METHODS AND MATERIALS FOR INCREASING TRANSCRIPTION FACTOR EB POLYPEPTIDE LEVELS

TECHNICAL FIELD

This document relates to methods and materials for increasing transcription factor EB (TFEB) polypeptide levels. For example, the document provides compounds (e.g., organic compounds) having the ability to increase TFEB polypeptide levels within cells, formulations containing compounds having the ability to increase TFEB polypeptide levels within cells, methods for making compounds having the ability to increase TFEB polypeptide levels within cells, methods for increasing TFEB polypeptide levels within cells, and methods for treating mammals (e.g., humans) having a condition responsive to an increase in TFEB polypeptide levels.

BACKGROUND

Lysosomes are membrane-bound cellular organelles that contain a variety of digestive enzymes responsible for metabolism and degradation of various biomolecules, such as proteins, lipids and nucleic acids, which are either damaged or no longer needed by the cell. In the absence of functional lysosomes, undegraded molecules rapidly accumulate within the lysosome and subsequently in the cytoplasm, leading to cellular damage and contributing to a number of pathological conditions.

TFEB is an important transcription factor that regulates the expression of hundreds of genes that control autophagy, lysosome biogenesis, and lipolysis (Sardiello et al., Science, 325(5939):473-7 (2009); and Wang et al., Nat. Commun., 8:2270 (2017)). When TFEB translocates from the cytoplasm of a cell to the nucleus, it activates expression of its target genes, which was shown to induce lysosomal biogenesis and increase the degradation of complex molecules including glycosaminoglycans and pathogenic protein aggregates such as those involved in Huntington's disease, Parkinson's disease, and Alzheimer's disease (Sardiello et al., Science, 325(5939):473-7 (2009); and Napolitano et al., J. Cell Sci., 129:2475-2481 (2016)). Several small-molecule activators of TFEB were shown to be useful for treating metabolic and age-related disorders (Wang et al., Nat. Commun., 8:2270 (2017)).

SUMMARY

This document provides methods and materials for increasing TFEB polypeptide levels. For example, the document provides compounds (e.g., organic compounds) having the ability to increase TFEB polypeptide levels within cells, formulations containing compounds having the ability to increase TFEB polypeptide levels within cells, methods for making compounds having the ability to increase TFEB polypeptide levels within cells, methods for making formulations containing compounds having the ability to increase TFEB polypeptide levels within cells, methods for increasing TFEB polypeptide levels within cells, and methods for treating mammals (e.g., humans) having a condition responsive to an increase in TFEB polypeptide levels. This document also provides compounds (e.g., organic compounds) having the ability to increase TFEB polypeptide levels within the nucleus of cells, formulations containing compounds having the ability to increase TFEB polypeptide levels within the nucleus of cells, methods for making compounds having the ability to increase TFEB polypeptide levels within the nucleus of cells, methods for making formulations containing compounds having the ability to increase TFEB polypeptide levels within the nucleus of cells, methods for increasing TFEB polypeptide levels within the nucleus of cells, and methods for treating mammals (e.g., humans) having a condition responsive to an increase in TFEB polypeptide levels within the nucleus of cells.

As described herein, the compounds provided herein can be used to increase TFEB polypeptide levels within cells in vitro or in vivo and/or within the nucleus of cells in vitro or in vivo. For example, the compounds provided herein can be used to increase the nuclear polypeptide levels of endogenously produced TFEB polypeptide within cells of a mammal (e.g., a human). In addition, the compounds provided herein can be used to treat mammals (e.g., humans) having a disease, disorder, or condition associated with a low cellular and/or nuclear level of TFEB polypeptides. In some cases, the compounds provided herein can be used to treat mammals (e.g., humans) having a disease, disorder, or condition that is responsive to an increase in TFEB polypeptide levels within cells and/or within the nucleus of cells.

In some embodiments, this document provides a method for increasing TFEB polypeptide levels within a cell and/or within the nucleus of a cell. The method comprises (or consists essentially of or consists of) administering, to a mammal (e.g., a human) containing the cell, a compound of Formula (I):

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or a pharmaceutically acceptable salt thereof, wherein X¹, X², X³, X⁴, X⁵, X⁶, R^A, R^B, L, and n are as described herein. In some cases, the administering step can result in an increase in the TFEB polypeptide level within the nucleus of the cell as compared to the TFEB polypeptide level within the nucleus of the cell before the administering step.

In some embodiments, this document provides a method for treating a disease, disorder, or condition selected from the group consisting of lysosomal storage diseases (LSDs), acute or chronic inflammatory disorders, neurological diseases, and conditions of age-related functional decline in a mammal (e.g., a human). The method comprises (or consists essentially of or consists of) administering, to a mammal (e.g., a human) having the disease, disorder, or condition, a compound of Formula (I):

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or a pharmaceutically acceptable salt thereof, wherein X¹, X², X³, X⁴, X⁵, X⁶, R^A, R^B, L, and n are as described herein. In some cases, the administering step can reduce the severity of a symptom of the disease, disorder, or condition. In some cases, the administering step can result in an increase in the TFEB polypeptide level within the nucleus of a cell of the mammal as compared to the TFEB polypeptide level within the nucleus of the cell before the administering step.

In some embodiments, this document provides a compound of Formula (IIa):

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or a pharmaceutically acceptable salt thereof, wherein X¹, X², X³, X⁴, X⁵, X⁶, R^A, R^B, and Y are as described herein.

In some embodiments, this document provides a compound of Formula (IIb):

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or a pharmaceutically acceptable salt thereof, wherein X¹, X², X³, X⁴, X⁵, X⁶, R^B, L, and n are as described herein.

In some embodiments, this document provides a compound selected from any one of the following Formulae:

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or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, R⁴, R⁵, R⁶, R^A, R^B, L, and n are as described herein.

In some embodiments, this document provides a compound of Formula (III):

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or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, R⁴, R⁵, and R⁶are as described herein.

In some embodiments, this document provides a pharmaceutical composition comprising any of the compounds described herein (or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier.

In some embodiments, this document provides a method for treating a disease, disorder, or condition selected from the group consisting of lysosomal storage diseases (LSDs), acute or chronic inflammatory disorders, neurological diseases, conditions of age-related functional decline in a mammal (e.g., a human), and inherited or acquired diseases of muscle. The method comprises (or consists essentially of or consists of) administering, to a mammal (e.g., a human) having the disease, disorder, or condition, a therapeutically effective amount of any one or more of the compounds described herein (or one or more pharmaceutically acceptable salts thereof).

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present application pertains. Methods and materials are described herein for use in the present application; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

Other features and advantages of the present application will be apparent from the following detailed description and figures, and from the claims.

DESCRIPTION OF DRAWINGS

FIG. 1. Amino acid sequence of human TFEB polypeptide (SEQ ID NO:1).

FIGS. 2A-C. BC1753 increases TFEB polypeptide levels. A. The structure of BC1753 is provided. B. MLE12 cells stably expressing TFEB-EGFP were treated with the indicated amounts of BC1753 for 24 hours before immunoblotting for TFEB-GFP and β-actin. C. MLE12 cells stably expressing TFEB-EGFP were treated with the indicated amounts of BC1753 for 24 hours before imaging by confocal microscopy (scale bar=10 μm).

FIG. 3. High content screen assay (384 well) measuring TFEB nuclear accumulation. Approximately 2500 primary and immortalized human bronchial epithelial cells (BEAS-2B) stably expressing TFEB-EGFP in 25 μL of HITEs media with 10% FBS were dispensed into 384 well plate (Black with glass bottom) and incubated for 8 hours. Compound serial dilution (DMEM low glucose media with 2% FBS, 25 μL volume) were prepared using a robotic liquid hander. Compound solutions were then added to the cell plate and incubated for 18 hours. Cells were then fixed with 4% PFA followed by DAPI staining. TFEB localization was imaged on the GFP channel along with the DAPI signal using a Cytation 5 high content imager. Images were processed through Biotek Gen5 software; specifically, the DAPI signal was used as the primary mask to quantify the nuclear TFEB-GFP signal. The cytosolic TFEB-GFP signal was quantified through expanding the primary mask. The TFEB nuclear/cytosol ratios were calculated from nuclear TFEB-GFP signal/cytosol TFEB-GFP signal, which determined the compound efficacy. The table shows the efficacy of the compound (with increased compound concentrations) in increasing TFEB nuclear/cytosol ratio. Compound activities (μM) were determined by the minimal compound concentration needed to increase TFEB nuclear/cytosol ratio by 25%. Activity: “−” equals >25 μM; “+” equals between 25 μM and >10 μM; “++” equals between ≤10 μM and >1 μM; and “+++” equals 1 μM. N=4.

FIGS. 4A-B. Compound 178 (BC1834) and Compound 160 (BC18200) increased lysosome quantity. A. Beas2B cells were treated with Cmpd. 178, Cmpd. 160, or the GSK3b inhibitor TWS119 (1 μM for 18 hours). Cells were then imaged through light microscope. B. Beas2B cells were treated with Cmpd. 178 for 18 hours at the indicated concentrations. Cells were then stained with lysotracker Red (100 nM) for 30 minutes. Cells then were washed and imaged through confocal microscopy.

FIGS. 5A-B. Compound 133 and Compound 115 increased lysosomal protein expression and secretion. A. Beas2B cells were treated with Cmpd. 133 at 10 μM for 24 hours. Cells then were collected and assayed for lysosomal protein gene expression. B. Beas2B cells were treated with Cmpd. 115 at the indicated concentration for 18 hours. Secreted b-hexosaminidase activity (a lysosomal enzyme) then was measured and normalized with cellular b-hexosaminidase activity.

FIGS. 6A-B. Compound 178 reduced Huntingtin gene expression. A-B. SH5Y cells stably transfected with GFP-72Q (Huntingtin) were treated with the indicated amounts of Cmpd. 178 for 24 hours. Cells then were imaged with a confocal microscope or collected and assayed for protein expression using a GFP-Huntingtin immunoblot.

FIG. 7. Compound 15 increases liver lysosomal activity. Female C57BL6 mice were intraperitoneally (i.p.) injected with Cmpd. 15 (50 mg/kg/d) for 4 days. Mice were then intravenously (i.v.) injected with dextran blue. 24 hours later, mice were sacrificed, and livers were removed and imaged through confocal microscopy. White fluorescent signal indicates dextran blue within lysosome and provides a measure of lysosomal number and activity within the hepatic tissue (Upper panels). In another experiment, histological slides from the liver obtained from the above experiment were immunostained with Lamp2 antibody (Lower panels) and revealed enhanced signals with Cmpd 15 treatment. Scale bar: 50 microns.

DETAILED DESCRIPTION

This document provides methods and materials for increasing TFEB polypeptide levels. For example, the document provides therapeutic compounds (e.g., therapeutic organic compounds) having the ability to increase TFEB polypeptide levels within cells, formulations containing therapeutic compounds having the ability to increase TFEB polypeptide levels within cells, methods for making therapeutic compounds having the ability to increase TFEB polypeptide levels within cells, methods for making formulations containing therapeutic compounds having the ability to increase TFEB polypeptide levels within cells, methods for increasing TFEB polypeptide levels within cells, and methods for treating mammals (e.g., humans) having a condition responsive to an increase in TFEB polypeptide levels. This document also provides therapeutic compounds (e.g., organic compounds) having the ability to increase TFEB polypeptide levels within the nucleus of cells, formulations containing therapeutic compounds having the ability to increase TFEB polypeptide levels within the nucleus of cells, methods for making therapeutic compounds having the ability to increase TFEB polypeptide levels within the nucleus of cells, methods for making formulations containing therapeutic compounds having the ability to increase TFEB polypeptide levels within the nucleus of cells, methods for increasing TFEB polypeptide levels within the nucleus of cells, and methods for treating mammals (e.g., humans) having a condition responsive to an increase in TFEB polypeptide levels within the nucleus of cells.

Methods of Treatment

The lysosome is the compartment within the cell which is responsible for the degradation of damaged proteins and organelles (e.g., mitochondria). Inside the lysosome, a very acidic pH is maintained, and there are a variety of digestive enzymes that can efficiently degrade organelles and various biomolecules such as proteins, lipids and nucleic acids, that are either damaged or no longer needed by the cell. Delivery of damaged contents to the lysosome can occur through multiple means, but one way the damaged cargo gets to the lysosome is through the process of macroautophagy (“autophagy” herein). In this case, the damaged biomolecules and organelles are wrapped within a double membrane structure known as the autophagosome that then fuses with the lysosome. This process is responsible for homeostatic maintenance of cells and tissues. In the absence of autophagic flux and functional lysosomes, damage biomolecules and organelles accumulate in the cell. These damaged and dysfunctional components can fuel a cycle of further damage. Breakdown of this system generally leads to a number of pathological conditions. In rare inherited conditions called lysosomal storage diseases (LSD), a child often has inherited two copies of a defective lysosomal enzyme. LSDs are a collection of roughly 50 different inherited conditions that render the patient's lysosomes incapable of metabolizing a specific molecule, which the missing enzyme normally degrades. This deficiency causes the undegraded molecules to build up within the lysosome and the lysosome to massively swell. As the lysosome enlarges and fills with undegraded material, it ultimately becomes dysfunctional not only for the degradation of the specific molecule typically digested by the missing enzyme, but for all of its recycling capacity. Although recently a number of disease-specific replacement therapies have become available in which the child is given back the ‘missing’ enzyme to partially compensate for their inherited defect, in many lysosomal storage diseases no replacement therapy is currently available. Moreover, even when replacement therapies exist, these protein-based therapies are often only modestly successful as they often cannot treat conditions in the central nervous system (due to the blood-brain barrier) or gain entry to certain cell types. Besides LSDs, it is known that this process of autophagy and lysosomal degradation naturally slows with aging. The natural consequence is the age-dependent accumulation of damaged contents within cells and tissues. This can be harmful and can contribute to a range of age-dependent diseases. Augmenting autophagy and lysosomal function as described herein can be used to reverse this damage. In other conditions, stimulation of autophagy and lysosomal function can be beneficial. This includes metabolic conditions (e.g., non-alcoholic steatohepatitis (NASH) or fatty liver), neurodegenerative conditions (e.g. Parkinson's disease, ALS, Alzheimer's disease, and Huntington's disease), a range of other general age-related conditions (e.g., macular degeneration, sarcopenia, and frailty), non-neurological disorders of protein aggregation (e.g., α-1 antitrypsin, amyloidosis, and retinitis pigmentosa), or in conditions of impaired immunity (e.g., aiding the removal of microbiological pathogens including intracellular pathogens such as Mycobacterium tuberculosis or in conditions characterized by chronic bacterial colonization such as cystic fibrosis).

TFEB is a master regulator of lysosomal biogenesis. Increasing TFEB polypeptide levels within cells and/or within the nucleus of cells using a compound provided herein (e.g., a compound set forth in Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) as described herein can result in one or more benefits for the cell and/or mammal. For example, increasing TFEB polypeptide levels within cells and/or within the nucleus of cells using a compound provided herein (e.g., a compound set forth in Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) as described herein can result in increased lysosomal numbers within cells and/or increased lysosomal function within cells. In some cases, increasing TFEB polypeptide levels within cells and/or within the nucleus of cells using a compound provided herein (e.g., a compound set forth in Formula (I), (IIa-Ill), or (III), or a pharmaceutically acceptable salt thereof) as described herein can result in (a) an increased level of lysosomal exocytosis (the process of excreting the contents of the lysosome out of the cell and into the serum), (b) transcriptionally augmenting multiple factors that regulate autophagy, and/or (c) a coordinated increase in intracellular recycling capacity and the removal of intracellular debris (e.g., increasing autophagy, lysosomal numbers, and lysosomal exocytosis). In some cases, increasing TFEB polypeptide levels within cells and/or within the nucleus of cells using a compound provided herein (e.g., a compound set forth in Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) as described herein can result in reducing one or more symptoms associated with a LSD, an α-1 antitrypsin deficiency, a neurodegenerative disease (e.g., Alzheimer's disease, Parkinson's disease, ALS, or Huntington's disease), a metabolic disease (e.g., NASH), or an age-related condition (e.g., sarcopenia).

In some cases, this document provides methods for increasing TFEB polypeptide levels within cells and/or within the nucleus of cells by contacting the cell with one or more compounds provided herein (e.g., a compound set forth in Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof). The increase in TFEB polypeptide levels can be as compared to the TFEB polypeptide levels prior to the contacting step. In some cases, methods for increasing TFEB polypeptide levels within cells and/or within the nucleus of cells can be performed in vivo. For example, one or more compounds provided herein (e.g., a compound set forth in Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) can be administered to a mammal (e.g., a human) to increase TFEB polypeptide levels within cells and/or within the nucleus of cells within that mammal. In some cases, methods for increasing TFEB polypeptide levels within cells and/or within the nucleus of cells can be performed in vitro. For example, one or more compounds provided herein (e.g., a compound set forth in Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) can be added to a cell culture containing cells (e.g., human cells) to increase TFEB polypeptide levels within those cells and/or within the nucleus of those cells. In some cases, such intervention can improve the quality of the cell while in culture or subsequently. In some cases, one or more of the compounds provided herein can be used during an ex vivo expansion of a genetically engineered T cell (e.g., CAR T cell) or tumor-infiltrating T cell (e.g., TIL) so that the treated T cells exhibit improved in vivo persistence and/or efficacy. A range of other cellular products that are to be ultimately infused into a mammal (e.g., a human) can be treated as described herein during their in vitro expansion.

In some cases, this document provides methods for increasing lysosomal exocytosis in a cell by contacting the cell with one or more compounds provided herein (e.g., a compound set forth in Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof). The increase in lysosomal exocytosis can be as compared to the lysosomal exocytosis levels prior to the contacting step. In some cases, methods for increasing lysosomal exocytosis in a cell can be performed in vivo. For example, one or more compounds provided herein (e.g., a compound set forth in Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) can be administered to a mammal (e.g., a human) to increase lysosomal exocytosis in a cell within that mammal. In some cases involving a LSD, one or more compounds provided herein can be administered to a mammal having a LSD so that undegraded lysosomal material that accumulated is released via exocytosis from the diseased cell, tissue, and/or organ. In some cases, methods for increasing lysosomal exocytosis in a cell can be performed in vitro. For example, one or more compounds provided herein (e.g., a compound set forth in Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) can be added to a cell culture containing cells (e.g., human cells) to increase lysosomal exocytosis in those cells.

