p62-ZZ chemical inhibitors

Abstract

A compound of formula I or a pharmaceutically acceptable salt thereof: (I) wherein Ar is arylene or heteroarylene; R 1 Having the structure: (II) wherein W is an alkanediyl, an alkenediyl, a carbonyl group or a combination thereof; X is NR 5 ‑, where R 5 is H or alkyl, or -O-; and Y is optionally substituted cycloalkyl, optionally substituted cycloalkyl-substituted alkyl, optionally substituted heterocycloalkyl or optionally substituted heterocycloalkyl-substituted alkyl; each R 2 are the same or different and have the structure: (III) wherein Z is ‑NR 6 ‑, where R 6 is H or alkyl, ‑O‑, ‑S‑ or ‑CH2‑; Z 1 Yes (‑CH2‑) m , wherein m is 0 to 5, or is an alkene diyl group having 2 to 6 carbon atoms; Cy is a 3-8 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; and each R 4 are the same or different and are selected from hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, or amino; and c is 0 to 5; and each R 3 are the same or different and are selected from hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or nitro, wherein a is 2 to 5, and b is 0 to 3. #imgabs0#

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 174,465, filed June 11, 2015, which is incorporated herein by reference.

[0002] background

[0003] Sequestosome-1 (SQSTM1 / p62) is rich in protein-interaction domains, including an N-terminal PB1 domain, a ZZ-type zinc finger domain, a TRAF6-binding domain (TBS), an LC3-interacting region (LIR), a KEAP1-interacting region (KIR), and a C-terminal ubiquitin-binding domain (UBA). While p62 may primarily function as a key adaptor for the selective autophagic degradation of protein aggregates, cytoplasmic bodies, and dysfunctional organelles, it continues to garner attention due to its intimate and complex involvement in numerous cellular signaling pathways and functions. In general, p62 has been shown to play an important role in protein ubiquitination, triggering autophagy and apoptosis in tumorigenesis, and is particularly implicated in the activation of the transcription factor NF-κB pathway, the p38 MAPK pathway, and the mTOR pathway, which contribute to the regulation of cellular homeostasis.

[0004] Research has revealed that p62 is involved in selective autophagy. Autophagy is a tightly regulated, conserved catabolic process that occurs in all cells and is therefore important for cellular homeostasis, development, and immune responses, among other functions. For example, microtubule-bound tau protein in neurons is transferred to the proteasome via p62. Interestingly, disruption of the p62 gene in mice results in a phenotype resembling Alzheimer's disease. Similarly, accumulation of aggregated mutant huntingtin protein (the pathological basis of Huntington's disease) has been found to contain p62, and deletion of its UBA domain has been shown to enhance cell death caused by mutant huntingtin. p62 has also been found in cytoplasmic aggregates described in Parkinson's disease and amyotrophic lateral sclerosis, as well as in breast cancer tumors. Furthermore, targeted deletion of p62 in mice has been found to lead to insulin and leptin resistance, type 2 diabetes, and obesity. Given emerging evidence supporting the relevance of p62 in several different diseases, targeting Sequestosome-1 (SQSTM1 / p62) has become of great significance for drug design and discovery.

[0005] p62 is known to play a key role in autophagy and cell signaling involving the NF-kB pathway, the p38 MAPK pathway, and the mTOR pathway. Specifically, studies using p62-deficient mice have demonstrated that one p62 function is to control osteoclastogenesis and bone remodeling. Normal osteoclast function is dependent on this regulation of the NF-kB pathway by p62. The ZZ domain is implicated in this mechanism because it binds to the RIP1 protein, which contains a "death" domain that interacts with the TNF receptor, which then activates NF-kB and p38 MAPK signaling. Given these and previous findings, p62 is an attractive drug target for a variety of diseases, particularly multiple myeloma (MM) and related cancers, as well as other conditions such as neurological and diabetic diseases.

[0006] Among these diseases, MM is an incurable hematologic malignancy characterized by dysregulated plasma cell proliferation and progressive bone destruction in up to 80% of patients. Despite the introduction of new and more effective treatment options, including thalidomide and bortezomib, MM remains the second most prevalent hematologic malignancy. According to the Leukemia & Lymphoma Society (Facts 2009-2010), the number of MM patients and newly diagnosed cases increases significantly each year. Therefore, new therapeutic agents that effectively inhibit tumor growth and overcome conventional drug resistance are urgently needed.

[0007] Overview

[0008] Disclosed herein are compounds having Formula I or pharmaceutically acceptable salts thereof:

[0009]

[0010] wherein Ar is an arylene or heteroarylene group;

[0011] R 1 With structure:

[0012]

[0013] wherein W is an alkanediyl group, an alkenediyl group, a carbonyl group, or a combination thereof;

[0014] X is -NR 5 -, where R 5 is H or alkyl, or -O-; and

[0015] Y is optionally substituted cycloalkyl, optionally substituted cycloalkyl substituted alkyl;

[0016] optionally substituted heterocycloalkyl or optionally substituted heterocycloalkyl-substituted alkyl;

[0017] Each R 2 are the same or different and have the structure:

[0018]

[0019] Where Z is -NR 6 -, where R 6 is H or alkyl, -O-, -S- or -CH2-;

[0020] Z 1 Yes (-CH2-) m , wherein m is 0 to 5, or is an alkenediyl group having 2 to 6 carbon atoms;

[0021] Cy is a 3-8 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; and

[0022] Each R 4 are the same or different and are selected from hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, or amino; and c is 0 to 5; and

[0023] Each R 3 are the same or different and are selected from hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or nitro,

[0024] wherein a is 2 to 5, and b is 0 to 3.

[0025] Also disclosed herein are methods for treating a p62-mediated disease in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of at least one p62-ZZ inhibitor compound disclosed herein.

[0026] Further disclosed herein are methods of modulating p62 activity in a stromal cell, the method comprising contacting the stromal cell with at least one p62-ZZ inhibitor compound disclosed herein.

[0027] Additionally disclosed herein are methods of inhibiting the growth of multiple myeloma cells comprising contacting the multiple myeloma cells with at least one p62-ZZ inhibitor compound disclosed herein.

[0028] The foregoing will become more apparent from the following detailed description made with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 is a schematic diagram showing various signal transduction pathways.

[0031] Figure 2is a schematic diagram showing an in vitro biological assay for validating compounds screened for multiple myeloma cell growth via inhibition of the p62-zz domain and PKCζ phosphorylation.

[0032] Figure 3 is a graph showing the anti-tumor activity of compound XIELP1-106 in treating RPMI-8226 human multiple myeloma xenograft model.

[0033] Figure 4 It is a graph showing the survival curve of mice bearing subcutaneous RPMI822 tumors.

[0034] Details

[0035] Overview

[0036] Described herein are novel p62-ZZ inhibitors that affect, for example, stromal cells and multiple myeloma cells. The novel p62-ZZ inhibitors can exhibit micromolar (approximately 2 μM) inhibitory activity against the growth of multiple myeloma cells, while lacking toxicity to normal stromal cells. In certain embodiments, the compounds are selective p62-ZZ inhibitors, meaning that the compounds exhibit selective inhibitory activity against the ZZ domain relative to other p62 domains.

[0037] Sequestosome 1 (p62) plays a key role in forming a signaling complex that leads to NF-κB, p38MAPK, and PI3K activation in the bone marrow microenvironment of MM patients. Compared to treating subjects with inhibitors of each of the multiple signaling pathways (e.g., NF-κB or p38MAPK) activated by MM cells in bone marrow stromal cells, blocking the function of p62 should inhibit the activation of multiple pathways mediated by p62 and have a broader effect on the bone marrow microenvironment.

[0038] the term

[0039] The following explanations of terms and methods are provided to better describe the compounds, compositions and methods of the present invention, and to guide those of ordinary skill in the art to practice the present disclosure. It should also be understood that the terms used in this disclosure are only for the purpose of describing specific embodiments and examples and are not intended to be limiting.

[0040] As used herein, the singular terms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise. Also, as used herein, the term "comprise" means "include."

[0041] "Administration" of a compound and "administering" a compound should be understood to mean providing a compound, a prodrug of a compound, or a pharmaceutical composition as described herein. Another person can administer the compound or composition to a subject (e.g., intravenously), or the subject can self-administer it (e.g., a tablet).

[0042] "Alkanediyl" refers to a group of the general formula -C n H 2n A lower alkanediyl group has 1 (also called a methylene group) to 10 carbon atoms, more particularly 1 to 5 carbon atoms.

