Aryl benzisoxazole compounds as IP6K and IPMK inhibitors and methods of use thereof

Abstract

The present invention provides aryl benzisoxazole compounds of Formula II wherein R1 and R2 are as defined herein, which are useful for inhibiting isoforms of IP6K and IPMK, and for the treatment of diseases and disorders, such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cancer, and viral infections. Also disclosed are methods of using compounds of Formula II for the prevention or treatment of such diseases and disorders, pharmaceutical compositions comprising the compounds, and methods of making the compounds. # imgabs0 #

Description

Technical Field

[0001] The present disclosure relates to compounds containing arylbenzisoxazoles for treating diseases and disorders mediated by IP6K and IPMK inhibitors. The present disclosure also relates to compositions comprising the compounds and methods of using the compounds to treat obesity and obesity-related diseases, including various forms of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), hyperphosphatemia, cancer, fungal infections, parasitic infections, and viral infections. Background Art

[0002] Global obesity rates have more than doubled since 1980. 1-3 In obesity, excessive fat accumulation leads to adipocyte dysfunction, releases inflammatory cytokines, promotes insulin resistance, and reduces the fat storage capacity of adipocytes. Therefore, obesity significantly increases the risk of comorbidities such as type 2 diabetes (T2DM), hypertension, dyslipidemia, cardiovascular disease, non-alcoholic fatty liver disease / non-alcoholic steatohepatitis (NAFLD / NASH), reproductive dysfunction, respiratory abnormalities, psychiatric disorders and neurodegenerative diseases, as well as certain types of cancer. 4-5 Therefore, obesity contributes greatly to the economic and social burden. 6 A combination of lifestyle changes and pharmacology has been shown to have a beneficial effect in combating obesity. 2,7-8 Even a 5% to 10% loss of body weight / fat has been shown to reduce hepatic and cardiometabolic disease in human patients. 9-10 However, limited success has been achieved in long-term weight loss. 1-3

[0003] The inositol pyrophosphate (PP-IP) biosynthetic pathway has been identified as a target in metabolic diseases, osteoporosis, thromboembolism, infection, cancer metastasis, and aging. 11-22 Inositol pyrophosphate is a conserved eukaryotic messenger molecule that possesses a functionally significant and high "energy" diphosphate group. 23-24 They play a vital role in a variety of cellular functions, including insulin secretion and signaling, 12,25-26 ATP production, 27 DNA damage sensing and 28 repair. 29 Many of these effects contribute to the primary role of PP-IP in regulating bioenergetic homeostasis. 23-24,30The starting and initial reaction in the PP-IP synthesis pathway is the phosphorylation of inositol hexaphosphate (InsP6) to 5-bisphosphate inositol pentaphosphate (5-InsP7) by a family of small molecule kinases called IP6K1, IP6K2, and IP6K3 ( Figure 1 ).

[0004] IP6K1 and IP6K2 are expressed in most tissues, whereas IP6K3 is primarily expressed in the heart, skeletal muscle, and brain. 16,20 IP6K1 regulates metabolism in vivo through several mechanisms. 14,20 This isoform promotes insulin secretion from pancreatic β cells. 25 But it weakens some aspects of insulin signaling. 12 Furthermore, IP6K1 reduces whole-body energy expenditure by inhibiting adipocyte thermogenesis. 11,15 Accordingly, systemic and adipocyte-specific Ip6k1-KO mice displayed increased insulin sensitivity and energy expenditure and were protected from high-fat diet (HFD)-induced obesity, hyperinsulinemia, and insulin resistance. 11-12,15 Furthermore, systemic or hepatocyte-specific Ip6k1 deletion ameliorates NAFLD and NASH in mice. 22 Deletion of Ip6k2 in mice reduces cancer cell migration, invasion, and tumor metastasis. 21 Loss of Ip6k3 protects mice from age-induced fat accumulation and insulin resistance. 16

[0005] These observations suggest that it would be useful to develop IP6K inhibitors to dissect the alternative biological functions of each isoform, 31 And it is likely that further development of candidate drugs will be useful, particularly targeting obesity and obesity-induced metabolic and other diseases. 14 Therefore, IP6K is a potential target for mediating diseases and disorders associated with IP6K function; for example, inositol hexaphosphate 5-kinase 1 (IP6K1) has become a potential target for the treatment of NAFLD / NASH due to its pleiotropic effects on metabolic parameters (Zhou et al. J. Med. Chem. 2022, 65, 9, 6869).

[0006] Recent publications have also demonstrated the use of IP6K inhibitors in hyperphosphatemia and IPMK inhibitors in fungal infections (Moritoh et al. Nature communications 2021, 12(1), 1-15; Desmarini et al. Biomolecularesm 2022, 12(10), 1526).

[0007] The subject matter of the present disclosure provides heterocyclic compounds with IP6K and IPMK inhibitory effects, which can be used as preventive or therapeutic agents for treating diseases such as NAFLD / NASH, hyperphosphatemia, fungal infections, glioblastoma, and coronavirus. These and other aspects are addressed by the disclosure herein. Summary of the invention

[0008] According to the purposes of the presently disclosed subject matter, as embodied and broadly described herein, in one aspect is directed to a compound of formula Ia:

[0009]

[0010] Where R 1 is a substituted or unsubstituted aryl or heteroaryl group, and R 2 is halo, alkyl, alkenyl, carboxylic acid, ester, amide, sulfonamide, sulfonic acid, phosphonate, heteroaryl or heterocycloalkyl.

[0011] In one embodiment, the compounds disclosed herein comprise a compound of Formula II:

[0012]

[0013] wherein X is an aryl or heteroaryl group;

[0014] In each case, R 3 Selected from the group consisting of: alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, -D, -OH, -OR 5 、-NH-COR 6 and-CONR 7 R 8 ;

[0015] p is an integer from 0 to 5;

[0016] Y is present or absent, and when present is selected from the group consisting of alkyl, cycloalkyl and alkenyl;

[0017] R 4 Selected from the group consisting of: -CO2H, -CO2R 5 、-CONR 7 R 8 、-SO2-NHR 6 、-SO3H、-P(O)(OH)(OR 9 ), heteroaryl and heterocycloalkyl;

[0018] Where R 5 is selected from the group consisting of alkyl, aryl, heteroaryl and heterocycloalkyl; R 6 is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl; R 7and R 8 are each independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; R 9 is selected from the group consisting of alkyl, aryl, heteroaryl and heterocycloalkyl; and R 10 and R 11 Each is independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.

[0019] In another aspect, the subject matter described herein relates to a pharmaceutical composition comprising a compound of formula I in a pharmaceutically acceptable carrier or excipient.

[0020] In another aspect, the subject matter described herein relates to a method for preventing or treating a disease or condition mediated by IP6K and / or IPMK, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I. In one embodiment, the disease or condition is: NAFLD, NASH, hyperphosphatemia, fungal infection, glioblastoma, or coronavirus.

[0021] In another aspect, the subject matter described herein relates to a method of preparing a compound of formula I, comprising the steps of: 1) contacting a compound having a structure of formula IV with a Wittig reagent, and 2) saponifying the ester group.

[0022] In another aspect, the subject matter described herein relates to a kit for treating a disease or condition mediated by IP6K and / or IPMK, the kit comprising: 1) a pharmaceutical composition comprising a compound of Formula I, and 2) instructions for use.

[0023] In another aspect, the subject matter described herein includes compounds of formula I for use as medicaments and for treating diseases or disorders mediated by IP6K and / or IPMK. In another aspect, the subject matter described herein includes the use of compounds of formula I in the manufacture of medicaments for treating diseases or disorders mediated by IP6K and / or IPMK. In one embodiment, the disease or disorder is: NAFLD, NASH, hyperphosphatemia, fungal infection, glioblastoma, or coronavirus.

[0024] These and other aspects are disclosed in further detail below. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 Depicted is a schematic diagram of the application of an enzyme-coupled assay to determine the potency of TNPs against IP6K1. Figure 1 The chair conformation of InsP6 and 5-InsP7 is shown in the graphical representation of the coupled enzyme assay; the released Pi was determined using the malachite green method.

[0026] FIG. 2A to FIG. 2E The results of the interaction of compound 20 with IP6K are shown. FIG. 2A to FIG. 2CThe dose / response relationships for inhibition of IP6K1, IP6K2, and IP6K3 by compound 20 are shown, respectively; data represent the mean and standard error from three or four independent experiments. Figure 2D Shown is the thermogram of the ITC analysis of the interaction of compound 20 with IP6K2 ("DP" = Differential Power). Figure 2E The corresponding Wiseman plots are shown. The ITC data are from a representative experiment, which is typical of the three.

[0027] FIG. 3A to FIG. 3E The results of the evaluation of the specificity and potency of Compound 20 are shown. Figure 3A Shown are representative HPLC analyses of InsP5, InsP6, InsP7, and InsP8 in HCT116 cells after 3 h of treatment with vehicle control (black symbols) or 2.5 μM Compound 20 (dark grey symbols). Figure 3B Shown from Figure 3A Means and standard errors of three independent experiments performed in . Figure 3C Shown is the determination of InsP7 kinase activity of PPIP5K2 in the presence of 2.5 μM Compound 20 (dark grey bars) or vehicle control (black bars). Figure 3D and Figure 3E Compound 20 is shown to have 33 Dose / dependence of 3-h and 18-h treatment of HCT116 cells. The dashed lines indicate total [ 33 P]-Pi efflux, which is not regulated by InsP8. FIG. 3C to FIG. 3E The data in represent the means and standard errors from three or four independent experiments. DETAILED DESCRIPTION

[0028] The present invention may be understood more readily by reference to the following detailed description of the invention and the Examples included therein.

[0029] Before disclosing and describing the compounds, compositions, articles, systems, devices and / or methods of the present invention, it should be understood that, unless otherwise stated, they are not limited to specific synthetic methods, or, unless otherwise stated, they are not limited to specific reagents, as they can of course vary. It should also be understood that the terms used herein are only used for the purpose of describing specific aspects and are not intended to be restrictive. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described.

[0030] N2-(m-trifluorobenzyl)-N6-(p-nitrobenzyl)purine (TNP) (Compound 1) (Scheme 1 below) is the only widely used small molecule pan-IP6K inhibitor that acts by competing with ATP binding. 32 Treatment of diet-induced obese mice with TNP improves obesity, insulin resistance, and fatty liver, suggesting that targeting the IP6K pathway is pharmacologically tractable. 33 However, TNP is not a high-quality chemical probe due to its low potency, poor solubility and off-target effects. 20, 33 In 2019, the Barrow laboratory reported modified TNP analogs with improved solubility, but the efficacy was still only limited. For example, the IC of their most active compound (compound 2) against IP6K1 was 50 The IC value is 0.75 μM for IP6K2 and IP6K3 50 The values ​​are 20 μM and 15 μM, respectively. 34

[0031] Other laboratories recently described a screened compound library generated by NCATS and identified LI-2242 (compound 4) as an IP6K inhibitor (IC 50 : IP6K1 31nM; IP6K2 42nM; IP6K3 8.7nM). 38 LI-2242 is structurally very similar to the IP6K inhibitor SC-919 (Compound 5), a compound first disclosed by Takeda Pharmaceutical Company Ltd. in 2018. 39 Recently, the activity of compound 5 in a mouse model of chronic kidney disease was described. 40

[0032]

[0033] Scheme 1. Examples of IP6K inhibitors.

[0034] Compared to previous approaches used to identify potential IP6K inhibitors, an alternative approach was used to identify new lead compounds as IP6K inhibitors based on the fact that the ATP binding sites of these enzymes are essentially similar to those of protein kinases, including the relative positions of the nucleotide binding residues. 35 IP6K has a unique structural element in its nucleotide-binding site that limits ATP affinity to values ​​less than one-tenth that of all other inositol phosphate kinases and nearly all protein kinases. 32,36This renders the inhibitor selective for IP6K; therefore, a targeted screen against IP6K2 was performed using a library of protein kinase inhibitors. 37 Compound 3 has a benzisoxazole scaffold and is one of the hits identified in this screen with micromolar potency against IP6K2 (IC 50 : 43.8 μM). Once compound 3 was identified, a ligand-based drug design approach was employed, in which various substituents were introduced into the benzisoxazole-based compound 3.

[0035] A ligand-based drug design approach is necessary because, to date, no crystal structure has been generated for any of the full-length human IP6Ks. Although the core structure of an IP6K ortholog from Entamoeba histolytica has been solved, 41 However, the construct lacks the G-loop, a key feature of the ATP binding pocket. 35 Since the pharmacophore space within IP6K is not yet defined, alternative options are needed for exploring inhibitor scaffolds.

[0036] The subject matter of the present disclosure provides heterocyclic compounds with IP6K and / or IPMK inhibitory effects, which can be used as preventive or therapeutic agents for treating diseases and disorders mediated by IP6K (such as NAFLD / NASH and hyperphosphatemia) and diseases and disorders mediated by IPMK (such as fungal infection, glioblastoma or coronavirus). In some embodiments, the heterocyclic compounds disclosed herein have a structure of Formula II, wherein X, Y, R 3 , R 4 and p are defined as described herein.

[0037]

[0038] Although aspects of the invention may be described and claimed in specific statutory categories, such as the system statutory category, this is for convenience only, and those skilled in the art will understand that aspects of the invention may be described and claimed in any statutory category. Unless expressly stated otherwise, it is not intended that any method or aspect described herein be construed as requiring that its steps be performed in a particular order. Therefore, in the event that a method claim does not specifically state in the claim or specification that the steps are limited to a particular order, in no way is it intended to infer an order. This applies to any possible non-express basis for interpretation, including matters regarding the logic of the arrangement of steps or operational flow, ordinary meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0039] A. Definition

[0040] Listed below are definitions of various terms used to describe the present invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0041] As used in the specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an alkyl group" or "a phenyl group" includes a mixture of two or more such alkyl groups or phenyl groups.

[0042] In this article, ranges can be expressed as from "about" a specific value and / or to "about" another specific value. When expressing such ranges, another aspect includes from a specific value and / or to another specific value. Similarly, when a value is expressed as an approximation by using the antecedent "about", it should be understood that a specific value forms another aspect. It should be further understood that the endpoints of each range are significant relative to the other endpoint, and independently of the other endpoint. It should also be understood that many values ​​are disclosed herein, and each value is also disclosed herein as "about" for the specific value in addition to the value itself. For example, if the value "10" is disclosed, "about 10" is also disclosed. It should also be understood that each unit between two specific units is also disclosed. For example, if 10 and 15 are disclosed, 11, 12, 13 and 14 are also disclosed. In addition, unless the term "integer" is specified, the specified number includes a fraction or a number with a decimal. For example, the range of "about 1 to about 5" includes numbers such as 1, 1.1, 1.5, 2.0, 2.2, etc. As used herein, the term "integer" refers to a number that is a whole number rather than a fraction.

[0043] References in the specification and in the concluding claims to parts by weight of a particular element or component in a composition denote the weight relationship between that element or component and any other elements or components in the composition or article, for which parts by weight are expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight of component Y, X and Y are present in a weight ratio of 2:5, and are present in such a ratio regardless of whether other components are also present in the composition.

[0044] Unless specifically indicated to the contrary, weight percent (wt %) of a component is based on the total weight of the vehicle or composition in which the component is contained.

[0045] As used herein, the terms "optional" and "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not occur.

[0046] Throughout this specification and claims, the words "comprise / comprises / comprising" are used in a non-exclusive sense unless the context requires otherwise. It should be understood that the embodiments described herein include "consisting of" and / or "consisting essentially of".