In some cases, this document provides methods for increasing cellular autophagy in a cell by contacting the cell with one or more compounds provided herein (e.g., a compound set forth in Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof). The increase in cellular autophagy can be as compared to the cellular autophagy levels prior to the contacting step. In some cases, methods for increasing cellular autophagy in a cell can be performed in vivo. For example, one or more compounds provided herein (e.g., a compound set forth in Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) can be administered to a mammal (e.g., a human) to increase cellular autophagy in a cell within that mammal. In some cases, methods for increasing cellular autophagy in a cell can be performed in vitro. For example, one or more compounds provided herein (e.g., a compound set forth in Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) can be added to a cell culture containing cells (e.g., human cells) to increase cellular autophagy in those cells.

In some cases, this document provides methods for increasing nuclear localization of TFEB polypeptides in a cell by contacting the cell with one or more compounds provided herein (e.g., a compound set forth in Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof). The increase in nuclear localization of TFEB polypeptides can be as compared to the level of nuclear localization of TFEB polypeptides prior to the contacting step. In some cases, methods for increasing nuclear localization of TFEB polypeptides in a cell can be performed in vivo. For example, one or more compounds provided herein (e.g., a compound set forth in Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) can be administered to a mammal (e.g., a human) to increase nuclear localization of TFEB polypeptides in a cell within that mammal. In some cases, methods for increasing nuclear localization of TFEB polypeptides in a cell can be performed in vitro. For example, one or more compounds provided herein (e.g., a compound set forth in Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) can be added to a cell culture containing cells (e.g., human cells) to increase nuclear localization of TFEB polypeptides in those cells.

This document also provides methods for treating diseases, disorders, and conditions in a mammal by administering one or more compounds provided herein (e.g., a compound set forth in Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) to a mammal in need thereof. In some cases, the disease, disorder, or condition being treated can be a disease, disorder, or condition that is responsive to an increase in TFEB polypeptide levels within cells and/or within the nucleus of cells within the mammal. In some cases, the disease, disorder, or condition being treated can be a disease, disorder, or condition that is associated with low TFEB polypeptide levels within cells and/or within the nucleus of cells within the mammal. Examples of diseases, disorders, and conditions that can be treated with one or more compounds provided herein (e.g., a compound set forth in Formula (I), (IIa-IIi), or or a pharmaceutically acceptable salt thereof) as described herein include, without limitation, lysosomal storage diseases, acute or chronic inflammation disorders, conditions associated with age-related functional decline, acute or chronic organ failure (e.g., kidney, lung, cardiac, or hepatic organ dysfunction), disorders of protein aggregation, neurodegenerative conditions, and inherited or acquired diseases of muscle. Examples of diseases, disorders, and conditions that can be treated with one or more compounds provided herein (e.g., a compound set forth in Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) as described herein include, without limitation, lysosomal storage diseases, acute or chronic inflammation disorders, conditions associated with age-related functional decline, acute or chronic organ failure (e.g., kidney, lung, cardiac, or hepatic organ dysfunction), disorders of protein aggregation, and neurodegenerative conditions.

Examples of lysosomal storage diseases that can be treated with one or more compounds provided herein (e.g., a compound set forth in Formula (I), (IIa-IIi), or or a pharmaceutically acceptable salt thereof) as described herein include, without limitation, Krabbe disease, Sanfilippo syndrome, multiple sulfatase deficiency, alpha-mannosidosis, Fabry disease, Hunter syndrome, Scheie syndrome, Sanfilippo syndrome, Maroteaux-Lamy syndrome, hyaluronidase deficiency, Sialidosis, mucolipidin 1 deficiency, Neuronal ceroid lipofuscinoses (Batten Disease), Mucopolysaccharidoses Type I, II, III, IV, VI, VII, and IX, Hurler-Scheie syndrome, Morquio syndrome, Glycoproteinosis, Glycogen storage disease, Metachromatic Leukodystrophy, Sly syndrome, I-cell disease, Danon disease, Niemann-Pick disease Type A, B, C1, and C2, Sandhoff disease, Lysosomal acid lipase deficiency, GM2 gangliosidoses, Tay-Sachs disease, Gaucher disease, Salla disease, Pompe disease, Danon disease, cholesteryl ester storage disease, Aspartylglucosaminuria, Cystinosis, Mucolipidosis Type I-IV, Schindler Disease Type I and II, Wolman disease, Fucosidosis, Pycnodysostosis, and Free Sialic Acid Storage Disease.

Examples of acute or chronic inflammation disorders that can be treated with one or more compounds provided herein (e.g., a compound set forth in Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) as described herein include, without limitation, asthma, chronic obstructive lung disease, pulmonary fibrosis, pneumonitis (e.g., hypersensitivity pneumonitis or radiation pneumonitis), pneumonia, cystic fibrosis, psoriasis, arthritis/rheumatoid arthritis, rhinitis, pharyngitis, cystitis, prostatitis, dermatitis, allergy including hayfever, nephritis, conjunctivitis, encephalitis, meningitis, opthalmitis, uveitis, pleuritis, pericarditis, myocarditis, atherosclerosis, human immunodeficiency virus related inflammation, diabetes, osteoarthritis, psoriatic arthritis, inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), colitis, sepsis, vasculitis, bursitis, connective tissue disease, autoimmune diseases (e.g., systemic lupus erythematosis (SLE)), polymyalgia rheumatica, scleroderma, Wegener's granulomatosis, temporal arteritis, vasculitis, cryoglobulinemia, multiple sclerosis, viral or influenza-induced inflammation, chronic bacterial colonization or persistent intracellular pathogen, and impaired responsiveness to antigenic challenge or vaccines administration.

Examples of conditions associated with age-related functional decline that can be treated with one or more compounds provided herein (e.g., a compound set forth in Formula (I), (IIa-Ill), or (III), or a pharmaceutically acceptable salt thereof) as described herein include, without limitation, neurodegenerative diseases (e.g., Alzheimer's, ALS, Huntington's disease, Parkinson's disease, primary age-related tauopathy, progressive supranuclear palsy, chronic traumatic encephalopathy, acute or chronic traumatic brain injury, and frontotemporal dementia), metabolic diseases (e.g., NASH), metabolic syndrome, diabetes, sarcopenia, frailty, macular degeneration, other inherited or acquired retinal degenerative diseases, age-related hearing loss, early cognitive decline, osteoporosis, acute or age-related organ dysfunction (e.g., heart and/or kidney dysfunction), age-related immune dysfunction (e.g., impaired response to vaccination or immunosenescence), and other non-neurological disorders of protein aggregations (e.g., amyloidosis or α-1 antitrypsin deficiency).

Examples of inherited or acquired diseases of muscle that can be treated with one or more compounds provided herein (e.g., a compound set forth in Formula (I), (IIa-Ill), or (III), or a pharmaceutically acceptable salt thereof) include, without limitation, myofibrillar myopathy, sporadic inclusion body myositis, inclusion body myopathy with frontotemporal dementia (IBMFTD), and cardiomyopathy (e.g., dilated cardiomyopathy, or proteotoxic cardiomyopathy such as advanced proteotoxic cardiomyopathy).

In some cases, one or more compounds provided herein (e.g., a compound set forth in Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) can be used as described herein (e.g., to increase TFEB polypeptide levels within the nucleus of cells and/or to treat a disease, disorder, or condition as described herein) as the sole active ingredient(s). For example, a composition containing a compound set forth in Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof can lack any other active ingredients that increase TFEB polypeptide levels within the nucleus of cells. In some cases, a composition containing a compound set forth in Formula (I), (IIa-Ill), or (III), or a pharmaceutically acceptable salt thereof can lack any other active ingredients that are effective to treat a disease, disorder, or condition as described herein.

Therapeutic Compounds

As described herein, any one or more of the compounds provided herein can be used to increase TFEB polypeptide levels within cells and/or within the nucleus of cells, to increase lysosomal exocytosis in a cell, to increase cellular autophagy in a cell, to increase nuclear localization of TFEB polypeptides in a cell, and/or to treat a disease, disorder, and condition described herein in a mammal.

In some embodiments, this document provides a compound of Formula (I):

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or a pharmaceutically acceptable salt thereof, wherein:

each L is independently selected from O, S, S(═O)₂, C_1-3alkylene, C(═O), and N(R^N), wherein said C_1-3alkylene is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO₂, OH, C_1-3alkoxy, amino, C_1-3alkylamino, and di(C_1-3alkyl)amino;

each R^Nis independently selected from H and C_1-6alkyl, wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO₂, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

n is an integer selected from 1, 2, and 3;

X¹is selected from N, N⁺—O⁻, and CR¹;

X²is selected from N, N⁺—O⁻, and CR²;

X³is selected from N, N⁺—O⁻, and CR³;

X⁴is selected from N, N⁺—O⁻, and CR⁴;

X⁵is selected from N, N⁺—O⁻, and CR⁵;

X⁶is selected from N, N⁺—O⁻, and CR⁶;

provided that no more than four of X¹, X², X³, X⁴, X⁵, and X⁶are N;

each of R¹, R², R³, R⁴, R⁵, and R⁶is independently selected from H, halo, CN, NO₂, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from CN, NO₂, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

R^Ais selected from Cy^A1, O-Cy^A1, and N(R^N)—Cy^A1;

Cy^A1is selected from C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R^Cy1;

R^Bis selected from C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, and Cy¹, wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy¹, CN, NO₂, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

or, when R^Bis attached to L which is N(R^N), R^Band R^Ntogether with the N atom to which they are attached form 4-14 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Cy¹, halo, CN, NO₂, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1,2, or 3 substituents independently selected from Cy¹, CN, NO₂, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

each Cy¹is independently selected from C_6-10aryl, C_3-4cycloalkyl, 5-10 membered heteroaryl, and 4-14 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R^Cy2;

R^Cy1and R^Cy2are each independently selected from oxo, halo, CN, NO₂, Cy², C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, OR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2S(O)₂R^b2, S(O)₂R^b2, and S(O)₂NR^c2R^d2; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy², halo, CN, NO₂, OR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR³², NR^c2R^d2, NR^c2C(O)R^b2, NR^C2C(O)OR^a2, NR^c2S(O)₂R^b2, S(O)₂R^b2, and S(O)₂NR^c2R^d2;

each Cy²is independently selected from C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO₂, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, OR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2S(O)₂R^b2, S(O)₂R^b2, and S(O)₂NR^c2R^d2; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO₂, OR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2S(O)₂R^b2, S(O)₂R^b2, and S(O)₂NR^c2R^d2;

each R^a1, R^b1, R^c1, R^d1, R^a2, R^b2, R^c2, and R^d2is independently selected from H, C_1-6alkyl, C_1-4haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkylene, C_3-10cycloalkyl-C_1-4alkylene, (5-10 membered heteroaryl)-C_1-4alkylene, and (4-10 membered heterocycloalkyl)-C_1-4alkylene, wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkylene, C_3-10cycloalkyl-C_1-4alkylene, (5-10 membered heteroaryl)-C_1-4alkylene, and (4-10 membered heterocycloalkyl)-C_1-4alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R^g;

or any R^c1and R^d1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from R^g;

or any R^c2and R^d2together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from R^g; and

each R^gis independently selected from OH, NO₂, CN, halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-4haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, cyano-C_1-3alkylene, HO—C_1-3alkylene, C_6-10aryl, C_6-10aryloxy, C_3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkylene, C_3-10cycloalkyl-C_1-4alkylene, (5-10 membered heteroaryl)-C_1-4alkylene, (4-10 membered heterocycloalkyl)-C_1-4alkylene, amino, C_1-6alkylamino, di(C_1-6alkyl)amino, thio, C_1-6alkylthio, C_1-6alkylsulfinyl, C_1-6alkylsulfonyl, carbamyl, C_1-6alkylcarbamyl, di(C_1-6alkyl)carbamyl, carboxy, C_1-6alkylcarbonyl, C_1-6alkoxycarbonyl, C_1-6alkylcarbonylamino, C_1-6alkylsulfonylamino, aminosulfonyl, C_1-6alkylaminosulfonyl, di(C_1-6alkyl)aminosulfonyl, aminosulfonylamino, C_1-6alkylaminosulfonylamino, di(C_1-6alkyl)aminosulfonylamino, aminocarbonylamino, C_1-6alkylaminocarbonylamino, and di(C_1-6alkyl)aminocarbonylamino.

In some embodiments:

R^Band R^Ntogether with the N atom to which they are attached form 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Cy¹, halo, CN, NO₂, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy¹, CN, NO₂, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; and

each Cy¹is independently selected from C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R^Cy2.

In some embodiments:

R^Ais selected from C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R^Cy1; and

R^Cy1and R^Cy2are each independently selected from halo, CN, NO₂, Cy², C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, OR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2S(O)₂R^b2, S(O)₂R^b2, and S(O)₂NR^c2R^d2; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy², halo, CN, NO₂, OR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR³², NR^c2R^d2, NR^c2C(O)R^b2, NR^C2C(O)OR^#2, NR^c2S(O)₂R^b2, S(O)₂R^b2, and S(O)₂NR^c2R^d2.

In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

In some embodiments, L is independently selected from C_1-3alkylene, C(═O), and N(R^N), wherein said C_1-3alkylene is optionally substituted with OH.

In some embodiments, L is C_1-3alkylene, which is optionally substituted with halo, CN, NO₂, OH, C_1-3alkoxy, or amino.

In some embodiments, L is C_1-3alkylene, which is optionally substituted with OH.

In some embodiments, L is C(═O).

In some embodiments, L is N(R^N).

In some embodiments, R^Nis selected from H and C_1-6alkyl, wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO₂, and C_1-3alkoxy.

In some embodiments, R^Nis selected from H and C_1-6alkyl. In some embodiments, R^Nis H. In some embodiments, R^Nis C_1-6alkyl, optionally substituted with halo, CN, NO₂, or C_1-3alkoxy.

In some embodiments, L is NH.

In some embodiments, each of R¹, R², R³, R⁴, R⁵, and R⁶is independently selected from H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1.

In some embodiments, each of R¹, R², R³, R⁴, R⁵, and R⁶is independently selected from H, halo, CN, C_1-6alkyl, OR^a1, NR^c1R^d1, and S(O)₂R^b1.

In some embodiments, each of R¹, R², R³, R⁴, R⁵, and R⁶is independently selected from H, halo, C_1-6alkyl, C_1-6haloalkyl, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1.

In some embodiments, each of R¹, R², R³, R⁴, R⁵, and R⁶is independently selected from H, halo, C_1-6alkyl, and C_1-6alkoxy.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, R³, R⁴, R⁵, and R⁶are each independently selected from H, halo, C_1-6alkyl, and C_1-6alkoxy. In some embodiments, R³, R⁴, R⁵, and R⁶are each H.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, each of R¹, R², R³, R⁴, R⁵, and R⁶is independently selected from H, halo, C_1-6alkyl, and C_1-6alkoxy. In some embodiments, each of R¹, R², R³, R⁴, R⁵, and R⁶is H.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹, R³, R⁴, R⁵, and R⁶are each independently selected from H, halo, C_1-6alkyl, and C_1-6alkoxy. In some embodiments, R¹, R³, R⁴, R⁵, and R⁶are each H.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, R², R³, R⁴, R⁵, and R⁶are each independently selected from H, halo, C_1-6alkyl, and C_1-6alkoxy. In some embodiments, R², R³, R⁴, R⁵, and R⁶are each H.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, R³, R⁴, and R⁵are each independently selected from H, halo, C_1-6alkyl, and C_1-6alkoxy. In some embodiments, R³, R⁴, and R⁵are each H.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, R⁴, R⁵, and R⁶are each independently selected from H, halo, C_1-6alkyl, and C_1-6alkoxy. In some embodiments, R⁴, R⁵, and R⁶are each H.

In some embodiments, the compound of Formula (I) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, R³, R⁵, and R⁶are each independently selected from H, halo, C_1-6alkyl, and C_1-6alkoxy. In some embodiments, R³, R⁵, and R⁶are each H.

In some embodiments of the compound of Formula (IIg), the compound of Formula (IIg) is not:

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In some embodiments, of the compound of Formula (IIg), R^Bis selected from 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy2.

In some embodiments, of the compound of Formula (IIg), R^Bis 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy2. In some embodiments of Formula (IIg), R^Bis not C_6-10aryl substituted with one halo.

In some embodiments, the compound of Formula (I) has formula (IIh):

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or a pharmaceutically acceptable salt thereof.

In some embodiments, of the compound of Formula (IIh), R^Bis 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy2.

In some embodiments, the compound of Formula (IIh) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IIh), each of R¹, R³, R⁴, and R⁵is independently selected from H, halo, CN, C_1-6alkyl, OR^a1, NR^c1R^d1, and S(O)₂R^b1.

In some embodiments of Formula (IIh), R³is selected from H, halo, CN, OR^a1, NR^c1R^d1, and S(O)₂R^b1. In some embodiments of Formula (IIh), R¹is selected from H, halo, and C_1-6alkyl.

In some embodiments, the compound of Formula (I) has formula (IIi):

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or a pharmaceutically acceptable salt thereof.

In some embodiments, of the compound of Formula (IIi), R^Bis 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy2. In some embodiments, of the compound of Formula (IIi), R^Ais 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1. In some embodiments, of the compound of Formula (IIi), R¹, R³, R⁴, and R⁶are each H.

In some embodiments, the present disclosure provides a compound selected from any one of the following Formulae (IIc)-(IIi), or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound selected from any one of the following Formulae (IIc)-(IIg), or a pharmaceutically acceptable salt thereof.

In some embodiments, R^Ais selected from C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R^Cy1.