[0043] "Alkenediyl" refers to a divalent radical formed from an alkane by removing two hydrogen atoms from the same carbon atom, the free valencies of which are part of a double bond. Lower alkenediyl groups have 2 to 10 carbon atoms, more particularly 1 to 5 carbon atoms.

[0044] The term "alkenyl" refers to a hydrocarbon group having from 2 to 24 carbon atoms and a structural formula containing at least one carbon-carbon double bond. "Lower alkenyl" groups have from 1 to 10 carbon atoms.

[0045] The term "alkyl" refers to a branched or unbranched saturated hydrocarbon radical having 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, amyl, hexyl, heptyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, etc. A "lower alkyl" group is a saturated branched or unbranched hydrocarbon radical having 1 to 10 carbon atoms. Preferred alkyl radicals have 1 to 4 carbon atoms. Alkyl radicals can be "substituted alkyl" radicals, wherein one or more hydrogen atoms are replaced by a substituent such as a halogen, cycloalkyl, alkoxy, amino, hydroxyl, aryl, or carboxyl group.

[0046] The term "alkylaryl" refers to a group in which an alkyl group replaces a hydrogen atom of an aryl group. An example is -Ar-R, where Ar is an arylene group and R is an alkyl group.

[0047] The term "alkoxy" refers to a straight, branched or cyclic hydrocarbon configuration and combinations thereof comprising 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 4 carbon atoms, containing an oxygen atom at the point of attachment. Examples of "alkoxy" are represented by the formula -OR, where R can be an alkyl group optionally substituted with an alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, haloalkyl or heterocycloalkyl group as described above. Suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, cyclopropyloxy, cyclohexyloxy and the like.

[0048] The term "amine" or "amino" refers to a group of the formula -NRR', where R and R' can independently be hydrogen or alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, haloalkyl, or heterocycloalkyl. For example, "alkylamino" or "alkylated amino" refers to -NRR', where at least one of R or R' is an alkyl group.

[0049] The term "aminoalkyl" refers to an alkyl group as defined above in which at least one hydrogen atom is replaced by an amino group (eg, -CH2-NH2).

[0050] "Aminocarbonyl," alone or in combination, refers to an amino-substituted carbonyl (carbamoyl) group wherein the amino group may be optionally mono- or disubstituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, alkoxycarbonyl, aralkyloxycarbonyl, and the like.

[0051] The term "amide" or "amido" is represented by the formula -C(O)NRR', where R and R' are independently hydrogen, alkyl, alkenyl, alkynyl, acyl, aryl, aralkyl, cycloalkyl, haloalkyl, or heterocycloalkyl as described above. A suitable amido group is acetamido.

[0052] "Animal" refers to a living multicellular vertebrate organism, a category that includes, for example, mammals and birds. The term mammal includes both humans and non-human mammals. Similarly, the term "subject" includes both humans and non-human subjects, including birds and non-human mammals, such as non-human primates, companion animals (such as dogs and cats), livestock (such as pigs, sheep, cattle), and non-domesticated animals (such as large cats). Regardless of which stage in the life cycle of an organism, the term subject is applicable. Therefore, depending on the organism (i.e., whether the organism is a mammal or a bird, such as domesticated or wild fowl), the term subject is applicable to organisms in the womb or in the egg.

[0053] An "analog" is a molecule that differs from the parent compound in chemical structure, such as a homologue (a difference in chemical structure or mass increment, such as a different length of the alkyl chain or the inclusion of one of multiple isotopes), a molecular fragment, a structure that differs in one or more functional groups, or a change in ionization. Analogs are not necessarily synthesized from the parent compound. Structural analogs are often discovered using quantitative structure activity relationships (QSAR) and techniques such as those disclosed in Remington (The Science and Practice of Pharmacology, 19th ed. (1995), Chapter 28). Derivatives are molecules derived from the basic structure.

[0054] The term "aralkyl" refers to a group in which an aryl group replaces a hydrogen atom of an alkyl group. An example of an aralkyl group is a benzyl group.

[0055] The term "aryl" refers to any group derived from an aromatic group, including but not limited to a phenyl ring or an optionally substituted benzene ring system fused to one or more optionally substituted phenyl rings. "Heteroaryl" is defined as an aryl group that introduces at least one heteroatom in the ring of an aryl group. Examples of heteroatoms include but are not limited to nitrogen, oxygen, sulfur and phosphorus. Aryl can be substituted by one or more groups, including but not limited to alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxyl, carboxylic acid or alkoxy, or the aryl group can be unsubstituted. Examples of aryl include but are not limited to phenyl, 2-naphthyl, 1-naphthyl, 1-anthryl etc.

[0056] The term "arylene" refers to a divalent or higher valent benzene ring group or a divalent or higher valent benzene ring system fused to one or more optionally substituted benzene rings. The arylene group may be substituted by one or more groups, including but not limited to alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxyl, carboxylic acid or alkoxy, or the arylene group may be unsubstituted. Examples of arylene groups include but are not limited to phenylene (e.g., benzene-1,4-diyl), naphthalene-1,8-diyl, benzenetriyl, benzenetetrayl, etc.

[0057] "Carbonyl" refers to a group of the formula -C(O)-. Carbonyl-containing groups include any substituent containing a carbon-oxygen double bond (C=O), including acyl, amide, carboxyl, ester, urea, carbamate, carbonate, and ketone, as well as aldehydes, such as substituents based on -COR or -RCHO, where R is aliphatic, heteroaliphatic, alkyl, heteroalkyl, hydroxy, or a secondary, tertiary, or quaternary amine.

[0058] The carbonylamino group can be -N(R)-C(O)-R (wherein each R is independently a substituent group such as, for example, alkyl, alkenyl, alkynyl, acyl, aryl, aralkyl, cycloalkyl, haloalkyl, or heterocycloalkyl, or H).

[0059] "Carboxyl" refers to a -COOH group. A carboxyl group can form a carboxylic acid. "Substituted carboxyl" refers to a -COOR group, where R is an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, haloalkyl, or heterocycloalkyl group. For example, a substituted carboxyl group can be a carboxylate or a salt thereof (e.g., a carboxylate).

[0060] The term "cycloalkyl" refers to a non-aromatic carbon-based ring consisting of at least three carbon atoms. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The term "heterocycloalkyl" is a cycloalkyl as defined above wherein at least one of the carbon atoms of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.

[0061] "Derivative": In chemistry, a derivative is a compound that is derived from a similar compound or that could conceivably be produced from another compound, for example, if one atom is replaced by another atom or group of atoms. The latter definition is common in organic chemistry. In biochemistry, a derivative is a compound that, at least in theory, could be formed from a precursor compound.

[0062] "Drug-resistant" or "multidrug-resistant" refers to a cancer that is resistant to treatment with at least one therapeutic agent historically used to treat the cancer. These recurrent cancers often occur after surgery, primary chemotherapy treatment, radiation therapy, or immunotherapy. In certain embodiments, the cancer is a chemotherapy-resistant cancer.

[0063] The term "haloalkyl" or "haloalkyl" refers to alkyl groups as defined above wherein one or more hydrogen atoms present on these groups are replaced by a halogen (F, Cl, Br, I).

[0064] The term "hydroxyl" is represented by the formula -OH.

[0065] The term "hydroxyalkyl" refers to an alkyl group having at least one hydrogen atom replaced by a hydroxy group. The term "alkoxyalkyl" is defined as an alkyl group having at least one hydrogen atom replaced by an alkoxy group as described above.

[0066] "Inhibit" refers to preventing the full development of a disease or condition."Inhibit" also refers to any quantitative or qualitative decrease in biological activity or binding relative to a control.

[0067] The term "neoplasm" refers to abnormal cell proliferation and includes benign and malignant tumors and other proliferative disorders.

[0068] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0069] The term "pharmaceutically acceptable salt or ester" refers to a salt or ester prepared by conventional means, including salts of inorganic and organic acids, including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid, and the like. "Pharmaceutically acceptable salts" of the compounds disclosed herein also include salts formed by cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and by bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide. These salts can be prepared by standard procedures, for example, by reacting the free acid with a suitable organic or inorganic base. Any chemical compound described in this specification may alternatively be administered as a pharmaceutically acceptable salt thereof. "Pharmaceutically acceptable salts" also include free acid, base, and zwitterionic forms. A description of suitable pharmaceutically acceptable salts can be found in Handbook of Pharmaceutical Salts, Properties, Selection and Use, Wiley VCH (2002). When the compounds disclosed herein contain an acidic functional group such as a carboxyl group, pharmaceutically acceptable cation pairs suitable for the carboxyl group are well known to those skilled in the art and include alkali metals, alkaline earth metals, ammonium, quaternary ammonium cations, and the like. These salts are known to those skilled in the art. For other examples of "pharmacologically acceptable salts," see Berge et al., J. Pharm. Sci. 66: 1 (1977).