[0047] As used herein, the terms "increase / increases / increased / increasing", "improvement", "enhancement" and the like indicate that the specified parameter is elevated by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 300%, 400%, 500% or more.

[0048] As used herein, the terms "reduce", "reduces", "reduced", "reduction", "inhibit" and similar terms refer to a reduction of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97% or 100% in the specified parameter.

[0049] As used herein, "contacting" means that reagents are in close proximity such that a reaction can occur.

[0050] As used herein, "ambient temperature" or "room temperature" refers to a temperature in the range of about 20°C to about 25°C.

[0051] As used herein, the term "alkyl" refers to a straight or branched hydrocarbon containing 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like. These groups may be substituted with a group selected from the group consisting of halo (e.g., haloalkyl), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, hydroxy, alkoxy (thereby producing a polyalkoxy group such as polyethylene glycol), alkenyloxy, alkynyloxy, haloalkoxy, cycloalkyloxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocycloalkyloxy, mercaptocarboxy, alkylamino, alkenylamino, alkynylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino, heterocycloalkylamino, disubstituted amino, ester, amide, nitro, or cyano.

[0052] The term "cycloalkyl" refers to a hydrocarbon 3- to 8-membered monocyclic or 7- to 14-membered bicyclic system having at least one saturated ring or having at least one non-aromatic ring, wherein the non-aromatic ring may have a certain degree of unsaturation. The cycloalkyl group may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3 or 4 atoms of each ring of the cycloalkyl group may be substituted with a substituent. Representative examples of cycloalkyl groups include: cyclopropyl, cyclopentyl, cyclohexyl, cyclobutyl, cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, etc.

[0053] As used herein, the term "heterocycloalkyl" refers to a non-aromatic 3- to 8-membered monocyclic, 7- to 12-membered bicyclic or 10- to 14-membered tricyclic ring system containing 1 to 3 heteroatoms (if monocyclic), 1 to 6 heteroatoms (if bicyclic) or 1 to 9 heteroatoms (if tricyclic), the heteroatoms being selected from O, N, S, B, P or Si, wherein the non-aromatic ring system is fully saturated. The heterocycloalkyl group may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3 or 4 atoms of each ring of the heterocycloalkyl group may be substituted with a substituent. Representative heterocycloalkyl groups include piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,3-dioxolane, tetrahydrofuranyl, tetrahydrothienyl, thienyl, etc.

[0054] As used herein, the term "alkenyl" and "alkene" refer to unsaturated aliphatic groups that are similar in length to the above-mentioned alkyl and may be substituted but contain at least one double bond. For example, the term "alkenyl" includes straight chain alkenyl groups (for example, vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl or decenyl), branched alkenyl groups and cycloalkenyl (alicyclic) groups (cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl) groups. The term alkenyl further includes alkenyl groups that include one or more carbons of oxygen, nitrogen, sulphur or phosphorus atoms to replace the hydrocarbon backbone. In certain embodiments, straight or branched alkenyl groups (for example, C2-C10 for straight chain, C3-C10 for side chain) with 10 or less carbon atoms in its main chain are used. Similarly, cycloalkenyl groups can have 3 to 8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure. The term C2-C10 includes alkenyl groups containing 2 to 10 carbon atoms. Some olefin compounds of the present invention can exist as a mixture of E and Z isomers, mainly as E isomers, or mainly as Z isomers. In certain embodiments, compounds of the present invention can be rich in E or Z isomers. For example, compounds of the present invention can have greater than 50%, 60%, 70%, 80%, 90% or 95% or more E or Z isomers.

[0055] As used herein, the term "heteroaryl" or "heteroaromatic" refers to a monovalent aromatic group of 5- or 6-membered rings and includes fused ring systems of 5 to 20 atoms (at least one of which is aromatic) containing one or more heteroatoms independently selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups are pyridyl (including, for example, 2-hydroxypyridyl), imidazolyl, imidazopyridyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl (including, for example, 3-amino-1,2-4-triazole or 3-mercapto-1,2,4-triazole), pyrazinyl (including, for example, aminopyrazine), tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrazolyl, In some embodiments, the heteroaryl group is monocyclic or bicyclic. The heteroaryl group is optionally substituted by one or more substituents as described herein.

[0056] As used herein, the term "aryl" refers to a hydrocarbon monocyclic, bicyclic or tricyclic aromatic ring system. The aryl group may optionally be substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, 4, 5 or 6 atoms of each ring of the aryl group may be substituted with a substituent. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, etc.

[0057] As used herein, the term "substituted" refers to a portion (such as an alkyl group) that is bonded to one or more additional organic groups. In some embodiments, the substituted portion comprises 1, 2, 3, 4 or 5 additional substituent groups or free radicals. Suitable organic substituents include, but are not limited to, hydroxyl, amino, monosubstituted amino, disubstituted amino, sulfhydryl, alkylthiol, alkoxy, substituted alkoxy or halogenated alkoxy, wherein the term is defined herein. Unless otherwise indicated herein, the organic substituent may comprise 1 to 4 or 5 to 8 carbon atoms. When the substituted portion has more than one substituent free radical bonded thereto, the substituent free radical may be the same or different.

[0058] As used herein, the term "unsubstituted" refers to a moiety (such as an alkyl group) that is not radically bonded to one or more additional organic or inorganic substituents as described above, meaning that such moiety is substituted only with hydrogen.

[0059] As used herein, the term "alkoxy", used alone or as part of another group, refers to the group -OR, wherein R is an alkyl group as defined herein.

[0060] As used herein, the terms "halo," "halogen," and "halide" refer to any suitable halogen including -F, -Cl, -Br, and -I.

[0061] As used herein, the term "thiol" refers to a -SH group.

[0062] As used herein, the term "cyano" refers to a -CN group.

[0063] As used herein, the term "carboxylic acid" refers to a -C(O)OH group.

[0064] As used herein, the term "hydroxy" refers to an -OH group.

[0065] As used herein, the term "nitro" refers to a -NO2 group.

[0066] As used herein, the term "sulfonyl" refers to SO2 -The “sulfonyl group” may refer to a sulfonyl group, for example, an alkylsulfonyloxy group such as a methylsulfonyloxy group or an ethylsulfonyloxy group, and an aromatic sulfonyloxy group such as a benzenesulfonyloxy group or a toluenesulfonyloxy group.

[0067] As used herein, the terms "ether" and "alkyl ether" are compounds of the formula R a -OR b Indicates that R a and R b can be independently an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl or heteroaryl group as described herein. As used herein, the term "polyether" is a group of formula -(R a -OR b ) x - indicates that R a and R b It may independently be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl or heteroaryl group as described herein, and "x" is from about 1 to about 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide and polybutylene oxide.

[0068] As used herein, the term "acyl", used alone or as part of another group, refers to a -C(O)R group, where R is any suitable substituent such as aryl, alkyl, alkenyl, alkynyl, cycloalkyl, or other suitable substituents as described herein.

[0069] As used herein, the term "acylsilane", used alone or as part of another group, refers to a -C(=O)-SiR3- group. R is any suitable substituent, such as aryl, alkyl, alkenyl, alkynyl, cycloalkyl, or other suitable substituents as described herein.

[0070] As used herein, the term "silyl" refers to a group of the formula: -Si(R 1 )(R 2 )(R 3 ), where R 1 , R 2 and R 3 Each of the following is independently hydrogen, alkyl, aryl, phenyl, phenyl-substituted alkyl, cycloalkyl or alkenyl; (R 1 R 2 R 3 Si) n O, where R 1 , R 2 and R 3 are independently selected from the group consisting of hydrogen and methyl; and R3Si-X, wherein X is a halide including chlorine, bromine and iodine, or p-toluenesulfonate.

[0071] As used herein, the term "silyl ether" refers to a silicon atom bonded to one or more carbon-containing groups via an oxygen atom (ie, an ether linkage).

[0072] As used herein, the terms "alkylthio" and "thio", used alone or as part of another group, refer to an alkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of alkylthio include, but are not limited to, methylthio, ethylthio, tert-butylthio, hexylthio, and the like.

[0073] As used herein, the term "amino" refers to the group -NH2.

[0074] As used herein, the term "alkylamino" or "monosubstituted amino," used alone or as part of another group, refers to the group -NHR, wherein R is an alkyl group.

[0075] As used herein, the term "disubstituted amino", used alone or as part of another group, means the group -NR a R b , where R a and R b Independently selected from the groups alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo and heterocycloalkyl.

[0076] As used herein, the term "ester", used alone or as part of another group, refers to a -C(O)OR group, where R is any suitable substituent, such as alkyl, cycloalkyl, alkenyl, alkynyl, or aryl.

[0077] As used herein, the term "amide", used alone or as part of another group, refers to -C(O)NR a R b Group, where R a and R b is any suitable substituent, such as alkyl, cycloalkyl, alkenyl, alkynyl or aryl.

[0078] It is understood that the structures provided herein and any statements to "substituted" or "substituted with" include the implicit proviso that such structures and substitutions are consistent with the allowed valencies of the atoms and substituents being substituted and that the substitutions result in stable compounds, e.g., which do not spontaneously undergo transformations such as by rearrangement, cyclization, elimination, and the like.

[0079] As used herein, the term "stereoisomers" refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. These "stereoisomers" have "stereocenters" which may be chiral centers.

[0080] As used herein, the term "chiral" refers to molecules that have the property of non-superimposability of their mirror image partner, while the term "achiral" refers to molecules that are superimposable on their mirror image partner.

[0081] As used herein, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Mixtures of diastereomers can be separated under high resolution analytical procedures such as electrophoresis and chromatography.

[0082] As used herein, the term "enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other. The stereochemical definitions and conventions used herein generally follow SP Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wiley, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention (including but not limited to diastereomers, enantiomers and atropisomers, and mixtures thereof, such as racemic mixtures) are intended to form part of the present invention.

[0083] As used herein, the term "treat / treatment / treating" or "improvement" refers to therapeutic treatment, wherein the purpose is to reverse, alleviate, improve, inhibit, slow down or stop the progression or severity of a condition associated with a disease or illness. The term "treatment" includes reducing or alleviating at least one adverse effect or symptom of a condition, disease or illness associated with a condition. If one or more symptoms or clinical markers are reduced, the treatment is generally "effective". Alternatively, if the progression of the disease is reduced or stopped, the treatment is "effective". That is, "treatment" not only includes the improvement of symptoms or markers, but also includes stopping or at least slowing down the progression or deterioration of symptoms compared to the expected symptoms without treatment. Beneficial or desired clinical results include, but are not limited to: relieving one or more symptoms of symptoms, alleviating the degree of disease, stabilizing (i.e., not worsening) the disease state, delaying or slowing the progression of the disease, improving or alleviating the disease state, alleviating (whether partially or completely) and / or reducing the mortality rate, whether detectable or undetectable. The term "treatment" of a disease also includes alleviating the symptoms or side effects of the disease (including palliative treatment).

[0084] As used herein, the term "pharmaceutical composition" refers to an active agent combined with a pharmaceutically acceptable carrier (e.g., a carrier commonly used in the pharmaceutical industry). The phrase "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions and / or dosage forms that are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications within the scope of reasonable medical judgment, and are commensurate with a reasonable benefit / risk ratio. In some embodiments of any aspect, the pharmaceutically acceptable carrier may be a carrier other than water. In some embodiments of any aspect, the pharmaceutically acceptable carrier may be a cream, emulsion, gel, liposome, nanoparticle and / or ointment. In some embodiments of any aspect, the pharmaceutically acceptable carrier may be an artificial or engineered carrier, for example, a carrier in which the active ingredient is not found to exist in nature.

[0085] The term "inhibitor" as used herein means a molecule that inhibits the activity of an enzyme such as IP6K. "Inhibition" herein means reducing the activity of the enzyme compared to the activity of the target enzyme when the inhibitor is not present. In some embodiments, the term "inhibition" means that the activity of IP6K is reduced by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95%. In other embodiments, inhibition means that the activity of IP6K is reduced by about 5% to about 25%, about 25% to about 50%, about 50% to about 75%, or about 75% to 100%. In some embodiments, inhibition means that the activity of IP6K is reduced by about 95% to 100%, for example, the activity is reduced by 95%, 96%, 97%, 98%, 99% or 100%. Such reduction can be measured using a variety of techniques recognizable by those skilled in the art, including in vitro kinase assays.

[0086] The term "administration" or "administering" includes a route of introducing a compound into a subject to achieve its intended function. Examples of routes of administration that can be used include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal), topical, oral, inhalation, rectal, and transdermal.

[0087] The term "effective amount" includes an effective amount measured in dosages and for the required period of time to achieve the desired result. The effective amount of a compound can vary depending on factors such as the disease state, age, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. The dosage regimen can be adjusted to provide the optimal therapeutic response. An effective amount is also an amount in which any toxic or deleterious effects (e.g., side effects) of the inhibitor compound are outweighed by the therapeutically beneficial effects.

[0088] As used herein, the phrases "systemic administration," "administering systemically," "peripheral administration," and "peripherally administering" refer to the administration of a compound, drug, or other substance so that it enters the patient's system and thereby undergoes metabolism and other similar processes.

[0089] The phrase "therapeutically effective amount" means an amount of a compound of the invention that (i) treats or prevents a particular disease, disorder or condition, (ii) reduces, ameliorates or eliminates one or more symptoms of a particular disease, disorder or condition, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, disorder or condition described herein.

[0090] The term "subject" refers to an animal, such as a mammal, including but not limited to primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In certain embodiments, the subject is a human. B. Arylbenzisoxazole-containing compounds

[0091] The compounds of formula Ia are as described herein. In some embodiments, the compounds of formula I are inhibitors of IP6K and / or IPMK. Thus, as embodied and broadly described herein, in one aspect, compounds of formula Ia are:

[0092]

[0093] Where R 1 is a substituted or unsubstituted aryl or heteroaryl group, and R 2 is halo, alkyl, alkenyl, carboxylic acid, ester, amide, sulfonamide, sulfonic acid, phosphonate, heteroaryl or heterocycloalkyl.

[0094] In one embodiment, the compound of Formula Ia has one, two, three or four R 2 groups, where in each case R 2 Selected from halo, alkyl, alkenyl, carboxylic acid, ester, amide, sulfonamide, sulfonic acid, phosphonate, heteroaryl or heterocycloalkyl.

[0095] In further embodiments, the compound of Formula Ia comprises a compound of Formula Ib:

[0096]

[0097] In separate embodiments, the compound comprises a compound of Formula Ic:

[0098]

[0099] Where R 1 and R 2 As defined herein.

[0100] In one embodiment, the compounds disclosed herein comprise a compound of Formula II:

[0101]

[0102] wherein X is an aryl or heteroaryl group;

[0103] In each case, R 3 Selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo (e.g., -F, -Cl), -D, -OH, -OCF3, -CF3, -OR 5 、-NH-COR 6 、-CONR 7 R 8 、-SO2-NHR 9 and NR 10 R 11 .

[0104] p is an integer from 0 to 5;

[0105] Y is present or absent, and when present is selected from the group consisting of alkyl, cycloalkyl and alkenyl;

[0106] R 4 Selected from the group consisting of: -CO2H, -CO2R 5 、-CONR 7 R 8 、-SO2-NHR 6 、-SO3H、-P(O)(OH)(OR 9 ), heteroaryl and heterocycloalkyl;

[0107] Where R 5 is selected from the group consisting of alkyl, aryl, heteroaryl and heterocycloalkyl; R 6 is selected from the group consisting of alkyl, cycloalkyl, aryl and heteroaryl; R 7 and R 8 are each independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; R 9 is selected from the group consisting of alkyl, aryl, heteroaryl and heterocycloalkyl; and R 10 and R 11 Each is independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.

