Imidazole compounds as ENPP1 inhibitors

Abstract

The present invention provides a compound having activity as an inhibitor of ENPP1. The compound has the following structure (I): TIFF2023553417000106.tif48160 (in the formula, L, R 1 , R 2a , R 2b , R 2c , R 2d , R 2e and n is as defined herein), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof. The disclosure provides methods related to the preparation and use of said compounds, pharmaceutical compositions containing said compounds, and methods for treating diseases associated with ENPP1 (e.g., uncontrolled cell growth, cancer, and viral or bacterial infections in mammals).

Description

[Technical Field]

[0001] Technical Field The present disclosure relates to novel imidazole compounds that have activity as inhibitors of ENPP1, as well as compositions obtained therefrom, methods for their preparation, and their use as therapeutic or prophylactic agents for treating diseases associated with dysfunction of ENPP1, such as the treatment of cancer (e.g., solid cancers and hematological cancers) and bacterial or viral infections. [Background technology]

[0002] Description of Related Technical Fields The ectonucleotide pyrophosphatase / phosphodiesterase (ENPP) family includes seven isoforms, ENPP1-7, which are type II transmembrane glycoproteins or ectoenzymes. Mass spectrometry and proteomic analysis of over 370 protein targets identified the extracellular protein ENPP1 as one of the top hits exhibiting high hydrolytic activity. ATP is the identified substrate for ENPP1, which is hydrolyzed to AMP and PPi. CD73 converts AMP to adenosine and inorganic phosphate (Pi). Kinetic experimental data indicate that ENPP1 can hydrolyze ATP. These ectonucleotide enzymes are involved in the hydrolysis of pyrophosphate (PPi) and phosphodiester bonds in extracellular nucleotides, such as triphosphates, oligonucleotides, and nucleoside 5'-monophosphates. One of the major isoforms, ENPP1 (plasma plasma membrane glycoprotein-1, PC-1), is involved in various physiological processes, such as development, formation, and transport, as well as pathophysiological conditions. Aberrant ENPP1 expression has been detected in breast cancer compared to normal mammary epithelium, providing evidence for a possible involvement of ENPP1 in the development of bone metastases (occurring in approximately 80% of cases), Hodgkin's lymphoma, hepatocellular carcinoma, follicular lymphoma, glioblastoma, and other malignant tumor tissues.

[0003] A recent report showed that cyclic dinucleotides (CDNs), substrates of ENPP1, mediate STING-dependent activation of interferon genes. nature It has been suggested that ENPP1 stimulates immunity. ENPP1 inhibition of STING pathway activation is essential for tumor control, as is the case with checkpoint inhibitors such as anti-PD-1 or PD-L1, which are promising immunotherapeutic agents for various cancers. Furthermore, mutations in ENPP1 are associated with several disorders, such as infantile arterial calcification (generalized arterial calcification of childhood or GACI), ossification of the posterior longitudinal ligament of the spine, and insulin signaling and resistance ENPP1 expression is highly correlated with the progression of pulmonary and renal fibrosis. ENPP1 expression is highly correlated with the aggressiveness of astrocytic tumors. Another study reported that ENPP1 is required for maintaining the undifferentiated and proliferative state of glioblastoma stem-like cells. Therefore, ENPP1 is an attractive druggable target for the development of novel anticancer, cardiovascular, diabetes, obesity, and antifibrotic therapeutic agents.

[0004] The importance of ENPP1 activity was further investigated using both direct binding assays and in vitro cellular potency in MDA-MB231 cells. siRNA-based knockdown of ENPP1 significantly reduced its catalytic activity in both cell-specific and in vivo experiments. These experiments demonstrated that ENPP1 activity was abolished by siRNA treatment, further supporting the validity of this target in certain diseases. It has recently been shown that bisphosphothionate analogs of endogenous cGAMP are resistant to hydrolysis by ENPP1 phosphodiesterase, and that cyclic dinucleotides (CDNs), in particular, are more potent at inducing IFN-β secretion in human THP1 cells, a mechanism that inhibits ENPP1 activity and the concomitant STING activation response.

[0005] There is ample evidence that ENPP1 expression is prominent in human primary breast tumors compared with normal mammary epithelium, with the highest levels observed in breast-bone metastases. These data support not only a possible role for ENPP1 in breast-bone metastasis but also its potential as a prognostic marker for breast cancer. The results of these target validation experiments clearly support the pharmacological role of ENPP1 in the development of novel cancer immunotherapeutics. Furthermore, ENPP1 activity is also involved in diseases caused by bacteria and / or viruses, and thus modulators of ENPP1 can be used to treat bacterial and / or viral diseases and conditions. Therefore, there is a need for improved inhibitors of ENPP1 and their use to treat various diseases. The present disclosure provides such inhibitors and their related advantages.

[0006] Summary of the Invention Briefly, embodiments of the present disclosure provide compounds, e.g., pharmaceutically acceptable salts, stereoisomers, tautomers, radioisotopic forms, or prodrugs thereof. Methods of using the compounds for the treatment of various diseases or conditions, such as uncontrolled cell proliferation, cancer, and bacterial or viral infections, are provided. DETAILED DESCRIPTION OF THE INVENTION

[0007] One embodiment is a compound having the following structure (I): [ka] (In the formula, L, R 1 , R 2a , R 2b , R 2c , R 2d , R 2e and n is as defined herein. or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof. Another embodiment provides a pharmaceutical composition comprising one or more compounds of structure (I) and a pharmaceutically acceptable carrier or excipient.

[0008] In yet another embodiment of the present disclosure, there is provided a method for treating an uncontrolled cell proliferation disorder in a mammal, the method comprising administering to the mammal an effective amount of a compound of structure (I) or a pharmaceutical composition comprising a compound of structure (I). In another embodiment of the present disclosure, there is provided a method for treating cancer in a mammal, the method comprising administering to the mammal an effective amount of a compound of structure (I) or a pharmaceutical composition comprising a compound of structure (I). In yet another embodiment of the present disclosure, there is provided a method for treating a bacterial or viral infection in a mammal, the method comprising administering to the mammal an effective amount of a compound of structure (I) or a pharmaceutical composition comprising a compound of structure (I). These and other aspects of the present disclosure will be understood by reference to the following detailed description.

[0009] (Detailed Description of the Invention) In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the present disclosure. However, it will be understood by those skilled in the art that the present disclosure may be practiced without these details.

[0010] Unless the context requires otherwise, throughout this specification and claims, the term "comprises" and variations thereof, e.g., "includes" and "comprising," are to be construed in an open-ended and inclusive sense, i.e., "including but not limited to."

[0011] As used herein, concentration ranges, percentage ranges, % ranges, or integer ranges are understood to include any integer and, where appropriate, fractions thereof (such as tenths and hundredths of integers) within the stated range, unless otherwise indicated. Numerical ranges referenced herein for physical characteristics such as polymer subunits, size, or thickness are also understood to include any integer within the stated range, unless otherwise indicated. As used herein, the terms "about" and "approximately" mean ±20%, ±10%, ±5%, or ±1% of a given range, value, or structure, unless otherwise indicated. The articles "a" and "an," as used herein, are understood to mean "one or more" of the listed components. The use of alternatives (e.g., "or") should be understood to mean either one, both, or any combination thereof.

[0012] References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment of the present disclosure. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0013] "Amino" refers to the group -NH2. "Carboxy" or "carboxyl" means a -CO2H group. "Cyano" refers to the radical -CN. "Hydroxy" or "hydroxyl" refers to the group --OH. "Oxo" means the radical =O. "Nitro" refers to the -NO2 group. "Thiol" or "thio" refers to the group --SH.

[0014] "Alkyl" refers to a saturated, straight or branched hydrocarbon chain radical composed solely of carbon and hydrogen atoms, e.g., 1 to 12 carbon atoms (C1-C 12 alkyl), 1 to 8 carbon atoms (C1-C8 alkyl), or 1 to 6 carbon atoms (C1-C6 alkyl), and is attached to the remainder of the molecule by a single bond, such as, for example, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1 dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, etc. Unless specifically stated otherwise in the specification, an alkyl group may be optionally substituted.

[0015] An "alkylene" or "alkylene chain" is a group that extends the remainder of the molecule. Bonding with functional groups , consisting only of carbon and hydrogen Direct refers to a chain or branched divalent hydrocarbon chain, saturated, e.g., of 1 to 24 carbon atoms (C1-C 24 alkylene) having 1 to 15 carbon atoms (C1-C 15 Alkylene, 1 to 12 carbon atoms (C1-C 12 alkylene), 1 to 8 carbon atoms (C1-C8 alkylene), 1 to 6 carbon atoms (C1-C6 alkylene), 2 to 4 carbon atoms (C2-C4 alkylene), and 1 to 2 carbon atoms (C1-C2 alkylene), such as methylene, ethylene, propylene, and n-butylene. The alkylene chain is connected to the rest of the molecule through a single bond. and It is attached to the functional group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and the functional group can be through one carbon or any two carbons within the chain. Unless stated otherwise in the specification, the alkylene chain may be optionally substituted.

[0016] "Alkoxy" means a group of the formula -OR a R in the formula a is a group of 1 to 12 carbon atoms (C1-C 12 "C-Calkoxy" refers to an alkyl group as defined above containing 1 to 8 carbon atoms (C-Calkoxy), 1 to 8 carbon atoms (C-Calkoxy), or 1 to 6 carbon atoms (C-Calkoxy), or any value within these ranges. Unless stated otherwise in the specification, an alkoxy group may be optionally substituted.

[0017] "Alkylamino" refers to a group of the formula -NR a R b R in the formula a is alkyl as defined above, and R b is H or alkyl as defined above. Unless stated otherwise in the specification, an alkylamino group may be optionally substituted.

[0018] "Alkylaminylalkyl" means a group of the formula -RcNR a R b R in the formula a is alkyl as defined above, and R b is H or alkyl as defined above, and R c is alkylene as defined above. Unless otherwise stated in this specification, a An alkylaminoalkyl group may be optionally substituted.

[0019] An "aromatic ring" refers to a cyclic, planar portion of a molecule (i.e., a group) having a resonance-bonded ring that exhibits increased stability relative to other bonding arrangements with the same set of atoms. Generally, an aromatic ring comprises a set of covalently bonded, coplanar atoms, forming an even number of π electrons (e.g., alternating double and single bonds) that is not a multiple of four (i.e., 4n+2 π electrons, where n=0, 1, 2, 3, etc.). Aromatic rings include, but are not limited to, phenyl, naphthenyl, imidazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridonyl, pyridazinyl, pyrimidonyl, and the like. Unless otherwise specified herein, "aromatic ring" encompasses all groups, including those that may be optionally substituted.

[0020] "Aryl" refers to a carbocyclic ring system (i.e., a ring system in which each ring atom is carbon) containing 6 to 18 carbon ring atoms and at least one aromatic ring. For purposes of embodiments of the present disclosure, an aryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and may include fused or bridged ring systems. Aryl groups include, but are not limited to, aryl groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise in this specification, the term "aryl" or the prefix "ar-" (e.g., "aralkyl") is meant to include aryl groups that are optionally substituted.

[0021] An "arylalkyl" or "aralkyl" is an alkyl group of the formula -R b R f R in the formula b is an alkylene chain as defined above, and R f is an aryl group as defined above. Unless stated otherwise in the specification, an alkylaryl group may be optionally substituted.

[0022] "Aryloxy" refers to a group of the formula -ORb R in the formula b is an aryl group as defined above. The aryl part of the aryloxy group may be optionally substituted as defined above.

[0023] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic carbocyclic group, which may include fused or bridged ring systems, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, saturated or partially unsaturated, and connected to the remainder of the molecule by a single bond. Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, adamantyl, norbornyl, decalinyl, 7,7 dimethylbicyclo[2.2.1]heptanyl, and the like. Unless otherwise specified in the specification, cycloalkyl groups may be optionally substituted.

[0024] "Fused" refers to any ring structure described herein that is fused to an existing ring structure in a compound of the present disclosure. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure that becomes part of the fused heterocyclyl ring or fused heteroaryl ring is replaced with a nitrogen atom.

[0025] "Halo" or "halogen" means bromo (Br), chloro (Cl), fluoro (F) or iodine (I).

[0026] "Haloalkyl" refers to an alkyl group, as defined above, that is substituted with one or more halo groups, as defined above, including, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless stated otherwise specifically in the specification, a haloalkyl group can be optionally substituted.

[0027] "Heterocyclyl" or "heterocycle" refers to a stable 3- to 18-membered non-aromatic ring group having 1 to 12 ring carbon atoms (e.g., 2 to 12) and 1 to 6 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless stated otherwise in the specification, a heterocyclyl group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and can include fused, spirocyclic ("spiroheterocyclyl"), and / or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocyclyl group can be optionally oxidized; the nitrogen atom is optionally quaternized; and the heterocyclyl group is partially or fully saturated. Examples of said heterocyclyl groups include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,2,3,4-tetrahydroquinolinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, a heterocyclyl group may be optionally substituted.

[0028] "Hydroxylalkyl" refers to an alkyl group containing at least one hydroxyl substituent. The OH substituent can be on a primary, secondary, or tertiary carbon. Unless otherwise stated in the specification, a hydroxylalkyl group can be optionally substituted.

[0029] "Heteroaryl" refers to a group of 5-18-membered (e.g., 5- or 6-membered) ring systems containing 1-13 ring carbon atoms, 1-6 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring. Heteroaryl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which can include fused or bridged ring systems; the nitrogen, carbon, or sulfur atoms in the heteroaryl group can be optionally oxidized; and the nitrogen atom can be optionally quaternized. Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, and isoindole. Examples of phenyl include, but are not limited to, phenyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group may be optionally substituted.

[0030] "Haloalkoxy" refers to a group of the formula -ORa In the formula, R a is a haloalkyl group as defined above containing 1 to 12 carbon atoms. Unless stated otherwise specifically in the specification, a haloalkoxy group may be optionally substituted.

[0031] "Heterocyclylalkyl" refers to a group of the formula -R b R e R in the formula b is an alkylene chain as defined above, and R e is a heterocyclyl group as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be optionally attached to the alkyl group at the nitrogen atom. Unless stated otherwise specifically in the specification, a heterocyclylalkyl group may be optionally substituted.

[0032] "Heteroarylalkyl" refers to a group of the formula -R b R f R in the formula b is an alkylene chain as defined above, and R f is a heteroaryl group as defined above. Unless stated otherwise in the specification, a heteroarylalkyl group can be optionally substituted. As used herein, the term "substituted" refers to any of the above groups in which at least one hydrogen atom (e.g., 1, 2, 3, or all hydrogen atoms) is replaced by a bond to a non-hydrogen substituent. Examples of non-hydrogen substituents include, but are not limited to, amino, carboxyl, cyano, hydroxyl, halo, nitro, oxo, thiol, thiooxo, alkyl, alkenyl, alkylcarbonyl, alkoxy, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, and / or hydroxylalkyl groups, each of which can be optionally substituted with one or more of the above substituents.

[0033] In one embodiment, Optionally present substitutions The groups include amino, carboxyl, cyano, halo, hydroxyl, C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Alkyl carbonyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkoxycarbonyl, C6-C 10 Aryl and C6-C 10 heteroaryl.

[0034] L, R 1 , R 2a , R 2b , R 2c , R 2d and R 2e It is understood that each of the selected groups for may be optionally substituted as described above, unless otherwise stated, provided that substitution satisfies all valences. Specifically, L, R 1 , R 2a , R 2b , R 2c , R 2d and R 2e Each of the selected groups for can be optionally substituted, unless otherwise specified, provided that such substitution results in a stable molecule (e.g., groups such as H and halo are not optionally substituted).

[0035] As used herein, the term "ENPP1" refers to an ectonucleotide pyrophosphatase / phosphodiesterase.

[0036] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein sufficient to effectively effect its intended application, including, but not limited to, the treatment of diseases as defined below. A therapeutically effective amount can vary depending on the intended therapeutic use (in vivo) or the subject and condition being treated, e.g., the subject's weight and age, the severity of the condition, the method of administration, etc., and can be readily determined by one of ordinary skill in the art. The term also applies to a dose that induces a specific response in target cells, e.g., a decrease in platelet adhesion and / or cell migration. The specific dose will vary depending on the particular compound selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system to which the compound is delivered.

[0037] As used herein, "treatment" or "treating" refers to an approach to achieving beneficial or desired results with respect to a disease, disorder, or medical condition, including, but not limited to, therapeutic benefit and / or preventative benefit. "Therapeutic benefit" refers to the eradication or alleviation of the underlying disease being treated. A therapeutic benefit also refers to the eradication or alleviation of one or more physiological symptoms associated with an underlying disease, resulting in an improvement in the subject, even though the subject may already be suffering from the underlying disease. In certain embodiments, for preventative benefit, the composition is administered to a subject at risk of developing a particular disease or who reports one or more physiological symptoms of the disease, even though the subject may not have been diagnosed with the disease.

[0038] As used herein, a "therapeutic effect" encompasses therapeutic and / or prophylactic benefits as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0039] As used herein, the terms "co-administration," "concomitant administration," and their grammatical equivalents include administering two or more drugs to an animal, including a human, such that both drugs and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration of separate compositions, administration at different times using separate compositions, or administration of a composition in which both drugs are present.

[0040] "Pharmaceutically acceptable salt" includes both acid and base addition salts.

[0041] "Pharmaceutically acceptable acid addition salts" refer to salts that retain the biological effectiveness and properties of the free bases and are not biologically or otherwise undesirable, and are formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like) as well as organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, Galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxoglutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylic acid, etc.

[0042] A "pharmaceutically acceptable base addition salt" refers to a salt that retains the biological effectiveness and properties of the free acid and is not biologically or otherwise objectionable. These salts are prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts include ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, primary amines, secondary amines, tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and salts of basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dianol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, and polyamine resins. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0043] The terms "antagonist" and "inhibitor" are used interchangeably and refer to compounds capable of inhibiting the biological function of a target protein by inhibiting the activity or expression of the protein (e.g., ENPP1). Thus, the terms "antagonist" and "inhibitor" are defined in the context of the biological role of the target protein. Preferred antagonists herein specifically interact (e.g., bind) with the target, but this definition also explicitly includes compounds that inhibit the biological activity of the target protein by interacting with other members of the signal transduction pathway in which the target protein participates. Preferred biological activities inhibited by antagonists are related to tumor development, growth, or metastasis.

[0044] The term "agonist" as used herein refers to a compound that has the ability to initiate or enhance the biological function of target protein by inhibiting the activity or expression of target protein.Therefore, the term "agonist" is defined in the context of the biological role of target polypeptide.Preferred agonists herein specifically interact (e.g., bind) with target, but this definition also specifically includes compounds that initiate or enhance the biological activity of target polypeptide by interacting with other members of the signal transduction pathway in which target polypeptide is involved.

