WO2014074715A1 - Cyclopropyl amide derivatives - Google Patents

Abstract

The present invention relates to certain cyclopropyl amide 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 cyclopropyl amide compounds for use in inhibiting nicotinamide phosphoribosyltransferase ("NAMPT").

Description

CYCLOPROPYL AMIDE DERIVATIVES

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application Serial No. 61/723,614, filed November 7, 2012, which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to certain cyclopropyl amide 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 cyclopropyl amide compounds for use in inhibiting nicotinamide phosphoribosyltransferase ("NAMPT").

BACKGROUND OF THE INVENTION

[0003] 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-1 -pyrophosphate to generate nicotinamide mononucleotide, which is a precursor in the biosynthesis of NAD.

[0004] 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. [0005] 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. /. Immunol. 2008, 181, 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.

[0006] 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/K22.175, a new inhibitor of intracellular NAD biosynthesis, in murine renal cell carcinoma," Anticancer Res. 2003, 23, 4853-4858.

[0007] 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. Commun. 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.

[0008] There remains a need for potent NAMPT inhibitors with desirable pharmaceutical properties. Certain cyclopropylamide derivatives have been found in the context of this invention to have NAMPT-modulating activity.

SUMMARY OF THE INVENTION

[0009] In one aspect, the invention is directed to compounds of Formula I:

wherein: R is a heteroaryl comprising at least one nitrogen ring atom, wherein said heteroaryl is unsubstituted or substituted with one or more substituents selected from the group consisting of -NH₂, halo, Ci-₄alkyl, -OH, and Ci-₄alkoxy;

A is

(1) aryl or heteroaryl; or

(2) heterocycloalkyl comprising at least one nitrogen ring atom;

R² is:

(a) R^a, where R^a is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each unsubstituted or substituted with one or more substituents selected from the group consisting of: halo, hydroxy, cyano, -NR^bR^c, -alkylenyl-NR^bR^c, oxo, alkyl, alkoxy, -S(O)₀-₂-R^b, alkenyl, alkynyl, -C(0)R^b, -C0₂R^b, -CONR^bR^c, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, or two adjacent substituents on a phenyl taken together form methylene- or

ethylenedioxy;

wherein alkyl and alkoxy are each unsubstituted or substituted with hydroxy, alkoxy, halo, cyano, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl;

R^b is H, alkyl, haloalkyl, alkoxyalkyl, cyanoalkyl, arylalkyl, -C(0)alkyl, -C0₂alkyl, or

-S0₂alkyl, cycloalkyl, heterocycloalkyl, aryl, or -C(0)aryl; and

R^c is H or alkyl;

(b) Ci-i₂alkyl or Ci-i₂alkenyl, each unsubstituted or substituted with one or more substituents selected from the group consisting of R^a, halo, hydroxy, cyano, alkoxy, haloalkoxy, -NR^UR^V, -C(0)R^u, C0₂R^u, -CONR^uR^v, -S(O)_{0 -2}R^U, and -S0₂NR^uR^v;

wherein R^a is as defined in (a) above; and

R^u and R^v are each independently H, alkyl, alkoxyalkyl, haloalkyl, -C(0)alkyl, or

-C0₂alkyl;

(c) -NR^dR^e;

wherein R^d and R^e are each independently, H, alkyl, -alkylenyl-R^a, or R^a;

wherein R^a is defined as in (a) above; and

alkyl is unsubstituted or substituted with hydroxy, cyano, alkoxy, halo, -NR^hR\

-CONR^hR\ or -C(0)R^j,

wherein R^h and R¹ are each independently H or alkyl, or R^h and R¹ taken together with the nitrogen to which they are attached form a monocyclic

heterocycloalkyl; and

R^J is alkyl, cycloalkyl, heterocycloalkyl, phenyl, or benzyl, each unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, halo, amino, hydroxy, and alkoxy;

n is 0, 1, or 2; and

X is -SO₂-, -C(O)-, -CO₂-, -C(0)NR^m-, -SO-, or -S0₂NR^m-; or when A is a bicyclic heteroaryl or bicyclic heterocycloalkyl, X may also be absent;

wherein R^m is H or Ci_₄alkyl;

and pharmaceutically acceptable salts of compounds of Formula I.

[0010] In a further aspect, the invention relates to pharmaceutical compositions each comprising an effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt of a compound of Formula I. Pharmaceutical compositions according to the invention may further comprise at least one pharmaceutically acceptable excipient.

[0011] 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 of Formula I or a pharmaceutically acceptable salt of a compound of Formula I, 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 of Formula I or a pharmaceutically acceptable salt of a compound of Formula I.

[0012] An aspect of the present invention concerns the use of compound of Formula I for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of cancer.

[0013] An aspect of the present invention concerns the use of a compound of Formula I 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, central nervous system (CNS) cancer, bladder cancer, pancreatic cancer and Hodgkin's disease.

[0014] An aspect of the present invention concerns the use of a compound of Formula I 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.

[0015] In another aspect, the compounds of Formula I 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 Formula I or a pharmaceutically acceptable salt of a compound of Formula I.

[0016] In yet another aspect, the present invention is directed to methods of making compounds of Formula I and pharmaceutically acceptable salts thereof.

[0017] In certain embodiments of the compounds, pharmaceutical compositions, and methods of the invention, the compound of Formula I 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.

[0018] 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 PREFERRED EMBODIMENTS

[0019] 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.

[0020] 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.

General Definitions

[0021] 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.

[0022] As used herein, the terms "including," "containing," and "comprising" are used in their open, non-limiting sense.

[0023] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0024] 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.

Chemical Definitions

[0025] As used herein, "alkyl" refers to a saturated, straight- or branched-chain hydrocarbon group having from 1 to 10 carbon atoms. Representative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2 -methyl- 1 -propyl, 2-methyl-2-propyl, 2-mefhyl- 1-butyl, 3 -methyl- 1 -butyl, 2-methyl-3-butyl, 2,2-dimethyl-l -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-dimethyl-l-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.

[0026] The term "alkylenyl" refers to a divalent alkyl group.

[0027] The term "alkoxy" as used herein includes -O-(alkyl), wherein alkyl is defined above.

[0028] The term "amino" as used herein refers to an -Nl¾ group.

[0029] "Aryl" means a mono-, bi-, or tricyclic aromatic group, wherein all rings of the group are aromatic and all ring atoms are carbon atoms. For bi- or tricyclic systems, the individual aromatic rings are fused to one another. Examples of aryl groups are 6 and 10 membered aryls. Further examples of aryl groups include, but are not limited to, phenyl, naphthalene, and anthracene.

[0030] The term "cyano" as used herein means a substituent having a carbon atom joined to a nitrogen atom by a triple bond.

[0031] The term "deuterium" as used herein means a stable isotope of hydrogen having one proton and one neutron.

[0032] The term "halo" represents chloro, fluoro, bromo, or iodo. In some embodiments, halo is chloro, fluoro, or bromo. The term "halogen" as used herein refers to fluorine, chlorine, bromine, or iodine.

[0033] The term "hydroxy" means an -OH group.

[0034] The term "oxo" means an =0 group and may be attached to a carbon atom or a sulfur atom. [0035] The term "N-oxide" refers to the oxidized form of a nitrogen atom.

[0036] As used herein, the term "cycloalkyl" refers to a saturated or partially saturated, monocyclic, fused polycyclic, bridged polycyclic, or spiro polycyclic carbocycle having from 3 to 15 carbon ring atoms. A non limiting category of cycloalkyl groups are saturated or partially saturated, monocyclic carbocycles having from 3 to 6 carbon atoms. Illustrative examples of cycloalkyl groups include, but are not limited the following moieties:

[0037] "Heterocycloalkyl" as used herein refers to a monocyclic, or fused, bridged, or spiro polycyclic ring structure that is saturated or partially saturated and has from three to 12 ring atoms selected from carbon atoms and up to three heteroatoms selected from nitrogen, oxygen, and sulfur. The ring structure may optionally contain up to two oxo groups on carbon or sulfur ring members, or an N-oxide. Illustrative heterocycloalkyl entities include, but are not limited to:

[0038] As used herein, the term "heteroaryl" refers to a monocyclic, or fused polycyclic, aromatic heterocycle having from three to 15 ring atoms that are selected from carbon, oxygen, nitrogen, and sulfur. Suitable heteroaryl groups do not include ring systems that must be charged to be aromatic, such as pyrylium. Suitable 5-membered heteroaryl rings (as a monocyclic heteroaryl or as part of a polycyclic heteroaryl) have one oxygen, sulfur, or nitrogen ring atom, or one nitrogen plus one oxygen or sulfur, or 2, 3, or 4 nitrogen ring atoms. Suitable 6-membered heteroaryl rings (as a monocyclic heteroaryl or as part of a polycyclic heteroaryl) have 1, 2, or 3 nitrogen ring atoms. Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl.

[0039] The term "bicyclic heteroaryl" refers to a heteroaryl as defined above, having two constituent aromatic rings, wherein the two rings are fused to one another and at least one of the rings is a heteroaryl as defined above. Bicyclic heteroaryls include bicyclic heteroaryl groups comprising 1, 2, 3, or 4 heteroatom ring atoms selected from O, N or S. In certain embodiments, wherein the heteroatom is N it can be an N-oxide. Bicyclic heteroaryls also include 8-, 9-, or 10-membered bicyclic heteroaryl groups. Bicyclic heteroaryls also include 8-, 9-, or 10- membered bicyclic heteroaryl groups that have 1, 2, 3, or 4 heteroatom ring atoms selected from O, N or S. Illus to:

[0040] Those skilled in the art will recognize that the species of heteroaryl, cycloalkyl, and heterocycloalkyl groups listed or illustrated above are not exhaustive, and that additional species within the scope of these defined terms may also be selected.

[0041] As used herein, the term "substituted" means that the specified group or moiety bears one or more suitable substituents. As used herein, the term "unsubstituted" means that the specified group bears no substituents. As used herein, the term "optionally substituted" means that the specified group is unsubstituted or substituted by the specified number of substituents. Where the term "substituted" is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system.

[0042] As used herein, the expression "one or more substituents" denotes one to maximum possible number of substitution(s) that can occur at any valency- allowed position on the system. In a certain embodiment, one or more substituent means 1, 2, 3, 4, or 5 substituents. In another embodiment, one or more substituent means 1, 2, or 3 substituents.

[0043] 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.

[0044] When any variable (e.g. , alkyl or R^a) appears in more than one place in any formula or description provided herein, the definition of that variable on each occurrence is independent of its definition at every other occurrence.

[0045] 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.

[0046] When a multifunctional moiety is shown, the point of attachment to the remainder of the formula can be at any point on the multifunctional moity. In some embodiments, the point of attachment is indicated by a line or hyphen. For example, aryloxy- 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.

Additional Definitions

[0047] 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 animals 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.

[0048] "Patient" includes both human and animals.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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

[0053] 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.

[0054] 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 IUPAC 1974 Recommendations.

[0055] 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 Formula I that is non-toxic, 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.

[0056] 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. [0057] 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, p-toluenesulfonate, and pamoate (i.e., l,l '-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 counterion 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.

[0058] 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.

[0059] 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.

[0060] 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, J. Pharm. Sci. (1977) 66(1) 1-19; P. Gould, Int. J. Pharm. (1986) 33 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, MD, available from FDA). These disclosures are incorporated herein by reference thereto.

[0061] 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.

[0062] 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. Pharm. Sci., 93(3), 601-611 (2004), describes the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates, and the like are described by E. C. van Tonder et al. , AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001). A typical, non- limiting process involves dissolving the inventive compound in 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).

[0063] The invention also relates to pharmaceutically acceptable prodrugs of the compounds of Formula I, 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 compound of Formula I). 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.

[0064] Examples of prodrugs include pharmaceutically acceptable esters of the compounds of the invention, which are also considered to be part of the invention. Pharmaceutically acceptable esters of the present compounds include the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, Ci-4alkyl, Ci-4alkoxy, or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a Ci-₂o alcohol or reactive derivative thereof, or by a 2,3-di(C6-2₄)acyl glycerol. Additional discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press.

[0065] For example, if a compound of Formula I 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-Cs)alkyl, (C2-Ci2)alkanoyloxymethyl, 1- (alkanoyloxy)ethyl having from 4 to 9 carbon atoms, l-methyl- l-(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, l-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(Ci- C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl), carbamoyl- (Ci-C₂)alkyl, N,N- di(Ci-C2)alkylcarbamoyl-(Ci-C₂)alkyl and piperidino-, pyrrolidino- or morpholine (C₂-C₃)alkyl, and the like.

[0066] Similarly, if a compound of Formula I contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (Ci-C6)alkanoyloxymethyl, l-((Ci-C6)alkanoyloxy)ethyl, 1 -methyl- l-((Ci- Ce)alkanoyloxy)ethyl, (Ci-C₆)alkoxycarbonyloxymethyl, N-(Ci-

C6)alkoxycarbonylaminomethyl, succinoyl, (Ci-C6)alkanoyl, a-amino(Ci-C4)alkanyl, arylacyl and -aminoacyl, or a-aminoacyl- -aminoacyl, where each a-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(0)(OH)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.

[0067] If a compound of Formula I incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R"-carbonyl, R'O-carbonyl, NR"R'-carbonyl where R" and R' are each independently (Ci-Cio)alkyl, (C3-C7) cycloalkyl, benzyl, or R"-carbonyl is a natural a-aminoacyl or natural a- aminoacyl, -C(OH)C(0)OY¹ wherein Y¹ is H, (Ci-C₆)alkyl or benzyl, -C(OY²)Y³ wherein Y² is (C1-C4) alkyl and Y³ is (Ci-C6)alkyl, carboxy(Ci-C6)alkyl, amino(Ci-C4)alkyl or mono-N- or di- N,N-(Ci-C6)alkylaminoalkyl, -C(Y⁴)Y⁵ wherein Y⁴ is H or methyl and Y⁵ is mono-N- or di- N,N-(Ci-C6)alkylamino morpholino, piperidin-l-yl or pyrrolidin- l-yl, and the like.

[0068] The present invention also relates to pharmaceutically active metabolites of compounds of Formula I, 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 of Formula I or salt thereof. Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini et al , J. Med. Chem. 1997, 40, 2011-2016; 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, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard- Larsen et al, eds., Harwood

Academic Publishers , 1991).

[0069] 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, ⁿC, ¹³C, ¹⁴C, ¹⁵N, ¹⁸0, ¹⁷0, ³¹P, ³²P,

35 18 36 125

S, F, CI, and I, respectively. Such isotopically labelled compounds are useful in metabolic studies (for example with ¹⁴C), reaction kinetic studies (with, for example ²H or H), 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 ¹⁸F or ⁿC 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. [0070] 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 inventive compounds.

[0071] The cyclopropyl ring of compounds of Formula I and related chemical intermediates are drawn herein as shown in the two structures belo

Each of these drawing conventions is intended to convey that the two substituents on the cyclopropane ring are in the trans configuration to one another. Although the structure on the right above is drawn with absolute stereochemistry, such a structure is intended to refer a racemic mixture of the two possible trans cyclopropanes, unless otherwise specified herein.

Compounds of the Invention

[0072] In some embodiments of Formula I, R¹ is a monocyclic heteroaryl comprising 1 or 2 nitrogen ring atoms, unsubstituted or substituted. In other embodiments, R¹ is unsubstituted or is substituted with one or two substituents selected from the group consisting of -NH₂, halo, Ci_ ₄alkyl, -OH, and Ci_₄alkoxy. In still other embodiments, R¹ is pyridyl, unsubstituted or substituted with -NH₂. In still other embodiments, R¹ is pyridin-3-yl, 6-aminopyridin-3-yl, or pyridin-4-yl.

[0073] In some embodiments of Formula I, A is phenyl or a monocyclic heteroaryl, unsubstituted or substituted. In other embodiments, A is phenyl or pyridyl. In other embodiments, A is a monocyclic or bicyclic heterocycloalkyl comprising at least one nitrogen ring atom, unsubstituted or substituted. In still other embodiments, A is an 8-, 9-, or 10- membered spirocyclic heterocycloalkyl ring comprising at least one nitrogen ring atom. In still other embodiments, A is 7-aza-spiro[3.5]nonan-2-yl, 6-aza-spiro[2.5]octan-2-yl, or l-oxa-8-aza- spiro[4.5]decan-3-yl.

[0074] In some embodiments, X is absent. In other embodiments, X is -S0₂-, -C(O)-, -C0₂-, -C(0)NR^m-, -SO-, or -S0₂NR^m-. In still other embodiments, X is -SO- or -S0₂-. In still other embodiments, X is -C0₂-. In still other embodiments, X is -S0₂-, -C(O)-, -C(0)NR^m-, -SO-, or -S0₂NR^m-. [0075] In some embodiments, R^m is H, methyl, ethyl, or isopropyl. In other embodiments, R^m is H or methyl.