[0108] A compound as in any of the above embodiments, wherein Y is alkenyl. In further embodiments, Y is -C=C- (ie, ethylene).

[0109] A compound as in any of the above embodiments, wherein Y is cycloalkyl. In further embodiments, Y is cyclopropyl.

[0110] A compound as in any of the above embodiments, wherein Y is ethylene or cyclopropyl and R 4 It is -CO2H.

[0111] A compound as in any of the above embodiments, wherein Y is absent and R 4 Selected from the group consisting of: -CO2H, -CO2R 6 、-CONR 7 R 8 、-SO2-NHR 6 、-SO3H、-P(O)(OH)(OR 9 ), heteroaryl and heterocycloalkyl. In some embodiments, R 4 is heteroaryl or heterocycloalkyl. 4 Select from the group consisting of: In some embodiments, R 4In some embodiments, R 4 It is 1,2,4-oxadiazol-5(4H)-one.

[0112] As in any of the above embodiments, R 4 For-CONR 7 R 8 , where R 7 and R 8 Each is independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl. 7 is hydrogen and R 8 In some embodiments, R 7 is hydrogen and R 8 is a C1-C5 alkyl group. 7 is hydrogen and R 8 is methyl, ethyl or isopropyl. In some embodiments, R 7 and R 8 In some embodiments, R 7 and R 8 Both are methyl, ethyl or isopropyl.

[0113] As in any of the above embodiments, R 4 -CO2R 5 , where R 5 is selected from the group consisting of alkyl, aryl, heteroaryl and heterocycloalkyl. 5 In some embodiments, R 5 It is methyl, ethyl or isopropyl.

[0114] A compound as in any of the above embodiments, wherein Y is absent and R 4 It is -CO2H.

[0115] A compound as in any of the above embodiments, wherein Y is absent and R 4 For tetrazole.

[0116] A compound as in any of the above embodiments, wherein Y is absent and R 4 It is 1,2,4-oxadiazol-5(4H)-one.

[0117] A compound as in any of the above embodiments, wherein R 5 In some embodiments, R 5 It is methyl.

[0118] A compound as in any of the above embodiments, wherein X is aryl. In some embodiments, X is phenyl. In some embodiments, X is unsubstituted phenyl.

[0119] A compound as in any of the above embodiments, wherein in each case, R 3 Selected from the group consisting of: alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, -D, -OH, -OR 5 、-NH-COR 6 、-CONR 7 R 8 、-SO2-NHR 9 and NR 10 R 11 In some embodiments, R 3 In some embodiments, R 3 is a C1-C6 alkyl group. 3 In some embodiments, R 3 is an alkyl group substituted by a halo, aryl or heteroaryl group. 3 It is -CF3 or -CH2-phenyl.

[0120] In some embodiments, R 3 In some embodiments, the heteroaryl group is pyridyl or pyrimidinyl. In some embodiments, the heteroaryl group is substituted with at least one substituent (e.g., halo or hydroxyl) (e.g., -OCH2(C6H5OCH3)). In some embodiments, R 3 In some embodiments, R 3 is piperidinyl, piperazinyl, morpholino or pyrrolidone. In some embodiments, R3 is a β-lactam moiety. In some embodiments, heterocycloalkyl (e.g., piperidinyl) is substituted by cycloalkyl, heterocycloalkyl, -CH2-(cycloalkyl), -CO-alkyl, -CO-cycloalkyl or -CO-heterocycloalkyl. In some embodiments, heterocycloalkyl (e.g., piperidinyl) is substituted by (C1-C6)cycloalkyl (e.g., cyclobutyl), heterocycloalkyl (e.g., trimethoxyester moiety, β-lactam moiety), -CH2-((C1-C6)-cycloalkyl) (e.g., cyclopropyl), -CO-((C1-C6)alkyl) (e.g., -methyl, -isopropyl), -CO-((C1-C6)cycloalkyl) (e.g., butyl) or -CO-heterocycloalkyl. In some embodiments, heterocycloalkyl is substituted by –CH2CH2CH2- to obtain a spirocyclic ligand, for example, In some embodiments, (C1-C6)cycloalkyl (e.g., cyclobutyl, cyclopentyl), -CH2-((C1-C6)-cycloalkyl) (e.g., cycloalkyl is cyclopropyl), -CO-((C1-C6)alkyl) (e.g., alkyl is -methyl, -isopropyl), -CO-((C1-C6)cycloalkyl) (e.g., alkyl is butyl), or -CO-heterocycloalkyl is substituted with halo, alkyl, and / or =O (e.g., )replace.

[0121] In some embodiments, R 3 In some embodiments, R 3 is substituted with halo, alkyl, aryl or heteroaryl. 3 In some embodiments, R 3 It is phenyl substituted by at least one of methyl, -OCH3, -OCF3, -NH2, -OC6H5, -C6H5 or halogen (such as chlorine).

[0122] In some embodiments, R 3 For-OR 5 , where R 5 is selected from the group consisting of alkyl, aryl, heteroaryl and heterocycloalkyl. 5 is an aryl group, such as a phenyl group. In some embodiments, R 5 is a heteroaryl group, such as pyridyl. In some embodiments, phenyl or pyridyl is substituted with one or two groups, such as halogen or alkyl. 5 For heterocycloalkyl, such as piperidinyl. In some embodiments, heterocycloalkyl (e.g., piperidinyl) is alkyl (e.g., methyl, ethyl, isopropyl), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl), heterocycloalkyl, -CH2-cycloalkyl (e.g., cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl), -CO-alkyl (e.g., alkyl is methyl, ethyl, isopropyl), -CO-cycloalkyl (e.g., alkyl is cyclopropyl, cyclobutyl, cyclopentyl), -CO-heterocycloalkyl or -CH2CH2OH substitution. In some embodiments, alkyl, cycloalkyl, heterocycloalkyl, -CH2-cycloalkyl, -CO-alkyl, -CO-cycloalkyl or -CO-heterocycloalkyl groups may be further substituted. Exemplary substituents include alkyl, halogen, cycloalkyl or -COOC(CH3)3 substituents.

[0123] In some embodiments, R 5 In some embodiments, R 5 is a C1-C6 alkyl group. 5 is methyl or ethyl. In some embodiments, R 5 is an alkyl group substituted by a halo, aryl, heteroaryl, amino, cycloalkyl or heterocycloalkyl group. 5 is -CF3, -CH2-phenyl, -CH2-CH2-N(CH3)2, -CH2-heterocycloalkyl or -CH2-CH2-heterocycloalkyl. In some embodiments, -CH2-CH2-heterocycloalkyl is -CH2-CH2-morpholino. In some embodiments, R 5is a heterocycloalkyl group, which may be further substituted. 5 is a substituted or unsubstituted piperidinyl. In some embodiments, R 5 It is a heterocycloalkyl group substituted by an alkyl group, a cycloalkyl group, a heteroarlkyl group, a -CO-cycloalkyl group, a CO-alkyl group, a -CH2-cycloalkyl group or a CH2CH2OH group.

[0124] In some embodiments, R 3 For -NH-COR 6 , where R 6 is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl. 6 is an alkyl group, which is a C1-C6 alkyl group. In some embodiments, the C1-C6 alkyl group is methyl, ethyl, or isopropyl. In some embodiments, the alkyl group is substituted with a heterocycloalkyl group such as morpholino, tetrahydropyranyl, or cyclopropyl. In some embodiments, the alkyl group is -CH2-CH2-morpholino, -CH2-CH2-tetrahydropyranyl, or -CH2-CH2-cyclopropyl. In some embodiments, R 6 is a cycloalkyl group selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. 6 is aryl, which is phenyl. In some embodiments, phenyl is substituted with alkyl or halo (such as chlorine). In some embodiments, R 6 is a heteroaryl group selected from pyridyl, pyrimidinyl and triazolyl. 6 R is a heterocycloalkyl group selected from piperidone, piperidinyl, morpholino, azetidinyl and pyrrolidinyl, any of which may be substituted with, for example, an alkyl substituent (i.e., methyl). In some embodiments, R is a heteroaryl group (e.g., pyridinyl) substituted with -OCH2(C6H5)OCH3 or -OH.

[0125] In some embodiments, R 3 For-CONR 7 R 8 , where R 7 and R 8 Each is independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl. 7 is hydrogen and R 8 In some embodiments, R 7 is hydrogen and R 8 is a C1-C5 alkyl group. 7 is hydrogen and R 8 is methyl, ethyl or isopropyl. In some embodiments, R 7 is hydrogen and R 8In some embodiments, R 8 is a heterocycloalkyl group selected from piperidone, piperidinyl, morpholino, azetidinyl and pyrrolidinyl, any of which may be substituted.

[0126] In some embodiments, R 3 -SO2-NHR 9 , where R 9 is selected from the group consisting of alkyl, aryl, heteroaryl and heterocycloalkyl. 9 is an aryl group, such as a phenyl group. In some embodiments, R 9 is a heteroaryl group, such as pyridinyl. In some embodiments, phenyl or pyridinyl is substituted with one or two groups, such as halogen or alkyl.

[0127] In some embodiments, R 9 In some embodiments, R 9 is a C1-C6 alkyl group. 9 is methyl or ethyl. In some embodiments, R 9 is an alkyl group substituted by a halo, aryl, heteroaryl, amino or heterocycloalkyl group. 9 is -CF3, -CH2-phenyl, -CH2-CH2-N(CH3)2 or -CH2-CH2-heterocycloalkyl. In some embodiments, -CH2-CH2-heterocycloalkyl is -CH2-CH2-morpholino. In some embodiments, R 9 is a heterocycloalkyl group, which may be further substituted. 9 is a substituted or unsubstituted piperidinyl group.

[0128] In some embodiments, R 3 For-NR 10 R 11 , where R 10 and R 11 Each is independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl. 10 is hydrogen and R 11 In some embodiments, R 10 is hydrogen and R 11 is a C1-C5 alkyl group. 10 is hydrogen and R 11 is methyl, ethyl or isopropyl. In some embodiments, R 10 is hydrogen and R 11 In some embodiments, R 10is a heterocycloalkyl group selected from piperidone, piperidinyl, morpholino, azetidinyl and pyrrolidinyl, any of which may be substituted.

[0129] Compounds as in any of the above embodiments, wherein alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of alkyl, hydroxy, cyano, F, Cl, Br, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2CH2CH2CH2 NH2, -CH2CH(CH3)NH2, -CH2CONH2, -CH2OH, -CH2CH2OH, -C(CH3)2OH, -CH(OH)CH(CH3)2, -C(CH3)2CH2OH, -CH2 C(CH3)2OH, -CH2CH2SO2CH3, -CN, -CF3, -CO2H, -COCH3, -CO2CH3, -CO2C(CH3)3, -COCH(OH)CH3, -CONH2, -CONH CH3, -CON(CH3)2, -C(CH3)2CONH2, -NO2, -NH2, -NHCH3, -N(CH3)2, -NHCOCH3, -N(CH3)COCH3, -NHS(O)2CH3, -N HCH2CH2NH2, -NHCH2CH2CH2NH2, -NHCH2CH2CH2CH2NH2, -N(CH3)C(CH3)2CONH2, -N(CH3)CH2CH2S(O)2CH3, -O, -OH, -OCH3, -OCH2CH2OCH3, -OCH2CH2NH2, -OCH2[(C6H4)OCH3], -S(O)2N(CH3)2, -SCH3, -CH2OCH3, -S(O)2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, piperazinyl, piperidinyl, (piperidin-4-yl)ethyl, pyranyl, (piperidin-4-ylmethyl), morpholinomethyl and morpholino.

[0130] Compounds as in any of the above embodiments, wherein -CO-alkyl, -CO-cycloalkyl or -CO-heterocycloalkyl is optionally substituted by one or more groups independently selected from the group consisting of alkyl, hydroxy, cyano, F, Cl, Br, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CH2CH2--CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2CH2 CH2CH2NH2, -CH2CH(CH3)NH2, -CH2CONH2, -CH2OH, -CH2CH2OH, -C(CH3)2OH, -CH(OH)CH(CH3)2, -C(CH3)2CH2OH, - CH2C(CH3)2OH, -CH2CH2SO2CH3, -CN, -CF3, -CO2H, -COCH3, -CO2CH3, -CO2C(CH3)3, -COCH(OH)CH3, -CONH2, -CONH CH3, -CON(CH3)2, -C(CH3)2CONH2, -NO2, -NH2, -NHCH3, -N(CH3)2, -NHCOCH3, -N(CH3)COCH3, -COOC(CH3)3, -NHS( O)2CH3, -NHCH2CH2NH2, -NHCH2CH2CH2NH2, -NHCH2CH2CH2CH2NH2, -N(CH3)C(CH3)2CONH2, -N(CH3)CH2CH2S(O)2C H3, =O, -OH, -OCH3, -OCH2CH2OCH3, -OCH2CH2NH2, -OCH2[(C6H4)OCH3], -S(O)2N(CH3)2, -SCH3, -CH2OCH3, -S(O)2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, piperazinyl, piperidinyl, (piperidin-4-yl)ethyl, pyranyl, (piperidin-4-ylmethyl), morpholinomethyl and morpholino.

[0131] In some embodiments, the compounds disclosed herein comprise a compound of Formula IIIa:

[0132]

[0133] where in each case, R 3 Selected from the group consisting of: alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, -OH, -OR 5 、-NH-COR 6 、-CONR 7 R 8、-SO2-NHR 9 and NR 10 R 11 ; where R 6 is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl; R 7 and R 8 are each independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; and p is an integer from 0 to 5.

[0134] A compound as in any of the above embodiments, wherein p is 1, 2, 3, 4 or 5. In some embodiments, p is 1.

[0135] A compound as in any of the above embodiments, wherein R 3 In some embodiments, R 3 It is 4-phenyl.

[0136] In some embodiments, p is 1 and the compound has the structure of Formula IIIa, IIIb, or IIIc.

[0137]

[0138] In some embodiments, the compound is of formula IIIc, wherein R 3 In a further embodiment, R 3 It is an unsubstituted phenyl group.

[0139] In some embodiments, when the compound of Formula I has R 2 =COOH, R 1 is not phenyl, 4-methylphenyl, 4-fluorophenyl, 4-bromophenyl, 4-methoxyphenyl or 2-methoxyphenyl. 2 =CONHCH3, R 1 In one embodiment, when the compound of formula I has R 2 =-CH=CHCOOH, R 1 Not phenyl.

[0140] In some embodiments, the compounds disclosed herein comprise a compound of Formula IV or a compound of Formula V:

[0141]

[0142] In some embodiments, the compound has one of the following structures:

[0143]

[0144] Compounds from any one of Formula I to Formula V can be selected from the compounds listed in the tables disclosed herein. Compounds of Formula I to Formula V that are not listed in the disclosed tables are also within the scope of Formula I to Formula V.

[0145] The compounds disclosed herein may be in the form of salts. Non-limiting examples thereof include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Preferred examples of metal salts include alkali metal salts such as sodium salts, potassium salts, and the like; alkaline earth metal salts such as calcium salts, magnesium salts, barium salts, and the like; aluminum salts, and the like. Preferred examples of salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, tris(hydroxymethyl)aminomethane, N,N'-dibenzylethylenediamine, and the like. Preferred examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Preferred examples of the salt with an organic acid include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Preferred examples of the salt with a basic amino acid include salts with arginine, lysine, ornithine, etc. Preferred examples of the salt with an acidic amino acid include salts with aspartic acid, glutamic acid, etc.