[0045] As used herein, "drug" or "biologically active agent" refers to a biological, pharmaceutical, or chemical compound or other moiety. Non-limiting examples include simple or complex organic or inorganic molecules, peptides, proteins, oligonucleotides, antibodies, antibody derivatives, antibody fragments, vitamin derivatives, carbohydrates, toxins, or chemotherapeutic compounds. A variety of compounds can be synthesized, including small molecules and oligomers (e.g., oligopeptides and oligonucleotides) and synthetic organic compounds based on various core structures. Additionally, compounds for screening can be provided from a variety of natural sources, such as plant or animal extracts.

[0046] "Anticancer agent," "anti-tumor agent," or "chemotherapeutic agent" refers to any agent useful in treating a neoplastic condition. One class of anti-cancer agents includes chemotherapeutic agents. "Chemotherapy" refers to the administration of one or more chemotherapeutic and / or other agents to a cancer patient by various methods, such as intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, transdermal, buccal, inhalation, or in suppository form.

[0047] "Cell proliferation" refers to the phenomenon of a change in cell number resulting from cell division. This term also includes changes in cell morphology (e.g., an increase in size) that accompany proliferation signals.

[0048] The term "selective inhibition" or "selectively inhibiting" refers to a biologically active agent and refers to the ability of the agent to preferentially reduce target signaling activity relative to off-target signaling activity through direct or indirect interaction with the target.

[0049] "Subject" refers to an animal, such as a mammal (e.g., a human). The methods described herein may be useful in both human therapeutics and veterinary applications. In some embodiments, the subject is a mammal, and in some embodiments, the subject is a human. The term does not denote a particular age or sex. Thus, it is intended to cover adult and newborn subjects, as well as fetuses, whether male or female. "Mammal" includes both humans and non-domestic animals, such as laboratory animals or domestic animals, such as household pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), and wild animals.

[0050] A patient refers to a subject suffering from a disease or disorder. The term "patient" includes human and veterinary subjects. In some embodiments of the disclosed methods, the subject has been diagnosed with a need for treatment of a disorder of uncontrolled cell proliferation associated with ENPP1 dysfunction prior to the administering step. In some embodiments of the disclosed methods, the subject has been diagnosed with a need for inhibition of ENPP1 prior to the administering step.

[0051] "Anticancer agent," "anti-tumor agent," or "chemotherapeutic agent" refers to any agent useful in treating a neoplastic condition. One class of anti-cancer agents includes chemotherapeutic agents. "Chemotherapy" refers to the administration of one or more chemotherapeutic and / or other agents to a cancer patient by various methods, such as intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, transdermal, buccal, inhalation, or suppository form.

[0052] Prodrugs of the disclosed compounds are included in various embodiments. "Prodrug" is meant to refer to a compound that can be converted under physiological conditions or by solvolysis into a biologically active compound described herein (e.g., a compound of structure (I)). Thus, the term "prodrug" refers to a pharmaceutically acceptable precursor of a biologically active compound. In some embodiments, a prodrug is inactive when administered to a subject, but is converted into an active compound in vivo, for example, by hydrolysis. Prodrug compounds often offer advantages of solubility, tissue compatibility, or delayed release in mammals; see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., "Prodrugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entirety. The term "prodrug" includes an optional covalently bonded carrier, which releases an active compound in vivo when such a prodrug is administered to a mammalian subject. Prodrugs of the active compounds described herein are typically prepared by modifying functional groups present in the active compound such that they are cleaved to the parent active compound, either by routine manipulation or in vivo. Prodrugs include compounds bonded to any group such that the hydroxy, amino, or mercapto group is cleaved to form a free hydroxy, amino, or mercapto group, respectively, when the prodrug of the active compound is administered to a mammalian subject.Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of hydroxy functional groups, or acetate, formamide and benzamide derivatives of amine functional groups in the active compounds.

[0053] The term "in vivo" refers to an event that takes place inside a subject's body.

[0054] The embodiments disclosed herein are also intended to encompass all pharmaceutically acceptable compounds of structure (I) that are isotopically labeled by having one or more atoms replaced by an atom having a different atomic mass or mass number (i.e., "isotopic forms" of compounds of structure (I)). Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I and 125 These radiolabeled compounds may be useful in determining or measuring the efficacy of compounds, for example, by characterizing the site or mode of action, or binding affinity to a pharmacologically important site of action. Certain isotopically labeled compounds of the compound of structure (I), for example, compounds incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) is particularly useful for this purpose in view of ease of incorporation and provision of detection means.

[0055] Deuterium, i.e. 2Substitution to heavier isotopes, such as H, may be preferable in some circumstances because they may confer certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage.

[0056] Positron-emitting isotopes, e.g. 11 C. 18 F, 15 O and 13 Substitution with N is useful in positron emission topography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of structure (I) can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the Examples below, substituting the appropriate isotopically labeled reagent for the previously employed unlabeled reagent.

[0057] Certain embodiments are also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily due to enzymatic processes. Accordingly, embodiments include compounds produced by a process comprising administering a compound of the present disclosure to a mammal for a period of time sufficient to yield its metabolic products. Such products are typically identified by administering a radiolabeled compound of the invention to an animal, such as a rat, mouse, guinea pig, monkey, or human, at a detectable dose, allowing sufficient time for metabolism to occur, and isolating the conversion products from urine, blood, or other biological sample.

[0058] "Stable compound" and "stable structure" mean a compound that is sufficiently robust to be isolated to a useful degree of purity from a reaction mixture and formulated as an efficacious therapeutic agent.

[0059] In many cases, crystallization produces a solvate of the compound of the present disclosure. As used herein, the term "solvate" refers to an aggregate comprising one or more molecules of the compound of the present disclosure and one or more molecules of solvent. In some embodiments, the solvent is water, in which case the solvate is a hydrate. Alternatively, in other embodiments, the solvent is an organic solvent. Thus, the compound of structure (I) can exist as a hydrate (e.g., monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, and tetrahydrate) and corresponding solvates. In some embodiments, the compound of the present disclosure is a true solvate, while in other embodiments, the compound of the present disclosure simply retains amorphous water or is a mixture of water and some amorphous solvent.

[0060] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes instances in which the event or circumstance occurs and instances in which it does not occur. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and includes both substituted and unsubstituted aryl groups.

[0061] A "pharmaceutical composition" refers to a formulation of a compound of the present disclosure with a vehicle generally accepted in the art for delivery of biologically active compounds to mammals (e.g., humans). Such vehicles include all pharmaceutically acceptable carriers, diluents, or excipients for pharmaceutical compositions.

[0062] A "pharmaceutically acceptable carrier, diluent, or excipient" includes, but is not limited to, an adjuvant, carrier, excipient, lubricant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration for human or veterinary use.

[0063] The compounds of the present disclosure (i.e., compounds of structure (I) and embodiments thereof), or pharmaceutically acceptable salts thereof, may contain one or more centers of geometric asymmetry and thus may give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined in terms of absolute stereochemistry as (R) or (S) for amino acids, or as (D) or (L). Accordingly, embodiments include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (−), (R) and (S), or (D) and (L) isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques, e.g., chromatography and fractional crystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from appropriate optically pure precursors, or separation of the racemate (or racemate of a salt or derivative) using, e.g., chiral high-performance liquid chromatography (HPLC). Where a compound described herein contains an olefinic double bond or other center of geometric asymmetry, and unless otherwise specified, the compound is intended to include both E and Z geometric isomers, as well as all tautomers.

[0064] The present disclosure includes rotamers and conformationally constrained forms of all aspects of the compounds of the present disclosure.

[0065] "Stereoisomers" refer to compounds in which the same atoms are bonded by the same bonds but have different three-dimensional structures and are not interchangeable. The present disclosure is directed to various stereoisomers and mixtures thereof, including "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other. Unless otherwise specified, stereoisomers include racemates, enantiomers, and diastereomers.

[0066] "Tautomer" refers to a proton migration from one atom of a molecule to another atom of the same molecule. Thus, embodiments include tautomers of the disclosed compounds.

[0067] The naming protocols and structural formulas of compounds used herein are a modified version of the IUPAC naming system using the ACD / Name Version 9.07 software program and / or the ChemDraw Ultra Version 11.0.1 software naming program (CambridgeSoft). In complex compound names used herein, substituents are typically listed before the group to which they are attached. For example, cyclopropylethyl has a cyclopropyl group attached to an ethyl skeleton. Except as noted below, in the chemical structural formulas herein, all bonds are identified, except for those on certain carbon atoms, and these bonds are considered to be connected to sufficient hydrogen atoms to satisfy the valence.

[0068] compound As detailed above, the present disclosure provides compounds that have activity as ENPP1 inhibitors.

[0069] In certain embodiments, the compounds are useful in treating disorders of uncontrolled cell proliferation. In further embodiments, the disorder of uncontrolled cell proliferation is cancer or tumor. In yet another embodiment, the disorder of uncontrolled cell proliferation is associated with ENPP1 dysfunction, as further described herein.

[0070] In another embodiment, the compounds are useful in treating diseases of bacterial or viral origin. Accordingly, the present disclosure provides a method of treating a disease caused by bacteria or a virus, comprising administering to a subject a therapeutically effective amount of a compound of the present disclosure, or a composition derived therefrom.

[0071] Thus, one embodiment is a compound having the following structure (I): [ka] [In the formula, L is S(O) z and; R1 CN, C(=O)R 1a , C(=O)NHSO2R 1b , C(=NR 1d )NR 1c R 1e , OR 1e , NHR 1e , NHS(O)2R 1b , S(O)NR 1b R 1e , PO3HR 1e , SO3H or 5-membered heteroaryl; R 1a is OR 1e or NR 1c R 1e and; R 1b is C1-C6 alkyl or C6-C 10 is aryl; R 1c is H, C1-C6 alkyl or C6-C 10 is aryl; R 1d is H, OH or C1-C6 alkyl; R 1e is H, C1-C6 alkyl, C1-C6 hydroxylalkyl, C1-C6 aminoalkyl, C1-C6 alkylaminylalkyl or C6-C 10 is aryl; R 2a , R 2b , R 2c , R 2d and R 2e are each independently H, amino, halo, hydroxyl, nitro, CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C6-C 10 aryloxy or 3- to 8-membered heterocyclyl; n is 0 or 1; and z is 0, 1 or 2; where each C1-C6 alkyl, C1-C6 alkoxy, C6-C 10 Aryl, C6-C 10The aryloxy, 3- to 8-membered heterocyclyl, and 5-membered heteroaryl are independently optionally substituted, provided that R 1 is C(=O)OCH3 or C(=O)OCH2CH3, R 2c is C1-C6 alkoxy, and R 2b and R 2d at least one of which is C1-C6 alkoxy] or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.

[0072] In yet another embodiment, R 1 CN, C(=O)R 1a ;C(=O)NHSO2R 1b ;C(=NR 1d )NR 1c R 1e Or a 5-membered heteroaryl.

[0073] In a more specific embodiment, R 1 is CN. In yet another specific embodiment, R 1 is C(=O)R 1a In another more specific embodiment, R 1a is OR 1e is.

[0074] In one embodiment, R 1e is H, C1-C6 alkyl, C1-C6 hydroxylalkyl, or C1-C6 alkylaminylalkyl.

[0075] In certain embodiments, R 1e is H. In another specific embodiment, R 1e is methyl or ethyl. In yet another specific embodiment, R 1e teeth, [ka] is.

[0076] In another embodiment, R 1a is NR 1c R 1e is.

[0077] In specific embodiments, R 1c and R 1e are each H. In another specific embodiment, R 1c is H and R 1e is C1-C6 alkyl.

[0078] In one embodiment, R 1 is C(=O)NHSO2R 1b In another embodiment, R 1 is C(=NR 1d )NR 1c R 1e is.

[0079] In more specific embodiments, R 1d is OH. In another specific embodiment, R 1c and R 1e are each H.

[0080] In another embodiment, R 1 is an optionally substituted 5-membered heteroaryl. In specific embodiments, the heteroaryl contains one or more ring nitrogen atoms. In another specific embodiment, the heteroaryl is tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl.

[0081] In more specific embodiments, the heteroaryl is substituted with hydroxyl. In yet other embodiments, the heteroaryl has one of the following structures: [ka] .

[0082] In one embodiment, R 2a , R 2b , R 2c , R2d and R 2e one of R is halo, C1-C6 alkyl, or C1-C6 alkoxy, and each remaining R 2a , R 2b , R 2c , R 2d and R 2e are each independently H, halo, C1-C6 alkyl, or C1-C6 alkoxy.

[0083] In another embodiment, R 2a , R 2b , R 2c , R 2d and R 2e one of R is C1-C6 alkoxy, and each remaining R 2a , R 2b , R 2c , R 2d and R 2e are each independently H, halo, or C1-C6 alkoxy.

[0084] In yet another embodiment, R 2b and R 2c are each independently halo or methoxy. 2b is the halo and R 2c is methoxy. In another specific embodiment, R 2b and R 2c are each methoxy.

[0085] In certain embodiments, the C1-C6 alkoxy is methoxy. In another specific embodiment, the halo is fluoro or chloro.

[0086] In one embodiment, [ka] has the following structure: [ka] It has one of the following.

[0087] In another embodiment, n is 0. In yet another embodiment, n is 1.

[0088] In one embodiment, z is 0. In another embodiment, z is 1. In yet another embodiment, z is 2.

[0089] In some more specific embodiments of the compound of structure (I), the compound is selected from the following Table 1. In any one of the foregoing embodiments, stereoisomers, tautomers, prodrugs, or pharmaceutically acceptable salts of the compound are also included.

[0090] [Table 1] [Table 2] [Table 3] [Table 4]

[0091] Pharmaceutical Composition Other embodiments relate to pharmaceutical compositions. The pharmaceutical composition comprises any one (or more) of the compounds of structure (I) (or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. In even more embodiments, the pharmaceutical composition comprises a compound as disclosed herein and an additional therapeutic agent. Non-limiting examples of such therapeutic agents are described herein below.

[0092] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. Further, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, and intramedullary injections, as well as intrathecal, direct intravenous, intraperitoneal, intralymphatic, and intranasal injections.

[0093] In certain embodiments, the compound of structure (I) is administered locally rather than systemically, for example, by injecting the compound directly into an organ, often in a depot or sustained-release formulation. In specific embodiments, the long-acting formulation is administered by implant (e.g., subcutaneous or intramuscular) or by intramuscular injection. In yet other embodiments, the agent is delivered in a targeted drug delivery system, for example, a liposome coated with an organ-specific antibody. In such embodiments, the liposome is targeted to and selectively taken up by the organ. In still other embodiments, the compound of structure (I) is provided in the form of an immediate-release formulation, a sustained-release formulation, or an intermediate-release formulation. In still other embodiments, the compound of structure (I) is administered locally.

[0094] The compounds of the present invention are effective over a wide range of dosages. For example, in the treatment of adult humans, dosages of 0.01 to 1000 mg, 0.5 to 100 mg, 1 to 50 mg / day, and 5 to 40 mg / day are exemplary dosages used in some embodiments. An exemplary dosage is 10 to 30 mg per day. The exact dosage will vary depending on the route of administration, the form in which the compound is administered, the subject being treated, the weight of the subject being treated, and the judgment and experience of the attending physician.

[0095] In some embodiments, the compounds of the present disclosure are administered in a single dose. Typically, the administration is by injection, such as intravenous injection, to rapidly introduce the drug. However, other routes may be used if appropriate. A single dose of the compounds of the present disclosure may also be used to treat acute symptoms.

[0096] In some embodiments, the compound of the present disclosure is administered in multiple doses. In some embodiments, administration is about once, twice, three times, four times, five times, six times, or more than six times per day. In other embodiments, administration is about once a month, once every two weeks, once a week, or once every other day. In another embodiment, the compound of the present disclosure and another agent are administered together about once a day to about six times a day. In another embodiment, administration of the compound of the present disclosure and another agent continues for less than about seven days. In yet another embodiment, administration continues for about 6, 10, 14, 28 days, 2 months, 6 months, or a year or more. Optionally, continuous administration is administered and maintained as long as necessary.

[0097] Administration of the disclosed compounds can continue as long as necessary. In some embodiments, the disclosed compounds are administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the disclosed compounds are administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the disclosed compounds are administered continuously, for example, chronically, to treat chronic effects.

[0098] In some embodiments, the compounds of the present disclosure are administered in multiple doses.It is known in the art that the pharmacokinetics of compounds vary between subjects, so individualized administration regimens are necessary for optimal treatment.The dosage of the compounds of the present disclosure can be found by routine experimentation in light of the present disclosure.

[0099] In some embodiments, the compound of structure (I) is formulated into a pharmaceutical composition.In certain embodiments, the pharmaceutical composition is formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliary agents that facilitate the processing of the active compound into a pharmaceutical preparation.The appropriate dosage form varies depending on the selected route of administration. Any pharmaceutically acceptable techniques, carriers, and excipients may be used as appropriate to formulate the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

[0100] Provided herein are pharmaceutical compositions comprising a compound of structure (I) and pharmaceutically acceptable diluent(s), excipient(s), or carrier(s). In certain embodiments, the described compounds are administered as pharmaceutical compositions in which the compound of structure (I) is mixed with other active ingredients in combination therapy. Included herein are all combinations of active ingredients as defined in the combination therapy section below and throughout this specification. In certain embodiments, the pharmaceutical composition comprises one or more compounds of structure (I).

[0101] As used herein, a pharmaceutical composition refers to a mixture of a compound of structure (I) and other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. In certain embodiments, the pharmaceutical composition facilitates administration of the compound to an organism. In some embodiments, practicing the methods of treatment or use provided herein involves administering a therapeutically effective amount of a compound of structure (I) provided herein to a mammal having a disease, disorder, or condition to be treated with the pharmaceutical composition. In certain embodiments, the mammal is a human. In certain embodiments, the therapeutically effective amount will vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compound of structure (I) is used alone or as a component of a mixture in combination with one or more therapeutic agents.

[0102] In certain embodiments, one or more compounds of structure (I) are formulated in an aqueous solution. In certain embodiments, the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank's solution, Ringer's solution, or physiological saline buffer. In other embodiments, one or more compounds of structure (I) are formulated for transmucosal administration. In certain embodiments, transmucosal formulations include penetrants appropriate for the barrier to be permeated. In yet other embodiments, where compounds of structure (I) are formulated for other parenteral injections, suitable formulations include aqueous or non-aqueous solutions. In specific embodiments, such solutions include physiologically compatible buffers and / or excipients.

[0103] In another embodiment, the compound of structure (I) is formulated for oral administration. The compound of structure (I) is formulated by combining the active compound with, for example, a pharmaceutically acceptable carrier or excipient. In various embodiments, the compound of structure (I) is formulated into oral administration forms, including, but not limited to, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, and the like.