In some embodiments, R^Ais selected from C_6-10aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1.

In some embodiments, R^Ais Cy^A1.

In some embodiments, R^Ais O-Cy^A1.

In some embodiments, R^Ais NH-Cy^A1.

In some embodiments, Cy^A1is selected from C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R^Cy1.

In some embodiments, Cy^A1is selected from C_6-10aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R^Cy1.

In some embodiments, Cy^A1is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1.

In some embodiments, Cy^A1is C_6-10aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1. In some embodiments, the C_6-10aryl has the formula:

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In some embodiments, Cy^A1is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1.

In some embodiments, the 5-10 membered heteroaryl has the formula selected from:

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In some embodiments, the 5-10 membered heteroaryl has the formula selected from:

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In some embodiments, Cy^A1is 4-10 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1.

In some embodiments, the 4-10 membered heterocycloalkyl has the formula selected from:

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In some embodiments, the 4-10 membered heterocycloalkyl has the formula selected from:

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In some embodiments, each R^Cy1is independently selected from halo, CN, NO₂, Cy², C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, OR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2S(O)₂R^b2, S(O)₂R^b2, and S(O)₂NR^c2R^d2; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy², halo, CN, NO₂, OR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2S(O)₂R^b2, S(O)₂R^b2, and S(O)₂NR^c2R^d2.

In some embodiments, each R^Cy1is independently selected from halo, NO₂, C_1-6alkyl, C_1-6haloalkyl, OR^a2, C(O)OR^a2, C(O)R^b2, C(O)NR^c2R^d2, NR^c2R^d2, and S(O)₂R^b2, wherein said C_1-6alkyl is optionally substituted with OR^a2.

In some embodiments, each R^Cy1is independently selected from halo, NO₂, C_1-6alkyl, OR^a2, and C(O)OR^a2.

In some embodiments, each R^Cy1is independently selected from halo, NO₂, C_1-6alkyl, OH, C_1-6alkoxy, and C(O)(C_1-6alkoxy).

In some embodiments, each R^Cy1is independently selected from halo, NO₂, C_1-6alkyl, C_1-6alkoxy, and C(O)(C_1-6alkoxy).

In some embodiments, R^Cy1is selected from C₁and F. In some embodiments, R^Cy1is NO₂. In some embodiments, R^Cy1is C_1-6alkyl or C_1-6alkoxy.

In some embodiments, R^Bis selected from C_1-6alkyl and Cy¹, wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy¹, CN, OR^a1, S(O)₂R^b1, and S(O)₂NR^c1R^d1.

In some embodiments, R^Bis C_1-6alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from Cy¹, CN, OR^a1, S(O)₂R^b1, and S(O)₂NR^c1R^d1.

In some embodiments, R^Bis C_1-6alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from Cy¹, CN, OH, S(O)₂CH₃, and S(O)₂NH₂.

In some embodiments, R^Bis Cy¹.

In some embodiments, Cy¹is C_6-10aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy2. In some embodiments, the C_6-10aryl has formula:

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In some embodiments, Cy¹is C_3-14cycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy2.

In some embodiments, Cy¹is C_3-14cycloalkyl having the formula selected from:

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In some embodiments, Cy¹is C_3-10cycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy2. In some embodiments, the C_3-10cycloalkyl has the formula selected from:

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In some embodiments, Cy¹is 4-14 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy2.

In some embodiments, Cy¹is 4-14 membered heterocycloalkyl having the formula selected from:

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In some embodiments, Cy¹is 4-10 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy2. In some embodiments, the 4-10 membered heterocycloalkyl has the formula selected from:

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In some embodiments, Cy¹is 3-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy2.

In some embodiments, the 3-10 membered heteroaryl has the formula selected from:

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In some embodiments, the 5-10 membered heteroaryl has the formula selected

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In some embodiments, wherein each R^Cy2is independently selected from halo, CN, NO₂, Cy², C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, OR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2S(O)₂R^b2, S(O)₂R^b2, and S(O)₂NR^c2R^d2; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1,2, or 3 substituents independently selected from Cy², halo, CN, NO₂, OR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2S(O)₂R^b2, S(O)₂R^b2, and S(O)₂NR^c2R^d2.

In some embodiments, each R^Cy2is independently selected from halo, Cy², C_1-6alkyl, C_1-6haloalkyl, OR^a2, C(O)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, and S(O)₂R^b2.

In some embodiments, each R^Cy2is independently selected from halo, CN, C_3-10cycloalkyl, C_1-6alkyl, C_1-6haloalkyl, OR^a2, C(O)R^b2, C(O)NR^c2R^d2, and NR^c2R^d2.

In some embodiments, each R^Cy2is independently selected from halo, CN, C_3-10-cycloalkyl, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C(O)(C_1-6alkyl), C(O)NH₂, and NH₂.

In some embodiments, R^Cy2is halo.

In some embodiments, R^Cy2is C_1-6alkyl, C_1-6haloalkyl, or C_1-6alkoxy.

In some embodiments, R^Cy2is NH₂.

In some embodiments, each R^a1, R^b1, R^c1, R^d1, R^a2, R^b2, R^c2, and R^d2is independently selected from H and C_1-6alkyl.

In some embodiments, R^Bis C_6-10aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy2; and R^Ais C_6-10aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1.

In some embodiments, R^Bis 3-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy2; and R^Ais C_6-10aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1.

In some embodiments, R^Bis 3-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy2; and R^Ais 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1.

In some embodiments, R^Bis C_6-10aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy2; and R^Ais 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1.

In some embodiments:

n is 1;

L is selected from C_1-3alkylene, C(═O), and N(R^N), wherein said C_1-3alkylene is optionally substituted with OH;

R^Nis selected from H and C_1-6alkyl;

R¹, R², R³, R⁴, R⁵, and R⁶are each independently selected from H, halo, CN, C_1-6alkyl, OR^a1, NR^c1R^d1, and S(O)₂R^b1;

R^Ais selected from Cy^A1, O-Cy^A1, and NH-Cy^A1;

each Cy^A1is selected from C_6-10aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1;

R^Bis selected from C_1-6alkyl and Cy¹, wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy¹, CN, OR^a1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

or, when R^Bis attached to N(R^N), R^Band R^Ntogether with the N atom to which they are attached form 4-14 membered heterocycloalkyl, which is optionally substituted with Cy¹, C_1-6alkyl, OR^a1, and halo;

each R^Cy1is independently selected from halo, NO₂, C_1-6alkyl, C_1-6haloalkyl, OR^a2, C(O)OR^a2, C(O)R^b2, C(O)NR^c2R^d2, NR^c2R^d2, and S(O)₂R^b2, wherein said C_1-6alkyl is optionally substituted with OR^a2;

each R^Cy2is independently selected from halo, Cy², C_1-6alkyl, C_1-6haloalkyl, OR^a2, C(O)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, and S(O)₂R^b2; and each R^a1, R^b1, R^c1, R^d1, R^a2, R^b2, R^c2, and R^d2is independently selected from H and C_1-6alkyl.

In some embodiments:

n is 1;

L is selected from C_1-3alkylene, C(═O), and N(R^N), wherein said C_1-3alkylene is optionally substituted with OH;

R^Nis selected from H and C_1-6alkyl;

R¹, R², R³, R⁴, R⁵, and R⁶are each independently selected from H, halo, CN, C_1-6alkyl, OR^a1, NR^c1R^d1, and S(O)₂R^b1;

R^Ais selected from Cy^A1, O-Cy^A1, and NH-Cy^A1;

R^Bis selected from C_1-6alkyl and Cy¹, wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy¹, CN, OR^a1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

or, when R^Bis attached to N(R^N), R^Band R^Ntogether with the N atom to which they are attached form 4-7 membered heterocycloalkyl, which is optionally substituted with OR^a1;

each R^Cy2is independently selected from halo, CN, C_3-10cycloalkyl, C_1-6alkyl, C_1-6haloalkyl, OR^a2, C(O)R^b2, C(O)NR^c2R^d2, and NR^c2R^d; and

each R^a1, R^b1, R^c1, R^d1, R^a2, R^b2, R^c2, and R^d2is independently selected from H and C_1-6alkyl.

In some embodiments:

n is 1;

L is selected from C_1-3alkylene, C(═O), and N(R^N), wherein said C_1-3alkylene is optionally substituted with OH;

R^Nis selected from H and C_1-6alkyl;

R¹, R², R³, R⁴, R⁵, and R⁶are each independently selected from H, halo, C_1-6alkyl, and OR^a1;

R^Ais selected from C_6-10aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1;

R^Bis selected from C_1-6alkyl and Cy¹, wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy¹, CN, OR*¹, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

or, when R^Bis attached to N(R^N), R^Band R^Ntogether with the N atom to which they are attached form 4-7 membered heterocycloalkyl, which is optionally substituted with OR*¹;

each R^Cy1is independently selected from halo, NO₂, C_1-6alkyl, OR^a2, and C(O)OR^a2;

each R^Cy2is independently selected from halo, CN, C_3-10cycloalkyl, C_1-6alkyl, C_1-6haloalkyl, OR^a2, C(O)R^b2, C(O)NR^c2R^d2, and NR^c2R^d; and each R^a1, R^b1, R^c1, R^d1, R^a2, R^b2, R^c2, and R^d2is independently selected from H and C_1-6alkyl.

In some embodiments, the compound of Formula (I) is selected from any one of the compounds in Table 1, Table 1a, Table 2, Table 3, Table 3, Table 5a, and Table 6, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is selected from any one of the compounds in Table 1, Table 1a, Table 2, Table 3, Table 3, and Table 6, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is selected from any one of the compounds in Table 1, Table 2, or Table 3, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is selected from any one of the compounds in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is selected from any one of the compounds in Table 1a, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is selected from any one of the compounds in Table 2, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is selected from any one of the compounds in Table 3, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is selected from any one of the compounds in Table 5, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is selected from any one of the compounds in Table 5a, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is selected from any one of the compounds in Table 6, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is selected from any one of Formulae (IIc)-(IIi).

In some embodiments, the compound of Formula (I) is selected from any one of the following compounds:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is selected from any one of the following compounds:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of any one of Formulae (IIc)-(IIi) is selected from any one of the following compounds:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of any one of Formulae (IIc)-(IIi) is selected from any one of the following compounds:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (IIh) is selected from any one of the compounds listed in Table 5, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (IIh) is selected from any one of the compounds listed in Table 5a, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (IIh) is selected from any one of the compounds listed in Table 5 or Table 5a, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (IIi) is selected from any one of the compounds listed in Table 6, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has Formula (IIa):

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or a pharmaceutically acceptable salt thereof, wherein:

Y is selected from C(═O) and C(R⁷)(R⁸);

R⁷and R⁸are each independently selected from H, halo, CN, NO₂, OH, C_1-3alkoxy, amino, C_1-3alkylamino, and di(C_1-3alkyl)amino;

X¹is selected from N, N⁺—O⁻, and CR¹;

X²is selected from N, N⁺—O⁻, and CR²;

X³is selected from N, N⁺—O⁻, and CR³;

X⁴is selected from N, N⁺—O⁻, and CR⁴;

X⁵is selected from N, N⁺—O⁻, and CR⁵;

X⁶is selected from N, N⁺—O⁻, and CR⁶;

provided that no more than four of X¹, X², X³, X⁴, X⁵, and X⁶are N;

R¹, R², R³, R⁴, R⁵, and R⁶are each independently selected from H, halo, CN, NO₂, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1,2, or 3 substituents independently selected from CN, NO₂, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

each R^Cy1and R^Cy2is independently selected from halo, CN, NO₂, Cy², C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, OR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2S(O)₂R^b2, S(O)₂R^b2, and S(O)₂NR^c2R^d2; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy², halo, CN, NO₂, OR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR³², NR^c2R^d2, NR^c2C(O)R^b2, NR^C2C(O)OR^#2, NR^c2S(O)₂R^b2, S(O)₂R^b2, and S(O)₂NR^c2R^d2;

each Cy²is independently selected from C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO₂, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, OR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR³², NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2S(O)₂R^b2, S(O)₂R^b2, and S(O)₂NR^c2R^d2; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1,2, or 3 substituents independently selected from halo, CN, NO₂, OR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2S(O)₂R^b2, S(O)₂R^b2, and S(O)₂NR^c2R^d2;

each R^a1, R^b1, R^c1, R^d1, R^a2, R^b2, R^c2, and R^d2is independently selected from H, C_1-6alkyl, C_1-4haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkylene, C_3-10cycloalkyl-C_1-4alkylene, (5-10 membered heteroaryl)-C_1-4alkylene, and (4-10 membered heterocycloalkyl)-C_1-4alkylene, wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkylene, C_3-10cycloalkyl-C_1-4alkylene, (5-10 membered heteroaryl)-C_1-4alkylene, and (4-10 membered heterocycloalkyl)-C_1-6alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R^g;

each R^gis independently selected from OH, NO₂, CN, halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-4haloalkyl, CM alkoxy, CM haloalkoxy, cyano-C_1-3alkylene, HO—C_1-3alkylene, C_6-10aryl, C_6-10aryloxy, C_3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkylene, C_3-10cycloalkyl-C_1-4alkylene, (5-10 membered heteroaryl)-C_1-4alkylene, (4-10 membered heterocycloalkyl)-C_1-4alkylene, amino, C_1-6alkylamino, di(C_1-6alkyl)amino, thio, C_1-6alkylthio, C_1-6alkylsulfinyl, C_1-6alkylsulfonyl, carbamyl, C_1-6alkylcarbamyl, di(C_1-6alkyl)carbamyl, carboxy, C_1-6alkylcarbonyl, C_1-6alkoxycarbonyl, C_1-6alkylcarbonylamino, C_1-6alkylsulfonylamino, aminosulfonyl, C_1-6alkylaminosulfonyl, di(C_1-6alkyl)aminosulfonyl, aminosulfonylamino, C_1-6alkylaminosulfonylamino, di(C_1-6alkyl)aminosulfonylamino, aminocarbonylamino, C_1-6alkylaminocarbonylamino, and di(C_1-6alkyl)aminocarbonylamino.

In some embodiments, the compound of Formula (Ha) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, R⁷is H, and R⁸is selected from H, halo, CN, NO₂, OH, and C_1-3alkoxy. In some embodiments, R⁷is H and R⁸is selected from H and OH.

In some embodiments, Y is CH₂.

In some embodiments, Y is CH(OH).

In some embodiments, Y is C(═O).

In some embodiments, the compound of Formula (IIa) has formula:

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or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula (IIa), R¹, R², R³, R⁴, R⁵, and R⁶are each independently selected from H, halo, C_1-4alkyl, and C_1-4alkoxy. In some embodiments, R³, R⁴, R⁵, and R⁶are each independently selected from H, halo, C_1-6alkyl, and C_1-6alkoxy. In some embodiments, R³, R⁴, R⁵, and R⁶are each H.

In some embodiments of Formula (IIa), R^Bis selected from C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy2.

In some embodiments of Formula (IIa), R^Bis C_6-10aryl, optionally substituted with halo.

In some embodiments of Formula (IIa), R^Ais selected from C_6-10aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1.

In some embodiments of Formula (IIa), R^Ais 5-10 membered heteroaryl, optionally substituted with halo, NO₂, C_1-6alkyl, or C_1-6alkoxy.

In some embodiments of Formula (IIa):

R⁷is H; and R⁸is selected from H and OH;

R¹, R², R³, R⁴, R⁵, and R⁶are each independently selected from H, halo, C_1-6alkyl, and C_1-6alkoxy;

R^Bis C_6-10aryl, optionally substituted with halo; and

R^Ais 5-10 membered heteroaryl, optionally substituted with halo, NO₂, C_1-6alkyl, or C_1-6alkoxy.

In some embodiments, the compound of Formula (IIa) is selected from any one of the following compounds:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) has Formula (IIb):

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or a pharmaceutically acceptable salt thereof, wherein:

n is an integer selected from 1, 2, and 3;

X¹is selected from N, N⁺—O⁻, and CR¹;

X²is selected from N, N⁺—O⁻, and CR²;

X³is selected from N, N⁺—O⁻, and CR³;

X⁴is selected from N, N⁺—O⁻, and CR⁴;

X⁵is selected from N, N⁺—O⁻, and CR⁵;

X⁶is selected from N, N⁺—O⁻, and CR⁶;

provided that no more than four of X¹, X², X³, X⁴, X⁵, and X⁶are N;

each of R¹, R², R³, R⁴, R⁵, and R⁶is independently selected from H, halo, CN, NO₂, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1,2, or 3 substituents independently selected from CN, NO₂, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

R^Cis selected from:

- (i) 4-10 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1; and
- (ii) a group selected from O-Cy^A1, N(R^N)—Cy^A1; and Cy^A1;
- each Cy^A1is a 5-10 membered heteroaryl group of the formula selected from:

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or, when R^Bis attached to N(R^N), R^Band R^Ntogether with the N atom to which they are attached form 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Cy¹, halo, CN, NO₂, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1,2, or 3 substituents independently selected from Cy¹, CN, NO₂, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

each Cy²is independently selected from C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO₂, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, OR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2S(O)₂R^b2, S(O)₂R^b2, and S(O)₂NR^c2R^d2; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1,2, or 3 substituents independently selected from halo, CN, NO₂, OR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2S(O)₂R^b2, S(O)₂R^b2, and S(O)₂NR^c2R^d2;

In some embodiments, R^Cis selected from 4-10 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy1; and a 5-10 membered heteroaryl group of the formula selected from:

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In some embodiments of the compound of Formula (IIb), the 4-10 membered heterocycloalkyl of R^Chas the formula selected from:

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In some embodiments of the compound of Formula (IIb), the 4-10 membered heterocycloalkyl of R^Chas the formula selected from:

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In some embodiments of the compound of Formula (IIb):

n is 1;

L is selected from C_1-3alkylene, C(═O), and N(R^N), wherein said C_1-3alkylene is optionally substituted with OH;

R^Nis selected from H and C_1-6alkyl;

R¹, R², R³, R⁴, R⁵, and R⁶are each independently selected from H, halo, CN, C_1-6alkyl, OR^a1, NR^c1R^d1, and S(O)₂R^b1;

R^Cis selected from:

- (i) 4-10 membered heterocycloalkyl selected from:

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and

- (ii) a group selected from O-Cy^A1, N(R^N)—Cy^A1; and Cy^A1, wherein each Cy^A1is a 5-10 membered heteroaryl group of the formula selected from:

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R^Bis selected from C_1-6alkyl and Cy¹, wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy¹, CN, OR^a1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

or, when R^Bis attached to N(R^N), R^Band R^Ntogether with the N atom to which they are attached form 4-7 membered heterocycloalkyl, which is optionally substituted with OR^a1;

each R^Cy2is independently selected from halo, CN, C_3-10cycloalkyl, C_1-6alkyl, C_1-6haloalkyl, OR^a2, C(O)R^b2, C(O)NR^c2R^d2, and NR^c2R^d; and

each R^a1, R^b1, R^c1, R^d1, R^a2, R^b2, R^c2, and R^d2is independently selected from H and C_1-6alkyl.