[0076] In some embodiments, R² is

(a) C_1-12alkyl; or

(b) a 3- to 8-membered cycloalkyl, 4- to 8-membered heterocycloalkyl, aryl, or 5- or 6- membered heteroaryl, each unsubstituted or substituted with one or more substituents selected from the group consisting of deuterium, Ci-₆alkyl, Ci-₆alkoxy, halo-Ci-₆alkyl, halo- Ci_₆alkoxy, halo, -OH, -NR^bR^c, cyano, -S0₂R^b, -CONR^bR^c, -COR^b, and oxo;

wherein R^b and R are each independently H or Ci_₄alkyl.

[0077] In some embodiments, R² is Ci_i₂alkyl. In other embodiments, R² is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec -butyl, or tert-butyl. In other embodiments, R² is methyl.

[0078] In other embodiments, R² is a 3- to 8-membered cycloalkyl, unsubstituted or substituted. In still other embodiments, R₂ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, unsubstituted or substituted.

[0079] In other embodiments, R² is a 4- to 8-membered heterocycloalkyl, unsubstituted or substituted. In still other embodiments, R² is a 5- or 6-membered monocyclic heterocycloalkyl, unsubstituted or substituted. In still other embodiments, R² is a 7- or 8-membered bicyclic heterocycloalkyl, unsubstituted or substituted. In still other embodiments, R² is pyrrolidinyl, tetrahydofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, morpholinyl, or thiomorpholinyl, each unsubstituted or substituted. In still other embodiments, R² is a 7- or 8- membered bridged bicyclic heterocycloalkyl, unsubstituted or substituted. In still other embodiments, R² is tetrahydropyran-4-yl, morpholin-4-yl, or 8-oxa-3-azabicyclo[3.2.1]octan-3- yi.

[0080] In other embodiments, R² is phenyl or naphthyl, unsubstituted or substituted. In still other embodiments, R² is phenyl, unsubstituted or substituted with one or two methyl, trifluoromethyl, trifluoromethoxy, fluoro, or -S0₂CH₃ groups. In still other embodiments, R² is phenyl, 3-trifluoromethoxyphenyl, 3-trifluoromethylphenyl, 3-methylsulfonylphenyl, or 3,5- difluorophenyl.

[0081] In some embodiments, R² is a 5- or 6-membered heteroaryl, unsubstituted or substituted. In other embodiments, R² is pyrrolyl, furanyl, thiophenyl, pyridinyl, pyrazinyl, or pyridazinyl, each unsubstituted or substituted. In other embodiments, R² is pyrrolyl or pyridinyl. In still other embodiments, R² is 6-methylpyridin-3-yl, l-(propan-2-yl)-lH-pyrazol-4-yl, or 1- propyl-lH-pyrazol-4-yl. [0082] In some embodiments, R² is -NR^dR^e. In some embodiments, R^d is H, alkyl, - alkylenyl-R^a, or R^a, and R^e is H or alkyl.

[0083] In some embodiments, R² is substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, fluoromethyl, fluoroethyl, difluoromethyl,

trifluoromethyl, trifluoromethoxy, fluoro, bromo, chloro, -OH, -NH₂, cyano, -SO₂CH₃, -CONH₂, -CONHCH₃, -CON(CH₃)₂, -COCH₃, and oxo. In still other embodiments, R² is substituted with one or more substituents selected from the group consisting of methyl, trifluoromethyl, trifluoromethoxy, fluoro, and -SO₂CH₃.

[0084] In some embodiments, R^b and R^c are each independently H or methyl.

[0085] In some embodiments, n is 0 or 1. In some embodiments, n is 0. In other

embodiments, n is i.

[0086] In some embodiments of Formula (I):

1 2

(1) when R is a 5-membered monocyclic heteroaryl, A is a bicyclic heteroaryl, and R is Ci_ i₂alkyl, X is not -S0₂-;

(2) when R¹ is pyridinyl, and A and R² are both phenyl, X is not -CONH-; and

1 2

(3) when R is pyridinyl, A is phenyl, and R is piperidinyl, X is not -S0₂-.

[0087] In some embodiments, the compound of Formula (I) is a compound of Formula (I- A):

wherein:

R¹ is a monocyclic or bicyclic heteroaryl comprising at least one nitrogen ring atom, wherein said heteroaryl is unsubstituted or substituted with one or more substituents selected from the group consisting of -NH₂, halo, Ci-₄alkyl, -OH, and Ci-₄alkoxy;

R² is Ci_i₂alkyl; and

R^s and R' taken together with the carbon to which they are attached form a monocyclic

cycloalkyl or heterocyclo alkyl ring;

or a pharmaceutically acceptable salt thereof.

[0088] In some embodiments, the compound of Formula (I) is a compound of Formula (I-B):

wherein

R¹ is a monocyclic or bicyclic heteroaryl comprising at least one nitrogen ring atom, wherein said heteroaryl is unsubstituted or substituted with one or more substituents selected from the group consisting of -NH₂, halo, C^alkyl, -OH, and Ci_₄alkoxy;

W is CH or N;

R² is phenyl or 5-6 membered heteroaryl, each of which is unsubstituted or substituted by one or more alkyl, haloalkyl, haloalkoxy, or halo groups; and

m is 1 or 2;

or a pharmaceutically acceptable salt thereof.

[0089] In certain embodiments, the compound of Formula I is a compound selected from the group consisting of:

0 butyl ester (Diastereomer 2);

pyridyl)cyclopropane-carboxamide;

and pharmaceutically acceptable salts thereof, and stereoisomers and pharmaceutically acceptable salts of such stereoisomers.

Pharmaceutical Description

[0090] 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 lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, and the like. See, e.g., Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975.

[0091] 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, trichloromonofluoromethane); 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 hydroxyanisole, 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, monoethanolamme (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 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, triacetin, triethyl 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.

[0092] 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 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, and cancers of the brain and central nervous system (CNS).

[0093] The inventive compounds 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.

[0094] 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, myelodysplasia 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. [0095] The compounds of the invention may induce or inhibit apoptosis.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] Still another embodiment of the invention is a pharmaceutical formulation comprising at least one compound of Formula I and a pharmaceutically acceptable excipient, and further comprising one or more adjunctive active agent.

[0100] The pharmaceutical formulations of the invention may further comprise a therapeutic effective amount of an adjunctive active agent.

[0101] 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.

[0102] 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. [0103] 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 role of nicotinamide and/or nicotinic acid as a rescuing or rescue agent for potential toxic effects of NAMPT inhibitors has been described, for example, by Beauparlant et al. , Anti-Cancer Drugs 2009, 20, 346-354 and by Rongvaux et al., J. Immunol. 2008, 181, 4685-4695.

[0104] 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, docetaxel, doxorubicin, flutamide, interferon-alpha, letrozole, leuprolide, megestrol, mitomycin, oxaliplatin, paclitaxel, plicamycin (Mithracin™), tamoxifen, thiotepa, topotecan, valrubicin, vinblastine, vincristine, and any combination of any of the foregoing.

[0105] 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.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] The invention is also directed to methods of synthesizing compounds of the present invention. [0110] 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.

[0111] In a certain embodiment, the compounds of formula I 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.

[0112] In a certain embodiment, the compounds of formula I 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.

[0113] 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.

[0114] 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.

[0115] 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 of a pharmaceutical composition comprising the compound as described herein.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] 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.

[0121] 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 II inhibitors (such as etoposide); topoisomerase I inhibitors (such as irinotecan (or CPT- 11), 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, SARASAR™.(4-[2-[4- [(HR)-3,10-dibromo-8-chloro-6,l l-dihydro-5H-benzo[5,- 6]cyclohepta[l,2-b]pyridin-l l-yl-]-l- piperidinyl]-2-oxoehtyl]-l-piperidine- carboxamide, or SCH 66336), tipifarnib (Zarnestra^® or Rl 15777 from Janssen Pharmaceuticals), L778,123 (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), GLEEVEC^® (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.

[0122] 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,

Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin,

Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine,

Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade^®, Zevalin, Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane, Ifosfomide, Rituximab, C225, and Campath, 5-fluorouracil and leucovorin, with or without a 5-HT₃ receptor inhibitor (e.g., dolansetron, granisetron, ondansetron) with or without dexamethasone.

[0123] 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 or nicotinamide, or variations thereof, including modified release formulations of niacin, such as NIASPAN^®.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.

[0129] 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 1211; 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. [0130] 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.

[0131] 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.

[0132] 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.

[0133] 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.

[0134] The compounds of this invention may also be delivered subcutaneously.

[0135] The compound can be administered orally or intravenously.

[0136] 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.

[0137] 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.

[0138] 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.

[0139] 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

[0140] Exemplary, non-limiting, chemical entities and methods useful in preparing compounds of the invention will now be described by reference to illustrative synthetic schemes 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.

[0141] 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 Formula I.

[0142] 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 II, Editors Katritzky and Rees, Elsevier, 1997, e.g. Volume 3; Liebigs Annalen der Chemie, (9): 1910-16, (1985); Helvetica Chimica Acta, 41: 1052-60, (1958);

Arzneimittel-Forschung, 40(12): 1328-31, (1990), each of which are expressly incorporated by reference. Starting materials are generally available from commercial sources such as Sigma- Aldrich Chemicals (Milwaukee, WI) 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).

[0143] 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.

[0144] 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 Formula I 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 Formula I, or pharmaceutically acceptable salts thereof.

[0145] 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.

[0146] 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), 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.

[0147] 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., J. Chromatogr. 1975, 113(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).

[0148] 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.

[0149] 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.L. 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 ¹H NMR spectrum for the presence of the two atropisomeric enantiomers or diastereomers (Jacob, et al. . 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 96/15111). 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, /.

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.

[0150] Abbreviations and acronyms used in the following Schemes and elsewhere herein are defined as follows:

LCMS Liquid chromatography - mass spectrometry

m-CPBA m-Chloroperoxybenzoic acid

MeOH Methanol

Me Methyl

MHz megahertz

min Minute

mL Milliliter

NaBH₄ Sodium Borohydride

NMP N-methylpyrrolidinone

Pd(PPh₃)₄ Tetrakis(triphenylphosphine)palladium

Pd₂(dba)₃ Tris(dibenzylideneacetone)dipalladium

PE Petroleum ether

Ph Phenyl

PMB Para-methoxy benzyl

Prep-TLC Preparative Thin Layer Chromatography

psi Pounds per square inch

Py Pyridine

PyBop (Benzotriazol-l-yloxy)tripyrrolidinophosphonium Hexafluorophosphate rt Room temperature

Raney-Ni Raney Nickel

Rf Retention factor

SFC Supercritical fluid chromatography

TEA Triethylamine

Tf Trifluoromethanesulfonate

TFA Trifluoroacetic acid

Tf₂0 Trifluoromethanesulfonic anhydride

THF Tetrahydrofuran

Ti(Oi-Pr)₄ Titanium tetraisopropoxide

TLC Thin layer chromatography

[0151] Exemplary general reaction schemes that are useful in preparing compounds of the invention are described below.

General Scheme A

A B (I)

[0152] Compounds of Formula I may be prepared as shown above in Scheme A. Compounds of formula A, in which LG is, for example, OH, chloro, or bromo, are reacted with amines B to produce compounds of Formula I. Amines B are commercially available, or are prepared by simple reactions. For example, suitably substituted amines B in which A is a monocyclic or bicyclic heterocycloalkyl are commercially available. [0153] Where LG is OH, coupling reactions may occur in the presence of a coupling reagent such as EDCI, HATU, or HOBt, and a base (e.g., K₂CO₃, CS₂CO₃, trialkylamine, sodium or potassium alkoxide) in an inert solvent such as dichloromethane, Ν,Ν-dialkylformamide (such as DMF), Ν,Ν-dialkylacetamide, dialkylethers, cyclic ethers, DMSO, or NMP, or a mixture thereof, at temperatures ranging from -78 °C to 60 °C. Alternatively, compounds A where LG is bromo or chloro may be reacted with amines B in the presence of a suitable base, such as triethylamine, K₂CO₃, or CS₂CO₃, to form compounds of Formula I. Such coupling reactions between amines and acids or acid derivatives are well-known in the art.

General Scheme B

[0154] Cyclopropyl analogs A may be prepared as shown in General Scheme B. Heteroaryl halides such as bromides C are commercially available or are readily prepared using methods known to one of ordinary skill in the art. Palladium-mediated coupling of compounds C with acrylate derivatives D provides esters E. Cyclopropanation of the double bond using conditions such as trimethylsulfoxonium iodide and NaH in a polar solvent such as DMSO provides cyclopropanes A where LG is an ester. Hydrolysis to the corresponding acid and optional conversion to compounds A where LG is, for example, chloride or bromide, are accomplished using standard methods. Alternatively, esters E may be in the form of the corresponding Weinreb amide. The Weinreb amide may be hydrolyzed to the acid under aqueous basic conditions following the cyclopropanation step.

General Scheme C

[0155] Amines B in which n is 0 and X is SO₂ or SO, may be prepared according to General Scheme C. Nitroaryl or heteroaryl compounds C, where Hal is, for example fluoro or bromo, are commercially available. Compounds C are reacted with suitably substituted thiols R²-SH, optionally in the presence of a base such as ₂CO₃ or CS₂CO₃, in a solvent such as DMSO, DMF, or NMP, preferably at elevated temperature, to form thioethers. The thioethers are then oxidized to the sulfone or sulfoxide using a suitable oxidant such as m-chloroperbenzoic acid in a solvent such as methylene chloride or chloroform. Alternatively, the Hal group of compounds C is displaced with a lithiosulfone derivative R²S0₂Li (prepared by halogen-metal exchange with a suitable bromoaryl compound and BuLi followed by reaction with S0₂ gas) to produce compounds D directly. The nitro group of compounds D is reduced under hydrogenation conditions using a hydrogen source such as hydrogen gas or the like, in the presence of a suitable metal catalyst such as Raney nickel or palladium, in a solvent such as methanol or ethanol, to form amines B.

[0156] One of skill in the art will also recognize that amines B of this type are available via sulfonylation of an aryl sulfonyl chloride with a suitable amine or by Mitsunobu reaction of a thiol with a suitable alcohol. Examples of these transformations are presented in the detailed experimental preparations below.

General Scheme D

[0157] Certain thiols useful in preparing compounds of Formula I may be prepared according to General Scheme D. Ketones or aldehydes F, where R¹¹ and R¹² are chosen as needed to produce compounds of Formula I, are reacted with hydrogen sulfide to form the analogous thiones G, which are then reduced with a suitable reducing agent such as sodium borohydride, to produce thiols H. Thiols H may then be used in methods such as those shown in General Scheme B.

General Scheme E

[0158] Aromatic thiols useful in preparing compounds of the invention may be prepared according to General Scheme E. Anilines J are reacted with sodium nitrite and a sulfur source such as a dithioate analog, to form compounds of formula K, which are then reduced with, for example, zinc, to form aromatic thiols L. Thiols L may then be used in methods such as those shown in General Scheme B.

General Scheme F

_/(CH₂)_n rOR^z/S0₂CI ^{R2N H R3}. _/(CH₂)_n

H,N H₂N -A^ R²

M B [0159] Amines B in which X is CONR^a or SC>₂NR^a may be prepared according to General Scheme F. Suitably protected amines M, bearing an activated acid derivative such as an acid or acid chloride (R^z is OH or CI), or a sulfonyl chloride group, are reacted with amines N, in the presence of a weak base such as triethylamine, to form amines B.

General Scheme G

_/(CH₂)_n cOR^{z r2QH} » _/(CH₂)_n

H₂N -A^ ^~ H₂N -A^ R²

M B

[0160] Amines B in which X is CO₂ may be prepared according to General Scheme G, by reaction of a suitably protected amine M, where R^z is OH or halogen, with an alcohol P, under standard ester coupling conditions.

General Scheme H

_/(CH₂)_n cOR^{z r2|J} » _/(CH₂)_n

H₂N -A^ 7 H₂N -A^ R²

M B

[0161] Amines B in which X is CO may be prepared according to General Scheme H, by reaction of a suitably protected amine M, where R is H, with an alcohol P, under standard ester coupling conditions.

[0162] Those having skill in the art will recognize that the starting materials, reagents, and conditions described in the above general schemes may be varied and additional steps employed to produce compounds encompassed by the present inventions.

