic acid 4-(tetrahydro- pyran-4-ylsulfamoyl)- benzylamide

1 H-Pyrazolo[3,4-b]pyndine-5- carboxylic acid 4-(tetrahydro- pyran-3-ylsulfamoyl)- benzylamide c/.y-Thieno[2,3-c]pyridine-2- carboxylic acid 4-(4-amino- cyclohexylsulfamoyl)- benzylamide [1 ,2,4]Triazolo[l ,5-a]pyridine-6- carboxylic acid 4- benzenesulfonyl-benzylamide

Furo[2,3-c]pyridine-2-carboxylic acid 4-(tetrahydro-pyran-4- ylsulfamoyl)-benzylamide

1 H-Pyrrolo[3,2-c]pyridine-2- carboxylic acid 4-(tetrahydro- pyran-3 -ylsulfamoyl)- benzylamide mmy-l H-Pyrrolo[3,2-c]pyridir)e- 2-carboxylic acid 4-[4-(2,2,2- trifluoro-ethylamino)- cyclohexylsulfamoyl]- benzylamide

/ram-Furo[2,3-c]pyridine-2- carboxylic acid 4-[4-(2,2,2- trifluoro-ethylamino)- cyclohexylsulfamoyl]- benzylamide

Thieno[2,3 -c]pyridine-2- carboxylic acid 4-(piperidin-4- ylsulfamoyl)-benzylamide

Thieno[2,3-c]pyridine-2- carboxylic acid 4-(9-aza- bicyclo[3.3. 1 ]non-3-ylsulfamoyl)- benzylamide

Pyrazolofl ,5-a]pyrimidine-5- carboxylic acid 4- benzenesulfonyl-benzylamide

3-Amino-imidazo[ 1 ,2-a]pyridine- 6-carboxylic acid 4-(3,5-difluoro- benzenesulfonyl)-benzylamide

N-[[4-(tetrahydropyran-3- ylsulfamoyl)phenyl]methyl]imida zo[l ,2-a]pyridine-6-carboxamide

N-[[4-(tetrahydropyran-3- ylsulfamoyl)phenyl]methyl]ftiro[ 2,3-c]pyridine-2-carboxamide

N-[[4-(tetrahydropyran-4- ylsulfamoyl)phenyl]methyl]-l H- pyrrolo [3 ,2-c]pyridine-2- carboxamide

N-[[4-(pyrrolidin-3- ylsulfamoyl)phenyl]methyl]thien o[2,3-c]pyridine-2-carboxamide

N-[[4-[(2,2,6,6-tetramethyl-4- piperidyl)sulfamoyl]phenyl]meth yI]furo[2,3-c]pyridine-2- carboxamide

N-[[4-[(2,2,6,6-tetramethyl-4- piperidyl)sulfamoyl]phenyl]meth yl]thieno[2,3-c]pyridine-2- carboxamide

126

and stereoisomers thereof, and pharmaceutically acceptable salts of said compounds and stereoisomers.

2. A pharmaceutical composition comprising: (a) an effective amount of at least one compound of claim 1 ; and (b) a pharmaceutically acceptable carrier.

3. The pharmaceutical composition of claim 2, further comprising

therapeutically effective amounts of one or more additional adjunctive active agents.

4. The pharmaceutical composition of claim 3, wherein said one or more additional adjunctive active agents are selected from the group consisting of cytotoxic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, the epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, tipifarnib

(Zarnestra^®), Rl 1 5777, L778, 123, BMS 214662, Iressa*, Tarceva^8', C225,

GLEEVEC^®, intron*, Peg-Intron*^', aromatase combinations, ara-C, adriamycin, Cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Tnethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine,

Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, oxaliplatin (ELOXATIN^®), Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin™, Deoxycoformycin, Mitomycin-C, L- Asparaginase, Teniposide 17a-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrol acetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone,

Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine,

Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene,

goserelin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane,

Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin, Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane,

Ifosfomide, Rituximab, C225, Campath, leucovorin, and dexamethasone, bicalutamide, carboplatin, chlorambucil, cisplatin, letrozole, megestrol, valrubicin, vinblastine and NIASPAN*.

5. The pharmaceutical composition of claim 2 further comprising a rescuing agent.

6. The pharmaceutical composition of claim 5, wherein the rescuing agent is selected from the group consisting of nicotinamide, nicotinic acid, and nicotinamide mononucleotide (NMN).

7. A method of treating a subject suffering from or diagnosed with a disease or medical condition mediated by NAMPT activity, comprising administering to the subject in need of such treatment an effective amount of at least one compound of claim 1.

8. The method of claim 7, wherein the disease or medical condition is a solid or liquid tumor, non-small cell lung cancer, leukemia, lymphoma, ovarian cancer, glioma, breast cancer, uterine cancer, colon cancer, cervical cancer, lung cancer, prostate cancer, skin cancer, rhino-gastric tumors, colorectal cancer, CNS cancer, bladder cancer, pancreatic cancer, Hodgkin's disease, rheumatoid arthritis, diabetes, atherosclerosis, sepsis, aging, inflammation.

9. The method of claim 7, further comprising administering to the subject an effective amount of at least one compound selected from the group consisting of: a cytotoxic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, the epothilones, tamoxifen, 5- fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, tipifarnib (Zarnestra^®), Rl 15777, L778.123, BMS 214662, Iressa^®, Tarceva*, C225, GLEEVEC^®, intron^®, Peg-Intron^®, aromatase combinations, ara-C, adriamycin, Cytoxan, gemcitabine, Uracil mustard, Chlormethine, lfosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine,

Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, leucovirin, oxaliplatin (ELOXATI ^®), Pentostatine, vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin ^rM, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17a-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone 130

propionate, Testolactone, Megestrol acetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone,

Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Carboplatin, Hydroxyurea, Amsacrine,

Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin, Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane, Ifosfomide, Rituximab, C225, Campath, leucovorin, dexamethasone, bicalutamide, chlorambucil, letrozole, megestrol, valrubicin, vinblastine, and NIASPAN*.

10. The method of claim 7 further comprising administering an effective amount of a rescuing agent.

1 1 . The method of claim 10, wherein the rescuing agent is selected from the group consisting of nicotinamide, nicotinic acid, and nicotinamide mononucleotide (NMN).