Methods and materials for increasing levels of transcription factor eb polypeptides

Abstract

The document provides methods and materials for increasing the level of a TFEB polypeptide. For example, provided are compounds (e.g., organic compounds) having the ability to increase the level of a TFEB polypeptide in a cell and / or in the nucleus of a cell, formulations comprising a compound having the ability to increase the level of a TFEB polypeptide in a cell and / or in the nucleus of a cell, methods for making a compound having the ability to increase the level of a TFEB polypeptide in a cell and / or in the nucleus of a cell, methods for making a formulation comprising a compound having the ability to increase the level of a TFEB polypeptide in a cell and / or in the nucleus of a cell, methods for increasing the level of a TFEB polypeptide in a cell and / or in the nucleus of a cell, and methods for treating a mammal (e.g., a human) having a disorder responsive to an increase in the level of a TFEB polypeptide.

Description

[0001] CLAIM OF PRIORITY

[0002] This application claims priority to U.S. Patent Application Serial No. 62 / 788,049, filed January 3, 2019, and U.S. Patent Application Serial No. 62 / 879,374, filed July 26, 2019, the entire contents of which are incorporated herein by reference.

[0003] FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0004] This invention was made with government support under Grant Nos. 1R35 HL139860 and 1R01 HL142777 awarded by the National Institutes of Health (NIH). The government has certain rights in the disclosed subject matter. TECHNICAL FIELD

[0005] This document relates to methods and materials for increasing levels of a transcription factor EB (TFEB) polypeptide. For example, this document provides compounds (e.g., organic compounds) having the ability to increase levels of a TFEB polypeptide in a cell, formulations comprising a compound having the ability to increase levels of a TFEB polypeptide in a cell, methods of making a compound having the ability to increase levels of a TFEB polypeptide in a cell, methods for increasing levels of a TFEB polypeptide in a cell, and methods for treating a mammal (e.g., a human) having a condition responsive to an increase in levels of a TFEB polypeptide. BACKGROUND

[0006] Lysosomes are membrane-bound organelles that contain a variety of digestive enzymes responsible for the metabolism and degradation of various biomolecules (e.g., proteins, lipids, and nucleic acids) that are damaged or no longer needed by the cell. In the absence of functional lysosomes, undegraded molecules rapidly accumulate in lysosomes and subsequently in the cytoplasm, causing cellular damage and leading to many pathological conditions.

[0007] 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 of the cell, it activates the expression of its target genes, which indicates inducible lysosome biogenesis and increased 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 have been shown to be useful in treating metabolic and age-related disorders (Wang et al., Nat. Commun., 8: 2270 (2017)). SUMMARY

[0008] The present document provides methods and materials for increasing the level of a TFEB polypeptide. For example, the present document provides compounds (e.g., organic compounds) having the ability to increase the level of a TFEB polypeptide in a cell, formulations comprising a compound having the ability to increase the level of a TFEB polypeptide in a cell, methods of making a compound having the ability to increase the level of a TFEB polypeptide in a cell, methods for making a formulation comprising a compound having the ability to increase the level of a TFEB polypeptide in a cell, methods for increasing the level of a TFEB polypeptide in a cell, and methods for treating a mammal (e.g., a human) having a disorder responsive to an increase in the level of a TFEB polypeptide. The present document also provides compounds (e.g., organic compounds) having the ability to increase the level of a TFEB polypeptide in a nucleus of a cell, formulations comprising a compound having the ability to increase the level of a TFEB polypeptide in a nucleus of a cell, methods of making a compound having the ability to increase the level of a TFEB polypeptide in a nucleus of a cell, methods for making a formulation comprising a compound having the ability to increase the level of a TFEB polypeptide in a nucleus of a cell, methods for increasing the level of a TFEB polypeptide in a nucleus of a cell, and methods for treating a mammal (e.g., a human) having a disorder responsive to an increase in the level of a TFEB polypeptide in a nucleus of a cell.

[0009] As described herein, the compounds provided herein can be used to increase the level of a TFEB polypeptide in a cell in vitro or in vivo and / or to increase the level of a TFEB polypeptide in the nucleus in vitro or in vivo. For example, the compounds provided herein can be used to increase the level of a nuclear polypeptide of an endogenously produced TFEB polypeptide in a cell of a mammal (e.g., a human). Additionally, the compounds provided herein can be used to treat a mammal (e.g., a human) having a disease, a condition, or a disorder associated with low cellular and / or nuclear levels of a TFEB polypeptide. In some cases, the compounds provided herein can be used to treat a mammal (e.g., a human) having a disease, a condition, or a disorder that is responsive to an increase in the level of a TFEB polypeptide in a cell and / or in the nucleus.