[0104] In certain embodiments, pharmaceutical preparations for oral use are prepared by mixing one or more solid excipients with one or more compounds of structure (I), optionally grinding the resulting mixture, and optionally adding suitable additives, followed by processing the granular mixture to obtain tablets or sugar-coated tablets.Suitable excipients include, in particular, fillers such as sugars (e.g., lactose, sucrose, mannitol, or sorbitol); cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.In certain embodiments, disintegrants are optionally added.Disintegrants include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate.

[0105] In some embodiments, dosage forms such as sugar-coated tablets and tablets are provided with one or more suitable coatings. In certain embodiments, concentrated sugar solutions are used to coat the dosage forms. The sugar solutions optionally contain additional ingredients, such as, but not limited to, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes and / or pigments are also optionally added to the coating for identification purposes. Furthermore, dyes and / or pigments are optionally used to distinguish different combinations of active compound doses.

[0106] In certain embodiments, a therapeutically effective amount of at least one compound of structure (I) is formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In certain embodiments, the push-fit capsules contain the active ingredient in admixture with one or more fillers. Fillers include, by way of example only, binders such as lactose or starch, and / or lubricants such as talc or magnesium stearate, and optionally, stabilizers. In other embodiments, soft capsules contain one or more active compounds dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers may be added as desired.

[0107] In other embodiments, at least one therapeutically effective amount of a compound of structure (I) is formulated for buccal or sublingual administration. Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges, or gels. In still other embodiments, a compound of structure (I) is formulated for parenteral injection, including formulations suitable for bolus injection or continuous infusion. In certain embodiments, the formulation for injection is provided in unit dosage form (e.g., in ampoules) or in multi-dose containers. Preservatives are optionally added to the injectable formulation. In still other embodiments, the pharmaceutical composition is formulated in a form suitable for parenteral injection as a sterile suspension, solution, or emulsion in an oily or aqueous vehicle. Parenteral injection formulations optionally contain pharmaceutical additives such as suspending agents, stabilizers, and / or dispersing agents. In certain embodiments, pharmaceutical formulations for parenteral administration comprise an aqueous solution of the active compound in water-soluble form. In additional embodiments, a suspension of the active compound (e.g., a compound of structure (I)) is prepared as a suitable oily injection suspension. Suitable lipophilic solvents or vehicles for use in pharmaceutical compositions of structure (I) include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. In certain embodiments, aqueous injection suspensions contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or agents that increase the solubility of the compound, allowing for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form, which is to be reconstituted with a suitable vehicle, such as sterile, pyrogen-free water, before use.

[0108] In yet other embodiments, the compounds of structure (I) are administered topically. The compounds of structure (I) are formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, or ointments. Such pharmaceutical compositions optionally include solubilizers, stabilizers, tonics, buffers, and preservatives.

[0109] In yet other embodiments, the compounds of structure (I) are formulated for transdermal administration. In specific embodiments, transdermal formulations employ transdermal delivery devices and transdermal delivery patches, which may be lipophilic emulsions or buffered aqueous solutions, dissolved and / or dispersed in polymers or adhesives. In various embodiments, such patches are designed to deliver pharmaceutical formulations continuously, intermittently, or on demand. In additional embodiments, transdermal delivery of the compounds of structure (I) is achieved by means of iontophoresis patches or the like. In certain embodiments, transdermal patches provide a controlled delivery system for the compounds of structure (I). In certain embodiments, the absorption rate is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. In another embodiment, absorption enhancers are used to increase absorption. The absorption enhancer or carrier comprises absorbable pharmaceutically acceptable solvents that aid in skin penetration. For example, in certain embodiments, the transdermal device is in the form of a bandage that includes a backing member, a reservoir containing the compound, optionally with a carrier, a rate-controlling barrier that delivers the compound to the host's skin at a controlled, predetermined rate over an extended period of time, and a means for securing the device to the skin.

[0110] In other embodiments, the compound of structure (I) is formulated for administration by inhalation. Various forms suitable for administration by inhalation include, but are not limited to, aerosols, mists, or powders. Any pharmaceutical composition of the compound of structure (I) is preferably delivered in the form of an aerosol spray from a pressurized pack or nebulizer using a suitable propellant (e.g., dichlorodifluoromethane, trichlorodifluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas). In a specific embodiment, the dosage unit of the pressurized aerosol is determined by providing a valve to deliver a metered amount. In certain embodiments, capsules and cartridges thereof, such as, for example, gelatin tablets for use in inhalers or insufflators, are formulated containing a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0111] In yet another embodiment, the compounds of structure (I) are formulated into rectal compositions (e.g., enemas, rectal gels, rectal forms, rectal aerosols, suppositories, jelly suppositories, etc.) containing conventional suppository bases (e.g., cocoa butter or other glycerides) and synthetic polymers (e.g., polyvinylpyrrolidone, PEG, etc.). In suppository forms of the composition, a low melting wax, such as, but not limited to, a mixture of fatty acid glycerides, optionally combined with cocoa butter, is first melted.

[0112] In certain embodiments, pharmaceutical compositions are formulated in any conventional manner using one or more physiologically acceptable carriers, including excipients and adjuvants that facilitate the processing of the active compound into a pharmaceutically usable preparation.The appropriate formulation varies depending on the selected route of administration.Pharmaceutically acceptable techniques, carriers, and excipients are used as appropriate where appropriate.Pharmaceutical compositions containing compounds of structure (I) are prepared in a conventional manner, for example, by conventional mixing, dissolving, granulating, sugar-coating, pulverizing, emulsifying, encapsulating, entrapping, or compressing processes, for example, by way of example only.

[0113] Pharmaceutical compositions comprise at least one compound of structure (I) as an active ingredient, along with at least one pharmaceutically acceptable carrier, diluent, or excipient. The active ingredient may be in the form of a free acid or free base, or in the form of a pharmaceutically acceptable salt. Additionally, the methods and pharmaceutical compositions of structure (I) also encompass the use of N-oxides, crystalline forms (also known as polymorphs), and active metabolites of these compounds having the same type of activity. All tautomers of the compounds of structure (I) are included within the scope of the compounds presented herein. Furthermore, compounds of structure (I) encompass unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents, such as water and ethanol. Solvated forms of the compounds presented herein are also considered to be within the scope of the present disclosure. Furthermore, pharmaceutical compositions may optionally include other medicinal or pharmaceutical ingredients, adjuvants (e.g., carriers, preservatives, stabilizers, wetting agents, or emulsifiers), solution enhancers, salts for regulating osmotic pressure, buffers, and / or other therapeutically valuable substances.

[0114] Thus, certain embodiments provide a pharmaceutically acceptable salt of any one of the compounds of structure (I) described herein. In more specific embodiments, the pharmaceutically acceptable salt is an acid addition salt (e.g., a trifluoroacetate or hydrochloride salt).

[0115] Methods for preparing compositions comprising compounds of structure (I) include blending the compounds of structure (I) with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid, or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which the compounds are dissolved, emulsions containing the compounds, or solutions containing liposomes, micelles, or nanoparticles containing the compounds as disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. Pharmaceutical compositions of structure (I) may take the form of liquid solutions or suspensions, solids suitable for solution or suspension in liquid prior to use, or as emulsions. These compositions may also contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and the like, if desired.

[0116] In some embodiments, pharmaceutical compositions comprising at least one compound of structure (I) are illustratively in the form of a liquid in which the drug is present in solution, suspension, or both. Typically, when the composition is administered as a solution or suspension, a first portion of the drug is present in solution, and a second portion of the drug is present in particulate form and suspended in a liquid matrix. In some embodiments, the liquid composition comprises a gel formulation. In other embodiments, the liquid composition is aqueous.

[0117] In certain embodiments, useful aqueous suspensions contain one or more polymers as suspending agents. Useful polymers include water-soluble polymers such as cellulose-based polymers, e.g., hydroxypropylmethylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers. Certain pharmaceutical compositions described herein contain a mucoadhesive polymer selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0118] Useful pharmaceutical compositions also optionally include a solubilizing agent to aid in the solubility of the compound of structure (I). The term "solubilizing agent" generally includes agents that cause the formation of a micellar or true solution of the drug. Certain acceptable nonionic surfactants, such as polysorbate 80, are useful as solubilizing agents, as are ophthalmically acceptable glycols, polyglycols, such as polyethylene glycol 400, and glycol ethers.

[0119] In addition, useful compositions optionally contain one or more pH adjusters or buffers, such as acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and trishydroxymethylaminomethane; and buffers such as citric acid / dextrose, sodium bicarbonate, and ammonium chloride. The acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition within an acceptable range.

[0120] In addition, useful compositions also optionally contain one or more salts in an amount necessary to make the composition tolerable in osmolality. Such salts include those having sodium, potassium, or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium sulfate, sodium bisulfite, and ammonium sulfate.

[0121] Other useful pharmaceutical compositions optionally contain one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances, such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds, such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

[0122] Still other useful compositions contain one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkylphenyl ethers, such as Octoxynol 10 and Octoxynol 40.

[0123] Still other useful compositions optionally include one or more antioxidants to enhance chemical stability. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

[0124] In certain embodiments, aqueous suspension compositions are packaged in single-dose non-reopenable containers. Alternatively, multi-dose reusable containers are used, in which case it is common to include a preservative in the composition.

[0125] In other embodiments, other delivery systems for hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are exemplary delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also used. In additional embodiments, the compounds of structure (I) are delivered using sustained-release systems, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials are useful herein. In some embodiments, sustained-release capsules release the compound over a period of several weeks to over 100 days. Depending on the chemical nature and biological stability of the therapeutic agent, additional strategies for protein stabilization are employed.

[0126] In certain embodiments, the formulations described herein include one or more antioxidants, metal chelators, thiol-containing compounds, and / or other general stabilizing agents. Examples of such stabilizers include, but are not limited to, (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrin, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

[0127] In certain embodiments, the concentration of the compound of structure (I) provided in the pharmaceutical composition is 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.08%, 0.09%, 0.10 ... less than 6%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% (w / w, w / v or v / v).

[0128] In certain embodiments, the concentration of the compound of structure (I) provided in the pharmaceutical composition is 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 1 5.25%, 15%, 14.75%, 14.50%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25%, 8%, 7.75%, 7.5 0%,7.25%,7%,6.75%,6.50%,6.25%,6%,5.75%,5.50%,5.25%,5%,4.75%,4.50%,4.25%,4%,3.75%,3.50%,3.25%,3%,2.75%,2.50%,2.25%,2%,1.75%,1.50%,125%,1%,0.5%,0.4%,0.3%,0.2%,0.1%,0.09%,0.08%,0.07%,0.06%, More than 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% (w / w, w / v or v / v).

[0129] In certain embodiments, the concentration of the compound of structure (I) provided in the pharmaceutical composition is from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 25%, from about 0.07% to about 24%, from about 0.08% to about 26%, from about 0.09% to about 28%, from about 0.10% to about 10%, from about 0.11% to about 11%, from about 0.12% to about 12%, from about 0.13% to about 13%, from about 0.14% to about 14%, from about 0.15% to about 15%, from about 0.16% to about 16%, from about 0.17% to about 17%, from about 0.18% to about 18%, from about 0.19% to about 19%, from about 0.20% to about 20%, from about 0.21% to about 21%, from about 0.22% to about 22%, from about 0.23% to about 23%, from about 0.24% to about 24%, from about 0.25% to about 25%, from about 0.26% to about 26%, from about 0.27% to about 27%, from about 0.28% to about 28%, from about 0.29% to about 29%, from about 0.30% to about 30%, from about 0.31% to about 30%, from about 0.32% to about 32%, from about 0.33% to about 3 The range is from about 0.08% to about 23%, from about 0.09% to about 22%, from about 0.1% to about 21%, from about 0.2% to about 20%, from about 0.3% to about 19%, from about 0.4% to about 18%, from about 0.5% to about 17%, from about 0.6% to about 16%, from about 0.7% to about 15%, from about 0.8% to about 14%, from about 0.9% to about 12%, or from about 1% to about 10% (w / w, w / v, or v / v).

[0130] In certain embodiments, the concentration of the compound of structure (I) provided in the pharmaceutical composition ranges from about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, or about 0.1% to about 0.9% (w / w, w / v, or v / v).

[0131] In certain embodiments, the amount of the compound of structure (I) provided in the pharmaceutical composition is 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0. and is equal to or less than 2g, 0.15g, 0.1g, 0.09g, 0.08g, 0.07g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g or 0.0001g.

[0132] In certain embodiments, the amount of the compound of structure (I) provided in the pharmaceutical composition is 0.0001g, 0.0002g, 0.0003g, 0.0004g, 0.0005g, 0.0006g, 0.0007g, 0.0008g, 0.0009g, 0.001g, 0.0015g, 0.002g, 0.00 025g, 0.003g, 0.0035g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0. 007g, 0.0075g, 0.008g, 0.0085g, 0.009g, 0.0095g, 0.01g, 0.015g, 0.02g, 0.025g , 0.03g, 0.035g, 0.04g, 0.045g, 0.05g, 0.055g, 0.06g, 0.065g, 0.07g, 0.075g, 0 .08g, 0.085g, 0.09g, 0.095g, 0.1g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35g, 0.4g, 0.45g , 0.5g, 0.55g, 0.6g, 0.65g, 0.7g, 0.75g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1.5g, 2g, 2.5, 3g, 3.5, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g or 10g.

[0133] In certain embodiments, the amount of the compound of structure (I) provided in the pharmaceutical composition ranges from 0.0001 to 10 g, 0.0005 to 9 g, 0.001 to 8 g, 0.005 to 7 g, 0.01 to 6 g, 0.05 to 5 g, 0.1 to 4 g, 0.5 to 4 g, or 1 to 3 g.

[0134] Kits / Products Kits and articles of manufacture are also provided for use in the therapeutic applications described herein. In certain embodiments, such kits have separate compartments for containing one or more containers, such as vials, tubes, etc. was The container includes a carrier, a package or a container, and each container (or containers) contains one of the separate elements used in the method described herein.Suitable containers include, for example, bottles, vials, syringes and test tubes.Containers are made of various materials, such as glass or plastic.

[0135] The products provided herein include packaging materials. Packaging materials for use in packaging pharmaceutical products include, for example, those described in U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for the selected formulation and intended mode of administration and treatment. For example, the container(s) optionally contain one or more compounds of structure (I), in a composition as disclosed herein or in combination with another drug. The container(s) optionally have a sterile access port (e.g., the container is an intravenous solution bag or a vial with a stopper pierceable by a hypodermic injection needle). Such kits optionally include an identifying description or a label or instructions for its use in the methods described herein. along with Contains compounds.

[0136] For example, a kit typically includes one or more additional containers each containing one or more of the various materials (e.g., reagents, optionally in concentrated form and / or equipment) desirable from a commercial and user standpoint for using the compound of structure (I). Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes, carriers, packages, containers, vial and / or tube labels describing the contents and / or instructions for use, and package inserts describing the instructions for use. A set of instructions is also typically included. A label is optionally on or associated with a container. For example, a label is on a container when letters, numbers, or other characters forming the label are attached, molded, or etched into the container itself, and a label is associated with a container when present within a container or carrier that also holds the container, e.g., as a package insert. Additionally, a label is used to indicate that the contents are to be used for a particular therapeutic application. Furthermore, the label indicates directions for using the contents, such as the methods described herein. In certain embodiments, the pharmaceutical compositions are present in a pack or dispenser device containing one or more unit dosage forms comprising a compound provided herein. The pack may, for example, comprise metal or plastic foil, such as a blister pack. Alternatively, the pack or dispenser device may be accompanied by instructions for administration. Alternatively, the pack or dispenser may bear a notice associated with the container in a format prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, indicating approval by the agency of the drug form for human or veterinary administration. Such notice may, for example, be labeling approved by the U.S. Food and Drug Administration (FDA) for prescription drugs or an approved product insert. In some embodiments, compositions comprising a compound provided herein in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0137] Treatment and Administration Methods Embodiments of the present disclosure provide a method of treating a disease associated with impaired ENPP1 activity in a mammal, comprising administering to the mammal an effective amount of a disclosed compound, or a pharmaceutically acceptable salt, tautomer, isomer, hydrate, solvate, polymorph thereof, or a pharmaceutical composition derived therefrom.

[0138] In another embodiment, there is provided a method for inhibiting ENPP1 activity in a mammal, comprising administering to the mammal an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt, tautomer, isomer, hydrate, solvate, polymorph thereof, or a pharmaceutical composition derived therefrom, to the mammal.

[0139] In another embodiment, a method for inhibiting ENPP1 activity in at least one cell comprises administering to the at least one cell , small with an effective amount of at least one compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, isomer, hydrate, solvate, polymorph thereof, or a pharmaceutical composition derived therefrom.

[0140] Also provided is a method for treating a disease associated with impaired ENPP1 activity in a mammal by inducing an immunotherapeutic response in the mammal, comprising administering to the mammal an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, isomer, hydrate, solvate, polymorph thereof, or a pharmaceutical composition derived therefrom, wherein the administration elicits an immunotherapeutic response beneficial for the treatment of a disease associated with ENPP1 activity, such as, but not limited to, any type of cancer in which ENPP1 activity is implicated, or any disease caused by bacteria and / or viruses.

[0141] Published data indicate that inhibition or deletion of ENPP1 reduces bacterial or viral pathogenicity. Furthermore, there is some evidence that bacterial or viral infection reduces IFN-β and NF-κB, particularly in cells with high ENPP1 expression. Inhibition or deletion of ENPP1 can reduce bacterial or viral pathogenicity. Furthermore, bacterial or viral infection reduces IFN-β and NF-κB, particularly in cells with high ENPP1 expression. Investigation of the molecular mechanism of ENPP1 during viral or bacterial infection revealed that ENPP1 is involved in cGAMP hydrolysis in infected or transfected cells, which inhibits IRF3 phosphorylation and reduces IFN-β secretion. These results further support the hypothesis that ENPP1, in combination with human cGAS, acts through cGAS to maintain cGAMP levels and contribute to viral or bacterial infection. Many more embodiments include pharmaceutical compositions comprising a pharmaceutically acceptable carrier and an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, isomer, hydrate, solvate, or polymorph thereof.

[0142] Also disclosed are kits that include at least one compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, isomer, hydrate, solvate, or polymorph thereof.

[0143] Also disclosed is a method for producing a medicament, comprising combining at least one compound of the present disclosure or at least one product of the present disclosure with a pharmaceutically acceptable carrier or diluent.In another embodiment, the present disclosure relates to the use of a compound of the present disclosure in the manufacture of a medicament for treating a disease associated with ENPP1 activity dysfunction.In another embodiment, the present disclosure relates to the use of a compound of the present disclosure in the manufacture of a medicament for treating a disease of uncontrolled cell proliferation.