Methods of Chemical Analysis

[0163] Unless otherwise indicated, ⁱH 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 of ¹H and ¹³C, 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. [0164] 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 LCMS-2010EV

Analysis Conditions:

LC Parameters:

Column: Waters Xselect C18 3.0x50mm, 3.5μπι

Mobile Phase A: Water / 0.1 % FA

Mobile Phase B: Acetonitrile/0.05% FA

Gradient: 5% to 100% B in 2.0 minutes, 100% B for 1.2 minutes, 100% to 5% B in 0.1 minutes, 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·

Report: Area Normalized Purity

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. 5kv

Method B

Instrument: SHIMADZU LCMS-2010EV

Analysis Conditions:

LC Parameters:

Column: Shim-pack XR-ODS 3.0x50mm, 2.2 μΐΉ

Mobile Phase A: Water/0.05% TFA

Mobile Phase B: Acetonitrile Gradient: 5% to 100% B in 2.0 minutes, 100% B for 1 minute, 100% to 5% B in 0.3 minutes, then stop.

Flow Rate: 1.0 mL/min

Column Temperature: 40 °C

Detector: 254nm and ELSD

Sample Preparation: 1 mg/mL in Methanol

Injection Volume: 1 μL·

Report: Area Normalized Purity

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 C

Instrument: SHIMADZU LCMS-2010EV

Analysis Conditions:

LC Parameters:

Column: Shim-pack XR-ODS 2.2um, 3.0x50mm

Mobile Phase A: Water/0.05% TFA

Mobile Phase B: Acetonitrile/0.05% TFA

Gradient: 5% to 100% B in 2.0 minutes, 100%B for 1.1 minutes, 100% to 5% B in 0.2 minutes, then stop.

Flow Rate: 1.0 mL/min

Column Temperature: 40 °C

Detector: 254nm and ELSD

Sample Preparation: 1 mg/mL in Methanol

Injection Volume: 1 μL·

Report: Area Normalized Purity

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: SHIMADZU LCMS-2020

Analysis Conditions:

LC Parameters:

Column: Shim-pack XR-ODS 2.2um, 3.0*50mm

Mobile Phase A: Water/0.05% TFA

Mobile Phase B: Acetonitrile

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

0.1 minutes, 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 μΐ_^

Report: Area Normalized Purity

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 E

Instrument: SHIMADZU LCMS-2020

Analysis Conditions:

LC Parameters:

Column: Shim-pack XR-ODS 2.2um, 3.0*50mm Mobile Phase A: Water/0.05% TFA

Mobile Phase B: Acetonitrile/0.05% TFA

Gradient: 5% to 100% B in 2.0 minutes, 100% B for 1.2 minutes, 100% to 5% B in 0.1 minutes, then stop.

Flow Rate: 1.0 mL/min

Column Temperature: 40 °C

Detector: 254nm and ELSD

Sample Preparation: 1 mg/mL in Methanol

Injection Volume: 1 μL·

Report: Area Normalized Purity

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 F

Instrument: SHIMADZU LCMS-2020

Analysis Conditions:

LC Parameters:

Column: Shim-pack XR-ODS 50*3.0nm, 2.2um

Mobile Phase A: Water/0.05% TFA

Mobile Phase B: Acetonitrile/0.05% TFA

Gradient: 5% B to 100% B for 2.0 minutes, 100% B for 1.2 minutes, 100% B to 5% in 0.1 minute, then stop.

Flow Rate: 1.0 mL/min

Column Temperature: 40 °C

Detector: 254nm and ELSD

Sample Preparation: 1 mg/mL in Methanol

Injection Volume: 1 μL·

Report: Area Normalized Purity

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 G

Instrument: SHIMADZU LCMS-2020

Analysis Conditions:

LC Parameters:

Column: Shim-pack XR-ODS 3.0x50mm, 2.2μ Mobile Phase A: Water/0.05% TFA

Mobile Phase B: Acetonitrile

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

Flow Rate: l.OmL/min

Column Temperature: 40 °C

Detector: 254nm and ELSD

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

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 H

Instrument: SHIMADZU LCMS-2020

Analysis Conditions:

LC Parameters: Column: Shim-pack XR-ODS 3.0x50mm, 2.2μ

Mobile Phase A: Water/0.1% FA

Mobile Phase B: Acetonitrile/0.05% FA

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: 254nm and ELSD

Sample Preparation: 1 mg/mL in Acetonitrile

Injection Volume: 1 μL·

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: 0.95 kv

Method I

Instrument: SHIMADZU LCMS-2020

Analysis Conditions:

LC Parameters:

Column: Gemini-NX 3u C18 11 OA

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 μL·

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 J

Instrument: SHIMADZU LCMS-2020EV

Analysis Conditions:

LC Parameters:

Column: Shim-pack XR-ODS 50mm*3.0mm, 2.2um

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 μΐ_^

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: l.lOkv

Method K

Instrument: SHIMADZU UPLCMS-2020EV

Analysis Conditions: LC Parameters:

Column: Shim-pack XR-ODS 50mm*2.0mm, 1.6um

Mobile Phase A: Water /0.1% FA

Mobile Phase B: Acetonitrile/0.05% FA

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: 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 L

Instrument: SHIMADZU UHPLCMS-2020EV (LC-30AD pump, Binary Solvent Manager, SIL- 30AC Auto Sampler, SPDM20A Detector, Alltech 3300 ELSD Detector)

Analysis Conditions:

LC Parameters:

Column: Shim-pack XR-ODS 50*2.0mm, 1.6um

Mobile Phase A: Water/0.1% FA

Mobile Phase B: Acetonitrile/0.05% FA

Gradient:

Flow Rate: 0.7 mL/min

Column Temperature: 40 °C Injection Volume: 1 μL·

DAD: 190-800 nm, Split width: 1.2 nm, Sampling: 12.5 Hz

ELSD: 65 °C, Gain: 1, Gas:1.6 L/min, Sampling: 10 Hz

MS Parameters: (Using tuning file)

Interface: ESI (Positive or Negative)

Interface Voltage: 4.0 kv

Heat Block: 200 °C

Nebuliziong Gas: 1.5 L/min

Scan Range: 90-900 (m/z)

Detector voltage: 0.9 kv

Method M

Instrument: SHIMADZU LCMS-2020EV

Analysis Conditions:

LC Parameters:

Column: Shim-pack XR-ODS 50mm*3.0mm, 2.2um

Mobile Phase A: Water /0.1% FA

Mobile Phase B: Acetonitrile/0.05% FA

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 Acetonitrile

Injection Volume: 1 μL·

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: 0.9 kv Method N

Instrument: HPLC- Agilent 1200

Analysis Conditions:

LC Parameters:

Column: Agilent ZORB AX SB-C18, 1.8mm, 30 x 2.1 mm

Mobile Phase A: Water/0.05% TFA

Mobile Phase B: Acetonitrile/0.05% TFA

Gradient: 3% to 95% B over 7.0 minutes, 95% B for 1.5 minutes, following equilibration for

1.5min, then stop.

Flow Rate: 0.4 mL/min

Column Temperature: 35 °C

Detector: 254nm and 220nm

Sample Preparation: 1 mg/mL in Methanol

Injection Volume: 1 μL·

Report: Area Normalized Purity

Mass Spec Information: Agilent quadrupole 6140

MS Parameters:

Interface: ESI (Positive)

Scan Range: 110-800amu

Detector typeSingle quadruple

Method O

Instrument: Waters Acquity UPLC

Analysis Conditions:

LC Parameters:

Column: Acquity UPLC BEH CI 8, 1.7mm, 2.1*50mm

Mobile Phase A: Water/0.05% TFA

Mobile Phase B: Acetonitrile/0.05% TFA

Gradient: 2% to 98% B over 17.5 minutes, 98% B for 1.5 minutes, following equilibration for 1.5min, then stop.

Flow Rate: 0.6 mL/min

Column Temperature: 40 °C Detector: 254nm and 220nm

Mass Spec Information: Waters LCT Premier XE

MS Parameters:

Interface: ESI (Positive)

Scan Range: 80- 1300amu

Detector type: Time of flight

[0165] 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.

Intermediate 1 : ?raras-2-(Pyridin-3-yl)cvclopropanecarbonyl chloride.

Synthesis A:

[0166] Step 1. CE)-Butyl 3-(pyridin-3-yl)acrylate. A mixture of 3-bromopyridine (5 g, 31.6 mmol, 1.00 equiv), butyl acrylate (6.1 g, 47.6 mmol, 1.50 equiv), triphenylphosphine (170 mg, 0.65 mmol, 0.02 equiv), potassium carbonate (8.8 g, 63.7 mmol, 2.00 equiv), and palladium(II) acetate (72 mg, 0.01 equiv) in DMF (100 mL) was stirred under nitrogen for 20 h at 130 °C. The reaction mixture was cooled to rt then diluted with 400 mL of EtOAc. The mixture was filtered through a pad of diatomaceous earth. The filtrate was washed with 3x100 mL of water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified on a silica gel column eluted with EtO Ac/petroleum ether (1 :2) to give 6 g (92%) of (£)-butyl 3- (pyridin-3-yl)acrylate as yellow oil. LCMS (Method H, ESI): RT = 1.87 min, m/z = 206.1

[M+H]⁺.

[0167] Step 2. Butyl fraraj^,-2-(pyridin-3-yl)cyclopropanecarboxylate. A mixture of trimethylsulfoxonium iodide (6.6 g, 30.5 mmol, 2.00 equiv) and sodium hydride (1.20 g, 50.0 mmol, 2.00 equiv) in DMSO (100 mL) was stirred at rt for 1 h. (£)-Butyl 3-(pyridin-3- yl)acrylate (3 g, 14.6 mmol, 1.00 equiv) was then added and the reaction mixture was stirred for 20 h at rt. The resulting solution was diluted with 400 mL of EtOAc and then washed with 3x100 mL of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with EtOAc/petroleum ether (1: 1) to give 1.2 g (37%) of the title compound as colorless oil. LCMS (Method B, ESI): RT = 1.72 min, m/z = 220.0 [M+H]⁺.

[0168] Step 3. frafts-2-(Pyridin-3-yl)cyclopropanecarboxylic acid. A mixture of butyl trans- 2-(pyridin-3-yl)cyclopropanecarboxylate (1.2 g, 5.47 mmol, 1.00 equiv) and KOH (1 g, 17.82 mmol, 3.26 equiv) in EtOH (10 mL) and water (10 mL) was stirred at rt for 2 h. The solution was adjusted to pH 6 with 1 M HC1 and then concentrated in vacuum to give 2 g of the title compound as a white solid. LCMS (Method A, ESI): RT= 0.32 min, m/z = 164.0 [M+H]⁺.

[0169] Step 4. fra»s-2-(Pyridin-3-yl)cyclopropanecarbonyl chloride. To a mixture of the crude irans-2-(pyridin-3-yl)cyclopropanecarboxylic acid (160 mg, 0.98 mmol, 1.00 equiv) and thionyl chloride (1 mL) in DCM (10 mL) at 0 °C was added DMF (0.05 mL). The resulting solution was stirred at 0 °C for 2 h then concentrated under vacuum to give 200 mg of the title compound as a white oil. TLC: EtOAc/petroleum ether (1 : 1), R_f = 0.6.

Synthesis B:

[0170] Step 1. (2£')-3-(Pyridin-3-yl)prop-2-enoic acid. To a solution of butyl 3-(pyridin-3- yl)prop-2-enoate (70 g, 341 mmol, 1.00 equiv) in EtOH (150 mL) was added a solution of KOH (40 g, 712.94 mmol, 2.09 equiv) in water (150 mL). The reaction mixture was stirred at rt for 20 h. The pH of the solution was adjusted to 6 with 12 M HC1. The precipitate was collected by filtration to give 50 g (98%) of the title compound as an off-white solid. LCMS (Method C, ES, m/z): RT = 0.78 min, m/z = 149.9 [M+H]⁺.

[0171] Step 2. (2£')-N-Methoxy-N-methyl-3-(pyridin-3-yl)prop-2-enamide. A solution of (2£^')-3-(pyridin-3-yl)prop-2-enoic acid (50 g, 335 mmol, 1.00 equiv), Ν,Ο- dimethylhydroxylamine hydrochloride (65 g, 666 mmol, 2.00 equiv), EDCI (127 g, 662.49 mmol, 2.00 equiv) and 4-dimethylaminopyridine (80 g, 655 mmol, 2.00 equiv) in DCM (1 L) was stirred at rt for 2 h. The reaction was then quenched by the addition of 200 mL of water then extracted with 2x1 L of DCM. The combined organic layers were washed with 3x500 mL of ¾0, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give 70 g of the title compound as a yellow oil. LCMS (Method L, ES, m/z): RT = 0.65 min, m/z = 193.2 [M+H]⁺.

[0172] Step 3. fra» ^,-N-Methoxy-N-methyl-2-(pyridin-4-yl)cvclopropane- 1 -carboxamide. To a solution of trimethylsulfoxonium iodide (145 g, 671 mmol, 2.00 equiv) in DMSO (500 mL) kept under nitrogen at 0 °C was added sodium hydride (26 g, 60%, 1.08 mol, 2.00 equiv). The resulting solution was stirred at rt for 1 h. (2£)-N-Methoxy-N-methyl-3-(pyridin-4-yl)prop-2- enamide (66 g, 343 mmol, 1.00 equiv) was then added and the reaction mixture was stirred at rt for 1 h. The reaction mixture was then poured into 400 mL of saturated aqueous NH₄C1 solution. The resulting solution was extracted with 3x1 L of EtOAc. The combined organic layers were washed with 3x500 mL of ¾0 and then concentrated under vacuum. The residue was purified on a silica gel column eluted with DCM/MeOH (5: 1) to give 56 g of the title compound as a yellow oil. LCMS (Method F, ESI): RT = 0.95 min, m/z = 207.1 [M+H]⁺.

[0173] Step 4. frflfts-2-(Pyridin-3-yl)cvclopropane-l-carboxylic acid. To a solution of trans- N-methoxy-N-methyl-2-(pyridin-3-yl)cyclopropane-l-carboxamide (50 g, 242 mmol, 1.00 equiv) in EtOH (50 mL) was added a solution of KOH (40 g, 712.94 mmol, 2.94 equiv) in water (100 mL). The resulting solution was stirred for 24 h at rt and then concentrated under vacuum. The residue was dissolved in 300 mL of water then washed with 3x100 mL of DCM. The pH value of the aqueous layer was adjusted to 6 with 12 M HC1 and then concentrated under vacuum. The resulting solution was diluted with 200 mL of MeOH and the solid was removed by filtration. The filtrate was concentrated under vacuum to give 34 g of the title compound as a light yellow solid. The crude product was recrystallized with a mixture of MeOH/EtOAc (1:5, 60 mL) to give 23 g of the title compound. LCMS (Method D, ESI): RT = 0.52 min, m/z = 164.0 [M+H]⁺. 1H NMR (300 MHz, DMSO-i₆, ppm): δ 8.82 (m, 1H), 8.70 (m, 1H), 8.27 (d, J = 8.4 Hz, 1H), 7.86 (m, 1H), 2.65 (m, 1H), 2.04 (m, 1H), 1.60-1.51 (m, 2H).

[0174] Step 5. fra s-2-(Pyridin-3-yl)cvclopropane-l-carbonyl chloride. A mixture of trans-2- (pyridin-3-yl)cyclopropane-l-carboxylic acid (1 g, 6.13 mmol, 1.00 equiv), DCM (5 mL), and sulfuroyl dichloride (10 mL) was stirred for 5 h at 40 °C. The resulting mixture was

concentrated under vacuum to give 1.34 g (crude) of the title compound as a off-white solid. LCMS (Method F, ESI): RT = 0.93 min, m/z = 178.0 [MX+H]⁺ (MX = methyl 2-(pyridin-3- yl)cyclopropane carboxylate).

Example 1. trans -N-[4-(Benzenesulfonyl)phenyl]-2-(pyridin-3-yl)cyclopropane-l-carboxamide.

[0175] A solution of /raras-2-(pyridin-3-yl)cyclopropanecarbonyl chloride (180 mg, 0.99 mmol, 1.00 equiv), 4-(benzenesulfonyl)aniline (300 mg, 1.29 mmol, 1.30 equiv), and Et₃N in DMF (10 mL) was stirred at rt for 4 h. The resulting mixture was concentrated in vacuum and the residue was purified on a silica gel column eluted with DCM/MeOH (5: 1) to give 300 mg of the crude product. It was then further purified by preparative HPLC under the following conditions: (l#-Prep-HPLC-005(Waters)), Column, XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase, Water with 10 mmol of NH₄HCO₃ and CH₃CN (33.0% CH₃CN up to 48.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 33.0% in 2 min);

Detector, UV 254/220 nm) to give 107.5 mg (29%) of the title compound as a light yellow solid. 1H NMR (300 MHz, DMSO- ₆, ppm) δ: 10.72 (s, 1H), 8.50 (s, 1H), 8.41 (d, J = 3.6 Hz, 1H), 7.93-7.79 (m, 6H), 7.70-7.55 (m, 4H), 7.34-7.30 (m, 1H), 2.40-2.27 (m, 1H), 2.16-2.10 (m, 1H), 1.58- 1.46 (m, 2H).