[0146] Among these salts, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, examples thereof include inorganic salts such as alkali metal salts (e.g., sodium salts, potassium salts, etc.), alkaline earth metal salts (e.g., calcium salts, magnesium salts, etc.), ammonium salts, etc., and when the compound has a basic functional group, examples thereof include salts with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.), and salts with organic acids (e.g., acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.).

[0147] In one embodiment, the compound of formula I is in the form of a salt. In a further embodiment, the salt is a hydrochloride salt.

[0148] In some embodiments, the compounds disclosed herein are selective inhibitors. As used herein, the term "selective inhibitor" refers to a compound that shows increased selectivity for inhibiting a specific IP6K (such as IP6K1) when compared to inhibiting other IP6Ks or IPMKs. In some embodiments, the compounds disclosed herein are pan-inhibitors. As used herein, the term "pan-inhibitor" refers to a compound that inhibits two or more IP6Ks within a similar range of efficacy.

[0149] C. Pharmaceutical Compositions

[0150] The compounds disclosed herein can be formulated into pharmaceutical compositions together with a pharmaceutically acceptable carrier. The compounds disclosed herein can be formulated into pharmaceutical compositions according to standard pharmaceutical practices. According to this aspect, a pharmaceutical composition is provided, comprising a compound as disclosed herein in combination with a pharmaceutically acceptable diluent, carrier or excipient.

[0151] Typical preparations are prepared by mixing the compounds disclosed herein with carriers, diluents or excipients. Suitable carriers, diluents and excipients are well known to those skilled in the art, and include materials such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc. The specific carrier, diluent or excipient used will depend on the mode and purpose of administering the compound. Solvents are usually selected based on solvents approved by those skilled in the art for safe (GRAS) administration to mammals. In general, safe solvents are nontoxic aqueous solvents, such as water and other nontoxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG 400, PEG 300), etc. and mixtures thereof. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, aromas, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., the compound disclosed herein or its pharmaceutical composition) or to facilitate the manufacture of the drug product (i.e., medicine).

[0152] The formulation can be prepared using conventional dissolution and mixing procedures. For example, the raw drug substance (i.e., a compound as disclosed herein or a stable form of the compound) (such as a complex with a cyclodextrin derivative or other known complexing agent) is dissolved in a suitable solvent in the presence of one or more of the above excipients. The compound is usually formulated into a pharmaceutical dosage form to provide an easily controlled dose of the drug and enable the patient to comply with the prescribed treatment regimen.

[0153] The pharmaceutical composition (or formulation) for administration can be packaged in a variety of ways, depending on the method used to administer the drug. In general, the article for distribution includes a container in which the pharmaceutical composition in an appropriate form is deposited. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), pouches, ampoules, plastic bags, metal cylinders, etc. The container may also include an anti-tampering component to prevent inadvertent contact with the contents of the package. In addition, the container is provided with a label describing the contents of the container. The label may also include appropriate warnings.

[0154] Pharmaceutical preparations can be prepared for various routes of administration and types. For example, compounds with desired purity as disclosed herein can be optionally mixed with pharmaceutically acceptable diluents, carriers, excipients or stabilizers in the form of lyophilized preparations, ground powders or aqueous solutions (Remington's Pharmaceutical Sciences (1980) 16th edition, Osol, A. editor). Can be prepared by mixing with a physiologically acceptable carrier (i.e., a carrier that is nontoxic to the recipient at the dose and concentration used) at ambient temperature, appropriate pH and desired purity. The pH of the preparation depends primarily on the specific use and concentration of the compound, but can be in the range of about 3 to about 8. Preparations in acetate buffer at pH 5 are suitable embodiments.

[0155] The compound can be sterile. In particular, the preparation for in vivo administration should be sterile. This sterilization is easy to complete by filtering through a sterile filtration membrane. The compound can usually be stored as a solid composition, a lyophilized preparation or an aqueous solution.

[0156] Pharmaceutical compositions comprising compounds disclosed herein can be formulated, dosed and administered in a manner consistent with good medical practice (i.e., amount, concentration, schedule, course of treatment, vehicle and route of administration). Factors considered in this case include the specific illness being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the illness, the delivery site of the medicament, the method of administration, the schedule of administration, and other factors known to the physician. The "therapeutically effective amount" of the compound to be administered will be determined by such factors and is the minimum amount necessary to prevent, improve or treat a coagulation factor-mediated illness. Such an amount is preferably less than an amount that is toxic to the host or makes the host significantly more susceptible to bleeding.

[0157] Acceptable diluents, carriers, excipients, and stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphates, citrates, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl alcohol, or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 1 0 residues) polypeptides; proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose or dextran; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn protein complexes); and / or nonionic surfactants such as TWEEN TM 、PLURONICS TM Or polyethylene glycol (PEG). Active pharmaceutical ingredients can also be embedded in microcapsules, prepared, for example, by coacervation techniques or by interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. ed. (1980).

[0158] Sustained-release formulations of the compounds can be prepared. Suitable examples of sustained-release formulations include semipermeable matrices of solid hydrophobic polymers containing the compounds disclosed herein, which are in the form of shaped articles, such as films or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and γ-ethyl-L-glutamic acid, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers (such as LUPRON DEPOT TM (Injectable microspheres composed of lactic acid-glycolic acid copolymer and leuproin)) and poly-D-(-)-3-hydroxybutyric acid.

[0159] Preparations include those suitable for the routes of administration described in detail herein. Preparations can be conveniently present in unit dosage form and can be prepared by any method known in the pharmaceutical field. Technology and preparations are generally found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). These methods include the step of combining the active ingredient with a carrier constituting one or more auxiliary ingredients. Typically, the preparation is prepared by uniformly and closely combining the active ingredient with a liquid carrier or a finely dispersed solid carrier or both, and then, if necessary, shaping the product.

[0160] Formulations of compounds disclosed herein suitable for oral administration may be prepared as discrete units such as pills, capsules, cachets or tablets, each containing a predetermined amount of the compound.

[0161] Compressed tablets can be prepared by compressing in a suitable machine an active ingredient in a free-flowing form (such as a powder or granular form) optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersant. Moulded tablets can be manufactured by moulding a mixture of powdered active ingredients moistened with an inert liquid diluent in a suitable machine. Tablets can be optionally coated or scored, and are optionally formulated to provide slow or controlled release of the active ingredient therefrom.

[0162] Tablets, lozenges, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, such as gelatin capsules, syrups or elixirs, can be prepared for oral administration. Preparations of compounds disclosed herein intended for oral administration can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more agents including sweeteners, flavoring agents, colorants and preservatives to provide a palatable preparation. Tablets containing active ingredients mixed with non-toxic pharmaceutically acceptable excipients suitable for making tablets are acceptable. These excipients can be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. Tablets can be uncoated or can be coated by known techniques (including microencapsulation) to delay disintegration and absorption in the gastrointestinal tract, thereby providing a longer lasting effect. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

[0163] For treatment of the eye or other external tissues, e.g., mouth and skin, the formulation may be applied as a topical ointment or cream containing the active ingredient in an amount of, for example, 0.075 to 20% w / w. When formulated as an ointment, the active ingredient may be employed with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with an oil-in-water cream base.

[0164] If desired, the aqueous phase of the cream base may include a polyol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, 1,3-butylene glycol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG 400) and mixtures thereof. Topical formulations may desirably include compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected area. Examples of such transdermal penetration enhancers include dimethyl sulfoxide and related analogs.

[0165] The oil phase of the emulsion can be composed of known ingredients in a known manner. Although this phase can contain only emulsifiers, it can also contain a mixture of at least one emulsifier and fats or oils or both fats and oils. Hydrophilic emulsifiers are included together with lipophilic emulsifiers that can act as stabilizers. Emulsifiers with or without stabilizers constitute so-called emulsifying waxes, and waxes together with oils and fats constitute so-called emulsifying ointment bases, which form the oily dispersed phase of cream formulations. Emulsifiers and emulsion stabilizers suitable for formulation include TWEEN TM 60. 80, cetearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.

[0166] The aqueous suspension of the compound contains an active substance mixed with an excipient suitable for preparing an aqueous suspension. Such excipients include suspending agents, such as sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, povidone, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and gum arabic; and dispersants or wetting agents, such as natural phospholipids (e.g., lecithin), condensation products of alkylene oxide and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain fatty alcohols (e.g., heptadecaned ethyleneoxyethanol), condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). Aqueous suspensions can also contain one or more preservatives (such as ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate), one or more coloring agents, one or more flavoring agents and one or more sweeteners (such as sucrose or saccharin).

[0167] The pharmaceutical composition of the compound can be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension. This suspension can be prepared according to known techniques using those suitable dispersants or wetting agents and suspending agents mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenteral acceptable diluent or solvent (such as 1,3-butanediol). The sterile injectable preparation can also be prepared as a lyophilized powder. The acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile non-volatile oils can be conventionally used as solvents or suspension media. For this purpose, any mild non-volatile oil containing synthetic monoglycerides or diglycerides can be used. In addition, fatty acids (such as oleic acid) can also be used to prepare injectables.

[0168] The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific mode of administration. For example, a delayed release formulation intended for oral administration to humans may contain about 1 mg to 1000 mg of active material, the active material being compounded with a suitable and appropriate amount of carrier material, the amount of which may vary from about 5% to about 95% of the total composition (weight: weight). A pharmaceutical composition may be prepared to provide an easily measurable amount for administration. For example, an aqueous solution intended for intravenous infusion may contain about 1 to 500 μg of active ingredient per milliliter of solution, enabling infusion of a suitable volume at a rate of about 10 mL / hr to about 50 mL / hr.

[0169] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickening agents.

[0170] Formulations suitable for topical administration to the eye also include eye drops in which the active ingredient is dissolved or suspended in a suitable carrier, particularly an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations at a concentration of about 0.5 to 20% w / w, such as about 0.5 to 10% w / w, such as about 1.5% w / w.

[0171] Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0172] Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.

[0173] Preparations suitable for intrapulmonary or intranasal administration have, for example, a particle size in the range of 0.1 to 500 microns (including particle sizes in the range between 0.1 and 500 microns, with increments of microns such as 0.5, 1, 30 microns, 35 microns, etc.), which are administered by rapid inhalation through the nasal passages or by inhalation through the oral cavity to reach the alveolar sacs. Suitable preparations include aqueous or oily solutions of the active ingredient. Preparations suitable for aerosol or dry powder administration can be prepared according to conventional methods and can be delivered together with other therapeutic agents such as compounds used to treat or prevent the conditions described below.

[0174] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

[0175] The preparation can be packaged in unit dose or multi-dose containers, such as sealed ampoules and vials, and can be stored under freeze drying (lyophilization) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, before use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the aforementioned types. Preferred unit dose formulations are those containing the active ingredient of a daily dose or unit daily subdose or its appropriate fraction as described above.

[0176] The present subject matter further provides veterinary compositions comprising at least one active ingredient as defined above and a veterinary carrier therefor. A veterinary carrier is a material that can be used to administer the composition and can be a solid, liquid or gaseous material that is inert or acceptable in the veterinary field and is compatible with the active ingredient. These veterinary compositions can be administered parenterally, orally or by any other desired route.

[0177] In certain embodiments, the pharmaceutical composition comprising a compound of the present disclosure further comprises a chemotherapeutic agent. In some of these embodiments, the chemotherapeutic agent is an immunotherapeutic agent.

[0178] The administration of the compounds of the present invention can be effected by any method capable of delivering the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, inhalation and rectal administration.

[0179] The amount of active compound administered will depend on the subject being treated, the severity of the illness or condition, the rate of administration, the disposal of the compound, and the judgment of the prescribing physician. However, the effective dose is in the range of about 0.001 to about 100 mg / kg body weight / day, preferably about 1 to about 35 mg / kg / day, in a single dose or divided dose. For a 70 kg person, this will be equivalent to about 0.05 to 7 g / day, preferably about 0.05 to about 2.5 g / day. In some cases, dosage levels below the lower limit of the aforementioned range may be more than sufficient, while in other cases, larger doses can be used without causing any harmful side effects, as long as such larger doses are first divided into several small doses for use throughout the day.

[0180] Dosages can be administered once a day (QID), twice a day (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism, and excretion of a particular compound. In addition, toxicity factors may affect dosage and administration regimens. When administered orally, pills, capsules, or tablets may be taken daily or at a lower frequency within a specified time. The regimen may be repeated for multiple treatment cycles.

[0181] The active compound may be used as a sole therapy or in combination with one or more therapeutic agents. Such treatment may be achieved by means of simultaneous, sequential or separate administration of the individual therapeutic components.

[0182] D.Products

[0183] In another embodiment of the subject matter of the present disclosure is an article of manufacture or "kit" containing materials that can be used to treat the diseases and disorders described herein. The kit comprises a container containing a compound of formula I. The kit may further comprise a label or package insert on or associated with the container. The term "package insert" is used to refer to instructions typically included in commercial packaging of therapeutic products, which contain information about the following items: indications, usage, dosage, administration, contraindications and / or warnings for the use of such therapeutic products. Suitable containers include, for example, bottles, vials, syringes, blister packs, etc. The container may be formed of a variety of materials (such as glass or plastic). The container may contain a compound of formula I or a formulation thereof that is effective in treating the condition, and may have a sterile access port (for example, the container may be an intravenous solution bag or a vial with a stopper that can be pierced by a hypodermic needle). At least one active agent in the composition is a compound of formula I. The label or package insert indicates that the composition is used to treat a preferred condition, such as cancer. In addition, the label or package insert may indicate that the patient to be treated is a patient suffering from a condition (such as NAFLD or NASH). The label or package insert may also indicate that the composition can be used to treat other conditions. Alternatively or additionally, the article of manufacture may further include a second container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffered saline, Ringer's solution, and dextrose solution. It may further include other materials required from a commercial and user's point of view, including other buffers, diluents, filters, needles, and syringes.

[0184] The kit may further comprise instructions for administration of the compound of Formula I and the second pharmaceutical formulation (if present). For example, if the kit comprises a first composition comprising a compound of Formula I and a second pharmaceutical formulation, the kit may further comprise instructions for administering the first pharmaceutical composition and the second pharmaceutical composition simultaneously, sequentially or separately to a patient in need thereof.

[0185] In another embodiment, the kit is suitable for delivering a solid oral form of a compound of formula I, such as a tablet or capsule. Such a kit preferably includes a plurality of unit doses. Such a kit may include a card with a dose oriented in the order of its intended use. An example of such a kit is a "blister pack". Blister packs are well-known and widely used in the packaging industry for packaging pharmaceutical unit dosage forms. If necessary, a memory aid may be provided, such as in the form of numbers, letters or other marks or with a calendar insert, specifying the date on which the dose may be administered in the treatment schedule.

[0186] According to one embodiment, the kit may include (a) a first container containing a compound of Formula I; and optionally (b) a second container containing a second pharmaceutical preparation, wherein the second pharmaceutical preparation comprises a second compound. Alternatively or additionally, the kit may further include a third container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and glucose solution. It may further include other materials required from a commercial and user's point of view, including other buffers, diluents, filters, needles, and syringes.

[0187] In certain other embodiments in which the kit comprises a composition of Formula I and a second therapeutic agent, the kit may comprise a container for accommodating the individual compositions, such as a separate bottle or a separate foil packet, however, the individual compositions may also be contained in a single, inseparable container. Typically, the kit comprises instructions for administering the individual components. The kit form is particularly advantageous when the individual components are preferably administered in different dosage forms (e.g., oral and parenteral), administered at different dosage intervals, or when the prescribing physician needs to titrate the individual components of the combination.