[0144] Also disclosed is the use of a compound of the present disclosure or a product of the present disclosure in the manufacture of a medicament for the treatment of a disease associated with ENPP1 dysfunction in a mammal.

[0145] The present disclosure also provides a method for treating a disease of uncontrolled cell proliferation in a mammal, the method comprising administering to the mammal an effective amount of any of the compounds of the present disclosure.

[0146] The present disclosure also provides a method for reducing ENPP1 activity in a mammal, the method comprising administering to the mammal an effective amount of any of the compounds of the present disclosure.

[0147] The present invention also provides a method for inhibiting ENPP1 activity in a mammal, the method comprising administering to the mammal an effective amount of any of the compounds of the present disclosure.

[0148] For therapeutic conditions requiring inhibition or negative modulation of ENPP1 protein activity, appropriate dosage levels are typically about 0.01 to 500 mg / kg of patient body weight per day, and can be administered in single or multiple doses. Preferably, dosage levels are about 0.1 to about 250 mg / kg per day; more preferably, 0.5 to 100 mg / kg per day. Suitable dosage levels can be about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0.1 to 50 mg / kg per day. Within this range, dosages can be 0.05 to 0.5, 0.5 to 5.0, or 5.0 to 50 mg / kg per day. For oral administration, the composition is preferably provided in the form of a tablet containing 1.0 to 1000 mg of active ingredient, particularly 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 mg of active ingredient, for dosage-related symptomatic control in the patient being treated. The compound may be administered on a dosage regimen of 1 to 4 times per day, preferably once or twice per day. This dosage regimen can be adjusted to provide the optimal therapeutic response.

[0149] However, it will be understood that the specific dose level for a particular patient will depend on a variety of factors, including the patient's age, weight, general health, sex, and diet, as well as the time and route of administration, rate of excretion, concomitant medications, and the type and severity of the particular disease being treated.

[0150] The present disclosure further relates to a method for manufacturing a medicament for inhibiting or negatively modulating ENPP1 protein activity in a mammal (e.g., a human) (e.g., treating a disorder of uncontrolled cell proliferation, or one or more neurodegenerative disorders associated with ENPP1 dysfunction), comprising combining one or more compounds, products, or compositions of the present disclosure with a pharmaceutically acceptable carrier or diluent. Accordingly, in one aspect, the present invention relates to a method for manufacturing a medicament, comprising combining at least one compound of the present disclosure or at least one product of the present disclosure with a pharmaceutically acceptable carrier or diluent.

[0151] The compounds of the present disclosure are useful for treating, preventing, ameliorating, managing, or reducing the risk of a variety of disorders in which a patient or subject would benefit from the inhibition or negative regulation of ENPP1. In certain embodiments, methods are provided for treating or preventing a disorder in a subject, comprising administering to the subject at least one compound of the present disclosure; at least one pharmaceutical composition of the present disclosure; and / or at least one disclosed product, in a dose and amount effective to treat the disorder in the subject.

[0152] Also provided are methods for treating one or more disorders in a subject in which ENPP1 inhibition is expected to be effective, the methods comprising administering to the subject at least one compound of the present disclosure; at least one pharmaceutical composition of the present disclosure; and / or at least one disclosed product, in a dose and amount effective to treat the disorder in the subject.

[0153] In another embodiment, a method for treating a disorder of uncontrolled cell proliferation is provided, comprising administering to a subject at least one compound of the present disclosure; at least one pharmaceutical composition of the present disclosure; and / or at least one product of the present disclosure, in a dose and amount effective to treat the disorder in the subject. In a further aspect, a method for treating or preventing a neurodegenerative disorder is provided, comprising administering to a subject at least one compound of the present disclosure; at least one pharmaceutical composition of the present disclosure; and / or at least one product of the present disclosure, in a dose and amount effective to treat the disorder in the subject. Also provided is a method for treating a disorder in a mammal, comprising administering to the mammal at least one compound, composition, or medicament of the present disclosure.

[0154] The present disclosure relates to the use of the aforementioned chemical compositions for treating diseases or disorders in which ENPP1 inhibition is expected to have a therapeutic effect, such as disorders of uncontrolled cell proliferation (e.g., cancer) and neurodegenerative disorders, such as Alzheimer's disease, Huntington's disease, and Parkinson's disease, and diseases caused by bacteria and / or viruses, in a patient (preferably a human) by administering one or more compounds or products of the present disclosure.

[0155] The compounds of the present disclosure can also be used in immunotherapy.

[0156] In certain embodiments, the compounds of the present disclosure treat disorders of uncontrolled cell proliferation and / or diseases caused by bacteria and / or viruses by immunotherapy, meaning that the compounds elicit an immunotherapeutic response that results in the treatment of these diseases.

[0157] The compounds disclosed herein are useful for treating, preventing, ameliorating, managing or reducing the risk of a variety of disorders of uncontrolled cell proliferation.

[0158] Methods of using the compounds, compositions, or medicaments of the present disclosure are also provided. In one embodiment, the methods of use relate to the treatment of disorders. In a further embodiment, the compounds of the present disclosure can be used as a single agent or in combination with one or more other agents (where the combination of agents is safer or more effective than either agent alone) to treat, prevent, manage, ameliorate, or reduce the risk of the diseases, disorders, and conditions described above for which the compounds or other agents are useful. The other agents can be administered simultaneously with the compounds of the present disclosure, or sequentially, by a route and in an amount commonly used for that agent. When a compound of the present disclosure is used concurrently with one or more other agents, a pharmaceutical composition in unit dosage form containing such agents and a compound of the present disclosure is preferred. However, the combination therapy can also be administered on an overlapping schedule. It is also contemplated that the combination of one or more active ingredients and a compound of the present disclosure may be more effective than either as a single agent.

[0159] Exemplary disorders that can be treated using the provided compounds include disorders of uncontrolled cell proliferation. In embodiments, the disorder of uncontrolled cell proliferation is cancer. In a particular aspect, the cancer is leukemia. In another particular aspect, the cancer is sarcoma. In yet another aspect, the cancer is a solid tumor. In yet another aspect, the cancer is lymphoma.

[0160] It is understood that cancer generally refers to or describes a physiological state in mammals characterized by uncontrolled cell proliferation.Cancer can be multidrug resistant (MDR) or drug sensitive.Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia.More specific examples of cancer include breast cancer, prostate cancer, colon cancer, squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, pancreatic cancer, cervical cancer, ovarian cancer, peritoneal cancer, liver cancer (e.g., liver cancer), bladder cancer, colorectal cancer, endometrial cancer, kidney cancer, and thyroid cancer.

[0161] In various embodiments, further examples of cancer are basal cell carcinoma, biliary tract cancer; bone cancer; brain and CNS cancer; choriocarcinoma; connective tissue cancer; esophageal cancer; eye cancer; head and neck cancer; gastric cancer; intraepithelial neoplasia; laryngeal cancer; lymphomas such as Hodgkin's and non-Hodgkin's lymphoma; melanoma; myeloma; neuroblastoma; oral cancer (e.g., lip, tongue, mouth, and pharynx); retinoblastoma; rhabdomyosarcoma; rectal cancer; cancer of the respiratory system; sarcoma; skin cancer; stomach cancer; testicular cancer; uterine cancer; cancer of the urinary system, and other cancers and sarcomas.

[0162] In another embodiment, the cancer is a blood cancer. In yet another aspect, the blood cancer is selected from acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, solitary myeloma, localized myeloma, and extramedullary myeloma. In yet another aspect, the cancer is selected from chronic lymphocytic leukemia, small lymphocytic lymphoma, B-cell non-Hodgkin's lymphoma, and large B-cell lymphoma.

[0163] In another embodiment, the cancer is brain cancer.In a particular aspect, brain cancer is selected from glioma, medulloblastoma, primitive neuroectodermal tumor (PNET), acoustic neuroma, glioma, meningioma, pituitary adenoma, schwannoma, CNS lymphoma, primitive neuroectodermal tumor, craniopharyngioma, chordoma, medulloblastoma, cerebral neuroblastoma, central neurocytoma, pineocytoma, pineoblastoma, atypical teratoid rhabdoid tumor, chondrosarcoma, chondroma, choroid plexus carcinoma, choroid plexus papilloma, craniopharyngioma, dysembryoplastic neuroepithelial tumor, gangliocytoma, germinoma, hemangioblastoma, hemangiopericytoma and metastatic brain tumor.In yet another aspect, glioma is selected from ependymoma, astrocytoma, oligodendroglioma and oligoastrocytoma. In yet another embodiment, the glioma is selected from juvenile pilocytic astrocytoma, subependymal giant cell astrocytoma, ganglioglioma, subependymoma, pleomorphic xanthoastrocytoma, anaplastic astrocytoma, glioblastoma multiforme, brain stem glioma, oligodendroglioma, ependymoma, oligoastrocytoma, cerebellar astrocytoma, desmoplastic infantile astrocytoma, subependymal giant cell astrocytoma, diffuse astrocytoma, mixed glioma, optic glioma, gliomatosis cerebri, multiple glioma tumors, multicentric glioblastoma multiforme tumor, paraganglioma, and ganglioneuroblastoma.

[0164] In certain embodiments, the cancer may be selected from cancer of the blood, brain, urinary tract, digestive tract, colon, rectum, breast, kidney, lymphatic system, stomach, lung, pancreas, and skin. In further embodiments, the cancer is selected from prostate cancer, glioblastoma multiforme, endometrial cancer, breast cancer, and colorectal cancer. In another embodiment, the cancer is selected from cancer of the breast, ovary, prostate, head, neck, and kidney. In yet another aspect, the cancer is selected from cancer of the blood, brain, urinary tract, digestive tract, colon, rectum, breast, liver, kidney, lymphatic system, stomach, lung, pancreas, and skin. In another aspect, the cancer is selected from cancer of the lung and liver. In yet another aspect, the cancer is selected from cancer of the breast, ovary, testicle, and prostate.

[0165] In other embodiments, the disorder associated with ENPP1 dysfunction is a neurodegenerative disease, hi another embodiment, the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, and Huntington's disease.

[0166] The compounds are further useful in a method for the prevention, treatment, management, amelioration, or reduction of risk of the diseases, disorders, and conditions described herein. The compounds are further useful in a method for the prevention, treatment, management, amelioration, or reduction of risk of the diseases, disorders, and conditions in combination with other agents.

[0167] The present disclosure further relates to the administration of ENPP1 inhibitors to improve therapeutic outcomes in the context of uncontrolled cell proliferation disorders, such as cancer, i.e., in certain embodiments, the present disclosure relates to combination therapies comprising administering to a mammal an effective amount and dose of at least one compound of the present disclosure in combination with a cancer therapy.

[0168] In a further embodiment, administration improves therapeutic results in the context of cancer therapy.Administration in the context of cancer therapy can be continuous or intermittent.Administration does not need to be simultaneous with therapy, but can be performed before, during and / or after therapy.For example, cancer therapy can be provided within 1, 2, 3, 4, 5, 6, or 7 days before or after the administration of the compound.As a further example, cancer therapy can be provided within 1, 2, 3, or 4 weeks before or after the administration of the compound.As yet another example, cognitive therapy or behavioral therapy can be provided before or after administration within 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 half-lives of the compound that is administered.

[0169] In certain embodiments, the compounds of the present disclosure can be used in combination with one or more other drugs to treat, prevent, manage, ameliorate, or reduce the risk of a disease or condition for which the compounds of the present disclosure or other drugs may be useful, and the combination of drugs is safer and more effective than either drug alone. The other drugs can be administered simultaneously or sequentially with the compounds of the present disclosure, by a route and in an amount commonly used. When the compounds of the present disclosure are used simultaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing the other drugs and the compounds of the present disclosure is preferred. However, combination therapy can also include therapy in which the compounds of the present disclosure and one or more other drugs are administered on different overlapping schedules. It is also contemplated that the compounds of the present disclosure and other active ingredients can be used in combination with one or more other active ingredients at lower doses than when each is used alone.

[0170] Accordingly, the pharmaceutical compositions include those that contain one or more other active ingredients, in addition to a compound of the present disclosure.

[0171] The above combinations include combinations of the compounds of the present disclosure with not only one other active compound, but also two or more other active compounds. Similarly, the compounds of the present disclosure can be used in combination with other drugs used in the prevention, treatment, management, amelioration, or reduction of risk of diseases or conditions for which the compounds of the present disclosure are useful. The other drugs can be administered simultaneously with or sequentially to the compounds of the present disclosure, by a route and in an amount commonly used for such drugs. When the compounds of the present invention are used simultaneously with one or more other drugs, a pharmaceutical composition containing the other drugs in addition to the compounds of the present disclosure is preferred. Thus, such pharmaceutical compositions include compositions containing one or more other active ingredients in addition to the compounds of the present disclosure.

[0172] The weight ratio of the compound of the present disclosure to the second active ingredient can vary and depends on the effective dose of each ingredient. Generally, an effective dose of each is used. Thus, for example, when the compound of the present disclosure is combined with another drug, the weight ratio of the compound of the present disclosure to the other drug is typically about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of the compound of the present disclosure and the other active ingredient are also included in the above ranges, but in each case, an effective dose of each active ingredient should be used.

[0173] In such combinations, the compounds of the present disclosure and the other active agents may be administered separately or together. Furthermore, the administration of one element may be prior to, concurrent with, or subsequent to the administration of the other agent.

[0174] Thus, the compounds can be used alone or in combination with other agents known to be useful in the subject indication or that affect receptors or enzymes to enhance the efficacy, safety, or convenience of the compounds of the present disclosure, or to reduce unwanted side effects or toxicity. The compounds and other agents can be co-administered in combination therapy or in a fixed combination.

[0175] In certain embodiments, the compounds may be used in combination with anti-cancer therapeutic agents or other known therapeutic agents.

[0176] In the treatment of conditions requiring inhibition or negative regulation of ENPP1, appropriate dosage levels are typically about 0.01 to 1000 mg / kg of patient body weight per day, which can be administered in single or multiple doses. Preferably, the dosage level is about 0.1 to about 250 mg / kg per day; more preferably, about 0.5 to about 100 mg / kg per day. Suitable dosage levels can be about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0.1 to 50 mg / kg per day. Within this range, the dosage can be 0.05 to 0.5, 0.5 to 5, or 5 to 50 mg / kg per day. For oral administration, the composition is preferably provided in tablet form containing 1.0 to 1000 milligrams of active ingredient, particularly 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams, for symptomatic adjustment of dosage to the patient being treated. The compound may be administered one to four times daily, preferably once or twice daily. This dosing regimen can be adjusted to provide the optimal therapeutic response. However, it will be understood that the specific dose level and frequency for a particular patient may vary and will depend on a variety of factors, such as the activity of the specific compound used, the metabolic stability and length of action of the compound, age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, co-administered medications, the severity of the particular condition, and the host being treated.

[0177] Thus, in certain embodiments, the present disclosure relates to a method of inhibiting or negatively modulating ENPP1 in at least one cell, comprising contacting the at least one cell with at least one compound of the present invention in an amount effective to, e.g., modulate or activate, an ENPP1 activity response in the at least one cell. In a further embodiment, the cell is mammalian, e.g., human. In a further embodiment, the cell is isolated from a subject prior to the contacting step. In another embodiment, the contacting is by administration to a subject.

[0178] Manufacturing method The compound of structure (I) can be prepared according to methods known in the art and disclosed herein. Generally, starting materials can be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI and Fluorochem USA, or can be synthesized according to sources well known to those skilled in the art (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)).

[0179] General Reaction Scheme 1 [ka] General Reaction Scheme 1 provides an example of a method for preparing compounds of structure (I). 1 , R 2a , R 2b , R 2c , R 2d , R 2e and n are as defined herein. X and Y are reactive groups (e.g., Br, Cl, OTf) selected to facilitate the desired reaction. PR 1 is R 1 This represents the form of protection. 1 The particular nature of may be selected (or, if necessary, modified) based on compatibility with other synthetic steps (e.g., the conditions required to couple A3 and A4 to form A5; or, if necessary, the steps required to prepare A4) in view of the overall reaction scheme. In other examples, PR 1 is the final stage of R 1 In yet another example, for some compounds of structure (I), PR1 is the group A5 (e.g., -C(=O)R 1a ) can withstand the reaction conditions to form R 1 Compounds of structures A1, A2, and A4 can be purchased or prepared according to methods known in the art; or as described herein. Reaction of A1 and A2 under appropriate conditions (e.g., using a base; or using a base in combination with heat) provides the coupling reaction product A3. Further reaction of A3 with an appropriate nucleophile A4 (e.g., L is -S- or -NH-) provides the coupling product A5. Of note, PR 1 is R as defined herein 1 A5 is also a compound of structure (I) when it is an acceptable group for PR. The conversion of A5 to a compound of structure (I) can be in a single step or multiple steps. For example, PR 1 is an ester functional group, R 1 to a compound of structure (I) in which is a carboxylic acid (e.g., with aqueous LiOH). Alternatively, for example, PR 1 is an ester functional group, R 1 In the conversion to compounds of structure (I) where is a cyano group, PR 1 is first converted to an amide (eg, using aqueous NH3 and heat) and then converted to a cyano group (eg, using Burgess reagent).

[0180] In one embodiment, a compound of structure (I) wherein L is -S- and R 1 is —COH) is represented by the following structure: [ka] (In the formula, R 2a , R 2b , R 2c , R 2d , R 2eand n is as described herein. Synthesis of compounds as provided herein is accomplished according to General Reaction Scheme 1, with more specific details provided below and the following examples: [ka]

[0181] General Method for Formation of Bromoacetates: To a stirred solution of amine A1 (1 eq) in dichloromethane (10 vol), a base (1.5 eq; e.g., K2CO3 or Et3N) and 2-bromoacetyl chloride (1.3 eq) are added, and the reaction solution is stirred at room temperature for 3 h. After completion of the reaction, the organic solvent is removed under reduced pressure to give the crude product. Water is added to the crude residue and stirred for 15 min. The resulting precipitate is collected by filtration to give 2-bromoacetamide A3-Br. [ka]

[0182] General Method for Sulfur Coupling Reactions: To a stirred solution of ethyl 2-mercapto-imidazole-4-carboxylate (1 equiv.) in acetonitrile (10 mL) at room temperature, triethylamine (2.5 equiv.) and 2-bromoacetamide A3-Br (1 equiv.) were added, and the reaction mixture was stirred at 80 °C for 1 h. The reaction progress was monitored by TLC. After completion of the reaction, the organic solvent was removed under reduced pressure, water was added to the crude residue, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with brine (200 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude material was purified by Combiflash chromatography, eluting with 50% to 80% ethyl acetate / petroleum ether to give the ethyl carboxylate A5-Et. [ka]

[0183] General Method for Ester Hydrolysis: To a stirred solution of ethyl carboxylate A5-Et (1 equivalent) in tetrahydrofuran (10 vol) and water (2 vol) was added lithium hydroxide monohydrate (4 equivalents) at 0°C and the reaction was allowed to proceed at 70°C for 16 hours. After completion of the reaction, the organic solvent was removed under reduced pressure, and water (20 mL) and 30% aqueous citric acid (10 mL) were added. The resulting mixture was extracted with 10% methanol / dichloromethane (50 mL), and the organic phase was concentrated under reduced pressure to obtain the crude product. This product was purified by preparative HPLC to obtain the pure carboxylic acid compound of structure (I).