Example 2. ira/is-N-[[4-(Benzenesulfonyl)phenyl]methyl]-2-(pyridin-3-yl)cyclopropane-l- carboxamide.

[0176] A solution of /rani-2-(pyridin-3-yl)cyclopropane- l-carboxylic acid (200 mg, 1.23 mmol, 1.00 equiv), [4-(benzenesulfonyl)phenyl]methanamine (260 mg, 1.05 mmol, 1.00 equiv), EDCI (280 g, 1.46 mol, 1.20 equiv), HOBt (200 mg, 1.48 mmol, 1.20 equiv), and DIPEA (0.5 g, 3.00 equiv) in DMF (10 mL) was stirred for 20 h at rt. The resulting mixture was concentrated under vacuum and the residue was first purified on a silica gel column eluted with DCM/MeOH (5: 1). The product was further purified by preparative HPLC (conditions as in Example 1) to yield 39.5 mg (8%) of the title compound as an off-white solid. 1H NMR (300 MHz, DMSO-d₆, ppm) δ: 8.72 (t, J = 5.4 Hz, 1H), 8.45-8.38 (m, 2H), 7.95-7.91 (m, 4H), 7.71-7.59 (m, 3H), 7.52- 7.46 (m, 4H), 7.32-7.28 (m, 1H), 4.38-4.35 (m, 2H), 2.27 (m, 1H), 1.93 (m, 1H), 1.44-1.28 (m, 2H).

Example 3. irarts-2-(6-Aminopyridin-3-yl)-N-[4-(benzenesulfonyl)phenyl]cyclopropane-l- carboxamide.

[0177] Step 1. 5-Bromo-N,N-bisr(4-methoxyphenyl)methyllpyridin-2-amine. To a solution of 5-bromopyridin-2-amine (5 g, 28.9 mmol, 1.00 equiv) in DMF (100 mL) maintained under nitrogen at 0 °C was added sodium hydride (4.5 g, 187.50 mmol, 3.00 equiv) in small portions. The resulting solution was stirred for 10 min at 0 °C and then a solution of l-(chloromethyl)-4- methoxybenzene (10 g, 63.8 mmol, 2.00 equiv) was added. The reaction mixture was stirred for 1 h at 0 °C then quenched by the addition of 5 mL of water. The resulting mixture was concentrated under vacuum and then diluted with 400 mL of EtO Ac. The mixture was washed with 3x50 mL of H₂0. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give 16 g of the title compound as a red oil. LCMS (Method C, ESI): RT = 1.75 min, m/z = 413.1 [M+H]⁺.

[0178] Step 2. Butyl (2£^,)-3-(6-rbisr(4-methoxyphenyl)methyllaminolpyridin-3-yl)prop-2- enoate. A mixture of 5-bromo-N,N-bis[(4-methoxyphenyl)methyl]pyridin-2-amine (5 g, 12.10 mmol, 1.00 equiv), butyl prop-2-enoate (2.5 g, 19.51 mmol, 1.50 equiv), potassium carbonate (3.5 g, 25.32 mmol, 2.09 equiv), PPh₃ (60 mg, 0.23 mmol, 0.02 equiv), and Pd(OAc)₂ (30 mg, 0.13 mmol, 0.01 equiv) in DMF (100 mL) was stirred under nitrogen at 140 °C for 18 h. The reaction mixture was cooled to rt and concentrated under vacuum. The residue was dissolved in 400 mL of EtO Ac then washed with 3x50 mL of H₂0. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified on a silica gel column eluted with EtOAc/petroleum ether (1: 10 and 1 :2) to give 3.5 g (63%) of the title compound as light yellow oil. LCMS (Method J, ESI): RT = 1.86 min, m/z = 461.2 [M+H]⁺.

[0179] Step 3. trans-Butyl 2-(6-rbisr(4-methoxyphenyl)methyllaminolpyridin-3- vDcyclopropane- 1 -carboxylate. To a solution of trimethylsulfoxonium iodide (2 g, 9.26 mmol, 2.00 equiv) in DMSO (50 mL) maintained under nitrogen at 0 °C was added sodium hydride (360 mg, 15.00 mmol, 2.00 equiv) in portions. The resulting solution was stirred for 1 h at rt. Butyl (2£)-3-(6-[bis[(4-methoxyphenyl)methyl]amino]pyridin-3-yl)prop-2-enoate (2 g, 4.34 mmol, 1.00 equiv) was then added and the resulting solution was stirred for an additional 20 h at rt. The reaction mixture was diluted with 400 mL of EtOAc, washed with 3x50 mL of H₂0. 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 EtO Ac/petroleum ether (1:2) to give 1 g (49%) of the title compound as a colorless oil. LCMS (Method J, ESI): RT = 1.72 min, m/z = 475.2 [M+H]⁺.

[0180] Step 4. rfl»5^,-2-(6-rBisr(4-methoxyphenyl)methyllaminolpyridin-3-yl)cyclopropane- 1-carboxylic acid. To a solution of fraras-butyl 2-(6-[bis[(4-methoxyphenyl)

methyl] amino]pyridin-3-yl)cyclopropane-l -carboxylate (1 g, 2.11 mmol, 1.00 equiv) in EtOH (10 mL) was added a solution of KOH (1 g, 17.82 mmol, 8.46 equiv) in H₂0 (10 mL). The reaction mixture was stirred for 20 h at rt. The pH of the solution was adjusted to 6 with 1 M HC1. The resulting mixture was concentrated under vacuum to give 2.5 g of the title compound as a white solid. LCMS (Method E, ESI): RT = 1.25 min, m/z = 419.2 [M+H]⁺. [0181] Step 5, frfl» ^,-2-(6-rBisr(4-methoxyphenyl)methyllaminolpyridin-3-yl)cvclopropane- 1-carbonyl chloride. To a solution of irans-2-(6-[bis[(4-memoxyphenyl)methyl]amino]pyridin- 3-yl)cyclopropane-l-carboxylic acid (350 mg, 0.84 mmol, 1.00 equiv) and a catalytic amount of DMF (0.1 mL) in DCM (20 mL) was added thionyl chloride (4 mL). The reaction mixture was stirred for 2 h at rt and then concentrated under vacuum to give 0.5 g of the title compound as a yellow solid. This was used in the next step without further purification.

[0182] Step 6. fra»s-N-r4-(Benzenesulfonyl)phenyl1-2-(6-rbis|Y4- methoxyphenyl)methyllamino1pyridin-3-yl)cyclopropane-l-carboxamide. A solution of 4- (benzenesulfonyl)aniline (400 mg, 1.71 mmol, 2.50 equiv), ira¾s-2-(6-[bis[(4- methoxyphenyl)methyl]amino]pyridine-3-yl)cyclopropane-l-carbonyl chloride (300 mg, 0.69 mmol, 1.00 equiv), and Et₃N (2 mL) in DMF (20 mL) was stirred for 20 h at rt. The reaction mixture was concentrated under vacuum and the residue was purified on a silica gel column eluted with EtOAc/hexanes (1: 1) to give 100 mg (23%) of the title compound as yellow oil. TLC: petroleum ether/EtOAc = 1/1, R_f = 0.6.

[0183] Step 7. To a solution of iran ^,-N-[4-(benzenesulfonyl)phenyl]-2-(6-[bis[(4- methoxyphenyl)methyl] amino] pyridin-3-yl)cyclopropane-l-carboxamide (200 mg, 0.32 mmol, 1.00 equiv) in DCM (10 mL), was added TFA (5 mL). The resulting solution was stirred at rt for 5 h and then concentrated under vacuum. The residue was purified on a silica gel column eluted with DCM/MeOH (5: 1) to give 200 mg of the crude product. It was then further purified by preparative HPLC (IntelFlash- 1 : Column, silica gel; mobile phase, CH₃CN:H₂0 = 25: 1 increasing to CH₃CN:H₂0 = 58% within 20 min; Detector, UV 254 nm) to give 31 mg (25%) of the title compound as an off-white solid. 1H NMR (300 MHz, DMSO-i¾, ppm) δ: 10.66 (s, 1H), 7.93-7.88 (m, 4H), 7.81-7.78 (m, 3H), 7.70-7.58 (m, 3H), 7.13 (dd, / = 8.4, 2.1 Hz, 1H), 6.37 (d, J = 8.4 Hz, 1H), 5.77 (d, J = 4.2 Hz, 2H), 2.20 (m, 1H), 1.91 (m, 1H), 1.37 (m, 1H), 1.23 (m, 1H).

Example 4. ira«s-2-(Pyridin-3-yl)-N-(4-[[3-(trifluoromethyl)benzene] sulfonyl]

phenyl)cyclopropane-l-carbox

[0184] Step 1. l-r(4-Nitrophenyl)sulfanyl1-3-(trifluoromethyl)benzene. A suspension of 3- (trifluoromethyl)benzene- 1 -thiol (500 mg, 2.81 mmol, 1.00 equiv), l-fluoro-4-nitrobenzene (700 mg, 4.96 mmol, 1.77 equiv) and potassium carbonate (2 g, 14.47 mmol, 5.16 equiv) in CH₃CN (50 mL) was stirred under nitrogen at 100 °C for 2 h. The solid material was removed by filtration and the filtrate was concentrated under vacuum to give 1 g of the title compound as a light yellow crude solid. TLC: R_f = 0.3; EtO Ac/petroleum ether = 1 :20.

[0185] Step 2. l-Nitro-4-rr3-(trifluoromethyl)benzenelsulfonyllbenzene. A mixture of 1- nitro-4-[[3-(trifluoromethyl)phenyl]sulfanyl]benzene (800 mg, 2.67 mmol, 1.00 equiv) and m- CPBA (2 g, 11.59 mmol, 4.34 equiv) in DCM (50 mL) was stirred for 18 h at rt. The reaction mixture was diluted with 200 mL of DCM and then washed with 2x100 mL of 10% aqueous potassium carbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give 1.1 g of the title compound as a light yellow solid. TLC: R_f = 0.3; EtO Ac/petroleum ether = 1 :2.

[0186] Step 3. 4-rr3-(Trifluoromethyl)benzene1sulfonyl1aniline. A suspension of l-[(4- nitrobenzene)sulfonyl]-3-(trifluoromethyl)benzene (700 mg, 2.11 mmol, 1.00 equiv) and Raney nickel (2 g) was stirred under 1 atmosphere of hydrogen gas in MeOH (100 mL) at rt for 2 h. The reaction mixture was filtered to remove the nickel catalyst. The filtrate was concentrated under vacuum and the residue was purified on a silica gel column eluted with EtO Ac/petroleum ether (1 :2) to give 0.3 g (47%) of the title compound as a light yellow solid. LCMS (Method K, ESI): RT= 0.86 min, m/z = 302.0 [M+H]⁺; TLC: R_f = 0.2; ethyl acetate/petroleum ether = 1 : 1.

[0187] Step 4. A mixture of 4-[[3-(trifluoromethyl)benzene]sulfonyl]aniline (300 mg, 1.00 mmol, 1.00 equiv), /ratts-2-(pyridin-3-yl)cyclopropane-l-carbonyl chloride hydrochloride (220 mg, 1.01 mmol, 1.01 equiv) and Et₃N (300 mg, 2.96 mmol, 2.98 equiv) in DCM (50 mL) was stirred under nitrogen for 18 h at rt. The resulting mixture was concentrated under vacuum and the residue was purified on a silica gel column eluted with EtOAc hexanes (1 : 1) to yield 59.4 mg (13%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-ife, ppm) δ 10.77 (s, IH), 8.49 (d, / = 1.8 Hz, IH), 8.42-8.40 (m, IH), 8.26-8.20 (m, 2H), 8.10-7.96 (m, 3H), 7.90- 7.81 (m, 3H), 7.58-7.54 (m, IH), 7.34-7.30 (m, IH), 2.45-2.41 (m, IH), 2.17-2.08 (m, IH), 1.58- 1.51 (m, 2H); TLC: R_f = 0.1, EtOAc/hexanes = 2: 1.

Example 5. iraws-N-[4-(Oxane-4-sulfonyl)phenyl]-2-(pyridin-3-yl)cyclopropane-l- carboxamide.

[0188] Step 1. 4-r(4-Nitrophenyl)sulfanylloxane. To a solution of tetrahydro-2H-pyran-4-ol (500 mg, 4.90 mmol, 1.00 equiv), 4-nitrobenzene- 1 -thiol (760 mg, 4.90 mmol, 1.00 equiv) and PPh₃ (1.54 g, 5.87 mmol, 1.20 equiv) in DCM (20 mL) at 0-5 °C was added diisopropyl azodicarboxylate (1.2 g, 5.93 mmol, 1.21 equiv). The resulting solution was stirred at rt for 1 h then concentrated under vacuum. The residue was purified on a silica gel column eluted with DCM/petroleum ether (1:5) to give 600 mg (51%) of the title compound as colorless oil. TLC: petroleum ether/EtOAc = 5: 1, R_f= 0.25.

[0189] Step 2. 4-r(4-Nitrobenzene sulfonylloxane. A solution of 4- [(4- nitrophenyl)sulfanyl]oxane (600 mg, 2.51 mmol, 1.00 equiv) and m-CPBA (2.2 g) in DCM (20 mL) was stirred at rt for 2 h. The reaction mixture was diluted with 500 mL of DCM then washed with 3x50 mL of saturated sodium carbonate solution and 1x50 mL of brine. The organic layer was concentrated under reduced pressure and the residue was purified on a silica gel column eluted with DCM/EtOAc (2: 1) to give 460 mg (68%) of the title compound as a white solid. TLC : R_f = 0.3 , petroleum ether/EtOAc = 1: 1.

[0190] Step 3. 4-(Oxane-4-sulfonyl)aniline. A suspension of 4-[(4- nitrobenzene)sulfonyl]oxane (200 mg, 0.74 mmol, 1.00 equiv) and 10% palladium on carbon (20 mg) was stirred under 1 atmosphere of hydrogen gas in MeOH (20 mL) at rt for 1 h. The catalyst was removed by filtration. The filtrate was concentrated under vacuum to give 140 mg (79%) of the title compound as an off-white solid. TLC: R_f = 0.2, MeOH/DCM = 1/10.

[0191] Step 4. A mixture of irans-2-(pyridin-3-yl)cyclopropane- l-carbonyl chloride (100 mg, 0.55 mmol, 0.95 equiv), 4-(oxane-4-sulfonyl)aniline (140 mg, 0.58 mmol, 1.00 equiv) and Et₃N (117 mg, 1.16 mmol, 1.99 equiv) in DCM (10 mL) was stirred at rt for 1 h. The reaction mixture was diluted with 100 mL of DCM then washed with 2x20 mL of water and 1x20 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with DCM/MeOH (20: 1) to give 14.1 mg (6%) of the title compound as a light brown solid. 1H NMR (300 MHz, DMSO-d_& ppm) δ 10.78 (s, IH), 8.52 (d, 7 = 1.8 Hz, IH), 8.41 (dd, .7 = 4.6, 1.6 Hz, IH), 7.85 (d, 7 = 9.0 Hz, 2H), 7.75 (d, J = 9.0 Hz, 2H), 7.60-7.56 (m, IH), 7.31 (dd, J = 7.8, 4.5 Hz, IH), 3.90-3.86 (m, 2H), 3.45 (m, IH), 3.31-3.26 (m, 2H), 2.43 (m, IH), 2.18-2.16 (m, IH), 1.73-1.69 (m, 2H), 1.57- 1.47 (m, 4H).

Example 6. raws-N-(4-[8-Oxa-3-azabicyclo[3.2. l]octane-3-sulfonyl]phenyl)-2-(pyridin-3- yl)cyclopropane- 1 -carboxamide.

[0192] Step 1 , 3-r(4-Nitrobenzene)sulfonyll-8-oxa-3-azabicyclor3.2. lloctane. A mixture of 8-oxa-3-azabicyclo[3.2.1]octane (1 g, 8.84 mmol, 1.00 equiv), 4-nitrobenzene-l-sulfonyl chloride (2 g, 9.02 mmol, 1.00 equiv) and Et₃N (2 mL) in DCM (30 mL) was stirred under nitrogen at rt for 1 h. The reaction was quenched by the addition of 5 mL of water. The resulting mixture was extracted with 3x30 mL of DCM. The organic combined layers were concentrated under vacuum. The residue was purified on a silica gel column eluted with EtO Ac/petroleum ether (1 :3) to yield 300 mg of the title compound as a yellow solid. TLC: R_f= 0.5,

EtO Ac/petroleum ether = 1 : 1.

[0193] Step 2. 4-r8-Qxa-3-azabicyclor3.2.11octane-3-sulfonyllaniline. A suspension of 3-[(4- nitrobenzene)sulfonyl]-8-oxa-3-azabicyclo[3.2.1]octane (250 mg, 0.84 mmol, 1.00 equiv) and Raney nickel (1 g) in MeOH (20 mL) was stirred at rt under 1 atmosphere of hydrogen gas for 1 h. The catalyst was removed by filtration. The filtrate was concentrated under vacuum and the residue was purified on a silica gel column eluted with EtOActo give 250 mg of the title compound as a white solid. TLC: R_f = 0.2, EtO Ac/petroleum ether = 1 : 1.