[0188] E. Preparation method

[0189] The compounds disclosed herein can be synthesized by synthetic routes that include methods analogous to those well known in the chemical art, particularly in light of the description contained herein, as well as those methods described for other heterocycles in Comprehensive Heterocyclic Chemistry II, ed. Katritzky and Rees, Elsevier, 1997, e.g., Vol. 3; Liebigs Annalen der Chemie, (9): 1910-16, (1985); Helvetica Chimica Acta, 41: 1052-60, (1958); Arzneimittel-Forschung, 40(12): 1328-31, (1990), each of which is expressly incorporated by reference. The starting materials are generally available from commercial sources or are readily prepared using methods well known to those skilled in the art (e.g., by methods generally described in Louis F. Fieser and Mary Fieser, Reagents / or Organic Synthesis, v. 1-23, Wiley, NY (1967-2006 editions), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed., Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database)).

[0190] Synthetic chemistry transformations and protecting group methods (protection and deprotection) and necessary reagents and intermediates useful for synthesizing compounds of Formula I are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.

[0191] The general procedures and examples provide an exemplary method for preparing compounds of formula I. It will be appreciated by those skilled in the art that other synthetic routes may be used to synthesize the compound. Although specific starting materials and reagents are depicted and discussed in the accompanying drawings, the general procedures and the examples, other starting materials and reagents may also be easily substituted to provide a variety of derivatives and / or reaction conditions. In addition, according to the present disclosure, conventional chemistry well known to those skilled in the art may be used to further modify many of the exemplary compounds prepared by the described methods.

[0192] When preparing compounds, it may be necessary to protect the remote functionality (e.g., primary or secondary amine) of the intermediate. The demand for such protection will vary according to the properties of the remote functional group and the conditions of the preparation method. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butyloxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The demand for such protection is easily determined by those skilled in the art. For a general description of protecting groups and their uses, see TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0193] F. How to use

[0194] The compounds and compositions disclosed herein may also be used in methods for treating various diseases and / or disorders that have been identified as being associated with any member of the IP6K family or IPMK.

[0195] Diseases and conditions to be treated include, but are not limited to, degenerative diseases, cancer, diabetes, autoimmune diseases, cardiovascular diseases, coagulation disorders, eye diseases, infectious diseases, and diseases caused by mutations in one or more genes.

[0196] More specifically, the diseases and conditions may include diabetes (e.g., type 1 diabetes, type 2 diabetes, gestational diabetes, obesity diabetes), cardiovascular disease (e.g., heart failure, arrhythmia, ischemic heart disease, valvular heart disease, arteriosclerosis), obesity (e.g., malignant mastocytosis, exogenous obesity, hyperinsulinemia obesity, protoplasmic hyperplasia obesity, pituitary obesity, protoplasmic hypoplasia obesity, hypothyroidism obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, obesity, upper body obesity, nutritional obesity, hypogonadal obesity, systemic mastocytosis, simple obesity, central obesity, etc.), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), excessive eating, hyperlipidemia / dyslipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, high LDL cholesterol, low HDL cholesterol, postprandial hyperlipidemia), hyperphosphatemia, hypophosphatemia, hyperkalemia, hypertension, complications of diabetes diseases (e.g., neuropathy, nephropathy, retinopathy, diabetic cardiomyopathy, cataract, macroangiopathy, osteopenia, hyperosmolar diabetic coma, infections (e.g., respiratory tract infection, urinary tract infection, gastrointestinal infection, skin and soft tissue infection, lower limb infection), diabetic gangrene, dry mouth, hearing loss, cerebrovascular disease, peripheral blood circulation disorder), metabolic syndrome (having no less than 3 pathologies selected from hypertriglyceridemia (TG) blood, low HDL cholesterol (HDL-C) blood, hypertension, abdominal obesity and impaired glucose tolerance), sarcopenia, mood disorders, sexual dysfunction, depression, anxiety, neurosis, arteriosclerosis, knee arthritis, acute kidney disease, glaucoma, ischemic diseases, myocardial infarction, cerebral stroke, dementia, neurodegenerative diseases (e.g., amyotrophic lateral sclerosis), mitochondrial diseases, retinitis pigmentosa, glaucoma, osteoporosis, fungal infections (i.e., yeast strains, such as but not limited to Cryptococcus neoformans (Cryptococcus neoformans and / or Candida albicans), parasitic infections (i.e. Toxoplasma gondii), etc.

[0197] According to the purposes of the presently disclosed subject matter, as embodied and broadly described herein, in one aspect relates to a method of preventing or treating a disease or condition mediated by IP6K, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula II, wherein the compound of formula II is:

[0198]

[0199] wherein X is an aryl or heteroaryl group;

[0200] In each case, R 3Selected from the group consisting of: alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, -D, -OH, -OR 6 、-N-COR 6 、-CONR 7 R 8 、-SO2-NHR 9 and NR 10 R 11 ;

[0201] p is an integer from 0 to 5;

[0202] Y is present or absent, and when present is selected from the group consisting of alkyl, cycloalkyl and alkenyl;

[0203] R 4 Selected from the group consisting of: -CO2H, -CO2R 6 、-CONR 7 R 8 、-SO2-NHR 6 、-SO3H、-P(O)(OH)(OR 9 ), tetrazolyl, triazolyl and oxazol-2(3H)-onyl; and

[0204] R 5 is halogenated or alkyl;

[0205] Where R 6 is selected from the group consisting of alkyl, cycloalkyl, aryl and heteroaryl, and

[0206] R 7 and R 8 are each independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl,

[0207] wherein the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted, and pharmaceutically acceptable salts thereof.

[0208] In one embodiment, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of halo, alkyl, hydroxy, cyano, F, Cl, Br, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2CH2CH2CH2 NH2, -CH2CH(CH3)NH2, -CH2CONH2, -CH2OH, -CH2CH2OH, -C(CH3)2OH, -CH(OH)CH(CH3)2, -C(CH3)2CH2OH, - CH2C(CH3)2OH, -CH2CH2SO2CH3, -CN, -CF3, -CO2H, -COCH3, -CO2CH3, -CO2C(CH3)3, -COCH(OH)CH3, -CONH2 , -CONHCH3, -CON(CH3)2, -C(CH3)2CONH2, -NO2, -NH2, -NHCH3, -N(CH3)2, -NHCOCH3, -N(CH3)COCH3, -NHS( O)2CH3, -NHCH2CH2NH2, -NHCH2CH2CH2NH2, -NHCH2CH2CH2CH2NH2, -N(CH3)C(CH3)2CONH2, -N(CH3)CH2CH2 S(O)2CH3, =O, -OH, -OCH3, -OCH2CH2OCH3, -OCH2CH2NH2, -S(O)2N(CH3)2, -SCH3, -CH2OCH3, -S(O)2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, piperazinyl, piperidinyl, (piperidin-4-yl)ethyl, pyranyl, (piperidin-4-ylmethyl), morpholinomethyl and morpholino;

[0209] and pharmaceutically acceptable salts thereof.

[0210] Specific embodiments of the subject matter described herein include:

[0211] Example 1: Compound of formula II:

[0212]

[0213] or a pharmaceutically acceptable salt thereof, wherein

[0214] X is an aryl or heteroaryl group;

[0215] In each case, R 3Selected from the group consisting of: alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, -D, -OH, -OR 5 、-NH-COR 6 、-CONR 7 R 8 、-SO2-NHR 9 and NR 10 R 11 ;

[0216] p is an integer from 0 to 5;

[0217] Y is present or absent, and when present is selected from the group consisting of alkyl, cycloalkyl and alkenyl; and

[0218] R 4 Selected from the group consisting of: -CO2H, -CO2R 5 、-CONR 7 R 8 、-SO2-NHR 6 、-SO3H、-P(O)(OH)(OR 9 ), heteroaryl and heterocycloalkyl; wherein

[0219] R 5 is selected from the group consisting of alkyl, aryl, heteroaryl and heterocycloalkyl; R 6 is selected from the group consisting of alkyl, cycloalkyl, aryl and heteroaryl; R 7 and R 8 are each independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; R 9 is selected from the group consisting of alkyl, aryl, heteroaryl and heterocycloalkyl; and R 10 and R 11 are each independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.

[0220] Embodiment 2: A compound according to Embodiment 1, wherein Y is absent.

[0221] Embodiment 3: A compound according to Embodiment 1 or 2, wherein R 4 is selected from the group consisting of -CO2H, heteroaryl and heterocycloalkyl.

[0222] Embodiment 4: A compound according to any one of the preceding embodiments, wherein R 4 Select from the group consisting of:

[0223] Embodiment 5: The compound according to embodiment 4, wherein R 4 for

[0224] Embodiment 6: The compound according to embodiment 4, wherein R 4 for

[0225] Embodiment 7: A compound according to any one of Embodiments 1 to 3, wherein R 4 It is -CO2H.

[0226] Embodiment 8: A compound according to any one of the preceding embodiments, wherein X is aryl.

[0227] Embodiment 9: The compound according to Embodiment 1, wherein the compound is selected from the compounds of Formula III, IV and V:

[0228]

[0229] Embodiment 10: A compound according to any one of embodiments 1 to 9, wherein R 3 It is C1-C6 alkyl, aryl or halogenated.

[0230] Embodiment 11: A compound according to any one of Embodiments 1 to 10, wherein R 3 It is methyl.

[0231] Embodiment 12: A compound according to any one of Embodiments 1 to 10, wherein R 3 It is 4-phenyl.

[0232] Embodiment 13: A compound according to any one of Embodiments 1 to 10, wherein R 3 is selected from the group consisting of alkyl, aryl, heteroaryl and heterocycloalkyl.

[0233] Embodiment 14: A compound according to any one of the preceding embodiments, wherein p is 1.

[0234] Embodiment 15: A compound according to any one of the preceding embodiments, wherein R 3 It is a heterocycloalkyl group.

[0235] Embodiment 16: A compound according to any one of the preceding embodiments, wherein R 3 It is piperidinyl.

[0236] Embodiment 17: A compound according to any one of the preceding embodiments, wherein R 3 For-OR 5 .

[0237] Embodiment 18: A compound according to any one of the preceding embodiments, wherein R 5 is selected from the group consisting of alkyl, aryl, heteroaryl and heterocycloalkyl.

[0238] Embodiment 19: A compound according to any one of the preceding embodiments, wherein R 5 is a heteroaryl group or a heterocycloalkyl group.

[0239] Embodiment 20: A compound according to any one of the preceding embodiments, wherein R 5 It is pyridyl or piperidinyl.

[0240] Embodiment 21: A compound according to Embodiment 19, wherein R 5 It is a heterocycloalkyl group.

[0241] Embodiment 22: A compound according to Embodiment 1, wherein X is phenyl, R 3 For -NH-COR 6 , and p is 1, where R 6 is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl.

[0242] Embodiment 23: A compound according to Embodiment 22, wherein R 6 It is a cycloalkyl group.

[0243] Embodiment 24: A compound according to Embodiment 22, wherein R 6 It is a heterocycloalkyl group.

[0244] Embodiment 25: A compound according to Embodiment 22, wherein R 6 It is cyclopropyl or cyclobutyl.

[0245] Example 26: A compound having one of the following structures:

[0246]

[0247]

[0248] Embodiment 27: A pharmaceutical composition comprising a compound according to any one of Embodiments 1 to 26 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0249] Embodiment 28: A method for preventing or treating a disease or condition mediated by IP6K and / or IPMK, the method comprising administering a therapeutically effective amount of a compound according to any one of Embodiments 1 to 26 to a subject in need thereof.

[0250] Embodiment 29: The method according to embodiment 28, wherein the disease or disorder is selected from obesity, obesity-related diseases, cancer and viral infection.

[0251] Embodiment 30: The method according to embodiment 28, wherein the obesity-related disease is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

[0252] Embodiment 31: The method according to embodiment 28, wherein the cancer is glioblastoma.

[0253] Embodiment 32: The method according to embodiment 28, wherein the viral infection is coronavirus.

[0254] Example 33: A kit for treating a disease or condition mediated by IP6K and / or IPMK, the kit comprising: 1) a pharmaceutical composition comprising a compound of formula II, and 2) instructions for use.

[0255] Embodiment 34: A compound according to Embodiment 1 for use as a medicament and for use in the treatment of a disease or condition mediated by IP6K and / or IPMK.

[0256] G. Examples

[0257] The following preparations and examples are given to enable those skilled in the art to more clearly understand and practice the present invention. They should not be considered as limiting the scope of the present invention, but are merely illustrative and representative.

[0258] General Information: Microwave reactions were performed using a CEM Discover-S reactor with a vertically focused IR external temperature sensor and an Explorer 72 autosampler. Dynamic mode was used to set the desired temperature and hold time with the following fixed parameters: pre-stirring, 1 min; pressure, 200 psi; power, 200 W; maximum power, off; agitation, high. Sonication was performed on a Branson 3510 Ultrasonic Cell. Centrifugation was performed on an Eppendorf Centrifuge 5418. Flash chromatography was performed on a Teledyne ISCO Combi with prepacked silica disposable columns or prepacked reversed phase C18 columns. R f 200. Analytical HPLC was performed using a protruding diode array detector (SPD-M20A). The samples were injected into a 3.6 μm PEPTIDE XB-C18 150 x 4.6 mm LC column. Flow rate was 1.0 mL / min. Various linear gradients were used, where A was H2O + 0.1% TFA and B was acetonitrile + 0.1% TFA. Analytical thin layer chromatography (TLC) was performed using pre-coated silica gel 60F 254 , 0.25 mm TLC plate. Using UV 254and phosphomolybdic acid (where charring was performed) to visualize the TLC plates. 1 H NMR spectra were obtained using a 400 or 500 MHz spectrometer using CDCl3 (7.26 ppm), DMSO-d 6 (2.50 ppm, quintet) or CD3OD (3.31 ppm, quintet) as internal reference. Signals are reported as m (multiplet), s (singlet), d (doublet), t (triplet), q (quartet) and bs (broad singlet); and coupling constants are reported in Hertz (Hz). 13 C NMR spectra were obtained with a 100 or 125 MHz spectrometer using CDCl3 (77.2 ppm, triplet), DMSO-d 6 (39.5ppm, septet) or CD3OD (49.3ppm, septet) as internal standard. LC / MS is performed using an analytical instrument with a UV detector set to 220nm, 254nm and 280nm, and a single quadrupole mass spectrometer (which uses an electrospray ionization (ESI) source). Samples were injected (2μL) onto a 4.6x 50mm, 1.8μM, C18 chromatographic column at room temperature. A linear gradient from 10% to 100% B (MeOH+0.1% acetic acid) in 5.0min, followed by pumping 100% B for 2min or 4min, where A is H2O+0.1% acetic acid. The flow rate is 1.0mL / min. High resolution (positive ion) mass spectrometry (HRMS) is obtained using an LCMS-TOF mass spectrometer. The purity (>95%) of all final compounds is determined by LC-MS.