[0184] It should be noted that various alternative strategies for preparing compounds of structure (I) are available to those skilled in the art. For example, other compounds of structure (I) can be prepared according to similar methods using appropriate starting materials. It will also be understood by those skilled in the art that in the process for preparing compounds of structure (I), functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include, but are not limited to, hydroxy, amino, mercapto, and carboxylic acid.

[0185] Suitable protecting groups for hydroxy include, but are not limited to, trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino, and guanidino include t-butoxycarbonyl ("Boc"), benzyloxycarbonyl, and the like. Protecting groups are added or removed, as appropriate, according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Green, TW and PGM Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. As will be appreciated by those skilled in the art, the protecting group may be a polymeric resin such as a Wang resin, a Rink resin, or a 2-chlorotrityl chloride resin.

[0186] It will also be understood by those skilled in the art that such protected derivatives of the compounds of the present invention may not have pharmacological activity themselves, but may be metabolized in the body after administration to a mammal to form a pharmacologically active compound of the present disclosure. Such derivatives may therefore be described as "prodrugs." Prodrugs of the compounds of the present disclosure are included within the scope of embodiments of the present invention.

[0187] The examples and preparations provided below further illustrate compounds of structure (I) and methods for preparing such compounds. It is understood that the scope of the present disclosure is not limited in any way by the scope of the following examples and preparations. In the following examples and throughout the specification and claims, molecules with one stereocenter exist as a racemic mixture unless otherwise specified. Molecules with two or more stereocenters exist as a racemic mixture of diastereomers unless otherwise specified. Single enantiomers / diastereomers can be obtained by methods known to those skilled in the art. [Example]

[0188] Example The following examples are provided for illustrative purposes. Other compounds of structure (I) illustrated in Table 1 were prepared according to analogous methods conventional in the art. For example, the following General Reaction Scheme I, which leads to compounds of structure (I), was generally used unless otherwise indicated.

[0189] Example 1 Synthesis of ethyl 2-mercaptoimidazole-4-carboxylate [ka] Synthesis of ethyl N-acetylglycinate: To a stirred solution of ethyl glycinate hydrochloride (50 g, 358.54 mmol) in dichloromethane (500 mL) at 0 °C, EtN (90 g, 896.05 mmol) was added, followed by dropwise addition of acetyl chloride (33.7 g, 430.1 mmol). After the addition, the reaction solution was stirred at ambient temperature for 3 hours. After completion of the reaction, water (500 mL) was added, and the mixture was extracted twice with DCM. The combined organic layers were washed with brine (500 mL), dried over sodium sulfate, and concentrated under reduced pressure to give ethyl N-acetylglycinate (31 g, 59% yield) as a pale yellow liquid. 1 H NMR: (400 MHz, DMSO) δ 8.26(brs, 1H), 4.07(q, 2H), 3.78(d, 2H), 1.84(s, 3H), 1.17(t, 3H).

[0190] Synthesis of ethyl 2-mercapto-1H-imidazole-4-carboxylate: To a stirred solution of sodium ethoxide (21.8 g, 320.7 mmol) in toluene (90 mL) was added ethyl formate (50 mL, 641.37 mmol) at 0°C. The mixture was cooled to -10°C, and a solution of ethyl acetylglycinate (31 g, 213.8 mmol) in toluene (30 mL) was added over 30 minutes. The reaction mixture was stirred at room temperature overnight. The reaction mixture was extracted with water (3 x 50 mL). The combined aqueous phase was cooled to 0°C, and potassium thiocyanate (31.1 g, 320.7 mmol) and concentrated HCl (80 mL) were slowly added. The reaction mixture was heated to 55°C for 2 hours, and the progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was extracted with ethyl acetate (2 x 150 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude material was purified by 100-200 mesh silica gel column chromatography eluting with 5% methanol / dichloromethane to give ethyl 2-mercapto-1H-imidazole-4-carboxylate (15 g, 87.209 mmol, 41% yield) as a brown solid. 1H NMR:(400 MHz, DMSO) δ 12.75(s, 1H), 12.54(s, 1H), 7.623-7.628(d, 1H), 4.17-4.23(q, 2H), 1.221-1.257(t, 3H). LCMS: (M+H + ): m / Z: 173.1.

[0191] Example 2 Synthesis of 2-mercapto-1H-imidazole-4-carboxylic acid [ka] To a stirred solution of ethyl 2-mercapto-1H-imidazole-4-carboxylate (200 mg, 1.163 mmol) in dioxane (5 mL) and water (2 mL) was added sodium hydroxide (93 mg, 2.325 mmol) at ambient temperature, and the reaction mixture was heated to 70° C. and stirred for 1 hour. After completion of the reaction, the organic solvent was removed under reduced pressure, and water (20 mL) and 30% aqueous citric acid (10 mL) were added. The resulting mixture was extracted with 10% methanol / dichloromethane (50 mL), and the organic phase was concentrated under reduced pressure to give 2-mercapto-1H-imidazole-4-carboxylic acid (150 mg, 1.034 mmol, 89% yield) as a light brown solid. 1 H NMR:(400 MHz, DMSO) δ 13.024(bs, 1H), 12.590(s, 1H), 12.457(s, 1H), 7.528(s, 1H). LCMS: (M+H + ): m / Z: 145.1.

[0192] Example 3 Synthesis of ethyl 2-mercaptooxazole-4-carboxylate [ka] To a stirred solution of ethyl 2-bromooxazole-4-carboxylate (200 mg, 0.909 mmol) in EtOH (4 mL) at RT, thiourea (103 mg, 1.36 mmol) was added, and the reaction mixture was stirred at reflux for 2 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to RT, and the formed precipitate was collected by filtration to give pure ethyl 2-mercaptooxazole-4-carboxylate (100 mg, 0.578 mmol, 63% yield) as a light brown solid. 1 H NMR: (400 MHz, DMSO) δ 14.0(brs, 1H), 8.47(s, 1H), 4.24-4.29(q, 2H), 1.25(t, 3H).

[0193] Example 4 Synthesis of 2-bromo-N-(3,4-dimethoxyphenyl)acetamide [ka] To a stirred solution of 3,4-dimethoxyaniline (2 g, 13.1 mmol) in dichloromethane (50 mL) were added potassium carbonate (2.7 g, 19.6 mmol) and 2-bromoacetyl chloride (2.66 g, 17.0 mmol), and the reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, water (100 mL) was added, and the mixture was stirred for 15 minutes. The precipitate that formed was collected by filtration to give 2-bromo-N-(3,4-dimethoxyphenyl)acetamide (3.4 g, 12.5 mmol, 95% yield) as a brown solid. 1 H NMR: (400 MHz, DMSO) δ 10.23(s, 1H), 7.25(s, 1H), 7.19-7.18(m, 1H), 6.89(d, 1H), 3.99(s, 2H), 3.71-3.70(m, 6H). LCMS: (M+H + ): m / Z: 274.0.

[0194] Example 5 Synthesis of 2-bromo-N-(3-bromobenzyl)acetamide [ka] The synthesis of 2-bromo-N-(3-bromobenzyl)acetamide was carried out according to the general method described above and is exemplified in Example 4 for 2-bromo-N-(3,4-dimethoxyphenyl)acetamide, but using (3-bromophenyl)methanamine instead of 3,4-dimethoxyaniline. 1 H NMR: (400 MHz, DMSO) δ 8.818(bs, 1H), 7.433-7.452(d, 2H) 7.245-7.7.310(m, 2H), 4.276-4.291(d, 2H), 3.910(s, 2H).

[0195] Example 6 Synthesis of 2-bromo-N-(4-morpholinophenyl)acetamide [ka] The synthesis of 2-bromo-N-(4-morpholinophenyl)acetamide was carried out according to the general method described above and is exemplified in Example 4 for 2-bromo-N-(3,4-dimethoxyphenyl)acetamide, but using 4-morpholinoaniline instead of 3,4-dimethoxyaniline. 1 H NMR: (400 MHz, DMSO) δ 10.17(s, 1H), 7.405-7.443(d, 2H), 6.887-6.936(d, 1H) 3.701-3.725(t, 2H), 3.024-3.048(t, 2H).

[0196] Example 7 Synthesis of 2-bromo-N-(3-chlorobenzyl)acetamide [ka] The synthesis of 2-bromo-N-(3-chlorobenzyl)acetamide was carried out according to the general method described above and is exemplified in Example 4 for 2-bromo-N-(3,4-dimethoxyphenyl)acetamide, but using (3-chlorophenyl)methanamine instead of 3,4-dimethoxyaniline. 1 H NMR: (400 MHz, CDCl3) δ 7.279-7.292(d, 2H), 7.241-7.262(m, 2H) 7.169-7.188(m, 1H), 4.456-4.489(d, 2H), 3.949(s, 2H).

[0197] Example 8 Synthesis of 2-bromo-N-(4-chlorobenzyl)acetamide [ka] The synthesis of 2-bromo-N-(4-chlorobenzyl)acetamide was carried out according to the general method described above and is exemplified in Example 4 for 2-bromo-N-(3,4-dimethoxyphenyl)acetamide, but using (4-chlorophenyl)methanamine instead of 3,4-dimethoxyaniline. 1 H NMR: (400 MHz, CDCl3) δ 7.316-7.337(d, 2H), 7.218-7.262(t, 2H) 6.761(bs, 1H), 4.443-4.458(d, 2H), 3.937(s, 2H).

[0198] Example 9 Synthesis of 2-bromo-N-(2,3,4-trimethoxyphenyl)acetamide [ka] The synthesis of 2-bromo-N-(2,3,4-trimethoxyphenyl)acetamide was carried out according to the general method described above and is exemplified in Example 4 for 2-bromo-N-(3,4-dimethoxyphenyl)acetamide, but using 2,3,4-trimethoxyaniline instead of 3,4-dimethoxyaniline. 1 H NMR: (400 MHz, DMSO) δ 9.559(s, 1H), 7.559-7.582(d, 1H), 6.747-6.770(d, 1H) 4.142(d, 2H), 3.748(s, 3H), 3.765(s, 3H), 3.778(s, 3H).

[0199] Example 10 Synthesis of 2-bromo-N-(3,5-dimethoxyphenyl)acetamide [ka] The synthesis of 2-bromo-N-(3,5-dimethoxyphenyl)acetamide was carried out according to the general method described above and is exemplified in Example 4 for 2-bromo-N-(3,4-dimethoxyphenyl)acetamide, but using 3,5-dimethoxyaniline instead of 3,4-dimethoxyaniline. 1 H NMR: (400 MHz, DMSO) δ 10.319(d, 1H), 6.802-6.816(m, 2H), 6.237-6.248(t, 1H), 3.996(s, 2H), 3.688-3.717(s, 6H).

[0200] Example 11 Synthesis of 2-bromo-N-(3,4-dimethoxybenzyl)acetamide [ka] The synthesis of 2-bromo-N-(3,4-dimethoxybenzyl)acetamide was carried out according to the general method described above and is exemplified in Example 4 for 2-bromo-N-(3,4-dimethoxyphenyl)acetamide, but using (3,4-dimethoxyphenyl)methanamine instead of 3,4-dimethoxyaniline.

[0201] Example 12 Synthesis of 2-bromo-N-(4-methoxybenzyl)acetamide [ka] The synthesis of 2-bromo-N-(4-methoxybenzyl)acetamide was carried out according to the general method described above and is exemplified in Example 4 for 2-bromo-N-(3,4-dimethoxyphenyl)acetamide, but using (4-methoxyphenyl)methanamine instead of 3,4-dimethoxyaniline. 1 H NMR: (400 MHz, DMSO) δ 7.164-7.185(d, 2H), 6.867-6.889(d, 2H), 4.195-4.219(t, 2H), 3.716(s, 3H).

[0202] Example 13 Synthesis of 2-bromo-N-(3,4-dimethylphenyl)acetamide [ka] The synthesis of 2-bromo-N-(3,4-dimethylphenyl)acetamide was carried out according to the general method described above and is exemplified in Example 4 for 2-bromo-N-(3,4-dimethoxyphenyl)acetamide, but using 3,4-dimethylaniline instead of 3,4-dimethoxyaniline. 1H NMR: (400 MHz, DMSO) δ 10.196(s, 1H), 7.335(s, 1H), 7.274-7.294(dd, 1H), 7.049-7.069(d, 1H), 3.991(s, 2H), 2.155(s, 3H), 2.178(s, 3H).

[0203] Example 14 Synthesis of 2-bromo-N-(3-fluoro-4-methoxyphenyl)acetamide [ka] The synthesis of 2-bromo-N-(3-fluoro-4-methoxyphenyl)acetamide was carried out according to the general method described above and is exemplified in Example 4 for 2-bromo-N-(3,4-dimethoxyphenyl)acetamide, but using 3-fluoro-4-methoxyaniline instead of 3,4-dimethoxyaniline. 1 H NMR: (400 MHz, DMSO) δ 10.394(s, 1H), 7.526-7.564(dd, 1H), 7.226-7.278(t, 1H), 7.103-7.150(t, 1H), 3.996(s, 2H), 3.794(s, 3H).

[0204] Example 15 Synthesis of 2-bromo-N-(3-fluoro-2,4-dimethoxyphenyl)acetamide [ka] The synthesis of 2-bromo-N-(3-fluoro-2,4-dimethoxyphenyl)acetamide was carried out according to the general method described above and is exemplified in Example 4 for 2-bromo-N-(3,4-dimethoxyphenyl)acetamide, but using 3-fluoro-2,4-dimethoxyaniline instead of 3,4-dimethoxyaniline. 1H NMR: (400 MHz, DMSO) δ 10.398(s, 1H), 7.526-7.601(dt, 1H), 7.227-7.281(dt, 1H), 3.996(s, 2H), 3.794(s, 3H), 3.780(s, 3H).

[0205] Example 16 Synthesis of 2-bromo-N-(4-(4-methoxyphenoxy)phenyl)acetamide [ka] The synthesis of 2-bromo-N-(4-(4-methoxyphenoxy)phenyl)acetamide was carried out according to the general method described above and is exemplified in Example 4 for 2-bromo-N-(3,4-dimethoxyphenyl)acetamide, but using 4-(4-methoxyphenoxy)aniline instead of 3,4-dimethoxyaniline. 1 H NMR: (400 MHz, DMSO) δ 7.63(d, 1H), 7.52(d, 1H), 7.12(6.99-6.93(m, 4H), 6.90-6.87(m, 2H), 4.0(s, 1H), 3.95(s, 1H), 3.72(s, 3H).

[0206] Example 17 Synthesis of 2-bromo-N-(2,4-dimethoxybenzyl)acetamide [ka] The synthesis of 2-bromo-N-(2,4-dimethoxybenzyl)acetamide was carried out according to the general method described above and is exemplified in Example 4 for 2-bromo-N-(3,4-dimethoxyphenyl)acetamide, but using (2,4-dimethoxyphenyl)methanamine instead of 3,4-dimethoxyaniline. 1H NMR: (400 MHz, DMSO) δ 7.08(s, 1H), 6.61(d, 1H), 6.48(d, 1H), 4.15(t, 2H), 3.87(s, 2H), 3.80(s, 3H), 3.75(s, 3H).

[0207] Example 18 Synthesis of 2-bromo-N-(4-bromophenyl)acetamide [ka] The synthesis of 2-bromo-N-(4-bromophenyl)acetamide was carried out according to the general method described above and is exemplified in Example 4 for 2-bromo-N-(3,4-dimethoxyphenyl)acetamide, but using 4-bromoaniline instead of 3,4-dimethoxyaniline. 1 H NMR: (400 MHz, DMSO) δ 10.50(s, 1H), 7.52(m, 4H) 4.02(s, 2H). LCMS: (M+H) + : m / Z: 291.28.

[0208] Example 19 Synthesis of 2-bromo-N-(4-chlorophenyl)acetamide [ka] The synthesis of 2-bromo-N-(4-chlorophenyl)acetamide was carried out according to the general method described above and is exemplified in Example 4 for 2-bromo-N-(3,4-dimethoxyphenyl)acetamide, but using 4-chloroaniline instead of 3,4-dimethoxyaniline. 1 H NMR: (400 MHz, DMSO) δ 10.50(s, 1H), 7.59(m, 2H), 7.37(m, 2H), 4.02(s, 2H). LCMS: (M+H) + : m / Z: 247.

[0209] Example 20 Synthesis of 2-bromo-N-(2,3-dimethylphenyl)acetamide [ka] The synthesis of 2-bromo-N-(2,3-dimethylphenyl)acetamide was carried out according to the general method described above and is exemplified in Example 4 for 2-bromo-N-(3,4-dimethoxyphenyl)acetamide, but using 2,3-dimethylaniline instead of 3,4-dimethoxyaniline. 1 H NMR:(400 MHz, DMSO) δ 9.77(s, 1H), 7.06( m, 3H), 4.05(s, 2H), 2.23(s, 3H), 2.05(s, 3H).

[0210] Example 21 Synthesis of 2-bromo-N-(2,6-dichlorophenyl)acetamide [ka] The synthesis of 2-bromo-N-(2,6-dichlorophenyl)acetamide was carried out according to the general method described above and is exemplified in Example 4 for 2-bromo-N-(3,4-dimethoxyphenyl)acetamide, but using 2,6-dichloroaniline instead of 3,4-dimethoxyaniline. 1 H NMR:(400 MHz, DMSO) δ 7.97(s, 1H), 7.42(d, 2H), 7.26(dd, 1H), 4.12(s, 2H). LCMS: (M+H) + : m / Z: 282.13.

[0211] Example 22 Synthesis of 2-bromo-N-(5-bromo-2-methoxyphenyl)acetamide [ka] The synthesis of 2-bromo-N-(5-bromo-2-methoxyphenyl)acetamide was carried out according to the general method described above and is exemplified in Example 4 for 2-bromo-N-(3,4-dimethoxyphenyl)acetamide, but using 5-bromo-2-methoxyaniline instead of 3,4-dimethoxyaniline. 1 H NMR: (400 MHz, DMSO) δ 8.79(s, 1H), 8.55(dd, 1H), 7.23(m, 1H), 6.81(m, 2H), 4.04(s, 2H), 3.92(s, 3H).