[0194] Step 3. A mixture of 4-[8-oxa-3-azabicyclo[3.2.1]octane-3-sulfonyl]aniline (250 mg, 0.93 mmol, 1.00 equiv), rraras-2-(pyridin-3-yl)cyclopropane-l-carbonyl chloride (170 mg, 0.94 mmol, 1.00 equiv) and Et₃N (2 mL) in DCM (10 mL) was stirred at rt for 20 h. The reaction mixture was concentrated under vacuum and the residue was first purified on a silica gel column eluted with DCM/MeOH (5: 1). The partially purified product (150 mg) was re-purified by preparative HPLC (conditions as in Example 3; 22 to 45% CH₃CN/H₂O in 17 min) to give 75.5 mg of the title compound as an off-white solid. 1H NMR (300 MHz, DMSO-cfe, ppm) δ 10.72 (s, 1H), 8.50 (s, 1H), 8.40 (d, / = 4.2 Hz, 1H), 7.81 (d, J = 8.7 Hz, 2H), 7.62 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 7.8 Hz, 1H) 7.29 (dd, J = 7.6, 4.9 Ηζ, ΙΗ), 4.31 (s, 2H), 3.31-3.20 (m, 3H), 2.49-2.26 (m, 2H), 2.16-2.14 (m, 1H), 1.77 (m, 4H), 1.57-1.52 (m, 2H).

Example 7. iraws-N-[4-(B cyclopropane-l-carboxamide.

[0195] Step 1. (2E)-N-Methoxy-N-methyl-3-(pyridin-4-yl)prop-2-enamide. A solution of (2£)-3-(pyridin-4-yl)prop-2-enoic acid (3 g, 20.1 mmol, 1.00 equiv), methoxy (methyl) amine hydrochloride (4 g, 41.01 mmol, 2.00 equiv), EDCI (8 g, 41.73 mmol, 2.00 equiv) and 4- dimethylaminopyridine (5 g, 40.9 mmol, 2.00 equiv) in DCM (150 mL) was stirred for 2 h at rt. The reaction was quenched by the addition of 100 mL of water and the resulting solution was extracted with 2x200 mL of DCM. The combined organic layers were concentrated under vacuum and the residue was purified on a silica gel column eluted with DCM/MeOH (5: 1) to give 3 g (78%) of the title compound as a yellow oil. LCMS (Method F, ESI): RT = 0.95 min, m/z = 193.1 [M+H]⁺.

[0196] Step 2. rfl?¾5^,-N-Methoxy-N-methyl-2-(pyridin-4-yl)cvclopropane- 1-carboxamide. To a solution of trimethylsulfoxonium iodide (6.6 g, 30.5 mmol, 2.00 equiv) in DMSO (30 mL) maintained under nitrogen at 0 °C was added sodium hydride (1.2 g, 60%, 50.00 mmol, 2.00 equiv) in portions. The resulting solution was stirred at rt for 1 h. (2£)-N-Methoxy-N-methyl-3- (pyridin-4-yl)prop-2-enamide (3 g, 15.6 mmol, 1.00 equiv) was then added and the resulting solution was stirred for an another 0.5 h at rt. The reaction mixture was poured into 100 mL of saturated NH₄C1 solution then extracted with 2x200 mL of EtOAc. The combined organic layers were washed with 3x50 mL of H₂O and concentrated under vacuum. The residue was purified on a silica gel column eluted with DCM/MeOH (5: 1) to give 3 g (93%) of the title compound as yellow oil. LCMS (Method D, ESI): RT - 0.41 min, m/z = 207.1 [M+H]⁺.

[0197] Step 3. fra»s-2-(Pyridin-4-yl)cyclopropane-l-carboxylic acid. To a solution of trans- N-methoxy-N-methyl-2-(pyridin-4-yl)cyclopropane- 1-carboxamide (3 g, 14.55 mmol, 1.00 equiv) in EtOH (10 mL) was added a solution of KOH (3 g, 53.47 mmol, 3.68 equiv) in water (10 mL). The resulting solution was stirred for 20 h at rt. The pH of the solution was adjusted to 6 with 2 M HC1. The resulting mixture was concentrated under vacuum and the residue was diluted with 200 mL of EtOH. The solid material was filtered off and the filtrate was concentrated under vacuum to give 2 g (84%) of the title compound as a yellow solid. LCMS (Method F, ESI): RT = 0.84 min, m/z = 164.0 [M+H]⁺.

[0198] Step 4. frfl»s-2-(Pyridin-4-yl)cyclopropane-l-carbonyl chloride. To a solution of ir w5-2-(pyridin-4-yl)cyclopropane-l-carboxylic acid (600 mg, 3.68 mmol, 1.00 equiv) in DCM (10 mL) was added 1 drop of DMF followed by dropwise addition of thionyl chloride (5 mL). The resulting solution was stirred at rt for 1 h then concentrated under vacuum to give 0.8 g of the title compound as a red oil. The crude product was used in the next step without further purification. [0199] Step 5, A solution of 4-(benzenesulfonyl)aniline (800 mg, 3.43 mmol, 1.00 equiv), ir w5-2-(pyridin-4-yl)cyclopropane-l-carbonyl chloride (1 g, 5.51 mmol, 1.00 equiv) and Et₃N (2 mL) in DCM (50 mL) was stirred at rt for 1 h. The resulting mixture was concentrated under vacuum and the residue was first purified on a silica gel column eluted with DCM/MeOH (5: 1) then repurified by preparative HPLC (conditions as in Example 3; 15 to 45% CH₃CN/H₂O in 20 min) to give 277 mg (13%) of the title compound as a light yellow solid. 1H-NMR (300 MHz, DMSO-de) δ 10.75 (s, 1H), 8.43 (dd, / = 4.8, 1.5 Hz, 2H), 7.93-7.88 (m, 4H), 7.80 d, J = 8.4 Hz, 2H), 7.70-7.58 (m, 3H), 7.20 (dd, / = 4.8, 1.5 Hz, 2H), 2.38 (m, 1H), 2.16 (m, 1H), 1.62- 1.48 (m, 2H).

Example 8. irarts-N-[4-(6-Methylpyridine-3-sulfonyl)phenyl]-2-(pyridin-3-yl)cyclopropane- 1- carboxamide.

[0200] Step 1. Lithio 6-methylpyridine-3-sulfinate. To a solution of 5-bromo-2- methylpyridine (5 g, 29.07 mmol, 1.00 equiv) in Et₂0 (20 mL) under nitrogen at -78 C was added n-butyl lithium (2.5 M in hexane; 12.8 mL) dropwise. Consumption of the starting material was monitored by TLC. Sulfur dioxide was then bubbled in and the resulting solution was stirred for 30 min at -78°C to rt. The solids were collected by filtration and washed with Et₂0. The solid was dried in an oven under reduced pressure. This resulted in 4.03 g (85%) of lithio 6-methylpyridine-3-sulfinate as a white solid. ^XH NMR (300 MHz, D₂0) δ 8.86-8.85 (d, J = 1.5 Hz, 1H), 8.24 (m, 1H), 7.75-7.72 (d, 7 = 8.1 Ηζ,ΙΗ), 2.87 (s, 3H).

[0201] Step 2. 2-Methyl-5-r(4-nitrobenzene)sulfonyll pyridine. A mixture of lithio 6- methylpyridine-3-sulfinate (2 g, 12.26 mmol, 1.00 equiv) and l-fluoro-4-nitrobenzene (1.73 g, 12.26 mmol, 1.00 equiv) in DMSO (20 mL) was stirred under nitrogen for 3 h at 100 °C. The resulting solution was diluted with 10 mL of H₂0 and was extracted with 3x20 mL of DCM. The combined organic layers were washed with 3x20 mL of brine, then dried over anhydrous sodium sulfate and concentrated under vacuum. The residue purified on a silica gel column, eluting with DCM/MeOH (100: 1-50: 1) to give 0.8 g (23%) of the title compound as a light brown solid. 1H NMR (400 MHz, DMSO-i¾) δ 9.07-9.06 (d, J = 2.0 Hz, 1H), 8.69 (m, 2H), 8.43-8.39 (m, 3H), 7.56-7.54 (d, J = 8.4 Hz, 1H), 2.57 (s, 3H). [0202] Step 3. 4-(6-Methylpyridine-3-sulfonyl)aniline. A mixture of 2-mefhyl-5-[(4- nitrobenzene) sulfonyl] pyridine (300 mg, 1.08 mmol, 1.00 equiv) and palladium on carbon (0.03 g) in MeOH (10 mL) was stirred for 5 h at rt under an atmosphere of hydrogen gas. The solids were then filtered off and the resulting mixture was concentrated under vacuum to give 0.24 g (90%) of the title compound as an off-white solid. LCMS (Method F, ESI): RT = 1.15 min, m/z = 249.0 [M+H]⁺.

[0203] Step 4. A mixture of 4-(6-methylpyridine-3-sulfonyl)aniline (240 mg, 0.97 mmol, 1.00 equiv), frafts-2-(pyridin-3-yl)cyclopropane-l-carbonyl chloride (210 mg, 1.16 mmol, 1.20 equiv), and Et₃N (290 mg, 2.87 mmol, 2.97 equiv) in DCM (5 mL) was stirred for 18 h at rt. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC (2#-Waters 2767-2(HPLC-08): Column, Xbridge Prep Phenyl, 5 urn, 19* 150 mm; mobile phase, CH₃CN in 50 mM aqueous ammonium bicarbonate (10.0 to 33.0% CH₃CN in 2 min, up to 53.0% in 8 min,up to 100.0% in 1 min, down to 10.0% in 1 min); Detector, UV 220 nm) to give 34.8 mg (9%) of the title compound as a off-white solid. 1H NMR (300 MHz, CD₃OD) δ 8.93-8.92 (d, / = 2.4 Hz, 1H), 8.44-8.38 (m, 2H), 8.22-8.18 (dd, / = 8.1, 2.4 Hz, 1H), 7.95-7.92 (m, 2H), 7.84-7.81 (m, 2H), 7.64-7.62 (m, 1H), 7.49-7.46 (d, J = 8.4 Hz, 1H), 7.40- 7.35 (m, 1H), 2.60-2.52 (m, 4H), 2.16-2.10 (m, 1H), 1.72- 1.65 (m, 1H), 1.50-1.43 (m, 1H).

Example 9. iraws-N-[4-[l-(Propan-2-yl)- lH-pyrazole-4-sulfonyl]phenyl]-2-(pyridin-3- yl)cyclopropane- 1 -carboxami

[0204] Step 1. Lithium l-(propan-2-yl)-lH-pyrazole-4-sulfinate, To a solution of 4-bromo-l- (propan-2-yl)-lH-pyrazole (2 g, 10.58 mmol, 1.00 equiv) in Et₂0 (20 mL) maintained under nitrogen at -78 °C was added dropwise a 2.5 M n-butyllithium solution (4.6 mL) in hexane. The reaction mixture was stirred at -78 °C for 1 h. Sulfur dioxide gas was then bubbled in for 30 min. The reaction mixture was stirred at -78 °C for 30 min and then warmed to rt. The solid was collected by filtration, washed with Et₂0 and dried in a vacuum to give 0.9 g (47%) of the title compound as a white solid. LCMS (Method G, ESI): RT =1.03 min, m/z = 191.0.

[0205] Step 2. 4-r(4-Nitrobenzene)sulfonyll-l-(propan-2-yl)-lH-pyrazole. A solution of lithium l-(propan-2-yl)- lH-pyrazole-4-sulfinate (900 mg, 5.00 mmol, 1.00 equiv) and 1-fluoro- 4-nitrobenzene (705 mg, 5.00 mmol, 1.00 equiv) in DMSO (10 mL) was stirred at 100 °C for 3 h. The resulting solution was diluted with 20 mL of H₂0 and then extracted with 3x50 mL of DCM. 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 EtOAc/petroleum ether (1:50-1:20) to give 0.25 g (17%) of the title compound as a light brown solid. LCMS (Method L, ESI): RT = 0.86 min, mJz = 337.0 [M+MeCN+H]⁺.

[0206] Step 3. 4-r i-(Propan-2-yl)-lH-pyrazole-4-sulfonyllaniline. A suspension of 4-[(4- nitrobenzene)sulfonyl]- l-(propan-2-yl)-lH-pyrazole (250 mg, 0.85 mmol, 1.00 equiv) and 10% palladium on carbon (0.03 g) in MeOH (10 mL) was stirred under 1 atmosphere of hydrogen gas at rt for 18 h. The catalyst was removed by filtration. The filtrate was concentrated under vacuum to give 0.17 g (76%) of the title compound as an off-white solid. LCMS (Method D, ESI): RT =1.20 min, m/z = 266.0 [M+H]⁺.

[0207] Step 4. A mixture of 4-[l-(propan-2-yl)- lH-pyrazole-4-sulfonyl]aniline (170 mg, 0.64 mmol, 1.00 equiv), ira«s-2-(pyridin-3-yl)cyclopropane-l-carbonyl chloride (140 mg, 0.77 mmol, 1.20 equiv) and Et₃N (190 mg, 1.88 mmol, 2.93 equiv) in DCM (5 mL) was stirred for 18 h at rt. The resulting mixture was concentrated under vacuum and the crude product was purified by preparative HPLC (conditions as in Example 8) to give 42.5 mg (16%) of the title compound as an off-white solid. 1H NMR (300 MHz, OMSO-d₆) δ 10.70 (s, 1H), 8.50-8.40 (m, 3H), 7.89- 7.77 (m, 5H), 7.57-7.55 (m, 1H), 7.32-7.29 (m, 1H), 4.56-4.51 (m, 1H), 2.50-2.49 (m, 1H), 2.17- 2.11 (m, 1H), 1.58- 1.50 (m, 2H), 1.48 (d, J = 2.1 Hz, 6H).

Example 10. iraras-N-[4-[(3-Methanesulfonyl benzene)sulfonyl]phenyl]-2-(pyridin-3- yl)cyclopropane- 1 -carbox

[0208] Step 1. Lithium 3-(methylthio)benzenesulfinate. To a stirred solution of 1 -bromo-3- (methylsulfanyl)benzene (2 g, 9.85 mmol, 1.00 equiv) in THF (40 mL) maintained under nitrogen at -78 °C was added dropwise a 2.5 M n-BuLi solution in hexane (5 mL). The reaction mixture was stirred at -78 °C for 30 min. Sulfur dioxide gas was bubbled into the reaction for 1 h and the resulting solution was stirred at rt under an atmosphere of sulfur dioxide for 18 h. The solid was collected by filtration to give 2.5 g of crude lithium 3-(methylthio)benzenesulfinate as a light yellow solid. The crude product was used in the next step without further purification. [0209] Step 2, Methyl (3-(4-nitrophenylsulfonyl)phenyl)sulfane, A solution of 3- (methylthio)benzenesulfinate (1.2 g, 6.18 mmol, 1.00 equiv) and l-fluoro-4-nitrobenzene (1.5 g, 10.63 mmol, 1.72 equiv) in DMSO ( 10 mL) was stirred at 100 °C for 2 h. The reaction mixture was cooled to rt and quenched with 30 mL of brine. The resulting solution was extracted with 2x50 mL of EtOAc. 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 EtOAc/petroleum ether (1 :5) to give 1.2 g (63%) of the title compound as a light yellow solid. TLC: EtOAc/petroleum ether = 1 :2, R_f = 0.3.

[0210] Step 3. l- r(3-Methanesulfonylbenzene)sulfonyll-4-nitrobenzene. A solution of methyl (3-(4-nitrophenylsulfonyl)phenyl)sulfane (300 mg, 0.97 mmol, 1.00 equiv) and m-CPBA (800 mg, 4.64 mmol, 4.78 equiv) in DCM (50 mL) was stirred for 18 h at rt. The resulting solution was diluted with 100 mL of DCM then washed with 2x60 mL of 10% aqueous potassium carbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give 0.3 g of the title compound as a light yellow solid. 1H NMR (300 MHz, DMSO-i¾ δ 8.49 (d, / = 8.4 Hz, 1H), 8.44-8.39 (m, 3H), 8.36-8.30 (m, 3H), 7.96 (t, J = 6.0 Hz, 1H).

[0211] Step 4. 4- r(3-Methanesulfonylbenzene)sulfonyllaniline. A suspension of 1- methanesulfonyl-3-[(4-nitrobenzene)sulfonyl]benzene (360 mg, 1.05 mmol, 1.00 equiv) and Raney nickel ( 1 g) in MeOH (100 mL) was stirred under 1 atmosphere of hydrogen at rt for 1 h. The nickel catalyst was removed by filtration. The filtrate was concentrated under vacuum to give 0.22 g of the title compound as a light yellow solid. LCMS (Metod J, ESI): RT= 1.27min, m/z = 312.0 [M+H]⁺.