[0259] Example 1: (E)-N-methyl-3-(3-phenylbenzo[c]isoxazol-5-yl)acrylamide and (1R,2R)-2-(3- Ethyl phenylbenzo[c]isoxazol-5-yl)cyclopropane-1-carboxylate

[0260]

[0261] NaOH pellets (40.0mg, 1.00mmol) are granulated and added to i-PrOH (1.00mL), to obtain a suspension. 2- (4- nitrophenyl) -1,3- dioxolane (39.0mg, 0.200mmol) and benzyl cyanide (57.7μL, 0.500mmol) are added to the resulting mixture. The reaction mixture is stirred at room temperature overnight. After the reaction is completed (monitored by LC-MS), the brown precipitate is filtered and washed with a small amount of i-PrOH, then washed with a large amount of water. The filter cake is collected and dried under reduced pressure to obtain 2,1- benzisoxazole. Without further purification, MeCN (1.5mL) and water (0.5mL) are added to the solid. TFA (100μL, 1.31mmol) is added to the resulting suspension. The reaction mixture is stirred at room temperature for 3h, then neutralized by saturated NaHCO solution and extracted with CH2Cl2 (3x). The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel column (hexane / EtOAc gradient) to give 3-phenylbenzo[c]isoxazole-5-carbaldehyde as a yellow solid (36.7 mg, 0.164 mmol, 82%). 1 H NMR (400MHz, CDCl3) δ10.01(s,1H),8.40(s,1H),8.12-8.04(m,2H),7.84(dd,J=9.3,1.3Hz,1H),7.69(dt,J=8.7,0.9Hz,1H),7.65-7.59(m,3H); 13 CNMR (126MHz,CDCl3)δ190.52,168.66,158.61,134.08,131.74,130.63,129.75,127.58,127.48,127.27,116.82,114.18; for [M+H + ](C 14 H 10 NO2 + ) MS (ESI): calculated value m / z: 224.07; found value m / z: 224.10; LC-MS: 97% purity.

[0262] To 3-phenylbenzo [c] isoxazole-5-carboxaldehyde (137mg, 0.612mmol) in CH2Cl2 (3.0mL) solution in (triphenylphosphoranylidene) ethyl acetate (224mg, 0.642mmol). The reaction mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue was dissolved in MeCN (0.62mL). Then, a solution of NaOH (73mg, 1.8mmol) in water (0.16mL) was added. The reaction mixture was heated at 60°C for 1.5h, then the reaction was cooled to room temperature and acidified to pH=1 by 1MHCl. The yellow precipitate was filtered and ultrasonicated in a minimum amount of 1:1 MeOH / H2O to remove trace cis isomers. The crude product was collected from centrifugation and further purified by reverse phase column (MeCN / H2O gradient) to give (E)-3-(3-phenylbenzo[c]isoxazol-5-yl)acrylic acid as a yellow solid (141 mg, 0.532 mmol, 87%). 1 H NMR (500MHz, DMSO-d6) δ8.43 (s, 1H), 8.17 (d, J = 7.4Hz, 2H), 7.85 (d, J = 9.4Hz, 1H), 7.75 (d, J = 16.0Hz, 1H), 7.71-7.58 (m, 4H), 6.62 (d, J = 16.0Hz, 1H); 13 C NMR (214 MHz, DMSO-d6) δ 167.73, 165.20, 157.27, 143.30, 131.70, 131.22, 129.74, 129.61, 127.13, 126.79, 124.09, 119.74, 115.73, 114.11; for [M+H] + (C 16 H 12 NO3 + ) MS (ESI): calculated value m / z: 266.08; found value m / z: 266.10; LC-MS: 98% purity.

[0263] At 0 ° C, to a solution of (E)-3-(3-phenylbenzo [c] isoxazol-5-yl) acrylic acid (21.6 mg, 81.4 μmol) in DMF (0.81 mL) was added DIPEA (43 μL, 0.24 mmol) and HATU (34.1 mg, 89.6 μmol). The mixture was stirred at 0 ° C for 30 min, and then methylamine hydrochloride (8.2 mg, 0.12 mmol) was added. The resulting reaction mixture was stirred at room temperature for one hour and then quenched with water (2.5 mL). The product was crushed and separated by centrifugation. The crude product was washed with water (2x) and dried under lyophilization to obtain (E)-N-methyl-3-(3-phenylbenzo [c] isoxazol-5-yl) acrylamide as a yellow solid (22.6 mg, 81.2 μmol, quantitative yield). 1 H NMR (400MHz, CDCl3) δ8.04-7.97 (m, 2H), 7.89 (s, 1H), 7.69 (d, J = 15.5Hz, 1H), 7.63-7.49(m,5H),6.40(d,J=15.5Hz,1H),5.80(s,1H),2.97(d,J=4.9Hz,3H); 13 C NMR (126 MHz, CDCl3) δ 166.44, 165.72, 157.83, 140.17, 131.74, 130.90, 129.56, 128.65, 128.12, 126.89, 122.98, 120.89, 116.41, 114.78, 26.78; for [M+H] + (C 17 H 15 N2O2 + ) MS (ESI): calculated value m / z: 279.11; found value m / z: 279.10; LC-MS: 99% purity.

[0264] At 0 ° C, a mixture of trimethylsulfonium iodide (139 mg, 0.630 mmol) and NaH (25.2 mg, 0.630 mmol, 60% by weight suspension in mineral oil) in anhydrous DMSO (0.5 mL) was added to a dried round-bottom flask. The resulting suspension was stirred for an additional 20 min. Then a solution of (E)-3-(3-(3,5-dimethylphenyl)benzo[c]isoxazole-5-yl)ethyl acrylate (96.4 mg, 0.300 mmol) in anhydrous DMSO (1.0 mL) was added dropwise to the suspension. The reaction solution was then stirred at room temperature for 24 hours. When the room temperature material was completely consumed, the resulting mixture was quenched by saturated NH4Cl. The mixture was extracted three times with EtOAc, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl (1R,2R)-2-(3-phenylbenzo[c]isoxazol-5-yl)cyclopropane-1-carboxylate as a yellow solid (35.3 mg, 0.105 mmol, 35%). 1 H NMR (400MHz, CDCl3) δ7.62-7.52(m,4H),7.14(d,J=2.0Hz,1H),7.02(dd,J=9.3,1.6Hz,1H),4.20(q,J=7.1Hz,2H),2.65-2.57(m,1 H),2.44(s,6H),1.96(ddd,J=8.5,5.3,4.2Hz,1H),1.64(dt,J=9.1,5.0Hz,1H),1.43-1.36(m,1H),1.30(t,J=7.1Hz,3H); for [M+H] + (C 21 H 22 NO3 + ) MS (ESI): calculated value m / z: 336.16; found value m / z: 336.20; LC-MS: 95% purity.

[0265] Table 1 describes the compounds prepared according to the procedure described in Example 1 using appropriate reagents. 50 (determined by enzyme-coupled assay): ++++ means <10 nM; +++ means between 10 nM-100 nM, ++ means between 100 nM-1 μM; + means between 1 μM-100 μM; - means inactive).

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272] Example 2: 3-(m-Tolyl)benzo[c]isoxazole-5-carboxylic acid

[0273]

[0274] NaOH pellets (60.0mg, 1.50mmol) are granulated and added to i-PrOH (3.00mL), to obtain a suspension. 2- (4- nitrophenyl) -1,3- dioxolane (58.6mg, 0.300mmol) and 2- (m-tolyl) acetonitrile (98 μL, 0.75mmol) are added to the resulting mixture. The reaction mixture is stirred at room temperature overnight. After the reaction is completed (monitored by LC-MS), the brown precipitate is filtered and washed with a small amount of i-PrOH, then washed with a large amount of water. The filter cake is collected and dried under reduced pressure to obtain 2,1- benzisoxazole intermediates. Without further purification, solid is added MeCN (2.0mL) and water (1.0mL). TFA (138 μL, 1.80mmol) is added to the resulting suspension. The reaction mixture is stirred at room temperature for 3h, then neutralized by saturated NaHCO solution and extracted with CH2Cl2 (3x). The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel column (hexane / EtOAc gradient) to give 3-(m-tolyl)benzo[c]isoxazole-5-carbaldehyde as a yellow solid (55.0 mg, 0.232 mmol, 77%). 1 H NMR (400 MHz, CDCl3) δ10.01 (s, 1H), 8.39 (t, J = 1.2 Hz, 1H), 7.90–7.80 (m, 3H), 7.68 (dt, J = 9.3, 0.9 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.43–7.38 (m, 1H), 2.51 (s, 3H); for [M+H] + (C 15 H 12 NO2 + ) by MS (ESI): calculated value m / z: 238.09; found value m / z: 238.10.

[0275] To a solution of 3-(m-tolyl)benzo[c]isoxazole-5-carboxaldehyde (23.7 mg, 0.100 mmol) in N,N-dimethylformamide (1.0 mL) was added potassium peroxymonosulfonate triple salt (61.5 mg, 0.100 mmol). The reaction mixture was stirred at room temperature for 18 hours. After the reaction was completed (monitored by LC-MS), the reaction mixture was purified by reverse phase column to obtain 3-(m-tolyl)benzo[c]isoxazole-5-carboxylic acid as a yellow solid (21.3 mg, 84.1 μmol, 84%). 1 H NMR (400MHz, DMSO-d6) δ13.39 (s, 1H), 8.63 (d, J = 1.4Hz, 1H), 7.96-7.90 (m, 2H), 7.87 (dd, J = 9. 4,1.4Hz,1H),7.73(d,J=9.4Hz,1H),7.57(t,J=7.9Hz,1H),7.46(d,J=7.6Hz,1H),2.47(s,3H); 13 C NMR (101 MHz, DMSO-d6) δ 167.19, 166.53, 157.49, 139.34, 132.26, 130.47, 129.74, 127.53, 127.18, 126.80, 125.32, 124.21, 115.12, 113.40, 20.96; for [M+H] + (C 15 H 12 NO3 + ) by MS (ESI): calculated value m / z: 254.08; found value m / z: 254.10.

[0276] Table 2 describes the compounds prepared according to the procedure described in Example 2 using appropriate reagents. 50 (determined by enzyme-coupled assay): ++++ means <10 nM; +++ means between 10 nM-100 nM, ++ means between 100 nM-1 μM; + means between 1 μM-100 μM; - means inactive).

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295] Example 3: 3-(4-Benzylphenyl)benzo[c]isoxazole-5-carboxylic acid

[0296]

[0297] Under nitrogen atmosphere, to a mixture of 3-(4-bromophenyl)-5-(1,3-dioxolane-2-yl)benzo[c]isoxazole (69.2 mg, 0.200 mmol), SPhos (3.28 mg, 8.0 μmol) and Pd(OAc)2 (0.90 mg, 4.0 μmol) in anhydrous THF (0.2 mL, no inhibitor) was slowly added benzylzinc bromide (0.50 mL, 0.5 M solution in THF, 0.24 mol). The reaction mixture was stirred at room temperature for 24 hours, then quenched by saturated NH4Cl solution and extracted with EtOAc (3x). The organic phase was washed with 10% thiourea aqueous solution and brine, dried (Na2SO4) and concentrated under reduced pressure. TFA (76.6 μL, 1.00 mmol) was added to a solution of the residue in MeCN (1.2 mL) and water (0.3 mL). The reaction mixture was stirred at room temperature for 3 hours, neutralized with saturated NaHCO solution, and extracted with CH Cl. The organic phase was dried (Na SO ) and concentrated under reduced pressure. The residue was purified by silica gel column (hexane / EtOAc gradient) to obtain 3-(4-benzylphenyl)benzo[c]isoxazole-5-carboxaldehyde as a yellow solid (36.4 mg, 0.116 mmol, 58%). 1 H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 8.38 (s, 1H), 8.02 (d, J = 8.3 Hz, 2H), 7.84 (dd, J = 9.4, 1.3 Hz, 1H), 7.73-7.65 (m, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.36 (dd, J = 8.0, 6.6 Hz, 2H), 7.31-7.21 (m, 3H), 4.12 (d, J = 1.2 Hz, 2H); for [M+H] + (C 21 H 16 NO2 + ) MS (ESI): calculated value m / z: 314.12; found value m / z: 314.10; LC-MS: 95% purity.

[0298] To a solution of 3-(4-benzylphenyl)benzo[c]isoxazole-5-carboxaldehyde (36.4 mg, 0.116 mmol) in N,N-dimethylformamide (1.2 mL) was added potassium peroxymonosulfonate triple salt (71.3 mg, 0.116 mmol). The reaction mixture was stirred at room temperature for 18 hours. After completion of the reaction (monitored by LC-MS), the reaction mixture was purified by reverse phase column to give 3-(4-benzylphenyl)benzo[c]isoxazole-5-carboxylic acid as a yellow solid (29.1 mg, 88.4 μmol, 76%). 1HNMR(400MHz, DMSO-d6)δ8.61(d,J=1.7Hz,1H),8.10-8.00(m,2H),7.86(d,J=9.3Hz,1H),7.71(d,J= 9.1Hz,1H),7.59-7.46(m,2H),7.36-7.24(m,4H),7.22(td,J=6.3,2.6Hz,1H),4.07(d,J=1.5Hz,2H). 13 C NMR (101 MHz, DMSO-d6) δ 167.07, 166.59, 157.51, 145.28, 140.49, 130.57, 130.12, 128.88, 128.63, 127.64, 127.17, 126.28, 125.28, 124.74, 115.03, 113.29, 40.96. For [M+H] + (C 21 H 16 NO3 + ) by MS (ESI): calculated value m / z: 330.11; found value m / z: 330.10.

[0299] Table 3 describes the compounds prepared according to the procedure described in Example 3 using appropriate reagents. 50 (determined by enzyme-coupled assay): ++++ means <10 nM; +++ means between 10 nM-100 nM, ++ means between 100 nM-1 μM; + means between 1 μM-100 μM; - means inactive.)

[0300]

[0301]

[0302]

[0303] Example 4: 3-(3-(piperidin-4-yloxy)phenyl)-5-(1H-tetrazol-5-yl)benzo[c]isoxazole hydrochloride and 1-(4-(3-(5-(1H-tetrazolyl-5-yl)benzo[c]isoxazol-3-yl)phenoxy)piperidin-1-yl)ethan-1-one

[0304]

[0305] At 0 ℃, to 2-(3-hydroxyphenyl)acetonitrile (2.00g, 15.0mmol), 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (3.33g, 16.5mmol) and PPh3(4.33g, 16.5mmol) solution in anhydrous THF (15mL) adds DIAD (3.28mL, 16.5mmol). The resulting mixture is stirred at room temperature for 24 hours. After completion, the reaction is passed through a short silica pad. The silica gel is then washed with eluent (hexane / EtOAc 2:1, 150mL). The organic phase is concentrated to about 50mL, and washed three times with 1M NaOH aqueous solution and washed once with brine. The organic layer is dried (Na2SO4) and concentrated under high vacuum. The residue is dissolved in a minimum amount of CH2Cl2 and loaded onto a silica gel column. The product (which is an oily substance) is isolated from silica gel column chromatography and poured into hexane (45mL). The mixture was sonicated until the white solid was crushed to give a fine suspension. The precipitate was filtered and washed with hexanes to give tert-butyl 4-(3-(cyanomethyl)phenoxy)piperidine-1-carboxylate as a white solid (3.82 g, 12.1 mmol, 80%). 1 H NMR (400 MHz, chloroform-d) δ7.31-7.26 (m, 1H), 6.94-6.82 (m, 3H), 4.49 (tt, J = 7.1, 3.5 Hz, 1H), 3.75-3.65 (m, 2H), 3.72 (s, 2H), 3.35 (ddd, J = 13.5, 7.6, 3.8 Hz, 2H), 1.98-1.87 (m, 2H), 1.75 (dtd, J = 13.8, 7.3, 3.7 Hz, 2H), 1.47 (s, 9H); for [M+Na] + ( 18 H 24 N2O3Na + ) MS (ESI): calculated value m / z: 339.17; found value m / z: 339.20; LC-MS: 96% purity.