[0212] Example 23 Synthesis of 2-bromo-N-(4-chloro-2,5-dimethoxyphenyl)acetamide [ka] The synthesis of 2-bromo-N-(4-chloro-2,5-dimethoxyphenyl)acetamide was carried out according to the general method described above and is exemplified in Example 4 for 2-bromo-N-(3,4-dimethoxyphenyl)acetamide, but using 4-chloro-2,5-dimethoxyaniline instead of 3,4-dimethoxyaniline. 1 H NMR: (400 MHz, DMSO) δ 8.78(s, 1H), 8.19(s, 1H), 6.95(s, 1H), 4.05(s, 2H), 3.90(s, 6H).

[0213] Example 24 Synthesis of 2-bromo-N-(3-bromo-4-methoxyphenyl)acetamide [ka] The synthesis of 2-bromo-N-(3-bromo-4-methoxyphenyl)acetamide was carried out according to the general method described above and is exemplified in Example 4 for 2-bromo-N-(3,4-dimethoxyphenyl)acetamide, but using 3-bromo-4-methoxyaniline instead of 3,4-dimethoxyaniline. 1 H NMR: (400 MHz, DMSO) δ 10.37(s, 1H), 7.89(d, 1H), 7.45(s, 1H), 7.09(d, 1H), 3.99(s, 2H), 3.80(s, 3H). LCMS: (M+H) + : m / Z: 321.9.

[0214] Example 25 Synthesis of 2-bromo-N-(3-chloro-4-methoxyphenyl)acetamide [ka] The synthesis of 2-bromo-N-(3-chloro-4-methoxyphenyl)acetamide was carried out according to the general method described above and is exemplified in Example 4 for 2-bromo-N-(3,4-dimethoxyphenyl)acetamide, but using 3-chloro-4-methoxyaniline instead of 3,4-dimethoxyaniline. 1 H NMR: (400 MHz, DMSO) δ 10.38(s, 1H), 7.74(d, 1H), 7.41(m, 1H), 7.11(d, 1H), 3.99(s, 2H), 3.81(s, 1H). LCMS: (M+H) + : m / Z: 277.9.

[0215] Example 26 Synthesis of 2-bromo-N-(2,3-dimethoxyphenyl)acetamide [ka] The synthesis of 2-bromo-N-(2,3-dimethoxyphenyl)acetamide was carried out according to the general method described above and is exemplified in Example 4 for 2-bromo-N-(3,4-dimethoxyphenyl)acetamide, but using 2,3-dimethoxyaniline instead of 3,4-dimethoxyaniline. 1 H NMR: (400 MHz, DMSO) δ 9.65(s, 1H), 7.61(d, 1H), 7.01(t, 1H), 6.83(d, 1H), 4.19(s, 2H), 3.79(s, 3H), 3.72(s, 3H). LCMS: (M+H) + : m / Z: 277.9.

[0216] Example 27 Synthesis of ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate (Compound I-6) [ka] To a stirred solution of ethyl 2-mercapto-1H-imidazole-4-carboxylate (500 mg, 2.903 mmol) in acetonitrile (10 mL) at ambient temperature, triethylamine (0.88 g, 8.711 mmol) and 2-bromo-N-(3,4-dimethoxyphenyl)acetamide (795 mg, 2.903 mmol) were added, and the reaction mixture was heated at 80° C. for 1 hour. The reaction progress was monitored by TLC. After completion of the reaction, the organic solvent was removed under reduced pressure. Water (200 mL) was added to the crude mixture, which was then extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude material was purified by Combiflash chromatography eluting with 80% ethyl acetate / petroleum ether to afford ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate I-6 (500 mg, 1.369 mmol, 47% yield) as a light brown solid. 1 H NMR: (400 MHz, DMSO) δ 12.92(s, 1H), 10.42(s, 1H), 7.88(s, 1H), 7.26(s, 1H), 7.08(d, 1H), 6.87(d, 1H), 4.21(d, 2H), 3.97(s, 2H), 3.69(s, 6H), 1.25(t, 3H). LCMS: (M+H + ): m / Z: 366.1.

[0217] Example 28 Synthesis of ethyl 2-((2-((3-bromobenzyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate [ka] The synthesis of ethyl 2-((2-((3-bromobenzyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate was carried out according to the general method described above and exemplified in Example 27 for ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate, but using 2-bromo-N-(3-bromobenzyl)acetamide instead of 2-bromo-N-(3,4-dimethoxyphenyl)acetamide. 1 H NMR:(400 MHz, DMSO) δ 8.674-8.806(dt, 1H), 7.415-7.477(d, 2H), 7.142-7.317(m, 2H), 4.197-4.315(m, 4H), 3.829-3.923(s, 3H), 1.191-1.258(t, 3H).

[0218] Example 29 Synthesis of ethyl 2-((2-((4-morpholinophenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate [ka] The synthesis of ethyl 2-((2-((4-morpholinophenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate was carried out according to the general method described above and exemplified in Example 27 for ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate, but using 2-bromo-N-(4-morpholinophenyl)acetamide instead of 2-bromo-N-(3,4-dimethoxyphenyl)acetamide. LCMS: (M+H + ): m / Z: 391.19.

[0219] Example 30 Synthesis of ethyl 2-((2-((3-chlorobenzyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate [ka] The synthesis of ethyl 2-((2-((3-chlorobenzyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate was carried out according to the general method described above and exemplified in Example 27 for ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate, but using 2-bromo-N-(3-chlorobenzyl)acetamide instead of 2-bromo-N-(3,4-dimethoxyphenyl)acetamide. 1 H NMR:(400 MHz, DMSO) δ 8.80(bs, 1H), 7.249-7.304(m, 2H), 7.18(d, 1H), 4.271-4.285(m, 2H), 4.20(m, 2H) 3.891(s, 2H), 1.223-1.258(t, 3H).

[0220] Example 31 Synthesis of ethyl 2-((2-((4-chlorobenzyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate [ka] The synthesis of ethyl 2-((2-((4-chlorobenzyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate was carried out according to the general method described above and exemplified in Example 27 for ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate, but using 2-bromo-N-(4-chlorobenzyl)acetamide instead of 2-bromo-N-(3,4-dimethoxyphenyl)acetamide. 1 H NMR: (400 MHz, DMSO) δ 8.728(bs, 1H), 7.285-7.390(m, 3H), 7.207-7.228(d, 2H), 4.187-4.285(m, 4H), 3.871(s, 2H), 1.232-1.268(t, 3H).

[0221] Example 32 Synthesis of ethyl 2-((2-oxo-2-((2,3,4-trimethoxyphenyl)amino)ethyl)thio)-1H-imidazole-4-carboxylate [ka] The synthesis of ethyl 2-((2-oxo-2-((2,3,4-trimethoxyphenyl)amino)ethyl)thio)-1H-imidazole-4-carboxylate was carried out according to the general method described above and exemplified in Example 27 for ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate, but using 2-bromo-N-(2,3,4-trimethoxyphenyl)acetamide instead of 2-bromo-N-(3,4-dimethoxyphenyl)acetamide. 1 H NMR: (400 MHz, DMSO) δ 12.913-13.301(s, 1H), 9.523-689(s, 1H), 7.908(s, 1H), 7.595-7.686(d, 1H), 6.740-6.763(d, 1H), 4.201-4.219(m, 2H), 4.079(s, 2H), 3.724(s, 3H), 3.740(s, 3H), 3.769(s, 3H), 1.233-1.285(t, 3H).

[0222] Example 33 Synthesis of ethyl 2-((2-((3,5-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate [ka] The synthesis of ethyl 2-((2-((3,5-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate was carried out according to the general method described above and exemplified in Example 27 for ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate, but using 2-bromo-N-(3,5-dimethoxyphenyl)acetamide instead of 2-bromo-N-(3,4-dimethoxyphenyl)acetamide. 1 H NMR: (400 MHz, DMSO) δ 10.551(s, 1H), 7.892(s, 1H), 6.801(s, 1H), 6.823(s, 1H), 6.204-6.215(d, 1H), 4.198-4.217(m, 2H), 3.977(s, 2H), 3.691(s, 3H), 3.709(s, 3H), 1.229-1.264(t, 3H).

[0223] Example 34 Synthesis of ethyl 2-((2-((3,4-dimethoxybenzyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate [ka] The synthesis of ethyl 2-((2-((3,4-dimethoxybenzyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate was carried out according to the general method described above and exemplified in Example 27 for ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate, but using 2-bromo-N-(3,4-dimethoxybenzyl)acetamide instead of 2-bromo-N-(3,4-dimethoxyphenyl)acetamide. 1 H NMR: (400 MHz, DMSO) δ 12.849-13.193(s, 1H), 8.595-8.667(m, 1H), 7.860-7.881(d, 1H), 7.547(s, 1H), 6.712-6.736(d, 1H), 6.813-6.858(m, 2H), 4.161-4.247(m, 4H), 3.850-3.910(d, 2H), 3.694(s, 3H), 3.702(s, 3H), 1.215-1.279(t, 3H).

[0224] Example 35 Synthesis of ethyl 2-((2-((4-methoxybenzyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate [ka] The synthesis of ethyl 2-((2-((4-methoxybenzyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate was carried out according to the general method described above and exemplified in Example 27 for ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate, but using 2-bromo-N-(4-methoxybenzyl)acetamide instead of 2-bromo-N-(3,4-dimethoxyphenyl)acetamide. LCMS: (M+H + ): m / Z: 350.2.

[0225] Example 36 Synthesis of ethyl 2-((2-((3,4-dimethylphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate [ka] The synthesis of ethyl 2-((2-((3,4-dimethylphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate was carried out according to the general method described above and exemplified in Example 27 for ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate, but using 2-bromo-N-(3,4-dimethylphenyl)acetamide instead of 2-bromo-N-(3,4-dimethoxyphenyl)acetamide. 1 H NMR: (400 MHz, DMSO) δ 10.146-10.368(d, 1H), 7.890(s, 1H), 7.246-7.350(m, 2H), 7.024-7.045(d, 1H), 4.187-4.264(m, 2H), 3.971-4.059(d, 2H), 2.144(s, 3H), 2.164(s, 3H), 1.231-1.278(t, 3H).

[0226] Example 37 Synthesis of ethyl 2-((2-((3-fluoro-4-methoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate [ka] The synthesis of ethyl 2-((2-((3-fluoro-4-methoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate was carried out according to the general method described above and exemplified in Example 27 for ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate, but using 2-bromo-N-(3-fluoro-4-methoxyphenyl)acetamide instead of 2-bromo-N-(3,4-dimethoxyphenyl)acetamide. 1 H NMR: (400 MHz, DMSO) δ 12.928-12.941(bs, 1H), 10.572-10.638(bs, 1H), 7.884(bs, 1H), 7.522-7.594(d, 1H), 7.230-7.254(d, 1H), 7.084-7.130(t, 1H), 4.192-4.245(m, 2H), 3.989(bs, 2H), 3.785(s, 3H), 1.233-1.269(t, 3H).

[0227] Example 38 Synthesis of ethyl 2-((2-((3-fluoro-2,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate [ka] The synthesis of ethyl 2-((2-((3-fluoro-2,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate was carried out according to the general method described above and exemplified in Example 27 for ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate, but using 2-bromo-N-(3-fluoro-2,4-dimethoxyphenyl)acetamide instead of 2-bromo-N-(3,4-dimethoxyphenyl)acetamide. LCMS: (M+H + ): m / Z: 384.1.

[0228] Example 39 Synthesis of ethyl 2-((2-((4-(4-methoxyphenoxy)phenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate [ka] The synthesis of ethyl 2-((2-((4-(4-methoxyphenoxy)phenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate was carried out according to the general method described above and exemplified in Example 27 for ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate, but using 2-bromo-N-(4-(4-methoxyphenoxy)phenyl)acetamide instead of 2-bromo-N-(3,4-dimethoxyphenyl)acetamide. LCMS: (M+H) + : m / Z: 428.2.

[0229] Example 40 Synthesis of ethyl 2-((2-((2,4-dimethoxybenzyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate [ka] The synthesis of ethyl 2-((2-((2,4-dimethoxybenzyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate was carried out according to the general method described above and exemplified in Example 27 for ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate, but using 2-bromo-N-(2,4-dimethoxybenzyl)acetamide instead of 2-bromo-N-(3,4-dimethoxyphenyl)acetamide. LCMS: (M+H) + : m / Z: 380.1.

[0230] Example 41 Synthesis of ethyl 2-((2-((4-bromophenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate [ka] The synthesis of ethyl 2-((2-((4-bromophenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate was carried out according to the general method described above and exemplified in Example 27 for ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate, but using 2-bromo-N-(4-bromophenyl)acetamide instead of 2-bromo-N-(3,4-dimethoxyphenyl)acetamide. 1 H NMR: (400 MHz, DMSO) δ 10.70(s, 1H), 7.79(s, 1H), 7.50(m, 5H), 4.23(q, 2H), 4.01(s, 2H), 1.24(t, 3H). LCMS: (M+H) + : m / Z: 384.16.

[0231] Example 42 Synthesis of ethyl 2-((2-((4-chlorophenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate [ka] The synthesis of ethyl 2-((2-((4-chlorophenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate was carried out according to the general method described above and exemplified in Example 27 for ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate, but using 2-bromo-N-(4-chlorophenyl)acetamide instead of 2-bromo-N-(3,4-dimethoxyphenyl)acetamide. 1 H NMR: (400 MHz, DMSO) δ 12.95(s, 1H), 10.68(s, 1H), 7.61(d, 2H), 7.41(d, 2H), 4.24(q, 2H), 4.11(s, 2H), 1.24(t, 3H). LCMS: (M+H) + : m / Z: 340.11.

[0232] Example 43 Synthesis of ethyl 2-((2-((2,3-dimethylphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate [ka] The synthesis of ethyl 2-((2-((2,3-dimethylphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate was carried out according to the general method described above and exemplified in Example 27 for ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate, but using 2-bromo-N-(2,3-dimethylphenyl)acetamide instead of 2-bromo-N-(3,4-dimethoxyphenyl)acetamide. LCMS: (M+H) + : m / Z: 334.11.

[0233] Example 44 Synthesis of ethyl 2-((2-((2,6-dichlorophenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate [ka] The synthesis of ethyl 2-((2-((2,6-dichlorophenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate was carried out according to the general method described above and exemplified in Example 27 for ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate, but using 2-bromo-N-(2,6-dichlorophenyl)acetamide instead of 2-bromo-N-(3,4-dimethoxyphenyl)acetamide. 1 H NMR: (400 MHz, DMSO) δ 7.69(s, 1H), 7.36(s, 2H), 7.18(t, 1H), 4.34(q, 2H), 3.96(s, 2H), 1.33(t, 3H). LCMS: (M+H) + : m / Z: 374.07.

[0234] Example 45 Synthesis of ethyl 2-((2-((5-bromo-2-methoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate [ka] The synthesis of ethyl 2-((2-((5-bromo-2-methoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate was carried out according to the general method described above and exemplified in Example 27 for ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate, but using 2-bromo-N-(5-bromo-2-methoxyphenyl)acetamide instead of 2-bromo-N-(3,4-dimethoxyphenyl)acetamide. 1 H NMR: (400 MHz, DMSO) δ 9.87(s, 1H), 8.24(s, 1H), 7.81(s, 1H), 7.23(m, 1H), 6.98(d, 1H), 4.24(q, 2H), 3.86(s, 3H), 1.24(t, 3H). LCMS: (M+H) + : m / Z: 414.

[0235] Example 46 Synthesis of ethyl 2-((2-((4-chloro-2,5-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate [ka] The synthesis of ethyl 2-((2-((4-chloro-2,5-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate was carried out according to the general method described above and exemplified in Example 27 for ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate, but using 2-bromo-N-(4-chloro-2,5-dimethoxyphenyl)acetamide instead of 2-bromo-N-(3,4-dimethoxyphenyl)acetamide. The crude material was not characterized before use in the next transformation.

[0236] Example 47 Synthesis of ethyl 2-((2-((3-bromo-4-methoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate [ka] The synthesis of ethyl 2-((2-((3-bromo-4-methoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate was carried out according to the general method described above and exemplified in Example 27 for ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate, but using 2-bromo-N-(3-bromo-4-methoxyphenyl)acetamide instead of 2-bromo-N-(3,4-dimethoxyphenyl)acetamide. 1 H NMR: (400 MHz, DMSO) δ 12.94(s, 1H), 10.52(s, 1H), 7.89(s, 1H), 7.85(s, 1H), 7.45(dd, 1H), 7.06(d, 1H), 4.21(q, 2H), 4.00(s, 2H), 3.81(s, 3H), 1.25(t, 3H). LCMS: (M+H) + : m / Z: 414.

[0237] Example 48 Synthesis of ethyl 2-((2-((3-chloro-4-methoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate [ka] The synthesis of ethyl 2-((2-((3-chloro-4-methoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate was carried out according to the general method described above and exemplified in Example 27 for ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate, but using 2-bromo-N-(3-chloro-4-methoxyphenyl)acetamide instead of 2-bromo-N-(3,4-dimethoxyphenyl)acetamide. 1 H NMR: (400 MHz, DMSO) δ 10.57(s, 1H), 7.89(s, 1H), 7.74(d, 1H), 7.42(dd, 1H), 7.1(d, 1H), 4.20-4.25(m, 2H), 3.8(s, 3H), 1.24(t, 3H).

[0238] Example 49 Synthesis of ethyl 2-((2-((2,3-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate [ka] The synthesis of ethyl 2-((2-((2,3-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate was carried out according to the general method described above and exemplified in Example 27 for ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate, but using 2-bromo-N-(2,3-dimethoxyphenyl)acetamide instead of 2-bromo-N-(3,4-dimethoxyphenyl)acetamide. 1H NMR: (400 MHz, DMSO) δ 12.89(s, 1H), 9.77(s, 1H), 7.88(s, 1H), 7.67(m, 1H), 6.98(m, 1H), 6.78(d, 1H), 4.21(q, 2H), 4.02(s, 2H), 3.79(s, 3H), 3.65(s, 3H), 1.24(t, 3H). LCMS: (M+H) + : m / Z: 366.1.

[0239] Example 50 Synthesis of 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid (compound I-3) [ka] To a stirred solution of ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate (I-6, 100 mg, 0.274 mmol) in tetrahydrofuran (2 mL) and water (0.5 mL) was added lithium hydroxide monohydrate (33 mg, 0.822 mmol) at 0° C., and the reaction solution was heated to 70° C. and stirred for 16 hours. After completion of the reaction, the organic solvent was removed under reduced pressure, and water (20 mL) and 30% aqueous citric acid solution (10 mL) were added. The resulting mixture was extracted with 10% methanol / dichloromethane (50 mL), and the organic phase was concentrated under reduced pressure. The crude material was purified by preparative HPLC to give pure compound 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid I-3 (10 mg, 0.03 mmol, 11% yield) as an off-white solid. 1H NMR: (400 MHz, DMSO) δ 10.499(bs, 1H), 7.638(bs, 1H), 7.245-7.251(d, 1H), 7.105(d, 1H), 6.856-6.878(d, 1H) 3.96(s, 2H), 3.696(s, 3H), 3.705(s, 3H). LCMS: (M+H + ): m / Z: 338.1.