[0212] Step 5. A mixture of 4- [(3-methanesulfonylbenzene)sulfonyl] aniline (320 mg, 1.03 mmol, 1.00 equiv), iraras-2-(pyridin-3-yl)cyclopropane- l-carbonyl chloride hydrochloride (230 mg, 1.05 mmol, 1.03 equiv) and Et₃N (600 mg, 5.93 mmol, 5.77 equiv) in DCM (50 mL) was stirred for 18 h at rt. The reaction mixture was concentrated under vacuum and the residue was purified on a silica gel column eluting with EtOAc/hexanes (1 :3-1 : 1) to give 109.5 mg (23%) of the title compound as a white solid. 1H NMR (300 MHz, CDC1₃) δ 9.16 (s, 1H), 8.48-8.39 (m, 3H), 8.21-8.18 (dd, J = 8.4 Hz, 1H), 8.14-8.10 (m, 1H), 7.90 (d, J = 9.0 Hz, 2H), 7.70 (d, J = 9.0 Hz, 2H), 7.51 (d, / = 7.8 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.27 (t, = 6.6 Hz, 1H), 3.09 (s, 3H), 2.62-2.55 (m, 1H), 1.97- 1.91 (m, 1H), 1.84- 1.77 (m, 1H), 1.39- 1.33 (m, 1H).

Example 11. ira«5^,-N-[4-(l-Propyl- lH-pyrazole-4-sulfonyl)phenyl]-2-(pyridin-3- yl)cyclopropane- 1 -carboxamide.

[0213] Step 1. 4-Bromo-l -propyl- lH-pyrazole. A suspension of 4-bromo-lH-pyrazole (10 g, 68.04 mmol, 1.00 equiv), 1-iodopropane (13.94 g, 82.00 mmol, 1.21 equiv), and potassium carbonate (14.1 g, 101.28 mmol, 1.49 equiv) in DMF (200 mL) was stirred under nitrogen at 80 °C for 18 h. The reaction mixture was cooled to rt and diluted with 200 mL of H₂0. The resulting mixture was extracted with 5x200 mL of DCM. The combined organic layers were washed with 3x200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with EtO Ac/petroleum ether (1:80-1 :20) to give 7.17 g (56%) of 4-bromo-l -propyl- lH-pyrazole as a colorless liquid. ^lH NMR (300 MHz, CDC1₃) δ 7.45 (s, 1H), 7.39 (s, 1H), 4.07-4.02 (t, J = 6.9 Hz, 2H), 1.92- 1.80 (m, 2H), 0.93-0.85 (t, J = 7.2 Hz, 3H).

[0214] Step 2. Lithium 1 -propyl- lH-pyrazole-4-sulfinate. To a stirred solution of 4-bromo-l - propyl- lH-pyrazole (4 g, 21.16 mmol, 1.00 equiv) in Et₂0 (100 mL) maintained under nitrogen at -78 °C was added a 2.5 M solution of n-butyllithium (8.5 mL) in hexanes. The reaction mixture was added at -78 °C for 45 min. Sulfur dioxide was bubbled into the reaction at -78 °C for 30 min. The resulting mixture was warmed to rt and stirred for 30 min. The solid was collected by filtration and dried in a vacuum oven to yield 1.04 g (27%) of lithium 1 -propyl- 1Η- pyrazole-4-sulfinate as a white solid. LCMS (Method K, ESI): RT = 0.64 min, mJz = 191.0.

[0215] Step 3. 4-r(4-Nitrobenzene)sulfonyH-l-propyl-lH-pyrazole. A mixture of lithium 1 - propyl- lH-pyrazole-4-sulfinate (1.04 g, 5.77 mmol, 1.00 equiv) and l-fluoro-4- nitrobenzene (810 mg, 5.74 mmol, 0.99 equiv) in DMSO (10 mL) was stirred at 100 °C for 5 h. The reaction was cooled to rt and quenched by the addition of 10 mL of water. The resulting mixture was extracted with 5x20 mL of DCM. The combined organic layers was 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 (100: 1-50: 1) to afford 0.29 g (17%) of the title compound as a light yellow solid. LCMS (Method D, ESI): RT = 1.42 min, m/z = 337.0 [M+MeCN+H]⁺.

[0216] Step 4. 4-(l -Propyl- lH-pyrazole-4-sulfonyl)aniline. A suspension of 4-[(4- nitrobenzene)sulfonyl]- l -propyl- lH-pyrazole (250 mg, 0.85 mmol, 1.00 equiv) and 10% palladium on carbon (0.03 g) in MeOH (10 mL) was stirred under 1 atmosphere of hydrogen gas at rt for 18 h. The catalyst was removed by filtration and the filtrate was concentrated under vacuum to give in 0.2 g (89%) of the title compound as an off-white solid. LCMS (Method L, ESI): RT = 0.78 min, m/z = 266.0 [M+H]⁺.

[0217] Step 5. A mixture of 4-(l-propyl-lH-pyrazole-4-sulfonyl)aniline (200 mg, 0.75 mmol, 1.00 equiv), £raws-2-(pyridin-3-yl)cyclopropane-l-carbonyl chloride (160 mg, 0.88 mmol, 1.17 equiv) and Et₃N (230 mg, 2.27 mmol, 3.02 equiv) in DCM (5 mL) was stirred at rt for 18 h. The reaction mixture was concentrated under vacuum. The crude product was purified by preparative HPLC (l#-Pre-HPLC-016(Waters): Column, SunFire Prep C18, 19* 150 mm 5 urn; mobile phase, CH₃CN in 0.05% aqueous NH4HCO3 (5% CH3CN up to 43% in 10 min); Detector, UV 254 nm) to give 79.2 mg (26%) of the title compound as an off-white solid. 1H NMR (300 MHz, DMSO-<¾) δ 10.70 (s, 1H), 8.50-8.40 (m, 3H), 7.89-7.77 (m, 5H), 7.58-7.54 (m, 1H), 7.34-7.29 (m, 1H), 4.10-4.05 (t, / = 6.9 Hz, 2H), 2.49-2.42 (m, 1H), 2.15-2.13 (m, 1H), 1.79- 1.72 (m, 2H), 1.56- 1.48 (m, 2H), 0.79-0.74 (t, / = 7.2 Hz, 3H).

Example 12. irarcs-2-(Pyridin-3-yl)-N-(4-[[3-

(trifluoromethoxy)benzene] sulfon l]phenyl)cyclopropane-l-carboxamide.

[0218] Step 1. l-r(4-Nitrophenyl)sulfanyll-3-(trifluoromethoxy)benzene. A solution of 3- (trifluoromethoxy)benzene- 1 -thiol (100 mg, 0.52 mmol, 1.00 equiv), l-fluoro-4-nitrobenzene (150 mg, 1.06 mmol, 2.06 equiv), and potassium carbonate (400 mg, 2.89 mmol, 5.62 equiv) in DMSO (10 mL) was stirred for 2 h at 100 °C. The reaction mixture was diluted with 20 mL of brine and the resulting solution was extracted with 2x50 mL of EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give 0.15 g of the title compound as a light yellow solid. The crude product was used in the next step without further purification.

[0219] Step 2. l-Nitro-4-rr3-(trifluoromethoxy)benzenel sulfonyllbenzene. A solution of 1- nitro-4-[[3-(trifluoromethoxy)phenyl]sulfanyl]benzene (300 mg, 0.95 mmol, 1.00 equiv) and m- CPBA (500 mg, 2.90 mmol, 3.04 equiv) in DCM (50 mL) was stirred for 18 h at rt. The reaction mixture was diluted with 100 mL of DCM then washed with 2x50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with EtO Ac/petroleum ether (1 :5) to give 0.28 g of the title compound as a light yellow solid. 1H NMR (300 MHz, DMSO-d₆) δ 8.44-8.40 (m, 2H), 8.34-8.29 (m, 2H), 8.13-8.06 (m, 2H), 7.91-7.79 (m, 2H).

[0220] Step 3. 4-rr3-(Trifluoromethoxy)benzenelsulfonyllaniline. A suspension of l-nitro-4- [[3-(trifluoromethoxy)benzene] sulfonyl]benzene (350 mg, 1.01 mmol, 1.00 equiv) and Raney nickel ( 1 g) in MeOH (60 mL) was stirred under 1 atmosphere of hydrogen gas for 1 h at rt. The nickel catalyst was removed by filtration. The filtrate was concentrated under vacuum to give 0.23 g of the title compound as a light yellow solid. 1H NMR (300 MHz, DMSO-d₆) δ 7.89-7.54 (m, 6H), 6.62 (m, 2H), 6.29 (s, 2H).

[0221] Step 4. A mixture of 4-[[3-(trifluoromethoxy)benzene] sulfonyl]aniline (320 mg, 1.01 mmol, 1.00 equiv), ira«s-2-(pyridin-3-yl)cyclopropane- l-carbonyl chloride hydrochloride (220 mg, 1.01 mmol, 1.00 equiv) and Et₃N (600 mg, 5.93 mmol, 5.88 equiv) in DCM (50 mL) was stirred for 18 h at rt. The reaction mixture was concentrated under vacuum and the residue was purified on a silica gel column eluted with EtOAc hexane (1 :2) to give 0.05 g (11 %) of the title compound as a white solid. ^lU NMR (400 MHz, DMSO-ci₆) δ 10.78 (s, 1H), 8.51 (d, J = 2.0 Hz, 1H), 8.42 (dd, J = 4.4, 1.2 Hz, 1H), 7.97 (m, 3H), 7.90 (s, 1H), 7.85-7.72 (m, 4H), 7.57 (d, / = 8.0 Hz, 1H), 7.31 (dd, J = 8.0, 4.8 Hz, 1H), 2.43 (m, 1H), 2.13 (m, 1H), 1.51- 1.59 (m, 2H).

Example 13. ir «5'-N-[5-(Benzenesulfonyl)pyridin-2-yl]-2-(pyridin-3-yl)cyclopropane-l- carboxamide.

[0222] Step 1. 2-Nitro-5-(phenylsulfanyl)pyridine. A suspension of 5-bromo-2-nitropyridine (2 g, 9.85 mmol, 1.00 equiv), benzenethiol ( 1.2 g, 10.89 mmol, 1.11 equiv) and potassium carbonate (2 g, 14.47 mmol, 1.47 equiv) in CH₃CN (50 mL) was heated at reflux under nitrogen for 2 h. The solid material was removed by filtration. The filtrate was concentrated under vacuum to yield 1.2 g of crude 2-nitro-5-(phenylsulfanyl)pyridine as a light yellow solid. ^!H NMR(300 MHz, CDC1₃) δ 8.31 (d, / = 7.2 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.60-7.55 (m, 3H), 7.53-7.45 (m, 2H).

[0223] Step 2. 5-(Benzenesulfonyl)-2-nitropyridine. A solution of 2-nitro-5- (phenylsulfanyl)pyridine ( 100 mg, 0.43 mmol, 1.00 equiv) and m-CPBA (400 mg, 2.32 mmol, 5.38 equiv) in DCM (50 mL) was stirred for 18 h at rt. The reaction mixture was diluted with 100 mL of DCM and washed with 2x60 mL of 10% aqueous potassium carbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column with EtOAc/hexanes (1:5) to yield 85 mg of the title compound as a light yellow solid. 1H NMR(300 MHz, DMSO-ifc) δ 9.27 (d, J = 2.4 Hz, 1H), 8.81-8.77 (m, 1H), 8.48-8.45 (m, 1H), 8.14-8.10 (m, 2H), 7.82-7.67 (m, 3H).

[0224] Step 3. 5-(Benzenesulfonyl)pyridin-2-amine. A suspension of 5-(benzenesulfonyl)-2- nitropyridine (200 mg, 0.76 mmol, 1.00 equiv) and Raney nickel (0.5 g) in MeOH (60 mL) was stirred under 1 atmosphere of hydrogen gas at rt for 1 h. The catalyst was removed by filtration. The filtrate was concentrated under vacuum to give 123 mg of the title compound as a light yellow solid. 1H NMR (300 MHz, DMSO- ) δ 8.43 (d, J = 2.4 Hz, 1H), 7.89 (d, / = 6.3 Hz, 1H), 7.78-7.58 (m, 5H), 7.10 (s, 2H).

[0225] Step 4. A mixture of 5-(benzenesulfonyl)pyridin-2-amine (250 mg, 1.07 mmol, 1.00 equiv), fra/is-2-(pyridin-3-yl)cyclopropane-l-carbonyl chloride hydrochloride (230 mg, 1.05 mmol, 0.99 equiv) and Et₃N (500 mg, 4.94 mmol, 4.63 equiv) in DCM (50 mL) was stirred for 18 h at rt. The reaction mixture was concentrated under vacuum and the residue was purified on a silica gel column eluted with EtOAc/hexanes (1 : 1) to give 29.1 mg (7%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO- ) δ 11.40 (s, 1H), 8.67 (s, 1H), 8.48 (s, 1H), 8.41 (s, 1H), 8.35-8.26 (m, 2H), 8.01-7.95 (m, 2H). 7.70-7.62 (m, 3H), 7.53 (d, = 7.2 Hz, 1H), 7.32 (s, 1H), 2.44-237 (m, 2H), 1.53-1.51 (m, 2H).

Example 14. ir w5^,-N-[5-[(3,5-Difluorobenzene)sulfonyl]pyridin-2-yl]-2-(pyridin-3- yl)cyclopropane- 1 -carboxamide

[0226] Step 1. 5-r(3,5-Difluorophenyl)sulfanyll-2-nitropyridine. A mixture of 3,5- difluorobenzene- 1 -thiol (2 g, 13.68 mmol, 1.00 equiv), 5-bromo-2-nitropyridine (3.2 g, 15.76 mmol, 1.00 equiv), and potassium carbonate (4.8 g, 34.73 mmol, 2.00 equiv) in DMSO (30 mL) was stirred under nitrogen at rt for 2 h. The reaction mixture was diluted with 200 mL of EtOAc then washed with 3x50 mL of H₂O. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give 2 g of the title compound as a gray solid. The crude product was used in the next step without further purification. TLC: 1 : 1 EtO Ac/petroleum ether, R_f = 0.8. [0227] Step 2, 5-r(3,5-Difluorobenzene)sulfonyll-2-nitropyridine. A solution of 5-[(3,5- difluorophenyl)sulfanyl]-2-nitropyridine (2 g, 7.46 mmol, 1.00 equiv) and m-CPBA (6 g, 34.77 mmol, 5.00 equiv) in DCM (100 mL) was stirred for 1 h at rt. The reaction was then quenched by the addition of a solution of 5 g K₂CO₃ and 5 g Na₂S₂0₃ in 20 mL of water. The resulting mixture was extracted with 3x100 mL of DCM. The combined organic layers was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give 2 g of the title compound as a yellow solid. TLC: 1 : 1 EtO Ac/petroleum ether, R_f = 0.6.

[0228] Step 3. 5-r(3,5-Difluorobenzene)sulfonyllpyridin-2-amine. A suspension of 5-[(3,5- difluorobenzene)sulfonyl]-2-nitropyridine (2 g, 6.66 mmol, 1.00 equiv) and Raney nickel (2 g) in MeOH (100 mL) was stirred under 1 atmosphere of hydrogen gas at rt for 30 min. The catalyst was removed by filtration. The resulting filtrate was concentrated under vacuum and the residue was purified on a silica gel column eluted with EtOAc to give 0.5 g of the title compound as a yellow solid. TLC: 1 : 1 EtO Ac/petroleum ether, R = 0.1.

[0229] Step 4. A mixture of 5-[(3,5-difluorobenzene)sulfonyl]pyridin-2-amine (270 mg, 1.00 mmol, 1.00 equiv), fraras-2-(pyridin-3-yl)cyclopropane-l-carbonyl chloride (200 mg, 1.10 mmol, 1.00 equiv) and Et₃N (1 mL) in DCM (20 mL) was stirred at rt for 1 h. The resulting mixture was concentrated under vacuum. The residue was first purified on a silica gel column eluted with EtOAc. The partially purified product (200 mg) was further purified by preparative HPLC (conditions as in Example 3 (15 to 45% CH₃CN/H₂0 in 20 min)) to give 26 mg (6%) of the title compound as a light yellow solid. 1H-NMR (300 MHz, DMSO-ife) δ 11.45 (s, 1H), 8.94 (d, J = 2.4 Hz, 1H), 8.48 (d, / = 2.1 Hz, 1H), 8.43-8.38 (m, 2H), 8.27 (d, J = 8.7 Hz, 1H), 7.79 (m, 1H), 7.67 (m, 1H), 7.53 (m, 1 H), 7.30 (m, 1H), 2.43-2.40 (m, 2H), 1.59-1.48 (m, 2H).