In some embodiments of the compound of Formula (IIb):

n is 1;

L is selected from C_1-3alkylene, C(═O), and N(R^N), wherein said C_1-3alkylene is optionally substituted with OH;

R^Nis selected from H and C_1-6alkyl;

R¹, R², R³, R⁴, R⁵, and R⁶are each independently selected from H, halo, C_1-6alkyl, and OR^a1;

R^Cis selected from:

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R^Bis selected from C_1-6alkyl and Cy¹, wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy¹, CN, OR^a1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

or, when R^Bis attached to L which is N(R^N), R^Band R^Ntogether with the N atom to which they are attached form 4-7 membered heterocycloalkyl, which is optionally substituted with OR^a1;

each R^Cy1is independently selected from halo, NO₂, C_1-6alkyl, OR^a2, and C(O)OR^a2;

each R^Cy2is independently selected from halo, CN, C_3-10cycloalkyl, C_1-6alkyl, C_1-6haloalkyl, OR^a2, C(O)R^b2, C(O)NR^c2R^d2, and NR^c2R^d; and

each R^a1, R^b1, R^c1, R^d1, R^a2, R^b2, R^c2, and R^d2is independently selected from H and C_1-6alkyl.

In some embodiments, the compound of Formula (IIb) is selected from any one of the following compounds:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (IIb) is selected from any one of the following compounds:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the document provides a compound of Formula (III):

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or a pharmaceutically acceptable salt thereof, wherein:

R¹is selected from C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, and Cy¹, wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy¹, CN, NO₂, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

R²is selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, and Cy¹, wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy¹, CN, NO₂, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

R³, R⁴, R⁵, and R⁶are each independently selected from H, halo, CN, NO₂, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from CN, NO₂, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1S(O)₂R^b1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

each R^Cy2is independently selected from halo, CN, NO₂, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, OR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2S(O)₂R^b2, S(O)₂R^b2, and S(O)₂NR^c2R^d2; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO₂, OR^a2, and C(O)R^b2, C(O)NR^c2R^d2;

each R^a1, R^b1, R^c1, R^d1, R^a2, R^b2, R^c2, and R^d2is independently selected from H, C_1-6alkyl, C_1-4haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkylene, C_3-10cycloalkyl-C_1-4alkylene, (5-10 membered heteroaryl)-C_1-4alkylene, and (4-10 membered heterocycloalkyl)-C_1-4alkylene, wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkylene, C_3-10cycloalkyl-C_1-4alkylene, (5-10 membered heteroaryl)-C_1-4alkylene, and (4-10 membered heterocycloalkyl)-C_1-6alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R^g;

each R^gis independently selected from OH, NO₂, CN, halo, C_1-6alkyl, CM alkenyl, C_2-6alkynyl, C_1-4haloalkyl, CM alkoxy, CM haloalkoxy, cyano-C_1-3alkylene, HO—C_1-3alkylene, C_6-10aryl, C_6-10aryloxy, C_3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-4alkylene, C_3-10cycloalkyl-C_1-4alkylene, (5-10 membered heteroaryl)-C_1-4alkylene, (4-10 membered heterocycloalkyl)-C_1-4alkylene, amino, C_1-6alkylamino, di(C_1-6alkyl)amino, thio, C_1-6alkylthio, C_1-6alkylsulfinyl, C_1-6alkylsulfonyl, carbamyl, C_1-6alkylcarbamyl, di(C_1-6alkyl)carbamyl, carboxy, C_1-6alkylcarbonyl, C_1-6alkoxycarbonyl, C_1-6alkylcarbonylamino, C_1-6alkylsulfonylamino, aminosulfonyl, C_1-6alkylaminosulfonyl, di(C_1-6alkyl)aminosulfonyl, aminosulfonylamino, C_1-6alkylaminosulfonylamino, di(C_1-6alkyl)aminosulfonylamino, aminocarbonylamino, C_1-6alkylaminocarbonylamino, and di(C_1-6alkyl)aminocarbonylamino.

In some embodiments, R¹is selected from C_1-6alkyl, C_2-6alkenyl, and Cy¹, wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy¹.

In some embodiments, R¹is C_1-6alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from Cy¹.

In some embodiments, R¹is Cy¹.

In some embodiments, R¹is C_2-6alkenyl.

In some embodiments, R²is selected from H and C_1-6alkyl, wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy¹, C(O)NR^c1R^d1, and NR^c1R^d1.

In some embodiments, R²is H.

In some embodiments, R²is C_1-6alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from Cy¹, C(O)NR^c1R^d1, and NR^c1R^d1.

In some embodiments, R²is C_1-6alkyl, optionally substituted with Cy¹.

In some embodiments, R²is C_1-6alkyl, optionally substituted with C(O)NR^c1R^d1or NR^c1R^d1.

In some embodiments, R²is C_1-6alkyl, optionally substituted with C(O)NR^c1R^d1.

In some embodiments, R²is C_1-6alkyl, optionally substituted with NR^c1R^d1. In some embodiments, R^c1and R^d1are each H. In some embodiments, R^c1and R^d1are each C_1-6alkyl. In some embodiments, R^c1and R^d1together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from R^g.

In some embodiments, R³, R⁴, R⁵, and R⁶are each independently selected from H and C(O)NR^c1R^d1.

In some embodiments, R³and R⁶are each H.

In some embodiments, R⁴is C(O)NR^c1R^d1. In some embodiments, R³, R⁵, and R⁶are each H. In some embodiments, R⁵is C(O)NR^c1R^d1. In some embodiments, R³, R⁴, and R⁶are each H. In some embodiments, R^c1is H and R^d1is selected from C_6-10aryl-C_1-4alkylene and (5-10 membered heteroaryl)-C_1-4alkylene.

In some embodiments, each Cy¹is independently selected from C_6-10aryl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy2.

In some embodiments, Cy¹is C_6-10aryl (e.g., phenyl), optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy2.

In some embodiments, Cy¹is 4-10 membered heterocycloalkyl (e.g., pyrrolidinyl, morpholinyl), optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy2.

In some embodiments, each R^Cy2is independently selected from halo, CN, C_1-6alkyl, OR^a2; wherein said C_1-6alkyl is optionally substituted with C(O)NR^c2R^d2.

In some embodiments, R^Cy2is halo.

In some embodiments, R^Cy2is CN, C_1-6alkyl, or C_1-6alkoxy.

In some embodiments, R^Cy2is C_1-6alkyl, optionally substituted C(O)NR^c2R^d2. In some embodiments, R^c2is H, and R^d2is selected from C_6-10aryl, 5-10 membered heteroaryl, C_6-10aryl-C_1-4alkylene, and (5-10 membered heteroaryl)-C_1-4alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^g.

In some embodiments, each R^a1, R^b1, R^c1, R^d1, R^a2, R^b2, R^c2, and R^d2is independently selected from H, C_1-6alkyl, C_6-10aryl, 5-10 membered heteroaryl, C_6-10aryl-C_1-4alkylene, and (5-10 membered heteroaryl)-C_1-4alkylene, wherein said C_1-6alkyl, C_6-10aryl, 5-10 membered heteroaryl, C_6-10aryl-C_1-4alkylene, and (5-10 membered heteroaryl)-C_1-4alkylene, are each optionally substituted with 1, 2, or 3 substituents independently selected from R^g.

In some embodiments, each R^gis independently selected from halo, C_1-6alkyl, and C_1-6alkoxy.

In some embodiments:

R¹is selected from C_1-6alkyl, C_2-6alkenyl, and Cy¹, wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy¹;

R²is selected from H and C_1-6alkyl, wherein said C_1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy¹, C(O)NR^c1R^d1, and NR^c1R^d1;

R³, R⁴, R⁵, and R⁶are each independently selected from H and C(O)NR^c1R^d1;

Cy¹is independently selected from C_6-10aryl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R^Cy2;

R^Cy2is independently selected from halo, CN, C_1-6alkyl, and OR^a2; wherein said C_1-6alkyl is optionally substituted with C(O)NR^c2R^d2;

each R^a1, R^b1, R^c1, R^d1, R^a2, R^b2, R^c2, and R^d2is independently selected from H, C_1-6alkyl, C_6-10aryl, 5-10 membered heteroaryl, C_6-10aryl-C_1-4alkylene, and (5-10 membered heteroaryl)-C_1-4alkylene, wherein said C_1-6alkyl, C_6-10aryl, 5-10 membered heteroaryl, C_6-10aryl-C_1-4alkylene, and (5-10 membered heteroaryl)-C_1-4alkylene are each optionally substituted with 1, 2, or 3 substituents independently selected from R^g; and

each R^gis independently selected from halo, C_1-6alkyl, and C_1-6alkoxy.

In some embodiments, the compound of Formula (III) is any one of the compounds provided in Table 4, or a pharmaceutically acceptable salt thereof.

In some embodiments, a salt of a compound of any Formulae disclosed herein is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt.

In some embodiments, acids commonly employed to form pharmaceutically acceptable salts of the compounds of any Formulae disclosed herein include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.

In some embodiments, bases commonly employed to form pharmaceutically acceptable salts of the compounds of any Formulae include hydroxides of alkali metals, including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH—(C1-C6)-alkylamine), such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the like.

In some embodiments, the compounds of any Formulae disclosed herein, or pharmaceutically acceptable salts thereof, are substantially isolated.

In some embodiments, a compound of any Formulae disclosed herein, or a pharmaceutically acceptable salt thereof, can have the ability to increase TFEB polypeptide levels within a cell and/or within a nucleus of a cell. Such cells can be in vitro or in vivo. For example, a compound of any Formulae disclosed herein, or a pharmaceutically acceptable salt thereof, can have the ability to increase TFEB polypeptide levels within the nucleus of cells present within a mammal (e.g., a human) following administration to that mammal.

Methods of Making Therapeutic Compounds

Compounds of any one of the Formulae disclosed herein, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes. For example, the compounds described herein can be prepared using methods and procedures similar to those described in the Examples 1a-1p herein. A person skilled in the art knows how to select and implement appropriate synthetic protocols, and appreciates that the processes described are not the exclusive means by which compounds provided herein may be synthesized, and that a broad repertoire of synthetic organic reactions is available to be potentially employed in synthesizing compounds provided herein.

Suitable synthetic methods of starting materials, intermediates, and products can be identified by reference to the literature, including reference sources such as: Advances in Heterocyclic Chemistry, Vols. 1-107 (Elsevier, 1963-2012); Journal of Heterocyclic Chemistry Vols. 1-49 (J. Heterocyclic Chemistry, 1964-2012); Carreira et al., (Ed.) Science of Synthesis, Vols. 1-48 (2001-2010) and Knowledge Updates KU2010/1-4; 2011/1-4; 2012/1-2 (Thieme, 2001-2012); Katritzky et al., (Ed.) Comprehensive Organic Functional Group Transformations, (Pergamon Press, 1996); Katritzky et al., (Ed.) Comprehensive Organic Functional Group Transformations II (Elsevier, 2^ndEdition, 2004); Katritzky et al., (Ed.) Comprehensive Heterocyclic Chemistry (Pergamon Press, 1984); Katritzky et al., Comprehensive Heterocyclic Chemistry II, (Pergamon Press, 1996); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6^thEd. (Wiley, 2007); Trost et al. (Ed.) Comprehensive Organic Synthesis (Pergamon Press, 1991).

The reactions for preparing the compounds provided herein can be carried out in suitable solvents that can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures that can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan.

Preparation of the compounds provided herein can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in P. G. M. Wuts and T. W. Greene, Protective Groups in Organic Synthesis, 4^thEd., Wiley & Sons, Inc., New York (2006).

Pharmaceutical Compositions and Formulations

This document also provides pharmaceutical compositions comprising an effective amount of a compound of any one of Formulae (I)-(III) disclosed herein, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. The pharmaceutical composition also can comprise any one of the additional therapeutic agents and/or therapeutic molecules described herein. The carriers) are “acceptable” in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament.

Pharmaceutically acceptable carriers, adjuvants, and vehicles that can be used in the pharmaceutical compositions provided herein include, without limitation, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

The compositions or dosage forms can contain any one or more of the compounds or therapeutic agents described herein in the range of 0.005 percent to 100 percent with the balance made up from the suitable pharmaceutically acceptable carriers or excipients. The contemplated compositions can contain from about 0.001 percent to about 100 percent (e.g., from about 0.1 percent to about 95 percent, from about 75 percent to about 85 percent, or from about 20 percent to about 80 percent) of any one or more of the compounds or therapeutic agents provided herein, wherein the balance can be made up of any pharmaceutically acceptable carrier or excipient described herein, or any combination of these carriers or excipients.

Routes of Administration and Dosage Forms

The therapeutic compounds and/or pharmaceutical compositions provided herein (e.g., a composition containing one or more compounds set forth in Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) can include those suitable for any acceptable route of administration. Acceptable routes of administration include, without limitation, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracistemal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intranasal, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, vaginal, intravitreal, subretinal or other intraocular routes of administrations.

Compositions and formulations described herein can conveniently be presented in a unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and can be prepared by any methods well known in the art of pharmacy. See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, Md. (20th ed. 2000). Such preparative methods include, without limitation, the step of bringing into association with the molecule to be administered ingredients such as a carrier that constitutes one or more accessory ingredients. In general, the compositions can be prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

In some embodiments, any one or more of the compounds or therapeutic agents described herein can be administered orally. Compositions described herein that are suitable for oral administration can be presented as discrete units such as capsules, sachets, granules, or tablets each containing a predetermined amount (e.g., effective amount) of the active ingredient(s); a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packed in liposomes; or as a bolus. Soft gelatin capsules can be useful for containing such suspensions, which can beneficially increase the rate of compound absorption. In the case of tablets for oral use, carriers that are commonly used include, without limitation, lactose, sucrose, glucose, mannitol, silicic acid, and starches. Other acceptable excipients can include, without limitation, (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. For oral administration in a capsule form, useful diluents include, without limitation, lactose and dried cornstarch. When aqueous suspensions are administered orally, the active ingredient(s) can be combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents can be added. Compositions suitable for oral administration include, without limitation, lozenges comprising ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient(s) in an inert basis such as gelatin and glycerin, or sucrose and acacia.

Compositions suitable for parenteral administration include, without limitation, aqueous and non-aqueous sterile injection solutions or infusion solutions that may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may include suspending agents and thickening agents. The formulations can be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injections, saline (e.g., 0.9% saline solution), or 5% dextrose solution, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets. The injection solutions can be in the form of, for example, a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. A sterile injectable preparation also can be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils can be used as a solvent or suspending medium. For this purpose, any bland fixed oil can be used including, without limitation, synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives can be used to prepare injectables. In some cases, natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated versions, can be used to prepare injectables. These oil solutions or suspensions also can contain a long-chain alcohol diluent or dispersant.

In some cases, a therapeutic compound and/or pharmaceutical composition provided herein can be administered in the form of suppository for rectal administration. These compositions can be prepared by mixing a compound described herein (e.g., a compound set forth in Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) with a suitable non-irritating excipient that is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components). Such materials include, without limitation, cocoa butter, beeswax, and polyethylene glycols.

In some cases, a therapeutic compounds and/or pharmaceutical composition provided herein can be administered by nasal aerosol or inhalation. Such compositions can be prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. See, for example, U.S. Pat. No. 6,803,031. Additional formulations and methods for intranasal administration are found in Ilium, L., J. Pharm. Pharmacol., 56:3-17 (2004); and Ilium, L., Eur. J. Pharm. Sci., 11:1-18 (2000).

In some cases, a therapeutic compounds and/or pharmaceutical composition provided herein can be prepared as a topical composition and used in the form of an aerosol spray, cream, emulsion, solid, liquid, dispersion, foam, oil, gel, hydrogel, lotion, mousse, ointment, powder, patch, pomade, solution, pump spray, stick, towelette, soap, or other forms commonly employed in the art of topical administration and/or cosmetic and skin care formulation. The topical compositions can be in an emulsion form. Topical administration of a therapeutic compounds and/or pharmaceutical composition provided herein can be useful when the desired treatment involves areas or organs readily accessible by topical application. In some cases, a topical composition can include a combination of any one or more of the compounds or therapeutic agents described herein (e.g., a compound set forth in Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof), and one or more additional ingredients, carriers, excipients, or diluents including, without limitation, absorbents, anti-irritants, anti-acne agents, preservatives, antioxidants, coloring agents/pigments, emollients (moisturizers), emulsifiers, film-forming/holding agents, fragrances, leave-on exfoliants, prescription drugs, preservatives, scrub agents, silicones, skin-identical/repairing agents, slip agents, sunscreen actives, surfactants/detergent cleansing agents, penetration enhancers, and thickeners.

In some cases, one or more compounds or therapeutic agent described herein (e.g., a compound set forth in Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) can be incorporated into a composition for coating an implantable medical device such as a prosthesis, artificial valve, vascular graft, stent, or catheter. Suitable coatings and the general preparation of coated implantable devices are known in the art and are exemplified in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings can be biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, or mixture thereof. In some cases, the coating can optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.