[0240] Example 51 Synthesis of 2-((2-((3-bromobenzyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid (compound I-11) [ka] The synthesis of 2-((2-((3-bromobenzyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid I-11 was carried out according to the general method described above and is exemplified in Example 50 for compound I-3, but using ethyl 2-((2-((3-bromobenzyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate instead of ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate. 1 H NMR: (400 MHz, DMSO) δ 12.766-13.011(bs, 1H), 8.748(bs, 1H), 7.497-7.784(d, 1H), 7.405-7.415(d, 2H), 7.206-7.266(m, 2H), 4.269-4.284(d, 2H), 3.883(bs, 2H). LCMS: (M+H + ): m / Z: 370.26.

[0241] Example 52 Synthesis of 2-((2-((4-morpholinophenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid (compound I-24) [ka] The synthesis of 2-((2-((4-morpholinophenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid I-24 was carried out according to the general method described above and is exemplified in Example 50 for compound I-3, but using ethyl 2-((2-((4-morpholinophenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate instead of ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate. 1 H NMR: (400 MHz, DMSO) δ 12.840(bs, 1H), 10.355(bs, 1H), 7.773(bs, 1H), 7.418-7.440(d, 2H), 6.863-6.886(d, 2H), 3.974(bs, 2H), 3.696-3.719(t, 4H), 3.009-3.033(t, 4H). LCMS: (M+H + ): m / Z: 363.14.

[0242] Example 53 Synthesis of 2-((2-((3-chlorobenzyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid (compound I-21) [ka] The synthesis of 2-((2-((3-chlorobenzyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid I-21 was carried out according to the general method described above and is exemplified in Example 50 for compound I-3, but using ethyl 2-((2-((3-chlorobenzyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate instead of ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate. 1 H NMR: (400 MHz, DMSO) δ 12.757(bs, 1H), 8.757(bs, 1H), 7.492-7.784(d, 1H), 7.260-7.329(m, 3H), 7.168-7.185(d, 2H), 4.274(d, 2H), 3.878(bs, 2H). LCMS: (M+H + ): m / Z: 323.14.

[0243] Example 54 Synthesis of 2-((2-((4-chlorobenzyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid (compound I-22) [ka] The synthesis of 2-((2-((4-chlorobenzyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid I-22 was carried out according to the general method described above and is exemplified in Example 50 for compound I-3, but using ethyl 2-((2-((4-chlorobenzyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate instead of ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate. 1H NMR: (400 MHz, DMSO) δ 12.756(bs, 1H), 8.721(bs, 1H), 7.484-7.792(d, 1H), 7.320-7.340(d, 2H), 7.223-7.243(d, 2H), 4.253(d, 2H), 3.855(bs, 2H). LCMS: (M+H + ): m / Z: 326.22.

[0244] Example 55 Synthesis of 2-((2-oxo-2-((2,3,4-trimethoxyphenyl)amino)ethyl)thio)-1H-imidazole-4-carboxylic acid (Compound I-26) [ka] The synthesis of 2-((2-oxo-2-((2,3,4-trimethoxyphenyl)amino)ethyl)thio)-1H-imidazole-4-carboxylic acid I-26 was carried out according to the general method described above and is exemplified in Example 50 for compound I-3, but using ethyl 2-((2-oxo-2-((2,3,4-trimethoxyphenyl)amino)ethyl)thio)-1H-imidazole-4-carboxylate instead of ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate. 1 H NMR: (400 MHz, DMSO) δ 12.754(bs, 1H), 9.599-9.625(bs, 1H), 7.614-7.722(d, 2H), 6.721-6.744(d, 1H), 4.046(s, 2H), 3.708(s, 3H), 3.731(s, 3H), 3.750(s, 3H). LCMS: (M+H + ): m / Z: 368.1.

[0245] Example 56 Synthesis of 2-((2-((3,5-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid (compound I-25) [ka] The synthesis of 2-((2-((3,5-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid I-25 was carried out according to the general method described above and is exemplified in Example 50 for compound I-3, but using ethyl 2-((2-((3,5-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate instead of ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate. 1 H NMR: (400 MHz, DMSO) δ 12.911(bs, 1H), 10.750(bs, 1H), 7.830(bs, 1H), 6.840(s, 2H), 6.196-6.6.207(s, 1H), 3.971(s, 2H), 3.690(s, 6H). LCMS: (M+H + ): m / Z: 338.1.

[0246] Example 57 Synthesis of 2-((2-((3,4-dimethoxybenzyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid (compound I-32) [ka] The synthesis of 2-((2-((3,4-dimethoxybenzyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid I-32 was carried out according to the general method described above and is exemplified in Example 50 for compound I-3, but using ethyl 2-((2-((3,4-dimethoxybenzyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate instead of ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate. 1 H NMR: (400 MHz, DMSO) δ 12.761(bs, 1H), 8.636(bs, 1H), 7.473-7.788(d, 1H), 6.838-6.866(d, 1H), 6.813-6.818(d, 1H), 6.719-6.738(dd, 1H), 4.192-4.228(d, 2H), 3.844-3.880(d, 2H), 3.692(s, 3H), 3.702(s, 3H). LCMS: (M+H + ): m / Z: 352.0.

[0247] Example 58 Synthesis of 2-((2-((4-methoxybenzyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid (compound I-37) [ka] The synthesis of 2-((2-((4-methoxybenzyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid I-37 was carried out according to the general method described above and is exemplified in Example 50 for compound I-3, but using ethyl 2-((2-((4-methoxybenzyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate instead of ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate. 1H NMR: (400 MHz, DMSO) δ 12.761(bs, 1H), 8.632(bs, 1H), 7.789-8.127(d, 1H), 7.112-7.134(d, 1H), 6.828-6.849(d, 1H), 4.187-4.202(d, 2H), 3.825-3.879(d, 2H), 3.707(s, 3H). LCMS: (M+H + ): m / Z: 322.1.

[0248] Example 59 Synthesis of 2-((2-((3,4-dimethylphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid (compound I-31) [ka] The synthesis of 2-((2-((3,4-dimethylphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid I-31 was carried out according to the general method described above and is exemplified in Example 50 for compound I-3, but using ethyl 2-((2-((3,4-dimethylphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate instead of ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate. 1 H NMR: (400 MHz, DMSO) δ 10.588(bs, 1H), 8.425(s, 1H), 7.353(bs, 1H), 7.285-7.305(d, 1H), 7.159(bs, 1H), 7.017-7.037(s, 1H), 3.894(bs, 2H), 2.142(s, 3H), 2.163(s, 3H). LCMS: (M+H + ): m / Z: 306.1.

[0249] Example 60 Synthesis of 2-((2-((3-fluoro-4-methoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid (compound I-10) [ka] The synthesis of 2-((2-((3-fluoro-4-methoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid I-10 was carried out according to the general method described above and is exemplified in Example 50 for compound I-3, but using ethyl 2-((2-((3-fluoro-4-methoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate instead of ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate. 1 H NMR: (400 MHz, DMSO) δ 12.477-12.820(bs, 2H), 10.328-10.657(d, 1H), 7.805-7.7.821(bs, 1H), 7.535-7.566(d, 1H), 7.245-7.264(s, 1H), 7.078-7.124(t, 1H), 3.982(s, 2H), 3.784(s, 3H). LCMS: (M+H + ): m / Z: 326.05.

[0250] Example 61 Synthesis of 2-((2-((3-fluoro-2,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid (Compound I-9) [ka] The synthesis of 2-((2-((3-fluoro-2,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid I-9 was carried out according to the general method described above and is exemplified in Example 50 for compound I-3, but using ethyl 2-((2-((3-fluoro-2,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate instead of ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate. 1 H NMR: (400 MHz, DMSO) δ 12.262-13.121(bs, 2H), 9.655-9.854(d, 1H), 7.550-7.7.809(t, 2H), 6.825-6.870(t, 1H), 4.054(s, 2H), 3.770(s, 3H), 3.791(s, 3H). LCMS: (M+H + ): m / Z: 356.1.

[0251] Example 62 Synthesis of 2-((2-((4-(4-methoxyphenoxy)phenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid (Compound I-16) [ka] The synthesis of 2-((2-((4-(4-methoxyphenoxy)phenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid I-16 was carried out according to the general method described above and is exemplified in Example 50 for compound I-3, but using ethyl 2-((2-((4-(4-methoxyphenoxy)phenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate instead of ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate. 1H NMR: (400 MHz, DMSO) δ 12.82(s, 1H), 10.47(s, 1H), 7.80(s, 1H), 7.53(d, 2H), 6.91(m, 6H), 3.99(s, 2H), 3.72(s, 3H). LCMS: (M+H) + : m / Z: 400.19.

[0252] Example 63 Synthesis of 2-((2-((2,4-dimethoxybenzyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid (compound I-15) [ka] The synthesis of 2-((2-((2,4-dimethoxybenzyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid I-15 was carried out according to the general method described above and is exemplified in Example 50 for compound I-3, but using ethyl 2-((2-((2,4-dimethoxybenzyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate instead of ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate. 1 H NMR: (400 MHz, DMSO) δ 12.75(s, 1H), 8.42(t, 1H), 7.78(s, 1H), 7.00(d, 1H), 6.50(d, 1H), 6.41(dd, 1H), 4.13(d, 2H), 3.84(s, 2H), 3.74(s, 3H), 3.72(s, 3H). LCMS: (M+H) + : m / Z: 351.89.

[0253] Example 64 Synthesis of 2-((2-((4-bromophenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid (compound I-23) [ka] The synthesis of 2-((2-((4-bromophenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid I-23 was carried out according to the general method described above and is exemplified in Example 50 for compound I-3, but using ethyl 2-((2-((4-bromophenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate instead of ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate. 1 H NMR:(400 MHz, DMSO) δ 10.62(s, 1H), 7.72(s, 1H), 7.55(d, 2H), 7.47(d, 2H), 4.03(s, 2H). LCMS: (M+H) + : m / Z: 356.06.

[0254] Example 65 Synthesis of 2-((2-((4-chlorophenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid (compound I-20) [ka] The synthesis of 2-((2-((4-chlorophenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid I-20 was carried out according to the general method described above and is exemplified in Example 50 for compound I-3, but using ethyl 2-((2-((4-chlorophenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate instead of ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate. 1H NMR: (400 MHz, DMSO) δ 12.67(s, 1H), 10.69(s, 1H), 7.60(d, 2H), 7.34(dd, 2H), 4.00(s, 2H). LCMS: (M+H) + : m / Z: 312.10.

[0255] Example 66 Synthesis of 2-((2-((2,3-dimethylphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid (compound I-19) [ka] The synthesis of 2-((2-((2,3-dimethylphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid I-19 was carried out according to the general method described above and is exemplified in Example 50 for compound I-3, but using ethyl 2-((2-((2,3-dimethylphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate instead of ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate. 1 H NMR: (400 MHz, DMSO) δ 12.84(s, 1H), 9.75(s, 1H), 7.81(s, 1H), 7.16(d, 1H), 7.00(m, 2H), 4.02(s, 2H), 2.21(s, 3H), 2.01(s, 3H). LCMS: (M+H) + : m / Z: 306.1.

[0256] Example 67 Synthesis of 2-((2-((2,6-dichlorophenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid (compound I-18) [ka] The synthesis of 2-((2-((2,6-dichlorophenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid I-18 was carried out according to the general method described above and is exemplified in Example 50 for compound I-3, but using ethyl 2-((2-((2,6-dichlorophenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate instead of ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate. 1 H NMR: (400 MHz, DMSO) δ 12.79(s, 1H), 10.28(d, 1H), 7.79(s, 1H), 7.51(d, 2H), 7.33(t, 1H), 4.08(s, 2H). LCMS: (M+H) + : m / Z: 346.05.

[0257] Example 68 Synthesis of 2-((2-((5-bromo-2-methoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid (compound I-36) [ka] The synthesis of 2-((2-((5-bromo-2-methoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid I-36 was carried out according to the general method described above and is exemplified in Example 50 for compound I-3, but using ethyl 2-((2-((5-bromo-2-methoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate instead of ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate. 1H NMR: (400 MHz, DMSO) δ 12.81(s, 1H), 10.06(s, 1H), 8.26(s,1H), 7.81(s, 1H), 7.22(t, 1H), 6.99(t, 1H), 4.05(s, 2H), 3.79(s, 3H). LCMS: (M+H) + : m / Z: 386.15.

[0258] Example 69 Synthesis of 2-((2-((4-chloro-2,5-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid (compound I-27) [ka] The synthesis of 2-((2-((4-chloro-2,5-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid I-27 was carried out according to the general method described above and is exemplified in Example 50 for compound I-3, but using ethyl 2-((2-((4-chloro-2,5-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate instead of ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate. 1 H NMR: (400 MHz, DMSO) δ 8.00(s, 1H), 7.11(s, 1H), 4.05(s, 2H), 3.76(s, 3H), 3.73(s, 3H). LCMS: (M+H) + : m / Z: 372.09.

[0259] Example 70 Synthesis of 2-((2-((3-bromo-4-methoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid (compound I-34) [ka] The synthesis of 2-((2-((3-bromo-4-methoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid I-34 was carried out according to the general method described above and is exemplified in Example 50 for compound I-3, but using ethyl 2-((2-((3-bromo-4-methoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate instead of ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate. 1 H NMR: (400 MHz, DMSO) δ 12.85(s, 1H), 10.61(s, 1H), 7.92(d, 1H), 7.77(s, 1H), 7.48(d, 1H), 7.06(d, 1H), 4.00(s, 2H), 3.81(s, 3H). LCMS: (M+H) + : m / Z: 385.8.

[0260] Example 71 Synthesis of 2-((2-((3-chloro-4-methoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid (compound I-35) [ka] The synthesis of 2-((2-((3-chloro-4-methoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid I-35 was carried out according to the general method described above and is exemplified in Example 50 for compound I-3, but using ethyl 2-((2-((3-chloro-4-methoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate instead of ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate. 1H NMR: (400 MHz, DMSO) δ 12.86(s, 1H), 10.65(s, 1H), 7.78(d, 2H), 7.42(d, 1H), 7.09(d, 1H), 3.97(s, 2H), 3.80(s, 3H). LCMS: (M+H) + : m / Z: 339.9.

[0261] Example 72 Synthesis of 2-((2-((2,3-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid (compound I-8) [ka] The synthesis of 2-((2-((2,3-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid I-8 was carried out according to the general method described above and is exemplified in Example 50 for compound I-3, but using ethyl 2-((2-((2,3-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate instead of ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate. 1 H NMR: (400 MHz, DMSO) δ 12.73(s, 1H), 9.43(brs, 1H), 7.66(d, 2H), 7.48(t, 2H), 6.77-6.79(m, 1H), 4.06(s, 2H), 3.78(s, 3H), 3.64(s, 3H). LCMS: (M+H) + : m / Z: 338.1.

[0262] Example 73 Synthesis of 2-((2-((4-chloro-2-fluorophenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid (compound I-7) [ka] Synthesis of 2-bromo-N-(4-chloro-2-fluorophenyl)acetamide To a stirred solution of 4-chloro-2-fluoroaniline (200 mg, 1.374 mmol) in dichloromethane (5 mL) at ambient temperature, potassium carbonate (284 mg, 2.061 mmol) and 2-bromoacetyl chloride (235 mg, 1.511 mmol) were added, and the reaction mixture was stirred for 3 hours. After completion of the reaction, water (10 mL) was added, and the reaction mixture was stirred for 15 minutes. The resulting precipitate was collected by filtration to give 2-bromo-N-(4-chloro-2-fluorophenyl)acetamide (250 mg, 0.943 mmol, 68% yield) as a brown solid. 1 H NMR: (400 MHz, DMSO) δ 8.348(bs, 1H), 8.215-8.259(t, 1H), 7.149-7.185(m, 1H), 4.045(s, 2H).

[0263] Synthesis of 2-((2-((4-chloro-2-fluorophenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid To a stirred solution of 2-mercapto-1H-imidazole-4-carboxylic acid (50 mg, 0.345 mmol, prepared above in Example 2) in acetonitrile (4 mL) at ambient temperature, triethylamine (87 mg, 0.862 mmol) and 2-bromo-N-(4-chloro-2-fluorophenyl)acetamide (91 mg, 0.345 mmol) were added, and the reaction mixture was stirred at 80° C. for 1 hour. The reaction progress was monitored by TLC. After completion of the reaction, the organic solvent was removed under reduced pressure, and the crude material was purified by preparative HPLC to give pure 2-((2-((4-chloro-2-fluorophenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid I-7 (500 mg, 1.369 mmol, 47% yield) as a light brown solid. 1H NMR: (400 MHz, DMSO) δ 12.810(bs, 1H), 10.350(bs, 1H), 7.940-7.983(t, 1H), 7.60-7.80(bs, 1H), 7.471-7.498(dd, 1H), 7.232-7.254(d, 1H), 4.074(s, 2H). LCMS: (M+H + ): m / Z: 330.06.

[0264] Example 74 Synthesis of 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxamide (Compound I-1) [ka] To a stirred solution of ethyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate I-6 (370 mg, 1.012 mmol) in tetrahydrofuran (2 mL) in a high-pressure reaction tube, 25% aqueous ammonia (12 mL) and ammonium chloride (162 mg, 3.037 mmol) were added. The tube was sealed, and the reaction mixture was stirred at 100° C. for 16 h. The reaction progress was monitored by TLC. After completion of the reaction, the organic solvent was removed under reduced pressure to give the crude product, which was purified by preparative HPLC to give 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxamide I-1 (80 mg, 0.238 mmol, 23% yield) as an off-white solid. 1 H NMR: (400 MHz, DMSO) δ 10.16(s, 1H), 7.60(s, 1H), 7.22(s, 1H), 7.08(m, 1H), 7.06(d, 1H), 6.86(d, 1H), 3.92(s, 2H), 3.69(s, 6H).