[0070] "Pharmaceutically acceptable esters" include esters derived from compounds described herein that have been modified to contain hydroxy or carboxyl groups. In vivo hydrolyzable esters are esters that hydrolyze in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters containing a carboxyl group include, C 1-6 Alkoxymethyl esters, such as methoxymethyl, C 1-6 Alkanoyloxymethyl esters such as pivaloyloxymethyl, phthalyl esters, C 3-8 Cycloalkoxycarbonyloxy, C 1-6 Alkyl esters such as 1-cyclohexylcarbonyl-oxyethyl; 1,3-dioxol-2-one methyl esters such as 5-methyl-1,3-dioxol-2-one methyl ester; and C 1-6 Alkoxycarbonyloxyethyl esters, such as 1-methoxycarbonyl-oxyethyl, may be formed at any carboxyl group of the compound.

[0071] Hydrolyzable esters containing hydroxyl groups include inorganic esters such as phosphates and α-acyloxyalkyl ethers and related compounds that are the result of hydrolysis in vivo of the parent hydroxyl group as a result of ester decomposition. Examples of α-acyloxyalkyl ethers include acetoxy-methoxy and 2,2-dimethylpropionyloxy-methoxy. Selection of groups that form hydrolyzable esters in vivo with hydroxyl groups include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonates), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl. Examples of substituents on the benzoyl group include morpholino and piperazinyl attached to the 3- or 4-position of the benzoyl ring from the ring nitrogen atom via a methylene group.

[0072] For therapeutic use, salts of a compound are salts wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also be useful, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0073] The pharmaceutically acceptable acid and base addition salts mentioned above are intended to comprise the nontoxic acid and base addition salt forms of the therapeutic activity that the compound can form. Pharmaceutically acceptable acid addition salts can be conveniently obtained by treating the base form with such suitable acid. Suitable acid includes, for example, inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids, such as, for example, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid (i.e., oxalic acid), malonic acid, succinic acid (i.e., succinic acid), maleic acid, fumaric acid, malic acid (i.e., hydroxysuccinic acid), tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylaminosulfonic acid (cyclamic acid), salicylic acid, para-aminosalicylic acid, methylene pamoic acid (pamoic acid / pamoic acid) and the like. On the contrary, the salt form can be converted into the free base form by treating with a suitable base.

[0074] Compounds containing acidic protons can also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Suitable basic salt forms include, for example, ammonium salts, alkali metal salts and alkaline earth metal salts (e.g., lithium salts, sodium salts, potassium salts, magnesium salts, calcium salts, etc.), salts with organic bases, such as N,N'-bisbenzylethylenediamine (benzathine) salts, N-methyl-D-glucamine salts, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine, etc.

[0075] The term "addition salt" as used herein also includes the solvates that the compounds described herein are able to form, such as hydrates, alcoholates, and the like.

[0076] The term "quaternary amine" used above defines a quaternary ammonium salt, which can be formed by the reaction between the basic nitrogen of the compound and a suitable quaternizing agent, such as, for example, an optional substituted alkyl halide, an aryl halide or an arylalkyl halide, for example, methyl iodide or benzyl iodide. Other reactants with a good leaving group can also be used, such as trifluoromethanesulfonic acid alkyl esters, methanesulfonic acid alkyl esters and p-toluenesulfonic acid alkyl esters. Quaternary amine has a positively charged nitrogen. Pharmaceutically acceptable counterions include chloride, bromide, iodide, trifluoroacetate and acetate. Ion exchange resins can be used to introduce selected counterions.

[0077] It will be appreciated that the compounds described herein may have metal binding, chelating, or complex forming properties and may therefore exist as metal complexes or metal chelates.

[0078] Some of the compounds described herein may also exist in their tautomeric forms.

[0079] "Preventing" a disease or condition refers to prophylactic administration of a composition to a subject who exhibits no signs of the disease or only early signs of the disease in order to reduce the risk of developing the pathology or condition or to lessen the severity of the pathology or condition.

[0080] Prodrugs of the disclosed compounds are also contemplated herein. A prodrug is an active compound or an inactive compound that is chemically modified to an active compound by physiological actions in vivo, such as hydrolysis, metabolism, etc., after the prodrug is administered to a subject. The term "prodrug" as used throughout this article refers to pharmacologically acceptable derivatives such as esters, amides, and phosphates, such that the in vivo biotransformation product of the resulting derivative is an active drug as defined in the compound described herein. The prodrug preferably has excellent water solubility, increased bioavailability, and is readily metabolized in vivo to an active inhibitor. Prodrugs of the compounds described herein can be prepared by modifying the functional groups present in the compound in such a manner that the modification is cleaved into the parent compound by conventional manipulation or in vivo. The suitability and techniques for preparing and using prodrugs are well known to those skilled in the art. For a general discussion of prodrugs involving esters, see Svensson and Tunek, Drug Metabolism Reviews 165 (1988) and Bundgaard, Design of Prodrugs, Elsevier (1985).

[0081] The term "prodrug" is also intended to include any covalently bonded carrier that releases the active parent drug of the present invention in vivo when the prodrug is administered to a subject. Since prodrugs generally have enhanced properties relative to active agent drugs, such as solubility and bioavailability, the compounds disclosed herein can be delivered in the form of prodrugs. Therefore, methods for prodrugs of the compounds disclosed herein, for delivering prodrugs, and for compositions containing such prodrugs are also contemplated. Prodrugs of the disclosed compounds are typically prepared by modifying one or more functional groups present in the compound in such a manner that the modification is cleaved to produce the parent compound during conventional operation or in vivo. Prodrugs include compounds having phosphonates and / or amino groups functionalized with any of the following groups: the groups are cleaved in vivo to produce the corresponding amino and / or phosphonate groups, respectively. Examples of prodrugs include, but are not limited to, compounds having acylated amino groups and / or phosphonates or phosphonamide groups. In specific examples, the prodrug is a lower alkyl phosphonate, such as isopropyl phosphonate.

[0082] Protected derivatives of the disclosed compounds are also contemplated. Various suitable protecting groups for the disclosed compounds are disclosed in Greene and Wuts, Protective Groups in Organic Synthesis; 3rd Edition; John Wiley & Sons, New York, 1999.

[0083] Typically, the protecting group is removed without affecting the remainder of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis, etc. A preferred method involves removing the ester, such as using Lewis acidic conditions (e.g., in TMS-Br mediated ester cleavage) to crack the phosphonate to produce a free phosphonate. A second preferred method involves removing the protecting group, such as by removing the benzyl group using palladium on carbon for hydrogenolysis in a suitable solvent system such as alcohol, acetic acid, or a mixture thereof. Tert-butoxy-based groups, including tert-butoxycarbonyl protecting groups, can be removed with mineral or organic acids, such as HCl or trifluoroacetic acid, in a suitable solvent system such as water, dioxane, and / or dichloromethane. Another exemplary protecting group suitable for protecting amino and hydroxyl-functional amino groups is trityl. Other conventional protecting groups are known, and suitable protecting groups can be selected by those skilled in the art in consultation with Greene and Wuts, Protective Groups in Organic Synthesis; 3rd edition; John Wiley & Sons, New York, 1999. When the amine is deprotected, the resulting salt can be readily neutralized to yield the free amine. Similarly, when an acid moiety such as a phosphonic acid moiety is revealed, the compound can be isolated as the acid compound or as a salt thereof.

[0084] The term "subject" includes human subjects and veterinary subjects.

[0085] "Substituted" or "substituted" refers to the replacement of a hydrogen atom of a molecule or an R group with one or more additional R groups. Unless otherwise defined, the term "optionally substituted" or "optional substituent" as used herein refers to a group that may or may not be further substituted with 1, 2, 3, 4 or more groups (preferably 1, 2 or 3, more preferably 1 or 2 groups). Substituents may be selected from, for example, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, hydroxy, oxo, C 1-6 Alkyloxy, aryloxy, C 1-6 Alkoxyaryl, halo, C 1-6 Alkyl halides (such as CF3 and CHF2), C 1-6 Alkoxy halides (such as OCF3 and OCHF2), carboxyl, ester, cyano, nitro, amino, substituted amino, disubstituted amino, acyl, ketone, amide, aminoacyl, substituted amide, disubstituted amide, sulfhydryl, alkylthio, thio, sulfate, sulfonate, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfonyl, sulfonamide, substituted sulfonamide, disubstituted sulfonamide, aryl, aryl C 1-6 Alkyl, heterocyclic and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclic and groups containing them may be further optionally substituted. Optional substituents in the case of N-heterocycles may also include, but are not limited to, C 1-6 Alkyl NC 1-3 Alkyl, more preferably methyl, especially N-methyl.