[0306] By NaOH pellet granulation (0.98g, 24mmol) and add to 2-PrOH (25mL).The mixture was stirred for 15 minutes, then 5-(4-nitrophenyl)-1H-tetrazole (703mg, 3.68mmol) was added.After tetrazole was dissolved, 4-(3-(cyanomethyl)phenoxy)piperidine-1-carboxylic acid tert-butyl ester (775mg, 2.45mmol) was added.The reaction mixture was stirred at room temperature and monitored by LCMS.After the reaction was completed, HOAc was added to the suspension so that the pH was adjusted to 5.The reaction mixture was poured into saline and extracted three times by EtOAc.The organic phase merged was dried (Na2SO4) and the solvent was removed. The residue was purified by reverse phase chromatography to give tert-butyl 4-(3-(5-(lH-tetrazol-5-yl)benzo[c]isoxazol-3-yl)phenoxy)piperidine-l-carboxylate as a yellow solid (310 mg, 0.671 mmol, 27%). 1 H NMR (500MHz, CD3OD) δ8.68(s,1H),8.03-7.96(m,1H),7.77-7.70(m,2H),7.67(d,J=2.2Hz,1H),7.58(t,J=8.0Hz,1H),7.25(dd,J=8.2 ,2.5Hz,1H),3.49(ddd,J=12.8,9.1,3.6Hz,2H),3.35-3.27(m,2H),2.27(ddd,J=12.9,9.0,3.7Hz,2H),2.13(dq,J=11.0,3.4Hz,2H); 13 C NMR (126 MHz, CD3OD) δ 166.21, 157.48, 157.27, 130.84, 129.12, 128.71, 121.34, 120.76, 119.74, 118.42, 116.17, 114.01, 113.85, 68.71, 40.52, 26.98 (missing one sp 2 carbon); for [M+H] + (C 19 H 19 N6O2 + ) MS (ESI): calculated value m / z: 363.16; found value m / z: 363.15; LC-MS: 98% purity.

[0307] To a solution of tert-butyl 4-(3-(5-(1H-tetrazol-5-yl)benzo[c]isoxazole-3-yl)phenoxy)piperidine-1-carboxylate (310mg, 0.671mmol) in MeOH (3.4mL) was added concentrated HCl (0.55mL, 37%). The resulting solution was stirred at room temperature for 3 hours. The reaction was concentrated under vacuum. The residue was sonicated in a minimum of 1:1MeOH / H2O and collected by centrifuge to obtain 3-(3-(piperidin-4-yloxy)phenyl)-5-(1H-tetrazol-5-yl)benzo[c]isoxazole hydrochloride as a yellow solid (229mg, 0.574mmol, 86%). 1 H NMR (500MHz, CD3OD) δ8.68(s,1H),8.03-7.96(m,1H),7.77-7.70(m,2H),7.67(d,J=2.2Hz,1H),7.58(t,J=8.0Hz,1H),7.25(dd,J=8.2 ,2.5Hz,1H),3.49(ddd,J=12.8,9.1,3.6Hz,2H),3.35-3.27(m,2H),2.27(ddd,J=12.9,9.0,3.7Hz,2H),2.13(dq,J=11.0,3.4Hz,2H); 13 C NMR (126 MHz, CD3OD) δ 166.21, 157.48, 157.27, 130.84, 129.12, 128.71, 121.34, 120.76, 119.74, 118.42, 116.17, 114.01, 113.85, 68.71, 40.52, 26.98 (missing one sp 2 carbon); for [M+H] + (C 19 H 19 N6O2 + ) MS (ESI): calculated value m / z: 363.16; found value m / z: 363.15; LC-MS: 99% purity.

[0308] To a solution of 3-(3-(piperidin-4-yloxy)phenyl)-5-(1H-tetrazol-5-yl)benzo[c]isoxazole hydrochloride (30.0 mg, 75.2 μmol), Et3N (11 μL, 75 μmol) and HOAc (6.5 μL, 0.113 mmol) in DMF (0.75 mL) was added cyclopropanecarboxaldehyde (11 μL, 0.150 mmol). The resulting mixture was stirred at room temperature for 20 minutes, then NaBH(OAc)3 (31.9 mg, 0.150 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours, then it was quenched by MeOH. The solvent was evaporated under reduced pressure and the residue was subjected to preparative HPLC to give 3-(3-((1-(cyclopropylmethyl)piperidin-4-yl)oxy)phenyl)-5-(1H-tetrazol-5-yl)benzo[c]isoxazole as a yellow solid (19.4 mg, 46.6 μmol, 62%). 1 H NMR(400MHz,CD3OD)δ8.76-8.69(m,1H),8.01(dd,J=9.4,1.4Hz,1H),7.81-7.65(m,3H) ,7.60(td,J=8.0,5.8Hz,1H),7.28(ddd,J=14.3,8.2,2.5Hz,1H),5.06-4.97(m,1H),3. 81(d,J=12.6Hz,1H),3.67–3.59(m,1H),3.51-3.24(m,2H),3.14(dd,J=11.2,7.4Hz,2H ),2.55-1.99(m,4H),1.26-.15(m,1H),0.88-0.73(m,2H),0.49(dd,J=4.8,1.5Hz,2H); 13 C NMR (101 MHz, CD3OD) δ 167.71, 159.06, 158.77, 158.75, 132.30, 130.54, 130.21, 122.76, 122.28, 121.29, 119.86, 117.66, 115.81, 115.23, 71.87, 68.30, 63.02, 62.11, 51.61, 29.71, 28.08, 6.55, 4.95; for [M+H] + (C 23 H 25 N6O2 + ) MS (ESI): calculated value m / z: 417.20; found value m / z: 417.20; LC-MS: 97% purity.

[0309] At 0 ° C, to 3- (3- (piperidin-4-yloxy) phenyl) -5- (1H- tetrazol-5-yl) benzo [c] isoxazole hydrochloride (44.2mg, 0.122mmol) and EtN (34 μ L, 0.24mmol) in THF (0.5mL) solution was added dropwise AcCl (8.7 μ L, 0.12mmol). The reaction was stirred at room temperature for 1 hour. After completion, the reaction was quenched by MeOH. The solvent was evaporated under vacuum, and the residue was washed in 1: 1 MeOH / H2O. The precipitate was collected by centrifuge to obtain 1- (4- (3- (5- (1H- tetrazol-5-yl) benzo [c] isoxazole -3-yl) phenoxy) piperidin-1-yl) ethane -1-one as a yellow solid (24.6mg, 60.8 μmol, 50%). 1 H NMR (500MHz, DMSO-d6) δ8.72(d,J=1.5Hz,1H),8.06(dd,J=9.4,1.4Hz,1H),7.91(d,J=9.4Hz,1H),7. 74(dd,J=7.7,1.6Hz,1H),7.67–7.61(m,2H),7.31(dd,J=8.3,2.5Hz,1H),4.83(tt,J=7.9,3.7Hz,1H ), 3.92 (dt, J = 13.2, 5.1 Hz, 1H), 3.77-3.70 (m, 1H), 3.26 (td, J = 9.3, 4.6 Hz, 1H), 2.03 (s, 4H), 2.01-1.94 (m, 1H), 1.68 (dp, J = 13.2, 4.7, 4.3 Hz, 1H), 1.57 (ddt, J = 13.2, 8.8, 4.3 Hz, 1H) (one proton overlaps with DMSO water); 13 C NMR (126 MHz, DMSO-d6) δ 168.17, 165.94, 164.02, 157.71, 156.97, 131.53, 131.17, 129.61, 128.17, 121.05, 119.40, 118.86, 116.55, 114.00, 113.67, 72.38, 42.94, 38.06, 30.92, 30.19, 21.29; for [M+H] + (C 21 H 21 N6O3 + ) MS (ESI): calculated value m / z: 405.17; found value m / z: 405.20; LC-MS: 98% purity.

[0310] Table 4 describes the compounds prepared according to the procedure described in Example 4 using appropriate reagents. 50(determined by enzyme-coupled assay): ++++ means <10 nM; +++ means between 10 nM-100 nM, ++ means between 100 nM-1 μM; + means between 1 μM-100 μM; - means inactive.)

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348] Example 5: 3-(3-phenylbenzo[c]isoxazol-5-yl)-1,2,4-oxadiazol-5(4H)-one

[0349]

[0350] To a mixture of 4-nitrobenzonitrile (1.48 g, 10.0 mmol) in EtOH (30.0 mL) and water (6.0 mL) was added hydroxylamine hydrochloride (2.78 g, 40.0 mmol) and Na2CO3 (3.18 g, 40.0 mmol). The mixture was heated to 85 ° C for 2 hr and then cooled to room temperature. The solvent was evaporated under reduced pressure. The residue was then poured into brine. The mixture was extracted three times with EtOAc. The combined organic phases were washed with brine and dried (Na2SO4). The solvent was then evaporated to obtain N'-hydroxy-4-nitrobenzamide as an off-white solid (1.80 g, 9.94 mmol, 99%) without further purification. 1 H NMR (400 MHz, DMSO-d6) δ7.47-7.42 (m, 2H), 7.11-7.05 (m, 2H); for [M+H] + (C7H8N3O3 +) MS (ESI): calculated value m / z 182.06; found value m / z 182.10; LC-MS: 97% purity; 1 H NMR 4:1 trans:cis.

[0351] To a mixture of N'-hydroxy-4-nitrobenzamide (1.80 g, 9.94 mmol) and DMAP (2.43 g, 19.9 mmol) in water (20 mL) was added phenyl chloroformate (1.87 mL, 14.9 mmol). The reaction mixture was refluxed at 100 ° C for 2 hr and then cooled to room temperature. 1M HCl was added to the mixture to adjust the pH to 3-4. The off-white precipitate was filtered and washed with water to obtain 3- (4-nitrophenyl) -1,2,4- oxadiazole -5 (4H) -one as an off-white solid (1.77 g, 8.54 mmol, 86%). 1 H NMR (400 MHz, DMSO-d6) δ 13.20 (s, 1H), 8.43 (d, J = 8.8 Hz, 2H), 8.07 (d, J = 8.9 Hz, 2H); for [M+H] + (C8H6N3O4 + ) MS (ESI): calculated value m / z: 208.04; found value m / z: 208.00; LC-MS: 98% purity.

[0352] NaOH pellets are granulated (80.0 mg, 2.00 mmol) and added to 2-PrOH (2.0 mL). The mixture is stirred for 15 minutes, and then 3- (4- nitrophenyl) -1,2,4- oxadiazole -5 (4H) -one (41.4 mg, 0.200 mmol) is added. After the oxadiazole ketone is dissolved, benzyl cyanide (58 μL, 0.50 mmol) is added. The reaction mixture is stirred at room temperature and monitored by LCMS. After the reaction is complete, HOAc is added to the suspension to adjust the pH to 5. The reaction mixture is poured into saline and extracted three times by EtOAc. The combined organic phase is dried (Na2SO4) and the solvent is removed. The residue is purified by reverse phase chromatography to obtain 3- (3- phenylbenzo [c] isoxazol-5-yl) -1,2,4- oxadiazole -5 (4H) -one, which is a yellow solid (50.6 mg, 0.181 mmol, 91%). 1 H NMR (400MHz, DMSO-d6) δ8.57(s,1H),8.21-8.10(m,2H),7.87-7.74(m,2H),7.75-7.62(m,3H). 13C NMR (101 MHz, DMSO-d6) δ 166.42, 160.11, 157.04, 156.98, 131.62, 129.73, 127.21, 126.80, 126.70, 121.63, 120.16, 116.51, 113.15. For [M+H] + (C 15 H 10 N3O3 + ) by MS (ESI): calculated value m / z: 280.07; found value m / z: 280.10.

[0353] Table 5 describes the compounds prepared according to the procedure described in Example 5 using appropriate reagents. 50 (determined by enzyme-coupled assay): ++++ means <10 nM; +++ means between 10 nM-100 nM, ++ means between 100 nM-1 μM; + means between 1 μM-100 μM; - means inactive.)

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365] Example 6: 3-phenylbenzo[d]isoxazole-5-carboxylic acid

[0366]

[0367] To a mixture of N-hydroxyphthalimide (200 mg, 1.23 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (441 mg, 2.45 mmol), CuCl (121 mg, 1.23 mg) in DCE (6.0 mL) was freshly added activated To the mixture of 4- ((1,3-dioxoisoindolin-2-yl)oxy)benzoic acid methyl ester (272 mg, 1.23 mmol, 75%) was added to 4- ((1,3-dioxoisoindolin-2-yl)oxy)benzoic acid methyl ester as a white solid (272 mg, 1.23 mmol, 75%). 1 H NMR (400 MHz, CDCl3) δ8.05 (dd, J = 7.1, 2.1 Hz, 2H), 7.97-7.92 (m, 2H), 7.87-7.83 (m, 2H), 7.17 (dd, J = 7.1, 2.1 Hz, 2H), 3.90 (s, 3H); for [M+H] + (C 16 H 12 NO5 + ) MS (ESI): calculated value m / z: 298.07; found value m / z: 298.10; LC-MS: 96% purity.

[0368] To a solution of methyl 4-((1,3-dioxoisoindolin-2-yl)oxy)benzoate (267 mg, 0.897 mmol) in CHCl (8.1 mL) and MeOH (0.9 mL) was added hydrazine monohydrate (218 μL, 4.49 mmol). The reaction was stirred at room temperature overnight. The white precipitate was filtered and washed with CHCl. ​​The filtrate was concentrated and purified by silica gel column chromatography (hexane / EtOAc gradient) to give methyl 4-(aminooxy)benzoate as a white solid (134 mg, 0.803 mmol, 90%). 1 H NMR (400 MHz, CDCl3) δ7.98 (d, J = 9.0 Hz, 2H), 7.17 (d, J = 9.0 Hz, 2H), 5.93 (s, 2H), 3.88 (s, 3H); for [M+H] + (C8H 10 NO3 + ) MS (ESI): calculated value m / z: 168.07; found value m / z: 168.10; LC-MS: 98% purity.

[0369] At 0 ℃, to 4-(aminooxy) methyl benzoate (130mg, 0.778mmol) and Et solution of N (217 μ L, 1.56mmol) in THF (3.7mL) adds AcCl (166 μ L, 2.34mmol). Reaction is warming up to room temperature and stirred for 3 hours. After completing, reaction mixture is quenched by MeOH and concentrated under reduced pressure. Residue is passed through reverse phase chromatography (MeCN / H o gradient) and purified, to obtain 4-(acetamidooxy) methyl benzoate, it is white solid (55.4mg, 0.265mmol, 34%), it is white solid. 1 H NMR (500 MHz, CDCl3) δ 8.04-7.97 (m, 2H), 7.24-7.17 (m, 2H), 3.89 (d, J = 0.5 Hz, 3H), 2.19 (d, J = 0.5 Hz, 3H) (missing one NH proton); for [M+H] + (C 10 H 12 NO4 + ) MS (ESI): calculated value m / z: 210.08; found value m / z: 210.10; LC-MS: 95% purity.

[0370] To 4-(acetylaminooxy)benzoic acid methyl ester (20.9mg, 0.100mmol) and Pd (TFA) 2 (3.32mg, 10.0μmol) solution in tert-amyl alcohol (0.4mL) add benzaldehyde (20.3μL, 0.200mmol) and TBHP (46μL, 5.5M solution in decane, 0.25mmol). The reaction is degassed, a nitrogen balloon is loaded therein, and heated to 60 ℃ and spend the night. The reaction mixture is then cooled to room temperature and poured into saline. The mixture is extracted by EtOAc. The organic phase merged is washed by 10% NaHSO 3 and saline, and then dried (Na 2 SO 4 ). The solvent is evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes / EtOAc gradient) to give methyl 3-phenylbenzo[d]isoxazole-5-carboxylate as an off-white solid (7.00 mg, 27.6 μmol, 28%). 1 H NMR (400 MHz, CDCl3) δ 8.71-8.63 (m, 1H), 8.31 (dd, J = 8.8, 1.7 Hz, 1H), 8.02-7.92 (m, 2H), 7.68 (d, J = 8.9 Hz, 1H), 7.59 (dd, J = 5.4, 2.0 Hz, 3H), 3.98 (s, 3H); for [M+H] + (C 15 H 12 NO3+ ) MS (ESI): calculated value m / z: 254.08; found value m / z: 254.10; LC-MS: 95% purity.