In some cases, this document provides an implantable drug release device impregnated with or containing one or more compounds or therapeutic agents described herein (e.g., a compound set forth in Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) such that the compound(s) or therapeutic agent(s) are released from the device and are therapeutically active.

Dosages and Regimens

A composition (e.g., pharmaceutical compositions provided herein) containing a compound provided herein (e.g., a compound set forth in Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) can include that compound in an effective amount (e.g., a therapeutically effective amount).

Effective doses can vary, depending on the diseases being treated, the severity of the disease, the route of administration, the sex, age and general health condition of the subject, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents, and the judgment of the treating physician.

In some embodiments, an effective amount of a compound of any one of Formulae (I)-(III), or a pharmaceutically acceptable salt thereof, can range, for example, from about 0.1 mg to about 1000 mg. In some cases, the effective amount can be from about 0.5 mg to about 500 mg of a compound disclosed herein, or any amount in between these two values, for example, one of about 0.5 mg, about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, or about 500 mg. The effective amount can be an amount sufficient to alleviate or reduce one or more of the symptoms associated with a disease, disorder, or condition being treated as described herein.

In some cases, an effective amount of a compound of any one of Formulae (I)-(III), or a pharmaceutically acceptable salt thereof, can range, for example, from about 0.001 mg/kg to about 500 mg/kg (e.g., from about 0.001 mg/kg to about 200 mg/kg; from about 0.01 mg/kg to about 200 mg/kg; from about 0.01 mg/kg to about 150 mg/kg; from about 0.01 mg/kg to about 100 mg/kg; from about 0.01 mg/kg to about 50 mg/kg; from about 0.01 mg/kg to about 10 mg/kg; from about 0.01 mg/kg to about 5 mg/kg; from about 0.01 mg/kg to about 1 mg/kg; from about 0.01 mg/kg to about 0.5 mg/kg; from about 0.01 mg/kg to about 0.1 mg/kg; from about 0.1 mg/kg to about 200 mg/kg; from about 0.1 mg/kg to about 150 mg/kg; from about 0.1 mg/kg to about 100 mg/kg; from about 0.1 mg/kg to about 50 mg/kg; from about 0.1 mg/kg to about 10 mg/kg; from about 0.1 mg/kg to about 5 mg/kg; from about 0.1 mg/kg to about 2 mg/kg; from about 0.1 mg/kg to about 1 mg/kg; from about 0.1 mg/kg to about 0.5 mg/kg, or from about 0.5 mg/kg to about 500 mg/kg).

In some cases, an effective amount of a compound of any one of Formulae (I)-(III), or a pharmaceutically acceptable salt thereof, can be about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, or about 5 mg/kg.

The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses, e.g., once daily, twice daily, thrice daily) or on a non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weekly, once every two weeks, or once a month). In some cases, the dosages can be administered every 4 hours, 6 hours, 8 hours, 12 hours, or 24 hours.

Kits

This document also provides pharmaceutical kits useful, for example, to increase TFEB polypeptide levels within cells and/or within the nucleus of cells within a mammal (e.g., a human). In some cases, this document provides pharmaceutical kits useful, for example, to treat diseases, disorders, and conditions referred to herein. Such pharmaceutical kits can include one or more containers containing a pharmaceutical composition that includes a therapeutically effective amount of a compound provided herein (e.g., a compound set forth in Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof). In some cases, such kits can further include, if desired, one or more of various conventional pharmaceutical kit components such as containers with one or more pharmaceutically acceptable carriers. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components also can be included in a kit provided herein.

Combination Therapy

In some cases, one or more compounds provided herein (e.g., a compound set forth in Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) can be combined with one or more therapeutic molecules. Examples of therapeutic molecules that can be used in combination with one or more compounds provided herein (e.g., a compound set forth in Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) include, without limitation, enzyme replacement therapy (e.g., approved enzyme therapy) for LSDs (e.g., fabrazyme or cerezyme). In such cases, the addition of one or more such compounds can aid in the treatment of central nervous system disease not approachable by enzyme replacement therapy due to the restriction imposed by the blood-brain barrier to serum proteins. In some cases, the addition of one or more such compounds can increase the cellular uptake of a given lysosomal enzyme replacement therapeutic protein in the periphery by augmenting expression of the mannose-6-phosphate receptor, a TFEB transcriptional target, and the receptor-mediated mechanism through which enzyme replacement therapies gain entry into a disease cell or tissue. Additional examples of therapeutic molecules that can be used in combination with one or more compounds provided herein (e.g., a compound set forth in Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) include, without limitation, anti-inflammatory agents (e.g., steroids and antibodies against IL-6 or TNF-alpha), antimicrobial agents (e.g., antibiotics, anti-mycobacterial drugs, and anti-viral agents), anti-cancer agents (e.g., chemotherapeutic agents and cellular products such as engineered T cells), anti-aging agents (e.g., nicotinamide riboside, or rapamycin), neurological agents (e.g., L-DOPA, memantine, and riluzole), therapies for a neurodegenerative disease (e.g., edaravone or tetrabenazine), and agents used to treat chronic organ dysfunction (e.g., ACE inhibitor and lactulose).

One or more compounds provided herein (e.g., a compound set forth in Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) and the one or more therapeutic molecules can be administered in any order or simultaneously. If simultaneously administered, they can be provided in a single, unified, form or in multiple forms (e.g., either as a single pill or as two separate pills). One of the items can be given in multiple doses, or both can be given as multiple doses. If not simultaneous, the timing between the multiple doses can vary from more than zero weeks to less than four weeks.

Definitions

As used herein, the term “about” means “approximately” (e.g., plus or minus approximately 10% of the indicated value).

At various places in this document, substituents of compounds provided herein are disclosed in groups or in ranges. It is specifically intended that these groups and ranges include each and every individual subcombination of the members of such groups and ranges. For example, the term “C_1-6alkyl” is specifically intended to individually disclose methyl, ethyl, C₃alkyl, C₄alkyl, C₅alkyl, and C₆alkyl.

At various places in this document various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by valency. For example, the term “a pyridine ring” or “pyridinyl” may refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.

It is further appreciated that certain features described herein, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features described herein which are, for brevity, described in the context of a single embodiment, also can be provided separately or in any suitable subcombination.

The term “aromatic” refers to a carbocycle or heterocycle having one or more polyunsaturated rings having aromatic character (i.e., having (4n+2) delocalized π (pi) electrons where n is an integer).

The term “n-membered” where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

As used herein, the phrase “optionally substituted” means unsubstituted or substituted. The substituents are independently selected, and substitution can be at any chemically accessible position. As used herein, the term “substituted” means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms. It is to be understood that substitution at a given atom is limited by valency.

Throughout the definitions, the term “Cn-m” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C_1-4, C_1-6, and the like.

As used herein, the term “C_n-malkyl”, employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons. Examples of alkyl moieties include, without limitation, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethyl propyl, and the like. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

As used herein, the term “C_n-mhaloalkyl”, employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+1 halogen atoms that may be the same or different, where “s” is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, “C_n-malkenyl” refers to an alkyl group having one or more double carbon-carbon bonds and having n to m carbons. Example alkenyl groups include, without limitation, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, “C_n-malkynyl” refers to an alkyl group having one or more triple carbon-carbon bonds and having n to m carbons. Example alkynyl groups include, without limitation, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, the term “C_n-malkylene”, employed alone or in combination with other terms, refers to a divalent alkyl-linking group having n to m carbons. Examples of alkylene groups include, without limitation, ethan-1,1-diyl, ethan-1,2-diyl, propan-1,1-diyl, propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl, butan-1,3-diyl, butan-1,2-diyl, 2-methyl-propan-1,3-diyl, and the like. In some embodiments, the alkylene moiety contains 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or 1 to 2 carbon atoms.

As used herein, the term “C_n-malkoxy”, employed alone or in combination with other terms, refers to a group of formula —O-alkyl, wherein the alkyl group has n to m carbons. Example alkoxy groups include, without limitation, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert-butoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, “C_n-mhaloalkoxy” refers to a group of formula —O-haloalkyl having n to m carbon atoms. An example haloalkoxy group is OCF₃. In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “amino” refers to a group of formula —NH₂.

As used herein, the term “C_n-malkylamino” refers to a group of formula —NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylamino groups include, without limitation, N-methylamino, N-ethylamino, N-propylamino (e.g., N-(n-propyl)amino and N-isopropylamino), N-butylamino (e.g., N-(n-butyl)amino and N-(tert-butyl)amino), and the like.

As used herein, the term “di(C_n-m-alkyl)amino” refers to a group of formula —N(alkyl)₂, wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_n-malkoxycarbonyl” refers to a group of formula —C(O)O-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkoxycarbonyl groups include, without limitation, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl (e.g., n-propoxycarbonyl and isopropoxycarbonyl), butoxycarbonyl (e.g., n-butoxycarbonyl and tert-butoxy carbonyl), and the like.

As used herein, the term “C_n-malkylcarbonyl” refers to a group of formula —C(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylcarbonyl groups include, without limitation, methylcarbonyl, ethylcarbonyl, propylcarbonyl (e.g., n-propylcarbonyl and isopropylcarbonyl), butylcarbonyl (e.g., n-butylcarbonyl and tert-butylcarbonyl), and the like.

As used herein, the term “C_n-malkylcarbonylamino” refers to a group of formula —NHC(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_n-malkylsulfonylamino” refers to a group of formula —NHS(O)₂-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminosulfonyl” refers to a group of formula —S(O)₂NH₂.

As used herein, the term “C_n-malkylaminosulfonyl” refers to a group of formula —S(O)₂NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_n-malkylaminosulfonyl” refers to a group of formula —S(O)₂N(alkyl)₂, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminosulfonylamino” refers to a group of formula —NHS(O)₂NH₂.

As used herein, the term “C_n-malkylaminosulfonylamino” refers to a group of formula —NHS(O)₂NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_n-malkyl)aminosulfonylamino” refers to a group of formula —NHS(O)₂N(alkyl)₂, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminocarbonylamino”, employed alone or in combination with other terms, refers to a group of formula —NHC(O)NH₂.

As used herein, the term “C_n-malkylaminocarbonylamino” refers to a group of formula —NHC(O)NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_n-malkyl)aminocarbonylamino” refers to a group of formula —NHC(O)N(alkyl)₂, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “carbamyl” to a group of formula —C(O)NH₂.

As used herein, the term “C_n-malkylcarbamyl” refers to a group of formula —C(O)—NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_n-m-alkyl)carbamyl” refers to a group of formula —C(O)N(alkyl)₂, wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “thio” refers to a group of formula —SH.

As used herein, the term “C_n-malkylthio” refers to a group of formula —S-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_n-malkylsulfinyl” refers to a group of formula —S(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_n-malkylsulfonyl” refers to a group of formula —S(O)₂-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “carbonyl”, employed alone or in combination with other terms, refers to a —C(═O)— group, which may also be written as C(O).

As used herein, the term “carboxy” refers to a —C(O)OH group. In some embodiments, the “carboxy” group also refers to a bioisostere replacement group selected from the group consisting of:

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and the like, where R refers to a hydrogen, (C₁-C₈) alkyl, or C₆aryl.

As used herein, the term “cyano-C_1-3alkyl” refers to a group of formula —(C_1-3alkylene)-CN.

As used herein, the term “HO—C_1-3alkyl” refers to a group of formula —(C_1-3alkylene)-OH.

As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments, a halo is F, Cl, or Br.

As used herein, the term “aryl,” employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which can be monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings). The term “C_n-maryl” refers to an aryl group having from n to m ring carbon atoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups can have from 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl.

As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and/or alkenyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocycles. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by 1 or 2 independently selected oxo or sulfide groups (e.g., C(O) or C(S)). Also included in the definition of cycloalkyl are moieties that have one or more aromatic or non-aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like. A cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. A cycloalkyl group may contain a fused heterocycloalkyl ring which itself may be fused with another ring such as an aromatic ring. In this situation, the cycloalkyl group can be attached through any ring forming atom, including ring forming atoms of the heterocycloalkyl ring or the aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (C_3-10). Cycloalkyl groups can also have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring-forming atoms (carbon atoms or heteroatoms if the cycloalkyl group is fused with a heterocycloalkyl ring) (C_3-4cycloalkyl). In some embodiments, the cycloalkyl is a C_3-10monocyclic or bicyclic cycloalkyl. In some embodiments, the cycloalkyl is a C_3-7monocyclic cycloalkyl. In some embodiments, the cycloalkyl is a C_3-14bicyclic or tricyclic cycloalkyl. Example cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbomyl, norpinyl, norcamyl, adamantyl, and the like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

As used herein, “heteroaryl” refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, any ring-forming N in a heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl is a 3-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a 3-14 membered monocyclic, bicyclic, or tricyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a 3-6 monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a five-membered or six-membered heteroaryl ring. A five-membered heteroaryl ring is a heteroaryl with a ring having five ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary five-membered ring heteroaryls include, without limitation, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazoyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. A six-membered heteroaryl ring is a heteroaryl with a ring having six ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary six-membered ring heteroaryls include, without limitation, pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

As used herein, “heterocycloalkyl” refers to non-aromatic monocyclic or polycyclic heterocycles having one or more ring-forming heteroatoms selected from O, N, or S. Included in heterocycloalkyl are monocyclic 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl groups. Included in heterocycloalkyl are mono-, bi-, tri-, and tetracyclic 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles. Example heterocycloalkyl groups include, without limitation, pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazdidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, and the like. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by 1 or 2 independently selected oxo or sulfido groups (e.g., C(O), S(O), C(S), or S(O)₂, etc.). The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic or non-aromatic rings fused (i.e., having a bond in common with) to the heterocycloalkyl ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. In some embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 4-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members.

At certain places, the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring can be attached at any position of the ring, whereas a pyridin-3-yl ring is attached at the 3-position.

As used herein, the term “oxo” refers to an oxygen atom as a divalent substituent, forming a carbonyl group when attached to a carbon (e.g., C═O), or attached to a heteroatom forming a sulfoxide or sulfone group.

The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds provided herein that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Any appropriate method can be used to prepare optically active forms from, for example, optically inactive starting materials. For example, techniques such as resolution of racemic mixtures or stereoselective synthesis can be used to prepare optically active forms of a compound provided herein. Many geometric isomers of olefins, C═N double bonds, N═N double bonds, and the like also can be present in a compound described herein, and all such stable isomers are contemplated herein. Cis and treats geometric isomers of the compounds provided herein are described and can be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, a compound provided herein has the (R)-configuration. In some embodiments, a compound provided herein has the (S)-configuration.

Compounds provided herein also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers that are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include, without limitation, ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. For example, in aqueous solution, pyrazoles can exhibit the following isomeric forms, which are referred to as tautomers of each other:

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As readily understood by one skilled in the art, a wide variety of functional groups and other structures can exhibit tautomerism, and all tautomers of compounds as described herein are within the scope provided herein.

As used herein, the term “cell” is meant to refer to a cell that is in vitro, ex vivo, or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal (e.g., a human). In some embodiments, an in vitro cell can be a cell in cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal (e.g., a human).

As used herein, the term “contacting” refers to the bringing together of indicated moieties or items in an in vitro system, an ex vivo system, or an in vivo system. For example, “contacting” a cell with a compound provided herein includes the act of administering that compound to a mammal (e.g., a human) containing that cell as well as, for example, introducing that compound into a cell culture containing that cell.

As used herein, the term “mammal” includes, without limitation, mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, elephants, deer, non-human primates (e.g., monkeys and apes), house pets, and humans.

As used herein, the phrase “effective amount” or “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, mammal, or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician.

As used herein, the term “treating” or “treatment” refers to (a) inhibiting a disease, disorder, or condition, for example, inhibiting a disease, disorder, or condition in a mammal (e.g., human) that is experiencing or displaying the pathology or symptomatology of the disease, disorder, or condition (e.g., arresting further development of the pathology and/or symptomatology), or (b) ameliorating the disease, disorder, or condition, for example, ameliorating a disease, disorder, or condition in a mammal (e.g., a human) that is experiencing or displaying the pathology or symptomatology of the disease, disorder, or condition (e.g., reversing the pathology and/or symptomatology).

As used herein, the term “preventing” or “prevention” of a disease, disorder, or condition refers to decreasing the risk of occurrence of the disease, disorder, or condition in a mammal or group of mammals (e.g., a mammal or group of mammals predisposed to or susceptible to the disease, disorder, or condition). In some embodiments, preventing a disease, disorder, or condition refers to decreasing the possibility of acquiring the disease, disorder, or condition and/or its associated symptoms. In some embodiments, preventing a disease, disorder, or condition refers to completely or almost completely stopping the disease, disorder, or condition from occurring.

EXAMPLES
Material and Methods

All non-aqueous reactions were carried out under a nitrogen atmosphere in oven- or flame-dried glassware unless otherwise noted. Anhydrous tetrahydrofuran and diethyl ether were distilled from sodium benzophenone ketyl solutions; anhydrous dichloromethane and toluene were distilled from CaH₂; alternatively, the same solvents were obtained from a solvent purification system using alumina columns. All other solvents and reagents were used as obtained from commercial sources without further purification unless noted. Reactions were monitored via TLC using 250 μm pre-coated silica gel 60 F254 plates, which were visualized with 254 nm and/or 365 nm UV light and by staining with KMnO₄(1.5 g KMnO₄, 10 g K₂CO₃, and 1.25 mL 10% NaOH in 200 mL water), cerium molybdate (0.5 g Ce(NH₄)₂(NO₃)₆, 12 g (NH₄)₆M₀₇O₂₄.4H₂O, and 28 mL cone. H₂SO₄in 235 mL water), or vanillin (6 g vanillin and 1.5 mL cone. H₂SO₄in 100 mL EtOH). Flash chromatography was performed with SiliCycle silica gel 60 (230-400 mesh) or with ISCO MPLC. ¹H and ¹³C NMR spectra were recorded on Bruker Avance 300,400, or 500 MHz spectrometers, using the residual solvent as an internal standard. IR spectra were obtained on a Smiths Identify IR or PerkinElmer Spectrum 100. HRMS data were obtained on a Thermo Scientific Exactive HRMS coupled to a Thermo Scientific Accela HPLC system using a 2.1×50 mm 3.5 μm Waters XTerra C18 column eluting with MeCN/H₂O containing 0.1% formic acid. Purity of compounds was assessed using the same HPLC system with either the PDA or an Agilent 385 ELSD. All final screening samples passed QC based on >95% purity by LC/MS/ELSD analysis.