[0086] "Therapeutically effective amount" refers to an amount of a specified agent sufficient to achieve the desired effect in a subject treated with the agent. Ideally, a therapeutically effective amount of an agent is an amount sufficient to inhibit or treat a disease or condition without causing substantial cytotoxic effects in the subject. The therapeutically effective amount of an agent will depend on the subject being treated, the severity of the affliction, and the mode of administration of the therapeutic composition.

[0087] "Treatment" refers to a therapeutic intervention to improve the signs or symptoms of a disease or pathological condition after they have begun to develop. As used herein, with reference to a disease or pathological condition, the term "improvement" refers to any observable beneficial effect of treatment. A beneficial effect can be demonstrated, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in the severity of some or all of the clinical symptoms of the disease, a slowing of the progression of the disease, an improvement in the subject's overall health or well-being, or by other parameters well known in the art that are specific to a particular disease. The phrase "treating a disease" includes inhibiting the full development of a disease or condition, for example, in a subject at risk for the disease or having a disease such as cancer (particularly metastatic cancer).

[0088] inhibitors

[0089] Unless the context clearly indicates otherwise, all compounds described herein can be provided as pharmaceutically acceptable salts thereof. In some embodiments, the inhibitor is not a salt. In some embodiments, the inhibitor is a salt. In certain embodiments, the inhibitor can be a low molecular weight compound ("LMWC," having a molecular weight of less than about, for example, but not limited to, 600 Daltons).

[0090] Specific examples of the compounds disclosed herein may include one or more asymmetric centers; therefore, these compounds can exist in different stereoisomeric forms. Thus, the compounds and compositions can be provided as individual pure enantiomers or as stereoisomeric mixtures (including racemic mixtures). In certain embodiments, the compounds disclosed herein are synthesized or purified to a substantially enantiomerically pure form, such as 90% enantiomeric excess, 95% enantiomeric excess, 97% enantiomeric excess, or even greater than 99% enantiomeric excess, such as in enantiomerically pure form.

[0091] The compounds disclosed herein may have at least one asymmetric center or geometric center, a cis-trans center (C=C, C=N). Unless otherwise indicated, all chiral isomers, diastereomers, racemic isomers, mesoisomers, rotational isomers and geometric isomers of the structure are contemplated. The compounds may be isolated as a single isomer or as a mixture of isomers. All tautomers of the compounds are also considered part of the present disclosure. The compounds disclosed herein also include all isotopes of atoms present in the compounds, which may include, but are not limited to, deuterium, tritium, 18 F, etc.

[0092] Disclosed herein are compounds having Formula I as p62-ZZ inhibitors:

[0093]

[0094] wherein Ar is an arylene or heteroarylene group;

[0095] R 1 With structure:

[0096]

[0097] wherein W is an alkanediyl group, an alkenediyl group, a carbonyl group, or a combination thereof;

[0098] X is -NR 5 -, where R 5 is H or alkyl, or -O-; and

[0099] Y is optionally substituted cycloalkyl, optionally substituted cycloalkyl-substituted alkyl, optionally substituted heterocycloalkyl, or optionally substituted heterocycloalkyl-substituted alkyl;

[0100] Each R 2 are the same or different and have the structure:

[0101]

[0102] Where Z is -NR 6 -, where R 6 is H or alkyl, -O-, -S- or -CH2-;

[0103] Z 1 Yes (-CH2-) m , wherein m is 0 to 5, or is an alkenediyl group having 2 to 6 carbon atoms;

[0104] Cy is a 3-8 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; and

[0105] Each R 4 are the same or different and are selected from hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, or amino; and c is 0 to 5; and

[0106] Each R 3 are the same or different and are selected from hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or nitro, wherein a is 2 to 5 and b is 0 to 3.

[0107] Ar can be, for example, a benzenetriyl group (eg, benzene-1,3,4-triyl group) or a benzenetetrayl group.

[0108] W can be, for example, a lower alkanediyl group, or a lower alkenediyl group, or a lower alkanediyl group further including a carbonyl group, or a lower alkenediyl group further including a carbonyl group. X can be, for example, -NR 5 -, where R5 is a lower alkyl group which may be optionally substituted. Y may be, for example, a cycloalkyl-substituted alkyl group wherein the alkyl group comprises 1 to 4 carbon atoms. In certain embodiments, R 1 is –CH2-X-(CH2) m -R 11 , wherein X is NH or O, m is 0 to 6; and R 11 is an optionally substituted cycloalkyl group (particularly an optionally substituted cyclohexyl group). 11 It is an unsubstituted cyclohexyl group.

[0109] In certain embodiments, Y is:

[0110]

[0111] In certain embodiments, R 2 With structure:

[0112]

[0113] Z can be, for example, -NR 6 -, where R 6 is lower alkyl, which may be optionally substituted, or Z may be -O-. 4 For example, it can be -F, -Cl, -OCH3, -OH, -CH3 or -NH2. In certain embodiments, c is 1 or 2. In certain embodiments, R 4 is 4-fluoro; 2,4-difluoro; or 4-methyl.

[0114] R 3 For example, it can be -F, -Cl, -OCH3, -OH or -NH2. In certain embodiments, R 3 is lower alkyl, lower alkoxy, C1-C4 alkylamino (the C1-C4 alkyl part of the alkylamino may be linear or branched), di(C1-C4 alkyl)amino, C3-C7 cycloalkyl (especially C3-C5 cycloalkyl, especially cyclopropyl), hydroxy-substituted C3-C7 cycloalkyl, 3 to 6-membered heterocycloalkyl containing at least one heteroatom selected from N, O and S; alkyl-substituted 3 to 6-membered heterocycloalkyl, hydroxy-substituted 3 to 6-membered heterocycloalkyl, or aryl such as phenyl, naphthyl or anthracenyl, or nitro.

[0115] In certain embodiments, a is 2, 3, 4, or 5. In preferred embodiments, a is 2. In certain embodiments, the first R 2 The group is on the Ar ring relative to R 1 The meta position of the group, and the second R 2 The group is on the Ar ring relative to R 1In certain embodiments, each R 2 The groups have the same structure.

[0116] In certain embodiments, b is 0, 1, 2, or 3.

[0117] In certain embodiments, c is 0, 1, 2, 3, 4, or 5.

[0118] In a more specific embodiment, the p62-ZZ inhibitor is selected from the group consisting of:

[0119]

[0120] where R 7 、R 8 and R 9 Each of the alkyl groups is the same or different and is selected from -F, -Cl, -OCH3, -OH, -CH3 or -NH2; d is 0 to 3; e is 0 to 5; and f is 0 to 5.

[0121] The compounds disclosed herein can be synthesized as shown below.

[0122] General synthesis route:

[0123]

[0124] Synthesis of compound XIELP1-106:

[0125]

[0126] First, 3,4-dihydroxybenzaldehyde (1.38 g, 10.0 mmol) was diluted with anhydrous dimethylformamide (DMF, 40 mL). 1-(Bromomethyl)-4-fluorobenzene (3.96 g, 21.0 mmol) was slowly added, followed by anhydrous K2CO3 (5.52 g, 40.0 mmol). The mixture was stirred at room temperature for 6 hours. The mixture was partitioned between H2O and diethyl ether (120 mL each). The organic layer was separated and the aqueous layer was extracted with diethyl ether (3×50 mL). The combined organic layers were washed with H2O (2×50 mL) and saturated aqueous NaCl solution (50 mL). The light straw-colored extract was dried over anhydrous sodium sulfate and concentrated to give 3,4-bis((4-fluorobenzyl)oxy)benzaldehyde (4.31 g, 82%) as a milky white solid after washing with hexane (75 mL) and drying.

[0127] Subsequently, 3,4-bis((4-fluorobenzyl)oxy)benzaldehyde (354 mg, 1 mmol) was dissolved in anhydrous ethanol, and cyclohexylmethylamine (0.13 mL, 1 mmol) was added. The reaction mixture was stirred at 60 ° C for 12 hours. The reaction solution was cooled to room temperature. NaBH4 (57 mg, 1.5 mmol) was slowly added in small portions, and the resulting solution was stirred for another 12 hours. The solvent was evaporated in vacuo, and the residue was dissolved in water and extracted with ethyl acetate. The organic layers were combined and dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by flash column to produce the desired product N-(3,4-bis((4-fluorobenzyl)oxy)benzyl)-1-cyclohexylmethylamine (260 mg, 57%).