Example 15. ir ra5^,-2-(Pyridin-3-yl)-N-(5-[[3-(trifluoromethyl)benzene]sulfonyl]pyridin-2- yl)cyclopropane- 1 -carboxamid

[0230] Step 1. 2-Nitro-5-rr3-(trifluoromethyl)phenyl1 sulf anvil pyridine. A mixture of 3- (trifluoromethyl)benzenethiol (1 g, 5.61 mmol, 1.00 equiv), 5-bromo-2-nitropyridine (1.2 g, 5.91 mmol, 1.05 equiv), and potassium carbonate (1.6 g, 11.49 mmol, 2.00 equiv) in DMF (20 mL) was stirred under nitrogen at 80 °C for 2 h. The reaction mixture was cooled to rt then diluted with 200 mL of EtOAc. The resulting mixture was washed with 3x50 mL of H₂0. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give 1.5 g of the title compound as a yellow oil. TLC: 1: 1 EtO Ac/petroleum ether, R_f = 0.8.

[0231] Step 2. 2-Nitro-5-rr3-(trifluoromethyl)benzenelsulfonyllpyridine. A solution of 2- nitro-5-[[3-(trifluoromethyl)phenyl]sulfanyl] pyridine (1.2 g, 4.00 mmol, 1.00 equiv) and m- CPBA (3 g, 17.38 mmol, 4.00 equiv) in DCM (50 mL) was stirred for 1 h at rt. The reaction was quenched by the addition of 20 mL of water and the mixture was extracted with 3x100 mL of DCM. The combined organic layers was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give 1 g of the title compound as yellow oil. TLC:

EtOAc/petroleum ether=l/l, R_f = 0.6.

[0232] Step 3. 5-rr3-(Trifluoromethyl)benzenel sulfonvHpyridin-2-amine. A suspension of 2- nitro-5-[[3-(trifluoromethyl)benzene] sulfonyl]pyridine (1 g, 3.01 mmol, 1.00 equiv) and Raney nickel (1 g) in MeOH (30 mL) was stirred under 1 atmosphere of hydrogen gas for 0.5 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 EtO Ac/petroleum ether (1 : 1) to yield 200 mg (22%) of the title compound as an off-white solid. LCMS (Method D, ESI): RT = 1.29 min, m/z = 303.0 [M+H]⁺.

[0233] Step 4. A solution of 5-[3-(trifluoromethyl)benzene]sulfonylpyridin-2-amine (270 mg, 0.89 mmol, 1.00 equiv), iraras-2-(pyridin-3-yl)cyclopropane-l-carbonyl chloride (200 mg, 1.10 mmol, 1.00 equiv) and Et₃N (2 mL) in DCM (10 mL) was stirred at rt for 0.5 h. The resulting mixture was concentrated under vacuum and the residue was first purified on a silica gel column eluted with EtOAc. The product (300 mg) was further purified by preparative HPLC (conditions as in Example 3 (15 to 58% CH₃CN:H₂0 in 20 min)) to give 132 mg (27%) of the title compound as an off-white solid. 1H-NMR (300 MHz, DMSO-rf₆) δ 11.42 (s, 1H), 8.96 (d, J = 2.4 Hz, 1H), 8.33-8.26 (m, 3H), 8.48-8.39 (m, 3H), 8.09 (d, J = 8.1 Hz, 1H), 7.86 (t, J = 7.8 Hz, 1H), 7.52 (dd, / = 6.0, 1.8 Hz, 1H), 7.29 (dd, / = 7.8, 4.8 Hz, 1H), 2.42-2.40 (m, 2H), 1.56- 1.48 (m, 2H).

Example 16. ir «5^,-N-[4-(Morpholine-4-sulfonyl)phenyl]-2-(pyridin-3-yl)cyclopropane-l- carboxamide.

[0234] Step 1. 4- r(4-Nitrobenzene)sulfonvHmorpholine. To a solution of morpholine (433 mg, 4.97 mmol, 0.85 equiv) and Et₃N (686 mg, 6.78 mmol, 1.16 equiv) in DCM (10 mL) kept at -5 to 0 °C was added 4-nitrobenzene- l-sulfonyl chloride (1.3 g, 5.87 mmol, 1.00 equiv). The resulting solution was stirred at rt for 1 h and then diluted with 100 mL of DCM. The solution was washed with 1x20 mL of water and 1x20 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 1.1 g (69%) of 4- [(4-nitrobenzene)sulfonyl] morpholine as an off-white solid. TLC: EtO Ac/petroleum ether = 1: 1 R_f = 0.15.

[0235] Step 2. 4-(Morpholine-4-sulfonyl)aniline. A suspension of 4-[(4- nitrobenzene)sulfonyl] morpholine (200 mg, 0.73 mmol, 1.00 equiv) and 10% palladium on carbon (20 mg) in MeOH (20 mL) was stirred under 1 atmosphere of hydrogen gas at rt for 30 min. The catalyst was removed by filtration and the filtrate was concentrated under vacuum to yield 140 mg of crude 4-(morpholine-4-sulfonyl)aniline as an off-white solid. LCMS (Method L, ESI): RT = 0.75 min, m/z = 243.0 [M+H]⁺.

[0236] Step 3. A solution of iraws-2-(pyridin-3-yl)cyclopropane-l-carboxylic acid (87 mg, 0.53 mmol, 1.00 equiv), 4-(morpholine-4-sulfonyl)aniline (100 mg, 0.41 mmol, 0.77 equiv), HATU (188 mg, 0.49 mmol, 0.93 equiv), and DIEA (106.6 mg, 0.82 mmol, 1.55 equiv) in DMF (2 mL) was stirred at 60 °C for 10 h. The reaction mixture was concentrated under vacuum and the residue was purified on a silica gel column eluted with DCM/MeOH (15: 1) to give 67 mg (32%) of the title compound as a light yellow solid. 1H-NMR (300 MHz, DMSO-d₆) δ 10.76 (s, 1H), 8.52 (d, 7 = 1.8 Hz, 1H), 8.46 (d, 7 = 4.8 Hz, 1H), 7.84 (d, 7 = 8.7 Hz, 2H), 7.67 (d, 7 = 8.7 Hz, 2H), 7.58 (d, 7 = 4.8 Hz, 1H), 7.31 (m, 1H), 3.61 (t, 7 = 5.1 Hz, 4H), 2.81 (t, 7 = 4.8 Hz, 4H), 2.48 (m, 1H), 2.17 (m, 1H), 1.56 (m, 2H).

Example 17. ir «5'-N-[4-(Benzenesulfinyl)phenyl]-2-(pyridin-3-yl)cyclopropane-l- carboxamide.

[0237] Step 1. l-Nitro-4-(phenylsulfanyl)benzene. A mixture of l-fluoro-4-nitrobenzene (500 mg, 3.54 mmol, 1.00 equiv), benzenethiol (429 mg, 3.89 mmol, 1.10 equiv) and potassium carbonate (978 mg, 7.08 mmol, 2.00 equiv) in CH₃CN (5 mL) was heated at reflux under nitrogen for 3 h. The reaction mixture was concentrated under vacuum and the residue was purified on a silica gel column eluted with EtOac/petroleum ether (1 :20) to give 600 mg (73%) of l-nitro-4-(phenylsulfanyl)benzene as a colorless oil. TLC: petroleum ethenEtOAc = 5: 1, R_f = 0.4.

[0238] Step 2. l-(Benzenesulfinyl)-4-nitrobenzene. A solution of l-nitro-4- (phenylsulfanyl)benzene (500 mg, 2.16 mmol, 1.00 equiv) and m-CPBA (335 mg, 1.94 mmol, 0.90 equiv) in DCM (10 mL) was stirred at rt for 1 h. The reaction mixture was diluted with 200 mL of DCM then washed with 2x40 mL of saturated 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 DCM/EtOac (10: 1) to give 350 mg (65%) of 1- (benzenesulfinyl)-4-nitrobenzene as a white solid. TLC: petroleum ethenEtOAc = 5: 1, R_f = 0.3.

[0239] Step 3. 4-(Benzenesulfinyl)aniline. A suspension of l-(benzenesulfinyl)-4- nitrobenzene (200 mg, 0.81 mmol, 1.00 equiv) and 10% palladium on carbon (20 mg) in MeOH (50 mL) was stirred under 1 atmosphere of hydrogen gas at rt for 1 h. The catalyst was removed by filtration and the filtrate was concentrated under vacuum to yield 140 mg of crude 4- (benzenesulfinyl)aniline as an off-white solid. LCMS (Method D, ESI): RT = 1.15 min, mJz = 218.0 [M+H]⁺.

[0240] Step 4. A solution of 4-(benzenesulfinyl)aniline (100 mg, 0.46 mmol, 1.00 equiv), ir w5-2-(pyridin-3-yl)cyclopropane-l-carboxylic acid (97 mg, 0.59 mmol, 1.29 equiv), HATU (210 mg, 0.55 mmol, 1.20 equiv), and DIEA (178 mg, 1.38 mmol, 2.99 equiv) in DMF (2 mL) was stirred for 10 h at 60 °C. The reaction mixture was concentrated under vacuum. The residue was purified on a silica gel column eluted with DCM/MeOH (10: 1) to give 33 mg (20%) of the title compound as an off-white solid. ^!H-NMR (300 MHz, DMSO-d₆) δ 10.55 (s, 1H), 8.49 (d, J = 2.1 Hz, 1H), 8.43 (d, / = 4.8 Hz, 1H), 7.72 (d, / = 9.0 Hz, 2H), 7.68-7.63 (m, 4H), 7.54-7.51 (m, 4H), 7.29 (m, 1H), 2.38 (m, 1H), 2.09 (m, 1H), 1.55-1.45 (m, 2H).

Example 18. ir «5^,-N-(2-Methyl- lH- l,3-benzodiazol-6-yl)-2-(pyridin-3-yl)cyclopropane-l- carboxamide.

[0241] To a solution of 2-methyl-lH-l,3-benzodiazol-6-amine hydrochloride (224 mg, 1.22 mmol, 1 equiv) and Et₃N (2 g, 19.76 mmol) in DCM (20 mL) was added a solution of trans-2- (pyridin-3-yl)cyclopropane-l-carbonyl chloride (220 mg, 1.21 mmol, 1.00 equiv) in DCM (10 mL) drop wise with stirring. The reaction mixture was stirred for 18 h at rt then concentrated under vacuum. The residue was purified on a silica gel column eluted with DCM/MeOH (10: 1) to afford 29.3 mg (8%) of the title compound as an off-white solid. 1H-NMR (400MHz, DMSO- d₆) δ 12.08 (s, 1H), 10.19 (s, 1H), 8.51 (d, / = 1.6 Hz, 1H), 8.41 (dd, J = 4.6, 1.4 Hz, 1H), 7.92 (s, 1H), 7.55 (d, / = 7.6 Hz, 1H), 7.31 (m, 2H), 7.14 (s, 1H), 2.50-2.41 (m, 4H), 2.12 (m, 1H), 1.55- 1.50 (m, 1H), 1.45- 1.41 (m, 1H).

Example 19. trans-tert-Butyl 6-[[2-(pyridin-3-yl)cyclopropane]amido]- lH-indazole-l- carboxylate.

[0242] To a solution of tert-butyl 6-amino-lH-indazole-l-carboxylate (259 mg, 1.11 mmol, 1 equiv) and Et₃N (3 g, 29.65 mmol) in DCM (20 mL) was added a solution of ir<ms-2-(pyridin-3- yl)cyclopropane-l-carbonyl chloride (200 mg, 1.10 mmol, 1.00 equiv) in DCM (10 mL). The resulting solution was stirred at rt for 18 h. The reaction mixture was concentrated under vacuum. The residue was purified on a silica gel column eluted with EtO Ac/petroleum ether (1: 1), followed by preparative HPLC (IntelFlash- 1 : Column, C18 silica gel; mobile phase, 50 to 64% CH₃CN in water (NH₄HCO₃) in 10 min; Detector, UV 254 nm) to give 85.4 mg (20%) of the title compound as a white solid. 1H NMR (400MHz, DMSO- ) δ 10.62 (s, 1H), 8.77 (s, 1H), 8.54 (d, / = 2.0 Hz, 1H), 8.43 (dd, 7 = 4.8, 1.6 Hz, 1H), 8.31 (s, 1H), 7.78 (d, = 8.8 Hz, 1H), 7.59 (d, / = 8.0 Hz, 1H), 7.43 (d, = 1.6 Hz, 1H), 7.33 (dd, J = 8.0 Hz, J = 4.8 Hz, 1H), 2.49-2.47 (m, 1H), 2.20 (m, 1H), 1.67 (s, 9H), 1.60-1.59 (m, 1H), 1.52-1.50 (m, 1H).

Example 20: trans-2-{ [(2-Pyridin-3-yl-cyclopropanecarbonyl)-amino]-methyl}-7-aza- spiro[3.5]nonane-7-carbox

[0243] A solution of irans-2-pyridin-3-yl-cyclopropanecarboxylic acid (102 mg, 0.62 mmol, 1.00 equiv), 2-aminomethyl-7-aza-spiro[3.5]nonane-7-carboxylic acid ierf-butyl ester ( 159 mg, 0.62 mmol, 1.00 equiv), HATU (245 mg, 0.62 mmol, 1.00 equiv), and TEA (0.44 mL, 3.12 mmol, 5.00 equiv) in DMF (3 mL) was stirred for 18 h at rt. The reaction was then quenched by the addition of 10 mL of saturated sodium bicarbonate solution, the resulting solution was extracted with 3x30 mL of EtOAc. The combined organic layers were washed with 20 mL of brine, dried over anhydrous sodium sulfate and then concentrated under vacuum. The crude residue was purified on a silica gel column eluted with DCM/MeOH (50: 1-20: 1) to give 145 mg (58%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO- d₆) δ 8.43 (d, / = 2.3 Hz, 1H), 8.40-8.36 (m, 1H), 8.08 (t, / = 5.6 Hz, 1H), 7.47 (dt, / = 7.9, 2.1 Hz, 1H), 7.28 (dd, J = 7.9, 4.8 Hz, 1H), 3.27 (m, 1H), 3.24 (t, / = 5.7 Hz, 2H), 3.19-3.08 (m, 4H), 2.41-2.34 (m, 1H), 2.30-2.23 (m, 1H), 1.95- 1.88 (m, 1H), 1.86-1.75 (m, 2H), 1.51- 1.41 (m, 3H), 1.37 (s, 9H), 1.37- 1.35 (m, 3H), 1.29- 1.24 (m, 1H).

Examples 21 and 22: Enantiomers of /rani'-2-{ [(2-Pyridin-3-yl-cyclopropanecarbonyl)-amino]- methyl}-7-aza-spiro[3.5]nonane-7-carboxylic acid Ze/t-butyl ester.

[0244] The enantiomers of the compound of Example 20 were isolated by Chiral-Prep-SFC (Column, Chiralpak AD, 21.2mm x 150mm, 5um; Mobile phase A: CO₂, Mobile phase B: Methanol with 0.1%NH₄OH, Flow rate: 70 mL/min, Isocratic conditions: 20% Mobile phase B, Back pressure: 100 Bar, Temperature: 40 °C) to yield 53.3 mg (21%) of Example 21 and 56.6 mg (23%) of Example 22.

[0245] Examples 21 and 22 were analyzed by Chiral Analytical SFC (Column: Chiralpak AD, 4.6 mm x 50 mm, 3 um, Mobile phase A: C0₂, Mobile phase B: methanol with 0.1% NH₄OH, Flow rate: 4 mL/min, Isocratic conditions: 20% Mobile phase B, Back pressure: 105 Bar, Temperature: 40 degrees C). Examlpe 21 RT = 0.43 min; Example 22 RT = 0.93 min.

[0246] LCMS and 1H NMR data for Examples 21 and 22 were consistent with the data provided for Example 20.

Examples 23 and 24: Diastereomers of trans-\-{ [(2-Pyridin-3-yl-cyclopropanecarbonyl)- amino]-methyl}-6-aza-spiro[2.5]octane-6-carboxylic acid ie/t-butyl ester.

[0247] A solution of l-aminomethyl-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (102 mg, 0.62 mmol, 1.00 equiv), iraws-2-(pyridin-3-yl)cyclopropanecarboxylic acid (150 mg, 0.62 mmol, 1.00 equiv), HATU (245 mg, 0.62 mmol, 1.00 equiv), and Et₃N (317 mg, 3.12 mmol, 5.00 equiv) in DMF (3 mL) was stirred for 18 h at rt. The reaction was then quenched by the addition of 10 mL of saturated sodium bicarbonate solution, the resulting solution was extracted with 3x30 mL of EtOAc. The combined organic layers were washed with 3x20 mL of brine, dried over anhydrous sodium sulfate and then concentrated under vacuum. The residue was purified on a silica gel column eluted with DCM/MeOH (50: 1-20: 1) to give Example 23 (Diastereomer 1; 46 mg, 19%) as a white solid and Example 24 (Diastereomer 2; 10 mg, 4%) as a light yellow solid.