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By way of example, to prepare the compounds of Formula (I) where n is 1 and L is NH (1), equimolar amounts of 4-chloroquinazoline analog (2) and an amine (3) are mixed in a suitable solvent (e.g., isopropanol). The resultant reaction mixture is stirred and refluxed for, e.g., 4 hours. Progression of the reaction is monitored by techniques known in the art. Upon consumption of the starting material, the reaction mixture is concentrated, and the target compound is purified through prep-TLC or flash chromatography. Products can be further purified by crystallization as is customary in the art. Referring to the general scheme, X¹, X², X³, X⁴, X⁵, X⁶, R^A, and R^Bare as described herein, and LG is a leaving group (e.g., Cl, Br, I, or OTf). The compounds of Formula (I) where L is other than NH can be prepared from similar starting materials using reactions and synthetic routes well known in the art. A skill chemist would be able to select and implement appropriate reaction protocols and conditions.

Example 1a—Synthesis of Compound 8 (BC18618)

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Preparation of Compound 3:

To a solution of 1 (1 g, 5.0 mmol, 1 eq) in i-PrOH (20 mL) was added 2 (615 mg, 5.5 mmol, 1.1 eq) and DIEA (1.29 g, 10 mmol, 2 eq). The reaction was stirred at 85° C. overnight. The mixture was concentrated and the residue was purified by silica column chromatography (PE/EA, 2:1) to give 1.2 g 3 (yellow oil, 87%). MS (ESI) m/z: 274 [M+H]+

Preparation of Compound 8 (BC18618)

To a solution of 3 (273 mg, 1 mmol, 1 eq) in dioxane/H₂O (1:1, 15 mL) was added 4 (248 mg, 2 mmol, 2 eq), K₂CO₃(276 mg, 2 mmol, 2 eq) and Pd(PPh₃)₄(124 mg, 0.1 mmol, 0.1 eq) under N₂. The mixture was stirred at 115° C. overnight. Then the mixture was filtered and the filter cake was washed by MeOH to give 205 mg BC18618 (compound 8) (off-white solid, 52%).

MS (ESI) m/z: 318[M+H]+, 316[M−H]−

¹H NMR (400 MHz, DMSO) δ 10.10 (s, 1H), 9.57 (s, 2H), 9.28 (s, 1H), 8.57 (d, J=8.1 Hz, 1H), 7.92-7.88 (m, 3H), 7.73 (d, J=8.2 Hz, 1H), 7.67 (dt, J=7.3, 3.8 Hz, 1H), 7.48 (dd, J=15.4, 8.2 Hz, 1H), 6.99 (td, J=8.5, 2.0 Hz, 1H).

Example 1b—Synthesis of Compound 76 (BC18703)

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General Procedure for the Preparation of Compound 3:

To a solution of 1 (0.5 g, 2.51 mmol, 1 eq) in i-PrOH (15 mL) was added 2 (367 mg, 2.76 mmol, 1.1 eq) and DIEA (650 mg, 5.02 mmol, 2 eq). The reaction was stirred at 85° C. overnight. The solution was concentrated and the residue was purified by silica column chromatography (PE/EA, 2:1) to give 0.45 g 3 (yellow oil, 61%). MS (ESI) m/z: 296 [M+H]+

General Procedure for the Preparation of Compound 5

To a solution of 3 (0.4 g, 1.36 mmol, 1 eq) in dioxane/H₂O (2:1, 1.5 mL) was added 4 (632 mg, 2.04 mmol, 1.5 eq), K₂CO₃(844 mg, 6.12 mmol, 4.5 eq) and PdCl₂(dppf) (95 mg, 0.13 mmol, 0.1 eq) under N₂. The mixture was stirred at 85° C. overnight. The mixture was filtered and the filter cake was washed by EA. The organic phase was washed by brine, then dried and concentrated. The residue was purified by silica column chromatography (PE/EA, 5:1) to give 0.4 g 5 (yellow solid, 70%). MS (ESI) m/z: 443[M+H]+.

General Procedure for the Preparation of Compound 6

To a solution of 5 (0.2 g, 0.45 mmol, 1 eq) in MeOH (5 mL) was added Pd(OH)₂(30 mg, 15% W/W) under N₂. The system was evacuated and backfilled with H₂three times. After stirred at rt overnight, the mixture was filtered and the filtrate was concentrated to give 0.16 g 6 (colorless oil, 80%). MS (ESI) m/z: 445[M+H]+.

General Procedure for the Preparation of Compound BC18703

To a solution of 6 (160 mg) in MeOH (2 mL) was added 3M HCl/EA (4 mL). After stirred at rt for 2 h, the solution was concentrated to give 120 mg of BC18703 (gray solid, 88%). MS (ESI) m/z: 345[M+H]+, 343[M−H]−

¹HNMR (400 MHz, DMSO) δ 11.85 (s, 1H), 9.13 (d, J=11.3 Hz, 1H), 8.96 (d, J=8.4 Hz, 1H), 8.22 (s, 1H), 8.14 (s, 1H), 8.07-8.03 (m, 2H), 7.79 (ddd, J=8.2, 5.3, 2.6 Hz, 1H), 7.75 (dd, J=9.0, 1.6 Hz, 1H), 7.65 (d, J=9.0 Hz, 1H), 3.36-3.33 (m, 1H), 3.29 (d, J=11.7 Hz, 2H), 2.94 (dd, J=21.0, 11.0 Hz, 2H), 2.11 (d, J=13.0 Hz, 2H), 2.05-1.92 (m, 2H).

Example 1c—Synthesis of Compound 78 (BC18705)

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General Procedure for the Preparation of Compound 3

To a solution of 1 (200 mg, 1.0 mmol, 1 eq) in i-PrOH (3 mL) was added DIEA (284 mg, 2.0 mmol, 2 eq) and 2 (146 mg, 1.1 mmol, 1.1 eq). The reaction was stirred at 85° C. overnight. The solution was concentrated and the residue was purified by silica column chromatography (PE/EA, 2:1) to give 150 mg 3 (yellow solid, 76%). MS (ESI) m/z: 295 [M+H]+

General Procedure for the Preparation of Compound BC18705

To a solution of 3 (100 mg, 0.339 mmol, 1 eq) in dioxane/H₂O (1:1, 3 mL) was added 4 (215 mg, 1.02 mmol, 3 eq), K₂CO₃(210 mg, 1.5 mmol, 4.5 eq) and Pd(dppf)Cl₂(25 mg, 0.034 mmol, 0.1 eq) under N₂. The mixture was stirred at 95° C. overnight. The mixture was concentrated and the residue was purified by Prep-HPLC to give 5 mg BC18705 (off-white solid, 4%). MS (ESI) m/z: 344[M+H]+, 342[M−H]−

¹H NMR (400 MHz, DMSO) δ 11.09 (s, 1H), 9.88 (s, 1H), 9.11 (s, 1H), 8.54 (d, J=8.2 Hz, 1H), 8.45 (s, 1H), 8.03 (s, 1H), 7.88-7.69 (m, 2H), 7.62-7.47 (m, 20H), 7.43 (d, J=8.6 Hz, 1H), 7.34 (t, J=2.7 Hz, 1H), 6.46 (s, 1H).

Example 1d—Synthesis of Compound 383 (BC18829)

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General Procedure for the Preparation of Compound 3-1

To a solution of 1 (0.2 g, 1.01 mmol, 1 eq) in i-PrOH (3 mL) was added 2 (148 mg, 1.11 mmol, 1.1 eq) and DIEA (260 mg, 2.02 mmol, 2 eq). The reaction was stirred at 85° C. overnight. The reaction was filtered. The cake was dried to give 0.29 g 3-1 (yellow solid, 97%). MS (ESI) m/z: 297 [M+H]+.

General Procedure for the Preparation of BC18829

To a solution of 3-1 (50 mg, 0.17 mmol, 1 eq) in dioxane/H₂O (4:1, 5 mL) was added 4-1 (40 mg, 0.19 mmol, 1.1 eq), K₂CO₃(47 mg, 0.34 mmol, 2 eq) and PdCl₂(dppf) (25 mg, 0.03 mmol, 0.2 eq) under N₂. The mixture was stirred at 95° C. for 4 h. The mixture was filtered. The filter cake was washed by EA and the organic phase was dried and concentrated. The residue was purified by Prep-TLC (DCM/MeOH, 10:1) to give 5 mg BC18829 (brown solid, 9%). MS (ESI) m/z: 346[M+H]+, 344[M−H]−

¹H NMR (400 MHz, DMSO) δ 10.77 (s, 1H), 9.37-9.15 (m, 2H), 9.06 (s, 1H), 8.63 (dd, J=7.1, 5.9 Hz, 1H), 8.37-8.05 (m, 2H), 7.89-7.48 (m, 3H).

Example 1e—Synthesis of Compound 384 (BC18830)

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General Procedure for the Preparation of Compound 3-2 ‘ ’

To a solution of 1 (0.2 g, 1.01 mmol, 1 eq) in i-PrOH (3 mL) was added 2 (167 mg, 1.11 mmol, 1.1 eq) and DIEA (260 mg, 2.02 mmol, 2 eq). The reaction was stirred at 85° C. overnight. The reaction was filtered. The cake was dried to give 0.3 g 3-2 (yellow solid, 96%). MS (ESI) m/z: 314 [M+H]+

General Procedure for the Preparation of BC18830

To a solution of 3-2 (0.1 g, 0.32 mmol, 1 eq) in DMSO (5 mL) was added 4-2 (34 mg, 0.38 mmol, 1.2 eq) and DIEA (83 mg, 0.64 mmol, 2 eq). The reaction was stirred at 95° C. for 2 h and quenched with H₂O (5 mL). The mixture was extracted with EA (10 mL×2). The organic phase was dried and concentrated. The residue was purified by Prep-TLC to give 49 mg BC18830 (yellow solid, 42%). MS (ESI) m/z: 365[M+H]+, 363[M−H]−.

¹H NMR (400 MHz, DMSO) δ 11.59 (s, 1H), 9.86 (s, 1H), 8.77-8.60 (m, 2H), 7.66 (s, 1H), 7.47-7.28 (m, 2H), 7.23-7.11 (m, 1H), 6.50 (s, 1H), 3.73 (brs, 4H), 3.62 (d, J=3.7 Hz, 7H).

Example 1f—Synthesis of Compound 385 (BC18831)

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General Procedure for the Preparation of 3-3

To a solution of 3-2 (as prepared in Example 1e) (150 mg, 0.48 mmol, 1 eq) in dioxane/H₂O (4:1, 5 mL) was added 2-3 (185 mg, 0.53 mmol, 1.1 eq), K₂CO₃(133 mg, 0.96 mmol, 2 eq) and Pd(dppf)Cl₂(37 mg, 0.05 mmol, 0.1 eq) under N₂. The mixture was stirred at 95° C. for 4 h. The mixture was filtered. The filter cake was washed by EA and the organic phase was dried and concentrated to give 245 mg 3-3 (yellow solid, 100%). MS (ESI) m/z: 483[M+H]+

General Procedure for the Preparation of Compound BC18831

To a solution of 3-3 (245 mg crude, 0.51 mmol, 1 eq) in THF (2 mL) was added 1 M TBAF in THF (1.02 mL, 1.02 mmol 2 eq). The reaction was stirred at rt for 4 h. The mixture was concentrated and the residue was purified by Prep-HPLC to give 44 mg BC18831 (yellow solid, 25%). MS (ESI) m/z: 345[M+H]+, 343[M−H]−

¹HNMR (400 MHz, DMSO) δ 11.58 (s, 1H), 11.18 (s, 1H), 9.83 (s, 1H), 8.88 (dd, J=15.9, 5.5 Hz, 2H), 8.13 (s, 1H), 7.92 (s, 1H), 7.66 (d, J=13.9 Hz, 1H), 7.50 (d, J=1.2 Hz, 1H), 7.47-7.37 (m, 2H), 6.82 (d, J=2.1 Hz, 1H), 6.71 (d, J=1.3 Hz, 1H), 6.57-6.50 (m, 1H).

Example 1g—Synthesis of Compound 43 (BC18663)

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General Procedure for the Preparation of Compound 3

To a solution of 1 (1.5 g, 6.1 mmol, 1 eq) in DMSO (6 mL) was added 2 (1.1 g, 9.1 mmol, 1.5 eq), cesium carbonate (4.0 g, 12.2 mol, 2.0 eq) and copper (I) bromide (86 mg, 0.6 mmol, 0.1 eq). The mixture was stirred at 80° C. for 4 h. The mixture was diluted with water (30 mL). The solid precipitated was collected and dried to give 1.3 g 3 (grey solid, 96%). MS (ESI) m/z: 223 [M+H]+

General Procedure for the Preparation of Compound 4

To a solution of compound 3 (220 mg, 1.0 mmol, 1 eq) in DMSO (0.6 mL) was added phosphorus oxychloride (465 mL, 5.0 mmol, 5 eq). The mixture was stirred at 80° C. for 3.5 h. After completion, the mixture was poured into ice (˜1 g). The solid was collected and dried to give 200 mg 4 (yellow solid, 84%). MS (ESI) m/z: 241[M+H]+

General Procedure for the Preparation of Compound BC18663

To a solution of 4 (83 mg, 0.33 mmol, 1.0 eq) in 4 M HCl/dioxane (2 mL) was added 5 (58 mg, 0.53 mmol, 1.5 eq). The reaction was stirred at 92° C. for 96 h. The solution was concentrated and the residue was purified by Prep-HPLC to give 19 mg BC18663 (yellow solid, 18%). MS (ESI) m/z: 316[M+H]+, 314[M−H]−

¹H NMR (400 MHz, DMSO) δ 9.50 (s, 1H), 8.67 (dd, J=4.6, 1.6 Hz, 2H), 8.56 (d, J=8.7 Hz, 1H), 8.05 (dd, J=4.5, 1.7 Hz, 3H), 8.00-7.91 (m, 2H), 7.83-7.72 (m, 2H), 7.68 (ddd, J=8.2, 6.9, 1.3 Hz, 1H), 7.39 (dd, J=15.3, 8.2 Hz, 1H), 6.82 (td, J=8.1, 1.9 Hz, 1H).

Example 1h—Synthesis of Compound 48 (BC18668)

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General Procedure for the Preparation of BC18668

To a solution of 6 (57 mg, 0.43 mmol, 1 eq) in DMF (2 mL) was added 60% NaH (52 mg, 1.29 mmol, 3 eq) at 0° C. The mixture was stirred for 10 min and then 4 (as prepared in Example 1g) (103 mg, 0.43 mmol, 1 eq) was added in. The mixture was stirred at 80° C. for 3 hours. Water (10 mL) was added in. The solid precipitated was collected and purified by Prep-HPLC to give 31 mg BC18668 (white solid, 22%). MS (ESI) m/z: 338[M+H]+

¹H NMR (400 MHz, DMSO) δ 8.73 (d, J=6.1 Hz, 2H), 8.70-8.63 (m, 2H), 8.23-8.17 (m, 4H), 8.15 (d, J=8.0 Hz, 1H), 7.86 (t, J=7.5 Hz, 1H), 7.77-7.69 (m, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.22 (s, 1H), 6.67 (dd, J=8.6, 1.7 Hz, 1H), 5.60 (s, 2H).

Example 1i—Synthesis of Compound 69 (BC18689)

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General Procedure for the Preparation of Compound BC18689

To a solution of 2 (111 mg, 1.0 mmol, 1.2 eq) in DMF (4 mL) was added 60% NaH (100 mg, 2.49 mmol, 3 eq) at 0° C. and the mixture was stirred for 15 min, then 1 (prepared by the same literature, 0.2 g, 0.83 mmol, 1 eq) was added into the above solution. The mixture was heated to 80° C. for 3 h. After cooled to rt, H₂O (5 mL) was added slowly. The mixture was extracted by EA (10 mL×2) and the organic phase was concentrated. The residue was purified by Prep-TLC to give 187 mg BC18689 (white solid, 72%). MS (ESI) m/z: 316 [M+H]+

¹H NMR (400 MHz, DMSO) δ 9.25 (s, 1H), 8.67 (dd, J=4.5, 1.6 Hz, 2H), 8.37 (dd, J=8.2, 0.8 Hz, 1H), 8.01-7.96 (m, 3H), 7.76 (ddd, J=8.3, 6.8, 1.2 Hz, 1H), 7.61 (s, 1H), 7.58 (ddd, J=8.2, 7.0, 1.2 Hz, 1H), 7.47-7.40 (m, 1H), 7.29 (dd, J=7.7, 2.3 Hz, 1H), 7.24 (dt, J=11.1, 2.3 Hz, 1H), 6.93 (td, J=8.5, 2.4 Hz, 1H).