[0128] Finally, 2-((3,4-bis(benzyloxy)benzyl)amino)ethan-1-ol (260 mg, 0.58 mmol) was dissolved in 25 mL of anhydrous methanol and HCl gas was applied to the pump for 1 hour. The mixture was stirred for an additional 2 hours and evaporated to approximately 1 mL. Hexane was then added to obtain a solid compound, which was filtered and dried to yield the final compound (210 mg, 74%). 1 H NMR(CDCl3):7.52-7.33(m,10H),7.01-6.84(m,3H),5.20(s,2H),5.17(s ,2H),3.71(s,2H),3.64(t,J=4.8,2H),2.93(s,2H),2.72(t,J=4.8,2H).

[0129] Treatment and pharmaceutical compositions

[0130] The compounds disclosed herein can be used to treat p62-mediated diseases. Exemplary p62-mediated diseases include multiple myeloma, autophagy-related diseases, metabolic syndrome, Alzheimer's disease and other neurodegenerative diseases, and infectious diseases such as those caused by Staphylococcus aureus, Enterococci, or Salmonella enterica.

[0131] The compounds disclosed herein are useful in treating cancers such as renal cancer, lung cancer, thyroid cancer, prostate cancer, multiple myeloma, and breast cancer.

[0132] In certain embodiments, the compounds disclosed herein inhibit the growth of multiple myeloma cells. In particular, the compounds can be used to treat multiple myeloma characterized by being selected from the following cell types: one or more OPM-2 cells, OPM-2-like cells, MM-IS cells, MM-IS-like cells, MM.1R cells, MM-1R-like cells, KMS-18 cells, KMS-18-like cells, S6B45 cells, S6B45-like cells, MR20 cells, MR20-like cells, ARD cells and / or ARD-like cells. Depending on the type of tumor and the stage of development of the disease, the anti-cancer effects of the treatment methods include, but are not limited to, inhibition of tumor growth, tumor growth delay, tumor regression, tumor shrinkage, increased time to tumor regrowth after cessation of treatment, slowing of disease progression, and prevention of metastasis. It is expected that when the treatment method is administered to a subject in need of such treatment, the treatment method will produce an effect as measured by, for example, the degree of anti-cancer effect, response rate, time to disease progression, or survival rate. In particular, the treatment method is suitable for human patients, particularly those who have relapsed or are refractory to previous chemotherapy, although first-line treatment is also envisioned. For example, the compounds disclosed herein can be used to treat cancer, particularly resistant multiple myeloma that is resistant to one or more of dexamethasone, alkylating agents (e.g., melphalan, cyclophosphamide), anthracyclines (e.g., doxorubicin), thalidomide, lenalidomide, CC-404, bortezomib, and multi-target kinase inhibitors. The compounds disclosed herein can also be co-administered with any of the above-mentioned agents. The compounds disclosed herein can block autophagy. Blocking autophagy can enhance the efficacy of DNA damaging agents used for cancer treatment (inhibition of autophagy by FIP200 deletion weakens DNA damage repair and increases cell death when treated with anticancer agents. Bae et al., Jl. Mol Cancer Res. 2011 Aug. 1) and possible other agents.

[0133] In certain embodiments, the compounds disclosed herein modulate p62 activity in stromal cells, which can reduce tumor growth and bone destruction.

[0134] In a specific embodiment, the compounds disclosed herein can be used to inhibit osteoclastogenesis and / or reduce osteoclast activation. Osteoclasts are the main bone resorbing cells under normal and pathological conditions. Increased osteoclast bone resorption can be produced by increased osteoclast formation and activation of preformed osteoclasts to absorb bone. In patients with bone metastasis, osteolytic bone destruction can lead to severe bone pain, pathological fractures, hypercalcemia and nerve compression syndrome. Several tumors show a high preference for bone, including renal cancer, lung cancer, thyroid cancer, prostate cancer, multiple myeloma and breast cancer, see, for example, Roodman, Journal of Clinical Oncology, vol.19, 2001, p.3562. The formation and activation of osteoclasts may also lead to osteolytic diseases and bone loss in individuals with osteoporosis (such as postmenopausal osteoporosis), Paget's disease, rheumatoid arthritis and head and neck squamous cell carcinoma, see, for example, U.S. Patent No. 7,462,646.

[0135] The disclosed compounds can be co-administered with another therapeutic agent, particularly another anticancer agent. In certain embodiments, a pharmaceutical composition comprising at least a p62-ZZ inhibitor and at least one other anticancer agent is provided. Exemplary chemotherapeutic agents include EGF receptor antagonists, arsenic sulfide, doxorubicin, cisplatin, carboplatin, cimetidine, caminomycin (carminomycin, caminomycin), nitrogen mustard hydrochloride, pentamethylmelamine (pentamethylmelamine), thiotepa, teniposide, cyclophosphamide, chlorambucil, demethoxyhypocrellin A, melphalan, ifosfamide, trofosfamide (chloroethamide), treosulfan, podophyllotoxin or podophyllotoxin derivatives. Biological, etoposide phosphate, teniposide, etoposide, isovinblastine, vinblastine epoxy, vindesine, 9-aminocamptothecin, camptoirinotecan, crisnatol, megestrol acetate, methotrexate, mitomycin C, ecteinascidin 743, busulfan, carmustine, lomustine, lovastatin, 1-methyl-4-phenylpyridinium ion, semustine, staurosporine, streptozotocin phthalocyanine, dacarbazine (dacarbazine), aminopterin, methotrexate, trimetrexate, thioguanine, mercaptopurine, fludarabine, pentastatin, cladribine, cytarabine, porfiromycin, 5-fluorouracil, 6-mercaptopurine, doxorubicin hydrochloride, leucovorin, mycophenolic acid, daunorubicin, deferoxamine, floxuridine, doxifluridine , raltitrexed, idarubicin, epirubicin, pirarubicin, daunorubicin, mitoxantrone, bleomycin sulfate, actinomycin D, safracin, saframycin, quinocardin, discodermolide, vincristine, vinblastine, vinorelbine tartrate, vortoporphyrin (verteporfin,vertoporfin), paclitaxel, tamoxifen, raloxifene, tiazofuran, thioguanine, ribavirin, EICAR, estramustine, estramustine sodium phosphate, flutamide, bicalutamide, buserelin, leuprorelin, pteridine, enediyne, levamisole, aflacon, interferon, interleukin, aldesleukin, filgrastim, sargramostim, rituximab, BCG, tretinoin, betamethasone, gemcitabine hydrochloride, verapamil, VP-16, hexamethylmelamine, thapsigargin, oxaliplatin, iproplatin, tetraplatin, lobaplatin, DCP, PLD-147, JM118, JM216, JM335, satraplatin, docetaxel, deoxypaclitaxel, TL-139, 5'-demethylanhydrovinblastine, camptothecin, irinotecan, topotecan, BAY 38-3441, 9-nitrocamptothecin, exatecan, lertotecan, gimatecan, homocamptothecin diflutecan and 9-aminocamptothecin, SN-38, ST 1481, karanitecin, indolocarbazole, protoberberine, indolizine, idenoisoquinolone, benzophenazine and NB-506.

[0136] The compounds disclosed herein can also be administered to subjects in need thereof to reduce food intake and body weight, reverse insulin and leptin resistance, reverse hepatic steatosis (fatty liver), and improve dyslipidemia. They can be used to treat obesity, diabetes (e.g., type 2 diabetes), and non-alcoholic and alcoholic fatty liver disease (NAFLD / AFLD), which is a risk factor for insulin resistance, cirrhosis, and liver cancer, dyslipidemia that predisposes to arteriosclerotic heart disease, diabetic nephropathy, gout, and fibrosis.

[0137] The diabetic condition may be type 1 diabetes, type 2 diabetes, impaired glucose tolerance and / or insulin resistance.

[0138] The compounds disclosed herein can also be administered to a subject in need thereof to treat a neurodegenerative disease or disorder, such as, for example, Alzheimer's disease, ataxia-telangiectasia, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease.

[0139] The compounds identified herein can be included in pharmaceutical compositions that, in addition to the agent, also contain at least one pharmaceutically acceptable additive, such as a carrier, a thickener, a diluent, a buffer, a preservative, a surfactant, and the like. The pharmaceutical composition can also contain one or more additional active ingredients, such as an antimicrobial agent, an anti-inflammatory agent, an anesthetic, and the like. Pharmaceutically acceptable carriers for these formulations are conventional. Remington's Pharmaceutical Sciences, by E.W. Martin, Mack Publishing Co., Easton, PA, 19th edition (1995), describes compositions and formulations suitable for drug delivery of the compounds disclosed herein.