[0265] Example 75 Synthesis of 2-((4-cyano-1H-imidazol-2-yl)thio)-N-(3,4-dimethoxyphenyl)acetamide (Compound I-4) [ka] To a stirred solution of 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxamide I-1 (70 mg, 0.208 mmol) in dichloromethane (2 mL) in a sealed tube at 0° C., Burgess reagent (149 mg, 0.625 mmol) was added, and the reaction solution was stirred at room temperature for 16 hours. After completion of the reaction, the organic solvent was removed under reduced pressure to give the crude product, which was purified by prep HPLC to give pure 2-((4-cyano-1H-imidazol-2-yl)thio)-N-(3,4-dimethoxyphenyl)acetamide I-4 (10 mg, 0.032 mmol, 15% yield) as an off-white solid. 1 H NMR: (400 MHz, DMSO) δ 13.26(bs, 1H), 10.149(s, 1H), 8.134(s, 1H), 7.232-7.238(d, 1H), 7.019-7.046(d, 1H), 6.864-6.886(d, 1H), 4.013(s, 2H), 3.699(s, 3H), 3.704(s, 3H). LCMS: (M+H + ): m / Z: 319.1.

[0266] Example 76 Synthesis of (Z)-N-(3,4-dimethoxyphenyl)-2-((4-(N'-hydroxycarbamimidoyl)-1H-imidazol-2-yl)thio)acetamide (Compound I-5) [ka] To a stirred solution of 2-((4-cyano-1H-imidazol-2-yl)thio)-N-(3,4-dimethoxyphenyl)acetamide I-4 (100 mg, 0.314 mmol) in ethanol (3 mL) in a sealed tube, ammonium hydroxide hydrochloride (24 mg, 0.346 mmol) and triethylamine (47 mg, 0.471 mmol) were added at 0 °C, and the reaction solution was stirred at room temperature for 16 h. After completion of the reaction, the organic solvent was removed under reduced pressure to give the crude product, which was purified by prep HPLC to give pure (Z)-N-(3,4-dimethoxyphenyl)-2-((4-(N'-hydroxycarbamimidoyl)-1H-imidazol-2-yl)thio)acetamide I-5 (15 mg, 0.042 mmol, 13% yield) as an off-white solid. 1 H NMR: (400 MHz, DMSO) δ 12.453(bs, 1H), 10.297(s, 1H), 9.140(s, 1H), 7.324(s, 1H), 7.227(s, 1H), 7.101(bs, 1H), 7.046(d, 1H), 6.853-6.875(d, 1H), 5.526-5.690(d, 2H), 3.881(bs, 2H), 3.696(s, 6H). LCMS: (M+H + ): m / Z: 352.1.

[0267] Example 77 Synthesis of 2,3-dihydroxypropyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate (Compound I-30) [ka] Synthesis of (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate To a stirred solution of 2-((2-((3,4-dimethoxyphenyl)-12-azanyl)-2-oxoethyl)thio)-1H-imidazole-4-carboxylic acid (200 mg, 0.5934 mmol) in DMF (2 mL), EDC·HCl (170 mg, 0.8901 mmol), and DMAP (37 mg, 0.2967 mmol) was added solketal (86 mg, 0.6528 mmol) at 0°C and stirred at room temperature for 16 hours. After completion of the reaction, water (20 mL) was added to the crude residue. The resulting mixture was extracted with 10% methanol / dichloromethane (50 mL), and the organic phase was concentrated under reduced pressure to give the crude product. The product was purified by prep HPLC method to obtain the pure compound (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate (400 mg, 0.02 mmol, 8% yield) as an off-white solid. LCMS: (M+H + ):m / Z: 352.

[0268] Synthesis of 2,3-dihydroxypropyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate (I-30) To a stirred solution of (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)-1H-imidazole-4-carboxylate (400 mg) in HCl, dioxane (4 mL) was added and the reaction mixture was stirred at RT for 16 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was thoroughly evaporated under reduced pressure to give the crude product. The product was purified by preparative HPLC to give 2-((2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)thio)thiazole-4-carboxamide I-30 (30 mg, 0.0729 mmol, 8% yield) as an off-white solid. 1H NMR: (400 MHz, DMSO) δ 12.93(s, 1H), 10.43(s, 1H), 7.91(s, 1H), 7.26(d, 1H), 7.08(d, 1H), 6.87(d, 1H), 4.90(t, 1H), 4.65(t, 1H), 3.97-4.21(m, 5H), 3.71(s, 6H), 3.39(t, 2H). LCMS: (M+H + ): m / Z: 412.08.

[0269] Example 78 ENPP1 inhibition assay material: Assay buffer: 1 mM CaCl2, 0.2 mM ZnCl2, 50 mM Tris (pH 9.0) Substrate: 8mM thymidine 5'-monophosphate p-nitrophenol ester sodium salt (Sigma Cat # T4510) Enzyme: 5 ng / L recombinant human ENPP-1 protein (R&D Cat #6136-EN-010) / DMSO in a 96-well clear assay plate method: Eight-point serial dilutions of drug were prepared 10x in assay buffer, starting with final assay concentrations of 10 μM, 3 μM, 1 μM, 0.3 μM, and 0 μM. DMSO dilutions were included as a control. Assay plates were set up in duplicate wells as follows: 81 μL assay buffer + 10 μL ENPP1 inhibitor or DMSO + 5 μL substrate + 4 μL enzyme. Both enzyme and substrate were added to opposite sides of the wells to ensure no interaction until all wells contained both components. Plates were then gently centrifuged for 10 seconds and then incubated at 37°C for 45 minutes. Reactions were quantified by measuring absorbance at 405 nm using an Envision.

[0270] I C 50 Calculation of: IC 50IC values ​​were determined using GraphPad Prism5 software. Data was entered into the software as an XY plot of percent inhibition for each drug concentration. Drug concentration values ​​were log-transformed and nonlinear regression was performed to model the data and calculate IC values ​​using the "Sigmoidal Dose Response (Variable Gradient)" option within GraphPad software. 50 The reported IC values ​​were calculated. 50 Values ​​are the drug concentrations at which 50% inhibition was achieved.

[0271] Table 2: Inhibition of ENPP1 [Table 5]

[0272] Example 79 Examples of pharmaceutical compositions "Active ingredient" as used throughout these examples refers to one or more compounds of the present disclosure or pharmaceutically acceptable salts, solvates, polymorphs, hydrates and stereochemical isomers thereof, or to pharmaceutical compositions derived therefrom.

[0273] Representative examples of formulations for the formulations of the present disclosure are shown below. Various other dosage forms are applicable to the invention of the present disclosure, for example, filled gelatin capsules, emulsions / suspensions, ointments, suppositories, or chewable tablets can be formed using the compounds of the present disclosure at the desired dosage amounts according to the present specification. Various conventional techniques for preparing suitable dosage forms can be used to prepare pharmaceutical compositions as disclosed herein and as described in standard references (e.g., British and United States Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.) and Martindale The Extra Pharmacopoeia (London The Pharmaceutical Press)). These references are incorporated herein by reference.

[0274] [Table 6]

[0275] Alternatively, each tablet contains approximately 100 mg of the compound of the present disclosure, 50 mg of lactose (monohydrate), 50 mg of domestic corn starch, 10 mg of polyvinylpyrrolidone (PVP25) (e.g., BASF, Ludwigshafen, Germany), and 2 mg of magnesium stearate. The mixture of active ingredient, lactose, and starch is granulated with a 5% (by weight) aqueous PVP solution. After drying, the granules are mixed with magnesium stearate for 5 minutes. This mixture is molded using a conventional tablet press (e.g., tablet format: diameter 8 mm, radius of curvature 12 mm). The molding pressure applied is typically about 15 kN.

[0276] Alternatively, the compounds of the present disclosure can be administered in a suspension formulated for oral administration. For example, the desired compound of the present disclosure (approximately 100-5000 mg), ethanol (96%) (1000 mg), xanthan gum (400 mg), and water (99 g) are combined with stirring. A single dose of the desired compound of the present disclosure (approximately 10-500 mg) can be provided in a 10 mL oral suspension.

[0277] In these examples, the active ingredient can be replaced with the same amount of any compound of the present invention, particularly the same amount of the compound of the examples. In some situations, it may be desirable to use capsules (e.g., filled gelatin capsules) instead of tablet forms, for example. The choice of tablet or capsule depends in part on the physiochemical characteristics of the particular compound of the present disclosure used.

[0278] Examples of other carriers useful for preparing oral preparations include lactose, sucrose, starch, talc, magnesium stearate, crystalline cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, glycerin, sodium alginate, gum arabic, etc. These other carriers can be used in place of the above-mentioned ones when necessary for the desired dissolution, absorption and manufacturing characteristics.

[0279] The amount of compound of the present disclosure to be used per tablet in a pharmaceutical composition for use in humans may be determined based on toxicity data and / or toxicity data obtained in a suitable animal model, e.g., rats and at least one non-rodent. Beauty The dosage level will be determined from both pharmacokinetic data and adjusted based on human clinical trial data. For example, it is believed appropriate for the compounds of the present disclosure to be present at a level of about 10-1000 mg / tablet dosage unit.

[0280] TIFF0007818600000095.tif61141

[0281] Alternatively, a pharmaceutical composition for intravenous injection can be used, which may comprise a compound of the present disclosure (approximately 100-5000 mg) in saline, polyethylene glycol 400 (15 g), and water (250 g), optionally with up to about 15% Cremophor EL, optionally up to 15% ethyl alcohol, and optionally up to 2 equivalents of a pharmaceutically suitable acid (e.g., citric acid or hydrochloric acid). The injectable composition can be prepared as follows: The compound of the present disclosure and polyethylene glycol 400 are dissolved in water with stirring. The solution is sterile filtered (pore size 0.22 μm) and filled into a heat-sterilized infusion bottle under aseptic conditions. The infusion bottle is sealed with a rubber seal.

[0282] In a further example, a pharmaceutical composition for intravenous injection can be used, which can include a compound of the present disclosure (approximately 10-500 mg) and normal saline, optionally with up to 15% by weight Cremophor EL, optionally with up to 15% by weight ethyl alcohol, and optionally with up to 2 equivalents of a pharmaceutically suitable acid (e.g., citric acid or hydrochloric acid). The composition can be prepared as follows: The desired compound of the present disclosure is dissolved in saline with stirring. Cremophor EL, ethyl alcohol, or acid is added, as desired. The solution is sterile filtered (0.22 μm pore size) and filled into a heat-sterilized infusion bottle under aseptic conditions. The infusion bottle is sealed with a rubber seal.

[0283] In this embodiment, the active ingredient may be replaced with an equivalent amount of any compound of the invention, particularly an equivalent amount of an exemplified compound.

[0284] The amount of the compound of the present disclosure to be used per ampoule in a pharmaceutical composition for humans will be determined from both toxicity and pharmacokinetic data obtained from an appropriate animal model (e.g., rats and at least one species other than rodents) and adjusted based on human clinical trial data. For example, it may be appropriate for the compound of the present disclosure to be present at dosage unit levels of about 10 to 1000 mg per tablet.

[0285] Suitable carriers for parenteral formulations are, for example, water, physiological saline, etc., which can be used together with tris(hydroxymethyl)aminomethane, sodium carbonate, sodium hydroxide, etc., which serve as solubilizing agents or pH adjusters. Parenteral formulations preferably contain 50 to 1000 mg of a compound of the present disclosure per dosage unit.

[0286] The various embodiments described above can be combined to provide further embodiments. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent literature referenced herein and / or listed in application data sheets are incorporated herein by reference in their entirety. Aspects of the embodiments can be modified, as necessary, to incorporate concepts from the various patents, applications, and publications to provide still further embodiments.

[0287] U.S. Provisional Application No. 63 / 120,597, filed December 2, 2020, is incorporated herein by reference in its entirety.

[0288] These and other changes can be made to the embodiments in light of the above detailed description. Generally, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which the claims are entitled. Accordingly, the claims are not limited by the present disclosure. The present invention further includes the following aspects. 1. The following structure (I): [ka] [In the formula, L is S(O) z and; R 1 CN, C(=O)R 1a , C(=O)NHSO 2 R 1b , C(=NR 1d )NR 1c R 1e , OR 1e , NHR 1e , NHS(O) 2R 1b , S(O) 2 NR 1b R 1e , P.O. 3 HR 1e , SO 3 H or 5-membered heteroaryl; R 1a is OR 1e or NR 1c R 1e and; R 1b is C 1 -C 6 Alkyl or C 6 -C 10 is aryl; R 1c is H, C 1 -C 6 Alkyl or C 6 -C 10 is aryl; R 1d is H, OH or C 1 -C 6 is alkyl; R 1e is H, C 1 -C 6 Alkyl, C 1 -C 6 Hydroxyl alkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Alkylaminylalkyl or C 6 -C 10 is aryl; R 2a 、R 2b 、R 2c 、R 2d and R 2e are each independently H, amino, halo, hydroxyl, nitro, CN, C 1 -C 6 Alkyl, C 1-C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 6 -C 10 aryloxy or 3- to 8-membered heterocyclyl; n is 0 or 1; and z is 0, 1 or 2; Here, each C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 6 -C 10 Aryl, C 6 -C 10 The aryloxy, 3- to 8-membered heterocyclyl, and 5-membered heteroaryl are independently optionally substituted, provided that R 1 But C(=O)OCH 3 or C(=O)OCH 2 CH 3 If R 2c is C 1 -C 6 is alkoxy, and R 2b and R 2d At least one of 1 -C 6 Alkoxy] or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof. 2. R 1 But CN, C(=O)R 1a , C(=O)NHSO 2 R 1b , C(=NR 1d )NR 1c R 1e or a 5-membered heteroaryl. 3. R 1 Item 1. The compound according to item 1, wherein is CN. 4. R 1 But C(=O)R 1a Item 2. The compound according to item 1, 5. R 1a But, OR 1e Item 5. The compound according to item 4, wherein 6. R1e But H, C 1 -C 6 Alkyl, C 1 -C 6 Hydroxyl alkyl or C 1 -C 6 Item 6. The compound according to item 5, which is alkylaminylalkyl. 7. R 1e Item 7. The compound according to item 6, wherein is H. 8. R 1e Item 7. The compound according to item 6, wherein is methyl or ethyl. 9. R 1e but,

change

change

change

change

change

change

change

change

Claims

1. The following structure (I): 【Chemistry 1】 [In the formula, L is S(O) ｚ and R １ is CN, C(=O)R １ａ , C(=NR １ｄ )NR １ｃ R1e or a 5-membered heteroaryl; R １ａ is OR １ｅ or NR １ｃ R １ｅ and R １ｂ is C １ -C ６ Alkyl or C ６ -C １０ is aryl; R １ｃ is H, C １ -C ６ Alkyl or C ６ -C １０ is aryl; R １ｄ is H, OH or C １ -C ６ is alkyl; R １ｅ is H, C １ -C ６ Alkyl, C １ -C ６ Hydroxyl alkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Alkylaminylalkyl or C ６ -C １０ is aryl; R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ and R ２ｅ are each independently H, halo, CN, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ６ -C １０ aryloxy or 3- to 8-membered heterocyclyl; n is 0 or 1; and z is 0; Here, each C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ６ -C １０ Aryl, C ６ -C １０ The aryloxy, 3- to 8-membered heterocyclyl, and 5-membered heteroaryl are independently optionally substituted, provided that R １ is C(=O)OCH ３ or C(=O)OCH ２ CH ３ If R ２ｃ is C １ -C ６ is alkoxy, and R ２ｂ and R ２ｄ At least one of １ -C ６ is an alkoxy group. or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

2. R １ CN, C(=O)R １ａ , C(=NR １ｄ )NR １ｃ R １ｅ or 5-membered heteroaryl, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

3. R １ａ But OR １ｅ 2. The compound of claim 1, wherein:

4. R １ｅ But H, C １ -C ６ Alkyl, C １ -C ６ Hydroxyl alkyl or C １ -C ６ 4. The compound of claim 3, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, which is alkylaminylalkyl.

5. R １ａ But NR １ｃ R １ｅ 2. The compound of claim 1, wherein:

6. R １ｃ and R １ｅ are each H or R １ｃ is H and R １ｅ is C １ -C ６ 6. The compound of claim 5, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein:

7. R １ But C(=NR １ｄ )NR １ｃ R １ｅ 2. The compound of claim 1, wherein:

8. R １ｄ is OH and / or R １ｃ and R １ｅ and R are each H, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

9. R １ 2. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein: is an optionally substituted 5-membered heteroaryl.

10. i) heteroaryl contains one or more ring nitrogen atoms; ii) heteroaryl is tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl; iii) the heteroaryl is substituted with hydroxyl; or The heteroaryl has the following structure: 【Chemistry 2】 having one of 10. The compound of claim 9, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

11. i) R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ and R ２ｅ One of them is Halo, C １ -C ６ Alkyl or C １ -C ６ Alkoxy, and each remaining R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ and R ２ｅ each independently represents H, halo, or C １ -C ６ Alkyl or C １ -C ６ is alkoxy; ii) R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ and R ２ｅ One of them is C １ -C ６ Alkoxy, and each remaining R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ and R ２ｅ are each independently H, halo, or C １ -C ６ is alkoxy; iii) R ２ｂ and R ２ｃ are each independently halo or methoxy; iv) R ２ｂ is the halo, and R ２ｃ is methoxy; or v) R ２ｂ and R ２ｃ are each methoxy; 11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

12. C １ -C ６ 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein alkoxy is methoxy.

13. 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein halo is fluoro, bromo, or chloro. 【Request Item 14】 【Chemistry 3】 has the following structure: 【Chemistry 4】 14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein

15. i) n is 0; or ii) n is 1; 15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

16. The following structure: 【Transformation 5】 【Transformation 6】 【Transformation 7】 2. The compound of claim 1, wherein:

17. a pharmaceutically acceptable excipient and a compound represented by the following structure (I): 【Transformation 8】 [In the formula, L is S(O) ｚ and R １ is CN, C(=O)R １ａ , C(=NR １ｄ )NR １ｃ R1e or a 5-membered heteroaryl; R １ａ is OR １ｅ or NR １ｃ R １ｅ and R １ｂ is C １ -C ６ Alkyl or C ６ -C １０ is aryl; R １ｃ is H, C １ -C ６ Alkyl or C ６ -C １０ is aryl; R １ｄ is H, OH or C １ -C ６ is alkyl; R １ｅ is H, C １ -C ６ Alkyl, C １ -C ６ Hydroxyl alkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Alkylaminylalkyl or C ６ -C １０ is aryl; R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ and R ２ｅ are each independently H, halo, CN, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ６ -C １０ aryloxy or 3- to 8-membered heterocyclyl; n is 0 or 1; and z is 0; Here, each C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ６ -C １０ Aryl, C ６ -C １０ The aryloxy, 3- to 8-membered heterocyclyl, and 5-membered heteroaryl are independently optionally substituted. or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

18. i) to treat diseases of uncontrolled cell proliferation in mammals; ii) to treat cancer in mammals; iii) to treat bacterial or viral infections in mammals; or iv) To inhibit host ENPP1 18. The pharmaceutical composition of claim 17.

Images