[0248] Example 23: 1H NMR (400 MHz, DMSO-i¾) δ 8.25 (t, J = 2.5 Hz, IH), 8.20 (dd, J =

4.6, 1.5 Hz, 1H), 7.95 (m, IH), 7.33-7.27 (m, IH), 7.11 (dd, 7 = 7.9, 4.7 Hz, IH), 3.28 (m, 2H), 3.07-2.95 (m, 3H), 2.87 (m, IH), 2.32 (q, J = 1.9 Hz, IH), 2.08 (m, IH), 1.84-1.76 (m, IH), 1.35 (m, IH), 1.24- 1.04 (m, 13H), 0.93 (m, IH), 0.63 (m, IH), 0.30 (m, IH).

[0249] Example 24: ^!H NMR (400 MHz, DMSO-d₆) δ 8.43 (t, J = 2.5 Hz, IH), 8.38 (dd, J =

4.7, 1.7 Hz, IH), 8.12 (m, IH), 7.53-7.44 (m, IH), 7.28 (dd, / = 8.0, 4.7 Hz, IH), 3.65-3.57 (m, IH), 3.52-3.38 (m, 2H), 3.22-3.12 (m, 3H), 3.10-2.98 (m, IH), 2.90 (br s, 2H), 2.25 (m, IH), 2.04- 1.92 (m, IH), 1.55- 1.47 (m, 2H), 1.43-1.22 (m, 9H), 0.88-0.73 (m, 2H), 0.48 (m, IH), 0.18 (m, IH).

Examples 25 and 26: Diastereomers of ir ns-3-[(2-Pyridin-3-yl-cyclopropanecarbonyl)-airrino]- l-oxa-8-aza-spiro[4.5]decane-8-carbox lic acid ieri-butyl ester.

[0250] ira«i'-3-[(2-Pyridin-3-yl-cyclopropanecarbonyl)-amino]-l-oxa-8-aza-spiro[4.5]decane- 8-carboxylic acid tert-b tyl ester was prepared using methods analogous to those described for Examples 23 and 24. The resulting mixture of diastereomers was further purified by Chiral- Prep-SFC (Conditions as in Examples 21 and 22) to yield 32.9 mg (21%) of Example 25and 32.9 mg (21%) of Example 26.

[0251] Example 25 (Diastereomer 1). Chiral Analytical SFC (conditions as in Examples 21 and 22), Peak 1 at RT = 0.38 min (50.7%), Peak 2 at RT = 0.42 min (49.27%). ^XH NMR (400 MHz, DMSO-< ) δ 8.43 (d, J = 2.3 Hz, IH), 8.38 (dd, / = 5.2, 1.5 Hz, IH), 8.32 (m, IH), 7.48 (dd, / = 7.9, 2.3 Hz, IH), 7.29 (dd, / = 7.9, 5.2 Hz, IH), 4.31 (m, IH), 3.90 (m, IH), 3.50 (m, IH), 3.43 (m, 2H), 3.27 (m, 3H), 2.27 (m, IH), 2.06 (m, IH), 1.98-1.89 (m, IH), 1.64- 1.54 (m, 2H), 1.55-1.42 (m, IH), 1.38 (m, 11H), 1.31- 1.21 (m, IH). [0252] Example 26 (Diastereomer 2) was analyzed by Chiral Analytical SFC (conditions as in Examples 21 and 22), RT = 0.73 min. 1H NMR (400 MHz, DMSO-i¾) δ 8.43 (d, J = 2.3 Hz, IH), 8.38 (dd, / = 5.2, 1.5 Hz, IH), 8.32 (m, IH), 7.48 (dd, / = 7.9, 2.3 Hz, IH), 7.29 (dd, / = 7.9, 5.2 Hz, IH), 4.31 (m, IH), 3.90 (m, IH), 3.50 (m, IH), 3.43 (m, 2H), 3.27 (m, 3H), 2.27 (m, IH), 2.06 (m, IH), 1.98-1.89 (m, IH), 1.64-1.54 (m, 2H), 1.55-1.42 (m, IH), 1.38 (m, 11H), 1.31-1.21 (m, IH).

[0253] Examples 27-42 may be prepared using methods analogous to those described above.

[0254] Additional examples of compounds of Formula I may be prepared using methods analogous to those described above. Analytical Characterization by LC/MS:

[0255] Each of the specifically exemplified compounds described herein was 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.

[0256] 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

[0257] 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.

[0258] 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 \xL of 100X compound plate containing controls (e.g. DMSO or blank). The compound and enzyme mixture was incubated for 15 min at rt, then 10

of 10X substrate and co-factors in Buffer A were added to the test well to make a final concentration of 1 μΜ NAM, 100 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 11 xL 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 cof actor mix.

[0259] 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.

[0260] Determination of ICso 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.

[0261] IC₅₀ values were then determined using the following formula:

IC₅₀ =10^A(LOGio(X) + (((50-% Inh at Cmpd Concentration 1)/(XX -

YY)*(LOGio(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).

[0262] The compounds of this invention have IC₅₀ values that are preferably under ΙμΜ, 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: In-Vitro Cell Proliferation Assay

[0263] Assay Method. A2780 cells were seeded in 96-well plates at 1 x 10³ cells/well in 180 pL of culture medium (10% FBS, 1% Pen/Strep Amphotecricin B, RPMI- 1640) with and without the addition of either NMN or nicotinamide (NAM). After incubation for 18 h 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 pL of each dilution was added to the plated cells with controls (e.g. DMSO and blank) to make a final volume of 200 pL. The final DMSO concentration in each well was 0.1%. The plates were then incubated for 72 h 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 h with the addition of 50 pL 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 h, whereupon 100 pL 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 μL· of lOmM 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. [0264] Determination of IC 0 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. IC₅₀ values were then determined using the following formula:

IC₅₀

Inh at Cmpd Concentration 1)/(XX- YY)*(LOG₁₀(X)-LOG₁₀(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).

[0265] 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.

[0266] The compounds of this invention have IC₅₀ values that are preferably under ΙμΜ, 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 μΜ, 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.

14 0.00975 0.0145

15 0.0118 0.0113

16 0.0208 0.0517

17 0.00515 0.00485

18 0.969 NT

19 0.607 2.0

20 0.10 2.0

21 0.0337 0.877

22 2 2.0

23 0.0669 0.189

24 0.182 0.525

25 0.566 2.0

26 2 2.0

27 0.0153 0.00371

28 0.00948 0.00335

29 0.269 2.0

30 0.00718 0.00848

31 0.00859 0.00824

32 0.00325 0.00959

33 0.0051 0.00204

34 0.0105 0.0127

35 0.0056 0.00181

36 0.013 0.0108

37 0.00976 0.0044

38 0.0206 0.049

39 0.00259 0.00123

40 0.00434 0.0269

41 0.00393 0.0031

42 0.35 0.238

[0267] 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

1. A compound of Formula (I) :

wherein:

R¹ is a heteroaryl comprising at least one nitrogen ring atom;

A is

(1) aryl or heteroaryl; or

(2) heterocycloalkyl comprising at least one nitrogen ring atom;

R² is:

(a) R^a, where R^a is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each unsubstituted or substituted with one or more substituents selected from the group consisting of: halo, hydroxy, cyano, -NR^bR^c, -alkylenyl-NR^bR^c, oxo, alkyl, alkoxy, -S(O)₀-₂-R^b, alkenyl, alkynyl, -C(0)R^b, -C0₂R^b, -CONR^bR^c, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, or two adjacent substituents on a phenyl taken together form methylene- or

ethylenedioxy;

wherein alkyl and alkoxy are each unsubstituted or substituted with hydroxy, alkoxy, halo, cyano, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl;

R^b is H, alkyl, haloalkyl, alkoxyalkyl, cyanoalkyl, arylalkyl, -C(0)alkyl, -C0₂alkyl, or

-SOialkyl, cycloalkyl, heterocycloalkyl, aryl, or -C(0)aryl; and

R^c is H or alkyl;

(b) Ci_i₂alkyl or Ci_i₂alkenyl, each unsubstituted or substituted with one or more substituents selected from the group consisting of R^a, halo, hydroxy, cyano, alkoxy, haloalkoxy, -NR^UR^V, -C(0)R^u, C0₂R^u, -CONR^uR^v, -S(O)₀-₂R^u, and -S0₂NR^uR^v;

wherein R^a is as defined in (a) above; and

R^u and R^y are each independently H, alkyl, alkoxyalkyl, haloalkyl, -C(0)alkyl, or

-C0₂alkyl;

(c) -NR^dR^e;

wherein R^d and R^e are each independently, H, alkyl, -alkylenyl-R^a, or R^a;

wherein R^a is defined as in (a) above; and

alkyl is unsubstituted or substituted with hydroxy, cyano, alkoxy, halo, -NR^hR\

-CONR^hR\ or -C(0)R^j, wherein R^h and R¹ are each independently H or alkyl, or R^h and R¹ taken together with the nitrogen to which they are attached form a monocyclic

heterocycloalkyl; and

R^J is alkyl, cycloalkyl, heterocycloalkyl, phenyl, or benzyl, each unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, halo, amino, hydroxy, and alkoxy;

n is 0, 1, or 2; and

X is -SO2-, -C(O)-, -CO2-, -C(0)NR^m-, -SO-, or -S0₂NR^m-; or when A is a bicyclic heteroaryl or bicyclic heterocycloalkyl, X may also be absent;

wherein R^m is H or Ci_₄alkyl;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein R¹ is a monocyclic heteroaryl comprising 1 or 2 nitrogen ring atoms, unsubstituted or substituted.

3. The compound of claim 1 or claim 2, wherein R¹ is unsubstituted or is substituted with one or two substituents selected from the group consisting of -NH₂, halo, Ci_₄alkyl, -OH, and Ci_ ₄alkoxy.

4. The compound of any one of claims 1 to 3, wherein R¹ is pyridyl, unsubstituted or substituted with -NH₂.

5. The compound of any one of claims 1 to 3, wherein R¹ is pyridin-3-yl, 6-aminopyridin- 3-yl, or pyridin-4-yl.

6. The compound of any one of claims 1 to 5, wherein A is phenyl or a monocyclic heteroaryl, unsubstituted or substituted.

7. The compound of any one of claims 1 to 5, wherein A is phenyl or pyridyl.

8. The compound of any one of claims 1 to 5, wherein A is a monocyclic or bicyclic heterocycloalkyl comprising at least one nitrogen ring atom, unsubstituted or substituted.

9. The compound of any one of claims 1 to 5, wherein A is an 8-, 9-, or 10-membered spirocyclic heterocycloalkyl ring comprising at least one nitrogen ring atom.

10. The compound of any one of claims 1 to 5, wherein A is 7-aza-spiro[3.5]nonan-2-yl, 6- aza-spiro[2.5]octan-2-yl, or l-oxa-8-aza-spiro[4.5]decan-3-yl.

11. The compound of any one of claims 1 to 10, wherein X is absent.

12. The compound of any one of claims 1 to 10, wherein X is -SO2-, -C(O)-, -CO2-, -C(0)NR^m-, -SO-, or -S0₂NR^m-.

13. The compound of any one of claims 1 to 12, wherein R^m is H, methyl, ethyl, or isopropyl.

14. The compound of any one of claims 1 to 13, wherein R² is:

(a) Ci-i₂alkyl; or

(b) a 3- to 8-membered cycloalkyl, 4- to 8-membered heterocycloalkyl, aryl, or 5- or 6- membered heteroaryl, each unsubstituted or substituted with one or more substituents selected from the group consisting of deuterium, Ci ^al yl, Ci ^alkoxy, halo-Ci ealkyl, halo- Ci_₆alkoxy, halo, -OH, -NR^bR^c, cyano, -S0₂R^b, -CONR^bR^c, -COR^b, and oxo;

wherein R^b and R^c are each independently H or Ci-₄alkyl.

15. The compound of any one of claims 1 to 13, wherein R² is Ci_i₂alkyl.

16. The compound of any one of claims 1 to 13, wherein R² is a 3- to 8-membered cycloalkyl, unsubstituted or substituted.

17. The compound of any one of claims 1 to 13, wherein R² is a 4- to 8-membered heterocycloalkyl, unsubstituted or substituted.

18. The compound of any one of claims 1 to 13, wherein R² is phenyl or naphthyl, unsubstituted or substituted.

19. The compound of any one of claims 1 to 13, wherein R² is a 5- or 6-membered heteroaryl, unsubstituted or substituted.

20. The compound of any one of claims 1 to 13, wherein R² is -NR^dR^e.

21. The compound of claim 20, wherein R^d is H, alkyl, -alkylenyl-R , or R^a; and R^eis H or alkyl.

22. The compound of any one of claims 1 to 19, wherein R² is substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, fhioromethyl, fluoroethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, fluoro, bromo, chloro, -OH, -NH₂, cyano, -SO2CH3, -CONH2, -CONHCH3, -CON(CH₃)₂, -COCH3, and oxo.

23. The compound of any one of claims 1 to 22, wherein n is 0 or 1.

24. The compound of any one of claims 1 to 23, wherein:

(1) when R¹ is a 5-membered monocyclic heteroaryl, A is a bicyclic heteroaryl, and R² is Ci_ 1₂alkyl, X is not -S0₂-;

(2) when R 1 is pyridinyl, and A and R 2 are both phenyl, X is not -CONH-; and

(3) when R¹ is pyridinyl, A is phenyl, and R² is piperidinyl, X is not -SO2-.

25. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (I- A):

wherein:

R¹ is a monocyclic or bicyclic heteroaryl comprising at least one nitrogen ring atom, wherein said heteroaryl is unsubstituted or substituted with one or more substituents selected from the group consisting of -NH₂, halo, C^alkyl, -OH, and Ci_4alkoxy;

R² is C_1-12alkyl; and

R^s and R' taken together with the carbon to which they are attached form a monocyclic

cycloalkyl or heterocyclo alkyl ring;

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

wherein

R¹ is a monocyclic or bicyclic heteroaryl comprising at least one nitrogen ring atom, wherein said heteroaryl is unsubstituted or substituted with one or more substituents selected from the group consisting of -NH₂, halo, Ci-₄alkyl, -OH, and Ci-₄alkoxy;

W is CH or N;

R² is phenyl or 5-6 membered heteroaryl, each of which is unsubstituted or substituted by one or more alkyl, haloalkyl, haloalkoxy, or halo groups; and

m is 1 or 2;

or a pharmaceutically acceptable salt thereof.

A compound selected from the group consisting of:

pyridyl)cyclopropanecarboxamide;

and pharmaceutically acceptable salts thereof.

28. A pharmaceutical composition comprising: (a) an effective amount of at least one compound of any one of claims 1 to 27; and (b) a pharmaceutically acceptable carrier.

29. The pharmaceutical composition of claim 28, further comprising one or more additional therapeutic agents 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 15777, L778, 123, BMS 214662, Iressa^®, Tarceva^®, C225, GLEEVEC^®, intron^®, Peg-Intron^®, aromatase combinations, ara-C, adriamycin, Cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, oxaliplatin (ELOXATIN^®), Pentostatine, 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, 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, Trastuzumab, Lerozole, Fulvestrant, Exemestane, Ifosfomide, Rituximab, Campath, leucovorin, and dexamethasone, bicalutamide, carboplatin, chlorambucil, letrozole, megestrol, valrubicin, vinblastine, and NIASPAN^®.

30. The pharmaceutical composition of claim 28, further comprising a rescuing agent.

31. The pharmaceutical composition of claim 30, wherein the rescuing agent is selected from the group consisting of nicotinamide, nicotinic acid, and nicotinamide mononucleotide (NMN).

32. 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 any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 28 to 31.

33. The method of claim 32, 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, or inflammation.

34. The method of claim 32, further comprising administering to the subject an effective amount of at least one compound 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 15777, L778,123, BMS 214662, Iressa^®, Tarceva^®, C225, GLEEVEC^®, intron^®, Peg-Intron^®, aromatase combinations, ara-C, adriamycin, Cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, oxaliplatin (ELOXATIN^®), Pentostatine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mifhramycin™, 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, 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, Trastuzumab, Lerozole, Fulvestrant, Exemestane, Ifosfomide, Rituximab, Campath, leucovorin, and dexamethasone, bicalutamide, carboplatin, chlorambucil, letrozole, megestrol, valrubicin, vinblastine, and NIASPAN^®.

35. The method of claim 32, further comprising administering an effective amount of a rescuing agent.

36. The method of claim 35, wherein the rescuing agent is selected from the group consisting of nicotinamide, nicotinic acid, and nicotinamide mononucleotide (NMN).