[0140] In general, the character of carrier will depend on the specific mode of administration adopted.For example, parenteral preparations usually contain injectable fluids, which include pharmaceutically and physiologically acceptable fluids, such as water, normal saline, balanced salt solution, glucose aqueous solution, glycerol etc. as vehicle (carrier, vehicle).For solid compositions (for example, powder, pill, tablet or capsule form), conventional nontoxic solid carrier can include for example pharmaceutical grade mannitol, lactose, starch or magnesium stearate.Except biologically neutral carrier, the pharmaceutical composition to be used can include a small amount of nontoxic auxiliary substances, such as wetting agents or emulsifying agents, preservatives and pH buffers etc., for example sodium acetate or sorbitan monolaurate.

[0141] Compounds disclosed herein can be administered to a subject by various mucosal administration methods, including oral, rectal, intranasal, intrapulmonary or transdermal delivery, or by topical delivery to other surfaces. Alternatively, the compound can be administered by non-mucosal routes, including intramuscular, subcutaneous, intravenous, intraarterial, intraarticular, intraperitoneal, intrathecal, intracerebroventricular or parenteral routes. In other alternative embodiments, the compound can be administered ex vivo by direct exposure to cells, tissues or organs derived from a subject.

[0142] In order to prepare pharmaceutical compositions, the compound can be combined with various pharmaceutically acceptable additives and substrates or vehicles for dispersing the compound. Desirable additives include, but are not limited to, pH control agents, such as arginine, sodium hydroxide, glycine, hydrochloric acid, citric acid, etc. In addition, local anesthetics (e.g., benzyl alcohol), isotonic agents (e.g., sodium chloride, mannitol, sorbitol), adsorption inhibitors (e.g., Tween 80 or Miglyol 812), solubility enhancers (e.g., cyclodextrin and its derivatives), stabilizers (e.g., serum albumin) and reducing agents (e.g., glutathione) can be included. Adjuvants such as aluminum hydroxide (e.g., Amphogel, Wyeth Laboratories, Madison, NJ), Freund's adjuvant MPLTM (3-O-deacylated monophosphoryl lipid A; Corixa, Hamilton, IN) and IL-12 (Genetics Institute, Cambridge, MA), as well as many other suitable adjuvants well known in the art, can be included in the composition. When the composition is a liquid, the tonicity of the formulation, measured as a unit of tonicity with reference to a 0.9% (w / v) saline solution, is typically adjusted to a value that does not cause substantial, irreversible tissue damage at the site of administration. Typically, the tonicity of the solution is adjusted to a value of about 0.3 to about 3.0, such as about 0.5 to about 2.0, or about 0.8 to about 1.7.

[0143] Compound can be dispersed in the substrate or the vehicle that can comprise the hydrophilic compound with the ability of dispersing compound and any required additive.Substrate can be selected from the suitable compound of wide scope, include but not limited to the copolymer of polycarboxylic acid or its salt, carboxylic anhydride (for example, maleic anhydride) and other monomers (for example, methyl (methyl) acrylate, acrylic acid etc.), hydrophilic vinyl polymer (such as polyvinyl acetate, polyvinyl alcohol, polyvinyl pyrrolidone), cellulose derivative (such as hydroxymethyl cellulose, hydroxypropyl cellulose etc.), and natural polymer, such as chitosan, collagen, sodium alginate, gelatin, hyaluronic acid and its nontoxic metal salt.Usually select biodegradable polymer as substrate or vehicle, for example polylactic acid, poly (lactic acid-glycolic acid) copolymer, polyhydroxybutyric acid, poly (hydroxybutyric acid-glycolic acid) copolymer and its mixture.Alternatively or additionally, synthetic fatty acid ester such as polyglycerol fatty acid ester, sucrose fatty acid ester etc. can be used as vehicle.Hydrophilic polymer and other vehicles can be used alone or in combination, and can give the structural integrity that vehicle enhances by partial crystallization, ionic bonding, crosslinking etc. The vehicle can be provided in a variety of forms, including those for direct application to mucosal surfaces, including fluid or viscous solutions, gels, pastes, powders, microspheres, and films.

[0144] The compound can be combined with a substrate or vehicle according to a variety of methods and the release of the compound can be achieved by diffusion, decomposition of the vehicle, or formation of associated water channels. In some cases, the compound is dispersed in microcapsules (microspheres) or nanocapsules (nanospheres) prepared from suitable polymers such as isobutyl 2-cyanoacrylate (see, for example, Michael et al., J. Pharmacy Pharmacol. 43: 1-5, 1991) and dispersed in a biocompatible dispersion medium, which produces sustained delivery and biological activity over an extended period of time.

[0145] The compositions of the present disclosure may alternatively contain substances as pharmaceutically acceptable vehicles as required to approximate physiological conditions, such as pH adjusters and buffers, tonicity adjusters, wetting agents, and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, and triethanolamine oleate. For solid compositions, conventional non-toxic pharmaceutically acceptable vehicles may be used, including, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like.

[0146] The pharmaceutical composition of the compound for use can also be formulated into a solution, microemulsion or other ordered structures suitable for high concentration active ingredients. Vehicle can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, etc.), and their suitable mixture. For example, by using a coating such as lecithin, by maintaining the required particle size in the case of a dispersible formulation and by using a surfactant, suitable solution fluidity can be maintained. In many cases, isotonic agents, such as sugar, polyols such as mannitol and sorbitol or sodium chloride are included in the composition and will be desirable. The extended absorption of the compound can be achieved by including the agent (for example, monostearate and gelatin) that delays absorption in the composition.

[0147] In certain embodiments, the compound can be administered in a time-release formulation, for example, in a composition comprising a slow-release polymer. These compositions can be prepared with a vehicle that prevents rapid release, for example, a controlled-release vehicle such as a polymer, a microencapsulated delivery system, or a bioadhesive gel. The delayed delivery in the various compositions of the present disclosure can be achieved by including an agent (for example, aluminum monostearate hydrogel and gelatin) that delays absorption in the composition. When a controlled-release formulation is needed, the controlled-release adhesive suitable for use according to the present disclosure includes any biocompatible controlled-release material that is inert to the active agent and can incorporate the compound and / or other bioactive agents. Many such materials are known in the art. Useful controlled-release adhesives are materials that are slowly metabolized under physiological conditions (for example, on a mucosal surface or in the presence of body fluids) after delivery. Suitable adhesives include, but are not limited to, biocompatible polymers and copolymers well known in the art for slow-release formulations. These biocompatible compounds are nontoxic and inert to surrounding tissues and do not cause significant adverse side effects, such as nasal irritation, immune response, inflammation, etc. They are metabolized into metabolites that are also biocompatible and easy to eliminate from the body.

[0148] Exemplary polymeric materials for the present disclosure include, but are not limited to, polymer matrices derived from copolyesters and homopolyesters with hydrolyzable ester bonds. Many of these are known in the art to be biodegradable and result in degradation products with non-toxic or low toxicity. Exemplary polymers include polyglycolic acid and polylactic acid, poly(DL-lactic acid-to-glycolic acid), poly(D-lactic acid-to-glycolic acid) and poly(L-lactic acid-to-glycolic acid). Other useful biodegradable or bioerodible polymers include, but are not limited to, polymers such as poly(ε-caprolactone), poly(ε-propiolactone-co-lactic acid), poly(ε-propiolactone-co-glycolic acid), poly(β-hydroxybutyric acid), poly(2-alkyl cyanoacrylates), hydrogels such as poly(hydroxyethyl methacrylate), polyamides, poly(amino acids) (e.g., L-leucine, glutamic acid, L-aspartic acid, etc.), poly(ester ureas), poly(2-hydroxyethyl DL-asparagine), polyacetal polymers, polyorthoesters, polycarbonates, polymaleamides, polysaccharides, and copolymers thereof. Many methods for preparing these formulations are well known to those skilled in the art (see, for example, Sustained and Controlled Release Drug Delivery Systems, JR Robinson, ed., Marcel Dekker, Inc., New York, 1978). Other useful formulations include controlled-release microcapsules (U.S. Pat. Nos. 4,652,441 and 4,917,893), lactic acid-glycolic acid copolymers for preparing microcapsules and other formulations (U.S. Pat. Nos. 4,677,191 and 4,728,721), and sustained-release compositions for water-soluble peptides (U.S. Pat. No. 4,675,189).