[0371] To a solution of methyl 3-phenylbenzo [d] isoxazole-5-carboxylate (7.00 mg, 27.6 μmol) in THF (0.28 mL) was added LiOH H O (5.80 mg, 0.138 mmol). The reaction was heated to 60 ° C for 1.5 hours and acidified by TFA (21 μL, 0.28 mmol) after being cooled to room temperature. The solvent was removed under reduced pressure. The residue was purified by reverse phase chromatography (MeCN / H O gradient) to obtain the title compound as a white solid (3.46 mg, 14.5 μmol, 52%). 1 HNMR (500MHz, CD3OD) δ8.68(s,1H),8.34(d,J=8.8Hz,1H),8.00(d,J=6.8Hz,2H),7.78(d,J=8.8Hz,1H),7.70-7.55(m,3H); 13 C NMR (214 MHz, CD3OD) δ 168.87, 167.28, 159.12, 132.75, 131.92, 130.48, 129.39, 129.15, 128.90, 126.21, 121.86, 111.07; for [M+H] + (C 14 H 10 NO3 + ) MS (ESI): calculated value m / z: 240.07; found value m / z: 240.10; LC-MS: 96% purity.

[0372] Table 6 describes the compounds prepared according to the procedure described in Example 6 using appropriate reagents. 50 (determined by enzyme-coupled assay): ++++ means <10 nM; +++ means between 10 nM-100 nM, ++ means between 100 nM-1 μM; + means between 1 μM-100 μM; - means inactive.)

[0373]

[0374]

[0375] Example 7: Synthesis of 3-(4-nitrophenyl)-1H-1,2,4-triazole

[0376]

[0377] At 0°C, AcCl (1.14 mL, 16.0 mmol) was added dropwise to a solution of 4-nitrobenzonitrile (296 mg, 2.00 mmol) in EtOH (1.5 mL) under a nitrogen atmosphere. The reaction was warmed to room temperature and stirred for 60 hours. The mixture became a pale yellow slurry and diluted with EtO. The resulting precipitate was filtered and washed with EtO to obtain 4-nitrobenzanilide ethyl ester hydrochloride as an off-white solid (307 mg, 1.33 mmol, 66%). 1 H NMR (400 MHz, DMSO-d6) δ12.11 (s, 1H), 8.42 (d, J = 8.4 Hz, 2H), 8.32 (d, J = 8.5 Hz, 2H), 7.47-7.17 (m, 1H), 4.63 (q, J = 6.8 Hz, 2H), 1.48 (t, J = 6.8 Hz, 3H); for [M+H] + (C9H 11 N2O3 + ) MS (ESI): calculated value m / z: 195.08; found value m / z: 195.10; LC-MS: 98% purity.

[0378] At 0 ℃, formic hydrazide (92.0mg, 1.53mmol) is added to the solution of 4-nitrobenzene formimidic acid ethyl ester hydrochloride (295mg, 1.28mmol) in pyridine (1.3mL). The reaction is slowly warmed to room temperature within 1 hour. The yellow slurries are diluted with water. The gained precipitate is filtered and washed with water, to obtain azoimido hydrazide, which is a brown solid, without further purification. Then azoimido hydrazide is dissolved in dimethylbenzene (5.2mL) and heated to 140 ℃, continues 6 hours. Then the reaction is cooled to room temperature and stirred overnight. The precipitate is filtered and washed with hexane and a few drops of methanol, to obtain the title compound, it is a pale solid (128mg, 0.671mmol, 52%). 1 H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.34 (d, J = 8.8 Hz, 2H), 8.27 (d, J = 8.9 Hz, 2H); for [M+H] + (C8H7N4O2 + ) MS (ESI): calculated value m / z: 191.06; found value m / z: 191.10; LC-MS: 99% purity.

[0379] Example 8: Synthesis of 1-(4-nitrophenyl)-1H-1,2,4-triazole

[0380]

[0381] A mixture of 1-bromo-4-nitrobenzene (202 mg, 1.00 mmol), 1H-1,2,4-triazole (104 mg, 1.50 mmol), Cu(I)MeSal (21.5 mg, 0.100 mmol) and K2CO3 (276 mg, 2.00 mmol) in DMSO (5.0 mL) was degassed and a nitrogen balloon was charged thereto. Then under a nitrogen atmosphere, the reaction mixture was heated to 110 ° C for 3 hours. The reaction was then cooled to room temperature and filtered. The filter cake was washed with DMSO, and the filtrate was poured into ice. The mixture was extracted three times with EtOAc. The combined organic phases were washed twice with brine and dried (Na2SO4). The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound as a white solid (68.9 mg, 0.362 mmol, 36%). 1 H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 8.44-8.37 (m, 2H), 8.17 (s, 1H), 7.96-7.89 (m, 2H); for [M+H] + (C8H7N4O2 + ) MS (ESI): calculated value m / z: 191.06; found value m / z: 191.10; LC-MS: 96% purity.

[0382] Example 9: Expression and purification of human recombinant IP6K

[0383] Recombinant human IP6K2 and human PPIP5K2 kinase domains were prepared as described previously. 41,44 Genscript synthesized codon-optimized cDNA for expression of 6xHis-MBP-tagged human IP6K1 (N-terminally tagged with 6x-His, then MBP) and IP6K3 (N-terminally tagged with 6x-His, then Sumo) in Escherichia coli. The procedures for expression and purification of IP6K1 and IP6K2 were the same as those for IP6K2. Cells were disrupted at 20 kPsi using a constant cell disruption system (Constant Systems). Recombinant IP6K was purified with a Ni-NTA agarose column (Qiagen) and then with a HiTrap Heparin HP column (GE Healthcare. As a final step, a Superdex200 gel filtration column (GE Healthcare) was used with a running buffer of 150 mM NaCl and 20 mM Tris-HCl (pH 7.5). The purity of these proteins was estimated to be >80% as judged by SDS-PAGE. The purified proteins were stored in aliquots at -80°C.

[0384] Example 10: Use of an enzyme-coupled assay to measure IP6K activity

[0385] Enzyme activity was measured in 50 μL reaction mixtures containing 100 nM IP6K1 or IP6K2, or 200 nM IP6K3 at 37°C for 60 to 120 min and, unless otherwise stated, the reaction mixtures contained 5.0 μM human Dipp1, 45 20mM HEPES (pH 7.2), 100mM KCl, 3.5mM MgCl2, 20μM EDTA, 25μM InsP6 and 500μM ATP. P i Release was determined using a malachite green colorimetric assay. 45 Where indicated, TNP (Cayman Chemical) was added to the assay ( FIG. 2A to FIG. 2E ).

[0386] Example 9: HPLC determination of inositol phosphate kinase activity

[0387] To measure IP6K activity, each reaction contained a trace amount (40,000 DPM) of 100 μL of incubation containing 20 mM HEPES (pH 7.2), 100 mM KCl, 3.5 mM MgCl2, 20 μM EDTA, 1.0 mM ATP, 10 μM InsP6 plus DMSO (or vehicle control) plus 4.8 nM IP6K1, 3.5 nM IP6K2, or 8.9 nM IP6K3. 3 H-InsP6 (American Radiolabeled Chemicals, Inc., ART 1915). To measure PPIP5K2 kinase activity, each reaction contained 12,500 dpm of 5-[ 3 H]InsP7 46 After 20 min (for PPIP5K2) or 180 min (for IP6K), the reaction was quenched by adding 0.2 volumes of 2.0 M perchloric acid + 1 mg / mL of InsP6 and subsequently neutralized.

[0388] All measurements were performed using PartiSphere SAX 5μm, 4.6x 125mm HPLC column was analyzed by HPLC. The elution gradient was generated by mixing buffer A (1 mm Na2EDTA) with buffer B (buffer A plus 2.5M NH4H2PO4, pH 3.9) and monitored by a β-RAM 6 online scintillation detector; 1.0 mL / min eluent was mixed with 2.5 mL / min single flow scintillation fluid ( FIG. 2A to FIG. 2E ).

[0389] Example 11: Isothermal Titration Calorimetry

[0390] Calorimetric experiments were performed using a MicroCal PEAQ-ITC (Malvern Panalytical) with 40 μM recombinant MBP-tagged IP6K2 in the sample cell and 400 μM inhibitor 20 in the syringe, each of which was maintained at 25°C in a buffer containing 20 mM Tris-HCl (pH 7.2), 150 mM KCl, 0.05 mM EDTA, and 0.8 mM MgCl2. The sample cell (volume = 204 μL) and the syringe were cleaned before each run. The thermogram was constructed from 20 injections, each of which involved 2.0 μL of ligand (delivered for 4.0 seconds) with an equilibration time of 150 to 300 seconds between each injection. The stirring speed was set to 750 rpm. The data were fit to a single binding site model using the analysis software provided by the manufacturer. At least three runs were performed ( FIG. 2A to FIG. 2E ).

[0391] Example 12: Cell culture and determination of intracellular inositol phosphates

[0392] HCT116 cells were cultured in DMEM / F-12 (Thermo Fisher Scientific) supplemented with 10% fetal bovine serum (FBS; Gemini Bio Products) and 100 units / mL penicillin-streptomycin (Thermo Fisher Scientific) at 37°C in 95% O2 / 5% CO2. 6 Cells were seeded in 10-cm dishes and supplemented with 10 μCi / mL [ 3H] Inositol (American Radiolabeled Chemicals) 7mL culture medium was cultivated for 3 days, and the confluence of the culture was 70%. Then the cells were incubated for 3 hours in the culture medium with 2.5 μM inhibitor 20 or vehicle control. Cells were acid quenched, and inositol phosphates were extracted and resolved by HPLC using a 250x4.6mm Synchropak Q100 HPLC column. 1 minute fractions were collected, continued for 66 minutes, mixed with 2.5mL Monoflow-4 (National Diagonstics), and radioactive labels were detected with a scintillation counter ( FIG. 3A to FIG. 3E ).

[0393] Example 13: Phosphate efflux assay

[0394] Phosphate efflux from cells was determined by slight modifications of a previously published procedure. 43 HCT116 cells were cultured in 96-well plates for 1 to 2 days until 70% confluence. Cells were pretreated with different concentrations of inhibitor 20 for 3 or 18 hours. The culture medium was then replaced with DMEM (Gibco catalog number: 11971-025) plus 10% FBS and 2.2×10 5 dpm 33 P]-Pi for 1 hour. 33 After the [P]-Pi labeling period, the cells were washed five times with 100 μL of phosphate-buffered saline (PBS) at room temperature and then incubated with 100 μL of prewarmed fresh DMEM at 37°C in 95% O2 / 5% CO2 for 2 h to determine [ 33 P]-Pi outflow. 33 P]-Pi uptake and efflux protocol, fresh 20 was added at concentrations equivalent to those used during pretreatment. The entire 100 μL of medium was then removed and added to scintillation fluid to assess [ 33 In addition, the remaining cells were lysed with 100 μL PBS plus 1% triton-X100, and the residual cell-related 33 Pi;[ 33 P]-Pi efflux is depicted as total [ 33 P]-Pi percentage ( FIG. 3A to FIG. 3E ).

[0395] It will be apparent to those skilled in the art that various modifications and variations may be made to the present invention without departing from the scope or spirit of the present invention. Other aspects of the present invention will be apparent to those skilled in the art in view of the specification and practice of the present invention disclosed herein. The specification and examples are intended to be considered as exemplary only, with the true scope and spirit of the present invention being indicated by the following claims.

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Claims

1. A compound of formula II: or a pharmaceutically acceptable salt thereof, wherein X is an aryl or heteroaryl group; In each case, R 3 Selected from the group consisting of: alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, -D, -OH, -OR 5 、-NH-COR 6 、-CONR 7 R 8 、-SO2-NHR 9 and NR 10 R 11 p is an integer from 0 to 5; Y is present or absent, and when present is selected from the group consisting of alkyl, cycloalkyl and alkenyl; and R 4 Selected from the group consisting of: -CO2H, -CO2R 5 、-CONR 7 R 8 、-SO2-NHR 6 、-SO3H、-P(O)(OH)(OR 9 ), heteroaryl and heterocycloalkyl; wherein R 5 is selected from the group consisting of alkyl, aryl, heteroaryl and heterocycloalkyl; R 6 is selected from the group consisting of alkyl, cycloalkyl, aryl and heteroaryl; R 7 and R 8 are each independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; R 9 is selected from the group consisting of alkyl, aryl, heteroaryl and heterocycloalkyl; and R 10 and R 11 Each is independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.

2. The compound according to claim 1, wherein Y is absent.

3. The compound according to claim 2, wherein R 4 Selected from the group consisting of: -CO2H, -CONR 7 R 8 , heteroaryl and heterocycloalkyl.

4. The compound according to claim 3, wherein R 4 Select from the group consisting of:

5. The compound according to claim 4, wherein R 4 for 6. The compound according to claim 4, wherein R 4 for 7. The compound according to claim 3, wherein R 4 It is -CO2H.

8. The compound according to claim 4, wherein X is aryl.

9. The compound according to claim 1, wherein the compound is selected from the group consisting of compounds of formula III, IV and V:

10. The compound according to claim 9, wherein R 3 It is aryl or halogenated.

11. The compound according to claim 9, wherein p is 1 and R 3 is selected from the group consisting of alkyl, aryl, heteroaryl and heterocycloalkyl.

12. The compound according to claim 11, wherein R 3 It is a heterocycloalkyl group.

13. The compound according to claim 12, wherein the heterocycloalkyl group is piperidinyl.

14. The compound according to claim 11, wherein R 3 For –OR 5 .

15. The compound according to claim 14, wherein R 5 is a heteroaryl group or a heterocycloalkyl group.

16. The compound according to claim 15, wherein R 5 It is pyridyl or piperidinyl.

17. The compound according to claim 9, wherein R 3 Alkyl, -NH-COR 6 , p is 1, where R 6 is alkyl, cycloalkyl or heterocycloalkyl.

18. The compound according to claim 17, wherein R 6 It is cyclopropyl or cyclobutyl.

19. A compound having one of the following structures:

20. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

21. A method for preventing or treating a disease or condition mediated by IP6K and / or IPMK, the method comprising administering a therapeutically effective amount of a compound according to claim 1 to a subject in need thereof.

22. The method of claim 21, wherein the disease or condition is selected from obesity, obesity-related diseases, hyperphosphatemia, cancer, fungal infection, parasitic infection, and viral infection.

23. The method of claim 22, wherein the obesity-related disease is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

24. The method of claim 22, wherein the cancer is glioblastoma.

25. The method of claim 22, wherein the viral infection is a coronavirus.

26. The method of claim 22, wherein the disorder is hyperphosphatemia.

27. The method of claim 22, wherein the fungal infection is caused by a yeast strain.

28. The method of claim 27, wherein the yeast strain is selected from Cryptococcus neoformans and Candida albicans.

29. The method of claim 22, wherein the parasitic infection is caused by the parasite Toxoplasma gondii.

30. A kit for treating a disease or condition mediated by IP6K and / or IPMK, the kit comprising: 1) a pharmaceutical composition comprising a compound of formula II, and 2) instructions for use.

31. A compound according to claim 1 for use as a medicament and for the treatment of a disease or condition mediated by IP6K and / or IPMK.

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