Example 1j—Synthesis of Compound 126 (BC18763)

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General Procedure for the Preparation of Compound 3

To a solution of 1 (7.7 g, 56 mmol, 1.0 eq) in DMF (80 mL) was added 2 (8.2 g, 67.2 mmol, 1.2 eq), HATU (27.6 g, 73 mmol, 1.3 eq) and DIEA (14.4 g, 112 mmol, 2.0 eq) under N₂. The reaction was stirred at rt overnight. The reaction mixture was concentrated and the residue was purified by silica column chromatography (DCM/MeOH, 50:1) to give 11.5 g 3 (yellow solid, 85%). MS (ESI) m/z:243 [M+H]+

General Procedure for the Preparation of Compound 4

A solution of 3 (2 g, 8.26 mmol, 1.0 eq) in KOH (1N, 20 mL) was heated to 100° C. and stirred for 3 h. TLC showed no 3 left. The mixture was adjusted to pH 7 with aq HCl (4 M). The mixture was filtered. The solid precipitated was collected and dried to give 1.4 g 4 (white solid, 70%). MS (ESI) m/z: 225 [M+H]+

General Procedure for the Preparation of Compound 5

A solution of 4 (1.4 g, 6.3 mmol, 1.0 eq) in POCl₃(10 mL) was stirred at 100° C. overnight. The reaction was concentrated and the residue was adjusted pH to 9˜10 with saturated Na₂CO₃. The mixture was extracted with CHCl₃(15 mL×3) and the organic phase was dried and concentrated to give 750 mg 5 (yellow solid, 50%). MS (ESI) m/z: 243 [M+H]+

General Procedure for the Preparation of BC18763

To a solution of 5 (50 mg, 0.21 mmol, 1 eq) in i-PrOH (3 mL) was added 6-1 (33 mg, 0.23 mmol, 1.1 eq). The reaction was stirred at 85° C. overnight. The reaction mixture was filtered. The cake was washed by i-PrOH and dried to give 30.1 mg BC18763 (brown solid, 41%). MS (ESI) m/z: 353 [M+H]+, 351 [M−H]−

¹H NMR (400 MHz, DMSO) δ 11.26 (s, 1H), 10.81 (s, 1H), 10.05 (s, 1H), 8.80 (d, J=37.3 Hz, 3H), 8.18 (s, 2H), 7.84 (d, J=5.4 Hz, 1H), 7.51-7.25 (m, 2H), 7.16 (d, J=8.3 Hz, 1H), 6.55 (s, 1H), 2.47 (s, 3H)

Example 1k—Synthesis of Compound 127 (BC18764)

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General Procedure for the Preparation of BC18764

To a solution of 5 (as prepared in Example 1j) (100 mg, 0.21 mmol, 1 eq) in i-PrOH (3 mL) was added 6-2 (33 mg, 0.23 mmol, 1.1 eq). The reaction was stirred at 85° C. overnight. The reaction mixture was concentrated and the residue was purified with Prep-HPLC to give 10.6 mg BC18764 (brown solid, 8%). MS (ESI) m/z: 351 [M+H]+, 349 [M−H]−

¹H NMR (400 MHz, DMSO) δ 10.85 (s, 1H), 9.95 (s, 1H), 8.85 (d, J=5.7 Hz, 2H), 8.76 (d, J=5.9 Hz, 2H), 8.55 (d, J=2.0 Hz, 1H), 8.42 (d, J=7.6 Hz, 1H), 8.27 (dd, J=5.4, 3.7 Hz, 3H), 8.11 (d, J=9.2 Hz, 1H), 7.77 (d, J=5.9 Hz, 1H), 7.55 (dd, J=8.1, 4.2 Hz, 1H).

Example 1l—Synthesis of Compound 120 (BC18757)

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General Procedure for the Preparation of BC18757

To a solution of 5 (as prepared in Example 1j) (100 mg, 0.41 mmol, 1 eq) in i-PrOH (3 mL) was added 6-3 (86 mg, 0.45 mmol, 1.1 eq). The reaction was stirred at 85° C. overnight. The reaction mixture was concentrated and the residue was purified with Prep-HPLC to give 20 mg BC18757 (yellow solid, 11%). MS (ESI) m/z:399 [M+H]+, 397 [M−H]−

¹H NMR (400 MHz, DMSO) δ 10.67 (s, 1H), 9.84 (s, 1H), 8.80 (d, J=5.8 Hz, 1H), 8.69 (d, J=5.5 Hz, 2H), 8.52 (d, J=1.8 Hz, 1H), 8.15 (d, J=5.8 Hz, 2H), 7.99 (d, J=8.7 Hz, 1H), 7.89 (dd, J=8.8, 1.9 Hz, 1H), 7.70 (d, J=5.7 Hz, 1H), 4.26 (s, 1H), 1.40 (d, J=6.9 Hz, 6H).

Example 1m—Synthesis of Compound 83 (BC18711)

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General Procedure for the Preparation of Compound 3

To a solution of 1 (1.0 g, 5.0 mmol, 1 eq) in i-PrOH (15 mL) was added 2 (726 mg, 5.5 mmol, 1.1 eq) and DIEA (1.29 g, 10.0 mmol, 2 eq). The reaction was stirred at 85° C. for 4 h. The mixture was filtered. The cake was washed by i-PrOH and dried to give 1.2 g 3 (yellow solid, 81%). MS (ESI) m/z: 296 [M+H]+

General Procedure for the Preparation of BC18711

To a solution of 3 (700 mg, 2.36 mmol, 1 eq) in dioxane/H₂O (4:1, 10 mL) was added 4 (348 mg, 2.83 mmol, 1.2 eq), K₂CO₃(651 mg, 4.72 mmol, 2 eq) and PdCl₂(dppf) (176 mg, 0.24 mmol, 0.1 eq) under N₂. The mixture was stirred at 119° C. overnight. The mixture was filtered. The filter cake was washed by EA and the organic phase was dried and concentrated. The residue was purified by Prep-HPLC to give 34 mg BC18711 (gray solid, 5%). MS (ESI) m/z: 339[M+H]+, 337[M−H]−

¹H NMR (400 MHz, DMSO) δ 12.33 (s, 1H), 11.43 (s, 1H), 10.09 (dd, J=4.2, 1.4 Hz, 1H), 9.92 (d, J=5.4 Hz, 2H), 9.44 (ddd, J=11.0, 6.8, 1.8 Hz, 4H), 9.09 (dd, J=8.5, 4.2 Hz, 1H), 8.89 (dd, J=8.7, 1.9 Hz, 1H), 8.65 (d, J=8.7 Hz, 1H), 8.56 (t, J=2.7 Hz, 1H), 7.68 (s, 1H).

Example 1n—Synthesis of Intermediate 8 (Useful in Making Compound BC18847)

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General Procedure for the Preparation of Compound 6

Compound 5 (44 g, 225 mmol, 1 eq), tert-butyl nitrite (45 mL, 375 mmol, 1.67 eq) and CuBr₂(60 g, 270 mmol, 1.2 eq) was suspended in acetonitrile (500 mL, 10 V) and stirred at room temperature for 1-2 hour. The progress of the reaction was monitored by TLC (PE: EA 5:1). The resulting reaction mixture was quenched with 1 N HCl aqueous solution (3 L) and extracted with CH₂Cl₂(3×2 L). The combined organic layers were dried over Na₂SO4, and concentrated to give compound 6 (66.4 g, 99%) as yellow powder, which was used for next step without further purification. MS (ESI) m/z: 259[M+H]+.

General Procedure for the Preparation of Compound 7

To a solution of 6 (50.0 g, 194 mmol, 1.0 eq) in toluene/H₂O (V/V=2:l, 2 L) was added 6-1 (50 g, 581 mmol, 3.0 eq), Cs₂CO₃(126 g, 389 mmol, 2.0 eq) and Pd(dppf)Cl₂(14.2 g, 19.4 mmol, 0.1 eq). The mixture was evacuated and backfilled with Ar three times and then stirred at 100° C. overnight. The mixture was filtered through a pad of Celite, and washed with ethyl acetate (mL). The organic layers were washed with water and brine and dried over sodium sulfate. Concentrated and the residue was purified by silica column chromatography (PE/EA, 10:1) to give 19.1 g 7 (off-white solid, 45%).

General Procedure for the Preparation of Compound 8

To a solution of compound 7 (20.0 g, 90.9 mmol, 1.0 eq) in MeOH (200 mL) was added 10% Pd—C (6 g, 20% W/W) and stirred under H₂at r.t for 3˜4 h. TLC showed 7 left, another batch of Pd—C (6 g, 20% W/W) was added and the reaction was continued to stir at r.t for 4˜6 h. TLC showed no 7 left but there was two spots on TLC. Another batch of Pd—C (6 g, 20% W/W) was added and the reaction was continued to stir at r.t for 3˜5 h. The progress of the reaction was monitored by HPLC. After TLC showed only one spot, the mixture was filtered through Celite, washed with methanol (50 mL), and the filtrate was concentrated to give the crude which was recrystallized by EA to give 12.1 g 8 (gray solid, 73%). MS (ESI) m/z: 191[M+H]+

Example 1o—Synthesis of Compound 241 (BC18847)

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General Procedure for the Preparation of Compound 2

Compound 1 (150.0 g, 960 mmol, 1.0 eq), 1-(pyridin-4-yl)ethanone (174.0 g, 1.44 mol, 1.5 eq), cesium carbonate (630 g, 1.93 mol, 2.0 eq) and copper(I) bromide (13.8 g, 9.6 mmol, 0.1 eq) was dissolved in N,N-dimethylformamide (750 mL) and stirred at 80° C. overnight, the mixture was diluted with water (2 L). The solid was filtered, washed with water, and dried to give a black residue (175.2 g) which was used for next step without further purification.

General Procedure for the Preparation of Compound 3

A solution of compound 2 (175.2 g) in phosphorus oxychloride (500 mL) was stirred at 110° C. overnight and the progress of the reaction checked by LCMS. Excess phosphorus oxychloride was distilled under reduced pressure. EA (400 mL) and water (200 mL) was added to the system. The mixture was adjusted to pH 7 with saturated aqueous NaHCO₃. The water phase was extracted with EA (500 mL×3). The organic phase was washed with brine and dried over anhydrous sodium sulfate, and concentrated to give a crude, which was purified by column chromatography on a silica gel (EA: PE=10:1 to 1:1) to afford 14.5 g 3 (yellow solid, 7%, 2 steps). MS (ESI) m/z: 242[M+H]+

General Procedure for the Preparation of Compound 4

To a suspension of NaH (2.4 g, 100 mmol, 3 eq) in DMF (65 mL) at 0° C. was added amine 8 (5.3 g, 33.7 mmol, 1.01 eq). The mixture was stirred at rt for 30 min. To above mixture was added compound 3 (8.0 g, 33.2 mmol, 1 eq). The mixture was stirred at 80° C. for 16 hours. After completion, the mixture was cooled to room temperature and water (350 mL) was added slowly. The solid collected was triturated with EA and dried to give 9.7 g 4 (yellow solid, 74%). MS (ESI) m/z: 396[M+H]+, 394[M−H]−

General Procedure for the Preparation of BC18847

To a solution of compound 4 (30 g, 75.9 mmol, 1 eq) in ACN (60 mL) was added 1N HCl (114 mL, 113.9 mmol, 1.5 eq.). The mixture was stirred for 0.5 h. Then the mixture was lyophilized to give 32 g BC18847 (red solid, 97%). MS (ESI) m/z: 396[M+H]+, 394[M−H]−

¹H NMR (400 MHz, DMSO) δ 9.02-8.91 (m, 2H), 8.71 (d, J=6.4 Hz, 2H), 8.37 (d, J=6.5 Hz, 2H), 8.18 (d, J=1.5 Hz, 1H), 7.90 (s, 1H), 7.73-7.62 (m, 3H), 2.47 (s, 1H), 1.30-1.15 (m, 2H), 1.09-0.94 (m, 2H).

Example 1p—Synthesis of Compound 244 (BC18850)

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General Procedure for the Preparation of BC18850

To a solution of 3 (as prepared in Example 1o) (0.12 g, 0.50 mmol, 1 eq) and 9 (0.17 g, 1.0 mmol, 2 eq) in NMP (1.5 mL) was added 4 M HCl/dioxane (0.13 mL, 0.50 mmol, 1 eq) and the mixture was stirred at 100° C. overnight. After cooled to rt, the mixture was purified by Prep-HPLC directly to give 17 mg BC18850 (yellow solid, 9%). MS (ESI) m/z: 378[M+H]+.

¹H NMR (400 MHz, DMSO) δ 10.80 (s, 1H), 9.39 (s, 1H), 9.04-8.90 (m, 2H), 8.62 (dd, J=4.6, 1.5 Hz, 2H), 8.05 (dd, J=4.6, 1.6 Hz, 2H), 7.87-7.78 (m, 2H), 7.59 (dd, J=8.4, 4.3 Hz, 1H), 7.40 (dd, J=8.6, 2.0 Hz, 1H), 7.25 (d, J=8.6 Hz, 1H), 6.09 (d, J=1.8 Hz, 1H), 1.99 (td, J=8.4, 4.1 Hz, 1H), 0.98-0.89 (m, 2H), 0.82-0.74 (m, 2H).

Example 1—Compound Structures

The compounds in Table 1 were prepared as shown in the general scheme from readily available starting materials.

TABLE 1

No.
BC code
Structure

1
BC18607

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2
BC18608

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3
BC18612

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4
BC18614

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5
BC18615

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6
BC18616

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7
BC18617

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8
BC18618

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9
BC18619

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10
BC18625

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11
BC18626

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12
BC18627

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13
BC18628

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14
BC18629

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15
BC18630

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16
BC18630

HCl salt

17
BC18631

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18
BC18633

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19
BC18634

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20
BC18635

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21
BC18636

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22
BC18637

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23
BC18639

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24
BC18640

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25
BC18641

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26
BC18642

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27
BC18643

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28
BC18644

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29
BC18645

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30
BC18646

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31
BC18647

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32
BC18648

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33
BC18649

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34
BC18652

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35
BC18653

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36
BC18654

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37
BC18655

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38
BC18656

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39
BC18657

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40
BC18658

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41
BC18659

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42
BC18660

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43
BC18663

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44
BC18664

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45
BC18665

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46
BC18666

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47
BC18667

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48
BC18668

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49
BC18669

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50
BC18670

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51
BC18671

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52
BC18672

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53
BC18673

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54
BC18674

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55
BC18675

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56
BC18676

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57
BC18677

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58
BC18678

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59
BC18679

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60
BC18680

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61
BC18681

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62
BC18682

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63
BC18683

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64
BC18684

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65
BC18685

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66
BC18686

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67
BC18687

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68
BC18688

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69
BC18689

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70
BC18690

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71
BC18693

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72
BC18695

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73
BC18697

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74
BC18698

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75
BC18702

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76
BC18703

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77
BC18704

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78
BC18705

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79
BC18706

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80
BC18707

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81
BC18708

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82
BC18709

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83
BC18711

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84
BC18713

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85
BC18714

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86
BC18717

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87
BC18718

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88
BC18720

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89
BC18722

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90
BC18724

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91
BC18725

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92
BC18726

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93
BC18727

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94
BC18728

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95
BC18729

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96
BC18730

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97
BC18731

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98
BC18732

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99
BC18733

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100
BC18734

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101
BC18735

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102
BC18736

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103
BC18737

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104
BC18738

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105
BC18739

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106
BC18740

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107
BC18742

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108
BC18743

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109
BC18744

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110
BC18745

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111
BC18746

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112
BC18747

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113
BC18748

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114
BC18749

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115
BC18750

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116
BC18752

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117
BC18754

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118
BC18755

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119
BC18756

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120
BC18757

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121
BC18758

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122
BC18759

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123
BC18760

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124
BC18761

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125
BC18762

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126
BC18763

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127
BC18764

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128
BC18765

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129
BC18766

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130
BC18767

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131
BC18768

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132
BC18769

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133
BC18770

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134
BC18771

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135
BC18772

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136
BC18773

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137
BC18774

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138
BC18775

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139
BC18776

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140
BC18778

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141
BC18779

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142
BC18780

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143
BC18782

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144
BC18783

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145
BC18784

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146
BC18785

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147
BC18786

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148
BC18787

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149
BC18788

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150
BC18789

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151
BC18790

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152
BC18791

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153
BC18792

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154
BC18793

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155
BC18794

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156
BC18816

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157
BC18813

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158
BC18815

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Note:

Cmpd 35 was isolated and tested as TFA salt. Compounds 42, 51, 59, 63, 64, and 65 were each isolated and tested as HCl salt. Compounds 82, 83, 89, 106, 107, 108, 113, 115, 116, 117, 119, 120, and 121 were each isolated and tested as formate salt.

The following compounds shown in Table 1a may prepared using chemical routes that would be readily apparent to one of ordinary skill in the art from readily available starting materials.

TABLE 1a

BC.

No.
Code
Structure

352
BC18795

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353
BC18796

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354
BC18797

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355
BC18798

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356
BC18799

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357
BC18800

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358
BC18801

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359
BC18802

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360
BC18803

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361
BC18804

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362
BC18805

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363
BC18806

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364
BC18807

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365
BC18808

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366
BC18809

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367
BC18810

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368
BC18811

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369
BC18812

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370
BC18814

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371
BC18817

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372
BC18818

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373
BC18819

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374
BC18820

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375
BC18821

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376
BC18822

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377
BC18823

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378
BC18824

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379
BC18825

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380
BC18826

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381
BC18827

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382
BC18828

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383
BC18829

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384
BC18830

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385
BC18831

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386
BC18832

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387
BC18833

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388
BC18834

embedded image

389
BC18835

embedded image

390
BC18836

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391
BC18837

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392
BC18838

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393
BC18839

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394
BC18840

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395
BC18841

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396
BC18845

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Note:

Compounds 353, 364, and 376 were isolated and tested as HCOOH salts.

The following compounds (free base) provided in Table 2 were obtained from commercial sources (ChemDIV, Inc. and Mol port, Inc.):

TABLE 2

No.
BC code
Structure

159
BC1820

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160
BC18200

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161
BC18201

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162
BC18202

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163
BC18203

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164
BC18204

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165
BC18205

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166
BC18206

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167
BC18207

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168
BC18208

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169
BC18209

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170
BC18210

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171
BC18211

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172
BC18212

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173
BC18213

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174
BC18214

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175
BC18215

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176
BC18216

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177
BC18217

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178
BC1834

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179
BC18601

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180
BC18602

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181
BC18603

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182
BC18604

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183
BC18605

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184
BC18606

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185
BC18609

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186
BC18610

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187
BC18611

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188
BC18613

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189
BC18623

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190
BC18624

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191
BC18632

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192
BC18651

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193
BC18661

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194
BC18715

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The following compounds shown in Table 3 may prepared using chemical routes that would be readily apparent to one of ordinary skill in the art from readily available starting materials.