[0149] The pharmaceutical compositions of the present disclosure are generally sterile and stable under the conditions of manufacture, storage and use. Sterile solutions can be prepared by mixing the desired amount of the compound in a suitable solvent with one or a combination of ingredients listed herein, as needed, and then filtering and sterilizing. Typically, dispersions are prepared by mixing the compound and / or other bioactive agents into a sterile vehicle containing a basic dispersion medium and the required other ingredients listed herein. In the case of sterile powders, preparation methods include vacuum drying and freeze drying, which produce a powder of the compound plus any additional required ingredients from its previously sterile filtered solution. Protection against microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0150] According to the various treatment methods of the present disclosure, the compounds can be delivered to the subject in a manner consistent with conventional methods associated with the management of the condition being treated or prevented. According to the disclosure herein, a prophylactically or therapeutically effective amount of a compound is administered to a subject in need of such treatment for a period of time and under conditions sufficient to prevent, inhibit and / or alleviate the selected disease or condition or one or more symptoms thereof.

[0151] The administration of the compound can be for preventive or therapeutic purposes. When provided prophylactically, the compound is provided before any symptoms. The prophylactic administration of the compound is used to prevent or alleviate any subsequent disease process. When provided therapeutically, the compound is provided at the onset of symptoms of the disease or infection (or shortly thereafter).

[0152] For prevention and treatment purposes, the compound can be delivered by oral route or in a single bolus, via continuous delivery (e.g., continuous transdermal, mucosal or intravenous delivery) over an extended period of time or in a repeated administration regimen (e.g., by the hour, daily or weekly, repeated administration regimen). The therapeutically effective dose of the compound can be provided as a repeated dose within an extended prevention or treatment regimen, and the extended prevention or treatment regimen will produce clinically significant results to alleviate one or more symptoms or detectable conditions associated with the target disease or condition as described herein. In this context, the determination of the effective dose is generally based on animal model studies followed by human clinical trials, and is guided by an administration regimen that significantly reduces the occurrence or severity of the target disease symptoms or conditions in the subject. In this regard, suitable models include, for example, rodents, rats, birds, pigs, felines, non-human primates, and other recognized animal model subjects known in the art. Alternatively, an in vitro model can be used to determine the effective dose. Using such a model, only ordinary calculations and adjustments are required to determine the appropriate concentration and dosage (e.g., the amount that effectively causes a desired immune response or alleviates one or more symptoms of the target disease) of the compound for administering a therapeutically effective amount. In alternative embodiments, for therapeutic or diagnostic purposes, an effective amount or effective dose of an agent may simply inhibit or enhance one or more selected biological activities associated with a disease or disorder as described herein.

[0153] The actual dosage of the compound will vary according to factors such as the disease indication and the specific state of the subject (e.g., the subject's age, size, health, degree of symptoms, susceptibility factors, etc.), the time and route of administration, other drugs or treatments administered simultaneously, and the specific pharmacology of the agent used to induce the desired activity or biological response in the subject. The dosage regimen can be adjusted to provide the best preventive or therapeutic response. A therapeutically effective amount is also the amount in which any toxic or adverse side effects of the compound are exceeded by the beneficial effects of the treatment during the clinical phase. A non-limiting range for the therapeutically effective amount of the compound in the methods and formulations of the present disclosure is from about 0.01 mg / kg body weight to about 20 mg / kg body weight, such as from about 0.05 mg / kg to about 5 mg / kg body weight, or from about 0.2 mg / kg to about 2 mg / kg body weight.

[0154] The attending physician can vary the dosage to maintain the desired concentration at the target site (e.g., lung or systemic circulation). Higher or lower concentrations can be selected based on the mode of delivery, such as transdermal, rectal, oral, pulmonary or intranasal delivery versus intravenous or subcutaneous delivery. The dosage can also be adjusted based on the release rate of the administered formulation, such as the release rate of intrapulmonary sprays and powders, sustained-release oral and injectable particles, or transdermal delivery formulations. Example

[0155] The bone marrow microenvironment is known to provide a key supportive role in MM and enhance both tumor growth and bone destruction by activating multiple signaling pathways in stromal cells. Sequestosome 1 (p62) plays a key role in the formation of signaling complexes that lead to NF-κB, p38MAPK, and PI3K activation in the bone marrow microenvironment of MM patients. p62 deletion constructs lacking specific p62 domains (ΔSH2, ΔPB1, ΔZZ, Δp38, ΔTBS, and ΔUBA) were generated to identify domains, particularly the ZZ domain of p62, that are responsible for increasing MM cell growth and osteoclast (OCL) formation mediated by NF-κB and p38MAPK signaling, as a means of developing inhibitory peptides / molecules as potential therapeutic agents for MM ( Figure 1 These constructs were then transfected into a p62-knockout stromal cell line and revealed that the ZZ domain of p62 was required for stromal cell support of MM cell growth, increased IL-6 and VCAM-1 expression, and OCL formation. These results suggest that dominant-negative constructs or small molecules targeting the ZZ domain of p62 should block p62 function and inhibit bone marrow microenvironmental support for MM cells and OCL formation.

[0156] like Figure 2 Systems biology studies of the inhibitors were performed as indicated.

[0157] Example 1

[0158] Compound XIELP1-106: N-(3,4-bis((4-fluorobenzyl)oxy)benzyl)-1-cyclohexylmethanamine hydrochloride

[0159]

[0160]

[0161] 1 H NMR (DMSO-d6): 9.16 (bs, 1H), 9.08 (bs, 1H), 7.92 (bs, 1H), 7.53-7.44 (m, 5H), 7.24-7.19 (m, 4H), 7.10-7.0 5(m, 2H), 5.13(s, 4H), 4.01(s, 2H), 2.61(bs, 2H), 1.75-1.60(m, 5H), 1.22-1.10(m, 4H), 0.93-0.84(m, 2H).

[0162] XIELP1-12b: N-(3,4-bis((4-fluorobenzyl)oxy)benzyl)cyclohexylamine

[0163]

[0164]

[0165] 1 H NMR(DMSO-d6): 7.51-7.46(m, 4H), 7.23-7.18(m, 4H), 7.07-7.06(m, 1H), 6.98-6.96(m, 1H), 6.84-6.82(m, 1H), 5.09(s, 2H) , 5.07 (s, 2H), 3.63 (s, 2H), 2.33-2.27 (m, 1H), 1.80-1.77 (m, 2H), 1.66-1.63 (m, 2H), 1.54-1.50 (m, 1H), 1.16-0.99 (m, 5H).

[0166] XIELP1-17b: N-(3,4-bis((2,4-difluorobenzyl)oxy)benzyl)-1-cyclohexylmethanamine

[0167]

[0168]

[0169]

[0170] 1H NMR(DMSO-d6): 7.58-7.52(m, 2H), 7.31-7.25(m, 2H), 7.12-7.00(m, 4H), 6.86-6.84(m, 1H), 5.10(s, 2H), 5.08(s, 2H), 3,58(s, 2H), 2.26-2.24(m, 2H), 1.73-1.63(m, 5H), 1.38-1.30(m, 1H), 1.24-1.10(m, 3H), 0.87-0.79(m, 2H).

[0171] XIELP1-20a: N-(3,4-bis((2,4-difluorobenzyl)oxy)benzyl)cyclohexylamine

[0172]

[0173]

[0174] 1 H NMR(DMSO-d6): 7.58-7.52(m, 2H), 7.31-7.25(m, 2H), 7.15-7.07(m, 3H), 7.01-6.98(m, 1H), 6.87-6.85(m, 1H), 5. 10(s, 2H), 5.08(s, 2H), 3.63(s, 2H), 2.32-2.27(m, 1H), 1.80-1.54(m, 6H), 1.17-1.12(m, 3H), 1.02-0.99(m, 2H).

[0175] XIELP1-24b: 2-((3,4-bis((4-methylbenzyl)oxy)benzyl)amino)ethan-1-ol

[0176]

[0177]

[0178] 1 H NMR(DMSO-d6): 7.35-7.30(m, 4H), 7.20-7.17(m, 4H), 7.05-7.04(m, 1H), 6.96-6.94(m, 1H), 6.81-6.79(m, 1H), 5.04(s, 2H), 5.03 (s, 2H), 4.44 (t, J=5.2, 1H), 3.60 (s, 2H), 3.47-3.43 (m, 2H), 2.53-2.50 (m, 2H), 2.31 (s, 3H), 2.30 (s, 3H), 1.98 (bs, 1H).

[0179] XIELP1-25b: N-(3,4-bis((4-methylbenzyl)oxy)benzyl)-1-cyclohexylmethanamine

[0180]

[0181]

[0182] 1 H NMR(DMSO-d6): 7.34-7.31(m, 4H), 7.19-7.17(m, 4H), 7.04-6.93(m, 2H), 6.79-6.77(m, 1H), 5.04(s, 2H), 5.03( s, 2H), 3.56 (s, 2H), 2.31 (s, 6H), 2.25 (d, J=6.8, 2H), 1.73-1,63 (m, 5H), 1.38-1.10 (m, 4H), 0.88-0.81 (m, 2H).