TABLE 3

No.
BC code
Structure

195
BC1816

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196
BC1835

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197
BC1836

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198
BC1837

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199
BC1838

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200
BC1839

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201
BC1840

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202
BC1841

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203

204

205

206

207

208

209

210

211

212

213

Note:

Compounds 197 and 199 were isolated and tested as HCl salts.

The following compounds shown in Table 4 were purchased from ChemDIV, Inc.

TABLE 4

No.
BC code
Structure

214
BC1770

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215
BC1771

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216
BC1772

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217
BC1773

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218
BC1774

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219
BC1775

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220
BC1776

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221
BC1777

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222
BC1753

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223
BC1780

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224
BC1781

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225
BC1782

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226
BC1783

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227
BC1784

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228
BC1785

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229
BC1786

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230
BC1787

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231
BC1811

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232
BC1812

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233
BC1813

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234
BC1814

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235
BC1815

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236
BC1817

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237
BC1818

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238
BC1819

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The following compounds shown in Table 5 may prepared using chemical routes that would be readily apparent to one of ordinary skill in the art from readily available starting materials.

TABLE 5

No.
BC code
Structure

239
BC18842

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240
BC18846

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241
BC18847

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242
BC18848

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243
BC18849

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244
BC18850

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245
BC18851

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246
BC18852

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247
BC18853

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248
BC18854

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249
BC191100

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250
BC191101

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251
BC191102

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252
BC191103

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253
BC191104

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254
BC191105

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255
BC191106

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256
BC191107

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257
BC191108

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258
BC191109

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259
BC191110

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260
BC191111

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261
BC191112

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262
BC191113

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263
BC191114

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264
BC191115

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265
BC191116

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266
BC191117

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267
BC191118

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268
BC191119

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269
BC191120

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270
BC191121

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271
BC191122

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272
BC191123

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273
BC191124

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274
BC191125

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275
BC191126

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276
BC191127

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277
BC191128

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278
BC191129

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279
BC191130

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280
BC191131

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281
BC191132

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282
BC191133

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283
BC191134

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284
BC191135

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285
BC191136

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286
BC191137

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287
BC191138

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288
BC191139

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289
BC191140

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290
BC191141

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291
BC191142

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292
BC191143

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293
BC191144

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294
BC191145

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295
BC191146

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296
BC191147

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297
BC191148

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298
BC191149

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299
BC191150

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300
BC191151

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301
BC191152

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302
BC191153

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303
BC191154

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304
BC191155

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305
BC191156

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306
BC191157

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307
BC191158

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308
BC191159

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309
BC191160

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310
BC191161

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311
BC191162

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312
BC191163

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313
BC191164

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314
BC191165

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315
BC191166

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316
BC191167

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317
BC191168

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318
BC191169

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319
BC191170

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320
BC191171

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321
BC191172

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322
BC191173

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323
BC191174

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324
BC191175

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325
BC191176

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326
BC191177

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327
BC191178

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328
BC191179

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329
BC191180

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330
BC191181

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331
BC191182

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332
BC191183

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333
BC191184

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334
BC191185

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335
BC191186

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336
BC191187

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337
BC191188

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338
BC191189

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339
BC191190

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340
BC191191

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341
BC191192

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342
BC191193

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343
BC191194

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344
BC191195

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345
BC191196

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346
BC191197

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347
BC191198

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348
BC191199

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349
BC191200

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350
BC191201

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351
BC191202

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Note:

Compounds 239, 240, 242, and 243 were isolated and tested as HCOOH salts compounds 246, 247, and 248 were isolated and tested as HCl salts.

The following compounds shown in Table 3a may prepared using chemical routes that would be readily apparent to one of ordinary skill in the art from readily available starting materials.

TABLE 5a

No.
BC Code
Structure

400
BC18858

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401
BC18859

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402
BC18860

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BC191500

BC191501

BC191502

BC191503

BC191504

BC191505

BC191507

BC191508

BC191509

BC191510

BC191511

BC191512

BC191513

BC191514

BC191515

BC191516

BC191517

BC191518

BC191519

BC191520

BC191521

BC191522

BC191524

BC191525

BC191526

BC191527

BC191528

BC191529

BC191530

BC191531

BC191532

BC191533

BC191534

BC191535

BC191536

BC191537

BC191538

BC191539

BC191540

BC191541

BC191542

BC191543

BC191544

The following compounds shown in Table 6 may prepared using chemical routes that would be readily apparent to one of ordinary skill in the art from readily available starting materials.

TABLE 6

No.
BC code
Structure

397
BC18855

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398
BC18856

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399
BC18857

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Note:

Compounds 397, 398, and 399 were isolated and tested as HCl salts.

Example 2—Assay Results
Assay Protocol

Approximately 2300 primary and immortalized human bronchial epithelial cells (BEAS-2B) stably expressing TFEB-EGFP in 25 μL of HITEs media with 10% FBS were dispensed into 384 well plate (Black with glass bottom) and incubated for 8 hours. Compound serial dilution (DMEM low glucose media with 2% FBS, 25 μL volume) were prepared using a robotic liquid hander. Compound solution were then added to the cell plate and incubated for 18 hours. Cells were then fixed with 4% PFA followed by DAPI staining. TFEB localization was imaged on the GFP channel along with the DAPI signal using a Cytation 5 high content imager. Images were processed through Biotek Gen5 software. Specifically, the DAPI signal was used as the primary mask to quantify the nuclear TFEB-GFP signal. Cytosolic TFEB-GFP signal was quantified through expanding the primary mask. The TFEB nuclear/cytosol ratios were calculated from nuclear TFEB-GFP signal/cytosol TFEB-GFP signal, which determined the compound efficacies.

Compounds efficacies (μM) were determined by the minimal compound concentration needed to increase TFEB nuclear/cytosol ratio by 25%. Activity: “+” equals >25 μM; “++” equals between ≤25 μM and >1 μM; and “+++” equals ≤1 μM.

Toxicity was determined by determining the compound concentration needed to induce greater than 50 percent of cell loss. For toxicity, cell loss of greater than 50 percent at a concentration that equals or is greater than 25 μM was represented as cell loss of greater than 50 percent at a concentration less than 25 μM and greater than 1 μM was represented as and cell loss of greater than 50 percent at a concentration that equals or is less than 1 μM was represented as “+++.” The assay results for compounds 1-202, 214-248, 332, 333, and 352-402 are shown in Table A.

TABLE A

Compound efficacy and toxicity results.

No.
BC code
efficacy
toxicity

1
BC18607
+++
+

2
BC18608
+++
+

3
BC18612
+++
+

4
BC18614
+++
+++

5
BC18615
+
+

6
BC18616
+
+

7
BC18617
+
+

8
BC18618
+
+

9
BC18619
+
+

10
BC18625
+
+

11
BC18626
+++
+

12
BC18627
+++
+

13
BC18628
+
+

14
BC18629
+
+

15
BC18630
+++
+

16
BC18630 HCl
+++
+

salt

17
BC18631
+
+

18
BC18633
+
+

19
BC18634
+
+

20
BC18635
++
+

21
BC18636
+
+

22
BC18637
+
+

23
BC18639
+++
+

24
BC18640
+++
+

25
BC18641
+++
++

26
BC18642
+++
+++

27
BC18643
+++
+

28
BC18644
+
+

29
BC18645
++
+

30
BC18646
+++
+++

31
BC18647
+++
+++

32
BC18648
+++
+++

33
BC18649
+
+

34
BC18652
+++
+

35
BC18653
+++
++

36
BC18654
+
+

37
BC18655
++
+

38
BC18656
+
+

39
BC18657
+
+

40
BC18658
++
+

41
BC18659
++
++

42
BC18660
+++
+

43
BC18663
++
+

44
BC18664
+++
+

45
BC18665
+
+

46
BC18666
+
+

47
BC18667
+++
+++

48
BC18668
+
+

49
BC18669
+
+

50
BC18670
+
+

51
BC18671
+
+

52
BC18672
+
+

53
BC18673
+
+

54
BC18674
+
+

55
BC18675
+
+

56
BC18676
++
+

57
BC18677
+++
+

58
BC18678
++
+

59
BC18679
++
+

60
BC18680
+
+

61
BC18681
+++
++

62
BC18682
+++
+++

63
BC18683
+
+

64
BC18684
++
++

65
BC18685
+
+

66
BC18686
+
+

67
BC18687
+
+

68
BC18688
+
+

69
BC18689
+
+

70
BC18690
+++
+

71
BC18693
+++
+

72
BC18695
+++
+++

73
BC18697
+++
+++

74
BC18698
+++
++

75
BC18702
+
+

76
BC18703
+
+

77
BC18704
+++
+

78
BC18705
++
+

79
BC18706
+
+

80
BC18707
++
+

81
BC18708
+++
++

82
BC18709
+++
+

83
BC18711
++
+

84
BC18713
+++
+

85
BC18714
+++
+

86
BC18717
+++
+++

87
BC18718
+
+

88
BC18720
+
+

89
BC18722
++
++

90
BC18724
+++
+

91
BC18725
+++
+

92
BC18726
++
+

93
BC18727
+
+

94
BC18728
+++
+

95
BC18729
+
+

96
BC18730
+
+

97
BC18731
+++
+

98
BC18732
+++
+

99
BC18733
+++
+

100
BC18734
+
+

101
BC18735
+
+

102
BC18736
+++
+

103
BC18737
+++
+

104
BC18738
+++
+

105
BC18739
+
+

106
BC18740
+
+

107
BC18742
+
+

108
BC18743
+++
+

109
BC18744
+++
+

110
BC18745
+++
+

111
BC18746
+
+

112
BC18747
+++
+

113
BC18748
+++
++

114
BC18749
+++
++

115
BC18750
+
+

116
BC18752
+++
+

117
BC18754
+++
+

118
BC18755
++
+

119
BC18756
+
+

120
BC18757
+
+

121
BC18758
+
+

122
BC18759
+
+

123
BC18760
++
+

124
BC18761
+++
+

125
BC18762
++
+

126
BC18763
++
+

127
BC18764
++
+

128
BC18765
+++
+

129
BC18766
+++
+

130
BC18767
+++
+

131
BC18768
+++
+

132
BC18769
+++
+

133
BC18770
+++
+

134
BC18771
+++
+

135
BC18772
++
+

136
BC18773
+++
+

137
BC18774
+++
+

138
BC18775
+++
+

139
BC18776
+
+

140
BC18778
+
+

141
BC18779
+++
++

142
BC18780
+++
+

143
BC18782
+++
+

144
BC18783
+
+

145
BC18784
+++
+

146
BC18785
+++
+

147
BC18786
++
+

148
BC18787
+++
+

149
BC18788
++
++

150
BC18789
+++
++

151
BC18790
+++
+

152
BC18791
++
+

153
BC18792
++
+

154
BC18793
+++
+

155
BC18794
+++
+

156
BC18795
+++
+

157
BC18796
+++
++

158
BC18797
+++
+

159
BC1820
+
+

160
BC18200
+++
++

161
BC18201
+
+

162
BC18202
+
+

163
BC18203
+
+

164
BC18204
+
+

165
BC18205
+
+

166
BC18206
+
+

167
BC18207
++
+

168
BC18208
+
+

169
BC18209
+
+

170
BC18210
+
+

171
BC18211
+
+

172
BC18212
+
+

173
BC18213
+
+

174
BC18214
+
+

175
BC18215
+
+

176
BC18216
++
+

177
BC18217
+
+

178
BC1834
+++
+

179
BC18601
++
+

180
BC18602
+
+

181
BC18603
+++
+

182
BC18604
+
+

183
BC18605
++
+

184
BC18606
++
+

185
BC18609
+++
+

186
BC18610
+++
+

187
BC18611
+++
+

188
BC18613
+
+

189
BC18623
++
+

190
BC18624
++
+

191
BC18632
+++
+

192
BC18651
+++
+

193
BC18661
++
++

194
BC18715
+++
+

195
BC1816
+
+

196
BC1835
+
+

197
BC1836
+
+

198
BC1837
+
+

199
BC1838
+
+

200
BC1839
++
+

201
BC1840
+
+

202
BC1841
+
+

214
BC1770
+
+

215
BC1771
++
++

216
BC1772
+
+

217
BC1773
+
+

218
BC1774
+
+

219
BC1775
+
+

220
BC1776
+
+

221
BC1777
+
+

222
BC1753
++
++

223
BC1780
+
+

224
BC1781
+
+

225
BC1782
+
+

226
BC1783
+
+

227
BC1784
+
+

228
BC1785
+
+

229
BC1786
+
+

230
BC1787
+
+

231
BC1811
++
+

232
BC1812
+
+

233
BC1813
+
+

234
BC1814
++
+

235
BC1815
++
+

236
BC1817
++
+

237
BC1818
++
+

238
BC1819
+
+

239
BC18842
++
+

240
BC18846
+++
+

241
BC18847
+++
+

242
BC18848
+++
+

243
BC18849
+++
+

244
BC18850
+++
+

245
BC18851
+++
+

246
BC18852
+++
+

247
BC18853
++
+

248
BC18854
++
+

332
BC191183/
+++
+

BC18861

333
BC191184/
+++
+

BC18862

352
BC18795
++
+

353
BC18796
++
+

354
BC18797
+
+

355
BC18798
++
+

356
BC18799
+++
+

357
BC18800
+
+

358
BC18801
++
+

359
BC18802
+
+

360
BC18803
+
+

361
BC18804
++
+

362
BC18805
+
+

363
BC18806
+++
+

364
BC18807
+
+

365
BC18808
+++
+

366
BC18809
+
+

367
BC18810
++
+

368
BC18811
++
+

369
BC18812
+
+

370
BC18814
+++
+

371
BC18817
+++
+

372
BC18818
+++
+

373
BC18819
++
+

374
BC18820
++
+

375
BC18821
+++
+

376
BC18822
+++
+

377
BC18823
++
+

378
BC18824
+++
+

379
BC18825
+++
+

380
BC18826
++
+

381
BC18827
+++
+

382
BC18828
+
+

383
BC18829
++
+

384
BC18830
+++
+

385
BC18831
++
+

386
BC18832
+++
+

387
BC18833
+
+

388
BC18834
+
+

389
BC18835
+
+

390
BC18836
+
+

391
BC18837
+++
+

392
BC18838
+
+

393
BC18839
++
+

394
BC18840
+
+

395
BC18841
+++
+

396
BC18845
+++
+

397
BC18855
++
+

398
BC18856
+++
+

399
BC18857
+++
+

400
BC18858
+++
+

401
BC18859
+++
+

402
BC18860
+++
+

Example 3—Using BC1753 to Increase TFEB Polypeptide Levels

BC1753 (FIG. 2A) was tested for its ability to increase TFEB polypeptide levels. Briefly, murine lung epithelial cells (MLE12) stably expressing TFEB-EGFP were treated with BC1753 in a dose dependent manner for 18 hours. Cells were then collected and assayed by immunoblotting for TFEB-GFP protein levels (FIG. 2B). Murine lung epithelial cells (MLE12) stably expressing TFEB-EGFP were treated with BC1733 in a dose dependent manner for 18 hours. Cells were then fixed with 4% PFA followed by DAPI staining. TFEB localization was imaged on the GFP channel along with the DAPI signal using a Nikon A1 confocal microscope (FIG. 2C). BC1753 drastically increased total TFEB polypeptide levels within cells (FIG. 2B) and increased nuclear TFEB polypeptide accumulation (FIG. 2C).

Example 4—Compounds for Increasing TFEB Polypeptide Levels within the Nucleus of Cells

A high-content imaging screen was conducted using Beas2B cells that stably express GFP-TFEB. This approach demonstrated robust and accurate measurement of TFEB nuclear/cytosol ratio upon various compound treatments (FIG. 3).

Example 5—Increasing Lysosome Quantity, Lysosomal Protein Expression, and Secretion of Lysosomal Enzymes

Compounds 178 (BC1834) and/or 160 (BC18200) at the indicated concentrations were found to increase lysosome quantity (FIGS. 4A-B), to increase lysosomal protein expression (FIG. 5A), and to increase secretion of the lysosomal enzyme beta hexosaminidase (FIG. 5B).

Example 6—Using Compounds Provided Herein to Reduce the Level of Huntingtin Polypeptides

Compound 178 (BC1834) was tested for the ability to reduce Huntingtin polypeptide levels within cells. Briefly, Compound 178 was administered to SH5Y cells stably expressing GFP-Huntingtin (72Q). As shown in FIGS. 6A-B, Compound 178 dose dependently reduced GFP-Huntingtin polypeptide levels. These results demonstrate that the compounds provided herein can be used to treat neurological conditions such as Huntington's disease.

Example 7—In Vivo Effects

Female C57BL6 mice were i.p. injected with Compound 15 (30 mg/kg/day) for 4 days. Mice were then i.v. injected with dextran blue. 24 hours later, mice were sacrificed, and liver samples were removed and imaged through confocal microscopy. As shown in FIG. 7, Compound 13 treatment drastically increased lysosomal dextran blue signal and lamp2 staining (pseudo-colored white). These results demonstrate that the compounds provided herein can increase in vivo lysosomal number and activity.

OTHER EMBODIMENTS

It is to be understood that while the present application has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the present application, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

	Number	Date	Country
	62879374	Jul 2019	US
	62788049	Jan 2019	US

METHODS AND MATERIALS FOR INCREASING TRANSCRIPTION FACTOR EB POLYPEPTIDE LEVELS

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Publication Number

Date Filed

Date Published

Inventors

Original Assignees

CPC

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Abstract

Description

Claims

CLAIM OF PRIORITY

FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

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Provisional Applications (2)