[0183] XIELP1-51: N-(3,4-bis((4-methylbenzyl)oxy)benzyl)cyclohexylamine

[0184]

[0185]

[0186] 1 H NMR(DMSO-d6): 7.34-7.30(m, 4H), 7.19-7.17(m, 4H), 7.05-6.93(m, 2H), 6.81-6.78(m, 1H), 5. 05(s, 2H), 5.03(s, 2H), 3.61(s, 2H), 2.28-2.34(m, 7H), 1.80-1.54(m, 5H), 1.20-0.96(m, 5H).

[0187] XIELP1-58: N-(3,5-bis((2,4-difluorobenzyl)oxy)benzyl)-1-cyclohexylmethanamine

[0188]

[0189]

[0190] 1H NMR(DMSO-d6): 7.64-7.58(m, 2H), 7.33-7.27(m, 2H), 7.15-7.10(m, 2H), 6.63-6.62(m, 2H), 6.56-6.55(m, 1H), 5.08( s, 4H), 3.61 (s, 2H), 2.27 (d, J=6.4, 2H), 1.74-1.60 (m, 5H), 1.39-1.22 (m, 1H), 1.23-1.10 (m, 3H), 0.88-0.82 (m, 2H).

[0191] XIELP1-60: N-(3,5-bis((2,4-difluorobenzyl)oxy)benzyl)cyclohexylamine

[0192]

[0193]

[0194] 1 H NMR(DMSO-d6): 7.64-7.58(m, 2H), 7.33-7.28(m, 2H), 7.15-7.13(m, 2H), 6.63-6.55(s, 3H), 5.08(s, 4H), 3.66(s, 2H), 2.33-2.28(m, 1H), 1.81-1.54(m, 5H), 1.14-1.00(m, 5H).

[0195] The therapeutic efficacy and tolerability of compound XIELP1-106 (also known as 10b) were evaluated in the treatment of the subcutaneous RPMI-8226 human multiple myeloma xenograft model. Figure 3 The tumor volumes in the two groups at different time points are shown. On day 39 after tumor implantation, the average tumor volume in the XIELP1-106 vehicle control group reached 1,452 mm 3 Treatment with XIELP1-106 (60 mg / kg, intraperitoneally, once every 3 days x 4 weeks) produced a strong antitumor activity with a T / C value of 23% (p = 0.001).

[0196] The median survival time (MST) of vehicle-treated mice was 42 days ( Figure 4 In the XIELP1-106 group, no animal death occurred until the end of the study (60 days after tumor inoculation).

[0197] Regarding the safety profile, mice treated with XIELP1-106 at the given dose level experienced a moderate weight loss of 11.2% after three doses and then developed tolerance to treatment over the remaining time. No other significant clinical abnormalities were observed. In summary, XIELP1-106 at the given dose level demonstrated strong anti-tumor efficacy in the RPMI-8226 human multiple myeloma xenograft model in this study and significantly prolonged the survival of mice bearing subcutaneous RPMI-8226 tumors.

[0198] In view of the many possible embodiments to which the principles of the disclosed compounds, compositions, and methods may be applied, it should be recognized that the illustrated embodiments are only preferred examples of the invention and should not be taken as limiting the scope of the invention.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: wherein Ar is a benzenetriyl group; R 1 is -CH2-X-(CH2) m -R 11 , wherein X is NH, m is 0 to 1, and R 11 is an unsubstituted cycloalkyl group; Each R 2 are the same or different and have the structure: Where Z is -O-, and each R 4 is selected from -F, -Cl, -OCH3, -OH, -CH3 or -NH2; and c is 0 to 5; wherein a is 2, and b is 0; and The first R 2 The group is on the Ar ring relative to R 1 The meta position of the group, and the second R 2 The group is on the Ar ring relative to R 1 The para position of the group; or the first R 2 The group is on the Ar ring relative to R 1 The meta position of the group, and the second R 2 The group is on the Ar ring relative to R 1 Another meta position of a group.

2. The compound according to claim 1, wherein c is 1 and R 4 It is 4-fluoro or 4-methyl.

3. The compound according to claim 1, wherein c is 2 and R 4 It is 2,4-difluoro.

4. The compound according to claim 1, wherein Each R 2 The groups have the same structure.

5. The compound according to claim 1, selected from:

6. The compound according to claim 1, wherein c is 0.

7. The compound according to claim 1, wherein c is 1.

8. The compound according to claim 1, wherein c is 2.

9. Use of a p62-ZZ inhibitor in the preparation of a medicament for treating a p62-mediated disease in a subject, wherein the p62-ZZ inhibitor is a compound having Formula I or a pharmaceutically acceptable salt thereof: wherein Ar is benzenetriyl; R 1 is -CH2-X-(CH2) m -R 11 , wherein X is NH, m is 0 to 1, and R 11 is an unsubstituted cycloalkyl group; Each R 2 are the same or different and have the structure: Where Z is -O-, and each R 4 is selected from -F, -Cl, -OCH3, -OH, -CH3 or -NH2; and c is 0 to 5; wherein a is 2, and b is 0; and The first R 2 The group is on the Ar ring relative to R 1 The meta position of the group, and the second R 2 The group is on the Ar ring relative to R 1 The para position of the group; or the first R 2 The group is on the Ar ring relative to R 1 The meta position of the group, and the second R 2 The group is on the Ar ring relative to R 1 Another meta position of a group.

10. The use according to claim 9, wherein: c is 1 and R 4 It is 4-fluoro or 4-methyl.

11. The use according to claim 9, wherein: c is 2 and R 4 It is 2,4-difluoro.

12. The use according to claim 9, wherein: Each R 2 The groups have the same structure.

13. The use according to claim 9, wherein: The p62-mediated disease is multiple myeloma.

14. The use according to claim 9, further comprising inhibiting osteoclastogenesis and / or reducing osteoclast activation.

15. The use according to claim 9, wherein: The p62-mediated disease is drug-resistant multiple myeloma.

16. The use according to claim 9, further comprising co-administering the compound with at least one anticancer agent.

17. The use according to claim 9, wherein: The p62-mediated disease is cancer.

18. The use according to claim 9, wherein: The p62-mediated disease is a neurodegenerative disease.

19. The use according to claim 9, wherein: The p62-mediated disease is a diabetic condition.

20. Use of a p62-ZZ inhibitor in the preparation of a drug for regulating p62 activity in stromal cells, wherein the p62-ZZ inhibitor is a compound having Formula I or a pharmaceutically acceptable salt thereof: wherein Ar is a benzenetriyl group; R 1 is -CH2-X-(CH2) m -R 11 , wherein X is NH, m is 0 to 1, and R 11 is an unsubstituted cycloalkyl group; Each R 2 are the same or different and have the structure: Where Z is -O-, and each R 4 is selected from -F, -Cl, -OCH3, -OH, -CH3 or -NH2; and c is 0 to 5; wherein a is 2, and b is 0; and The first R 2 The group is on the Ar ring relative to R 1 The meta position of the group, and the second R 2 The group is on the Ar ring relative to R 1 The para position of the group; or the first R 2 The group is on the Ar ring relative to R 1 The meta position of the group, and the second R 2 The group is on the Ar ring relative to R 1 Another meta position of a group.

21. Use of a p62-ZZ inhibitor in the preparation of a medicament for inhibiting the growth of multiple myeloma cells, wherein the p62-ZZ inhibitor is a compound having Formula I or a pharmaceutically acceptable salt thereof: wherein Ar is a benzenetriyl group; R 1 is -CH2-X-(CH2) m -R 11 , wherein X is NH, m is 0 to 1, and R 11 is an unsubstituted cycloalkyl group; Each R 2 are the same or different and have the structure: Where Z is -O-, and each R 4 is selected from -F, -Cl, -OCH3, -OH, -CH3 or -NH2; and c is 0 to 5; wherein a is 2, and b is 0; and The first R 2 The group is on the Ar ring relative to R 1 The meta position of the group, and the second R 2 The group is on the Ar ring relative to R 1 The para position of the group; or the first R 2 The group is on the Ar ring relative to R 1 The meta position of the group, and the second R 2 The group is on the Ar ring relative to R 1 Another meta position of a group.

22. A pharmaceutical composition comprising at least one pharmaceutically acceptable additive and a compound according to any one of claims 1 to 8.

23. The pharmaceutical composition of claim 22, further comprising at least one anticancer agent.

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