[0010] In some embodiments, the document provides a method for increasing the level of a TFEB polypeptide in a cell and / or in the nucleus. The method includes (or consists essentially of or consists of) administering to a mammal (e.g., a human) comprising a cell a compound of Formula (I):

[0011]

[0012] or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , R A , R B , L and n are as described herein. In certain cases, the administration step can result in an increase in the level of a TFEB polypeptide in the nucleus compared to the level of a TFEB polypeptide in the nucleus prior to the administration step.

[0013] In some embodiments, the document provides a method for treating a disease, a disorder, or a condition selected from the group consisting of lysosomal storage disorders (LSDs), acute or chronic inflammatory diseases, diseases of the nervous system, and conditions associated with age-related functional decline in a mammal (e.g., a human). The method includes (or consists essentially of or consists of) administering to a mammal (e.g., a human) having the disease, the condition, or the disorder a compound of Formula (I):

[0014]

[0015] or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , R A , R B, L and n are as described herein. In certain instances, the administering step can reduce the severity of symptoms of the disease, disorder, or condition. In certain instances, the managing step can result in an increase in the level of the TFEB polypeptide within the nucleus of the mammal as compared to the level of the TFEB polypeptide within the nucleus prior to the administering step.

[0016] In some embodiments, the document provides a compound of Formula (IIa):

[0017]

[0018] or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , R A , R B and Y are as described herein.

[0019] In some embodiments, the document provides a compound of Formula (IIb):

[0020]

[0021] or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , R C , R B , L and n are as described herein.

[0022] In some embodiments, the document provides a compound selected from one of the following formulae:

[0023]

[0024]

[0025] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R A , R B , L and n are as described herein.

[0026] In some embodiments, the document provides a compound of Formula (III):

[0027]

[0028] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 as described herein.

[0029] In some embodiments, the document provides a pharmaceutical composition comprising any of the compounds (or a pharmaceutically acceptable salt thereof) described herein and a pharmaceutically acceptable carrier.

[0030] In some embodiments, the document provides a method for increasing the level of a TFEB polypeptide in a cell and / or in the nucleus of a cell. The method comprises (or consists essentially of or consists of) administering to a mammal (e.g., a human) comprising the cell a therapeutically effective amount of any one or more of the compounds described herein (or one or more pharmaceutically acceptable salts thereof).

[0031] In some embodiments, the document provides a method for treating a disease, a condition, or a disorder selected from the group consisting of lysosomal storage disorders (LSDs), acute or chronic inflammatory diseases, neurological diseases, and age-related functional decline in a mammal (e.g., a human), and inherited or acquired muscle diseases. The method comprises (or consists essentially of or consists of) administering to a mammal (e.g., a human) having said disease, condition, or disorder a therapeutically effective amount of any one or more of the compounds described herein (or one or more pharmaceutically acceptable salts thereof).

[0032] In some embodiments, the document provides a method for treating a disease, a condition, or a symptom selected from the group consisting of lysosomal storage disorders (LSDs), acute or chronic inflammatory diseases, neurological diseases, and 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 said disease, condition, or symptom a therapeutically effective amount of any one or more of the compounds described herein (or one or more pharmaceutically acceptable salts thereof).

[0033] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Methods and materials are described herein for use of 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.

[0034] Other features and advantages of the present application will become apparent from the following detailed description, taken in conjunction with the accompanying drawings, and by referring to the claims. BRIEF DESCRIPTION OF DRAWINGS

[0035] Figure 1 Amino acid sequence of human TFEB polypeptide (SEQ ID NO: 1).

[0036] Figure 2A -C. BC1753 increases levels of TFEB polypeptide. A. Structure of BC1753 is provided. B. MLE12 cells stably expressing TFEB-EGFP were first treated with the indicated amounts of BC1753 for 24 hours, then immunoblotting was performed for TFEB-GFP and β-actin. C. MLE12 cells stably expressing TFEB-EGFP were first treated with the indicated amounts of BC1753 for 24 hours, then imaged by confocal microscopy (scale bar = 10 μm).

[0037] Figure 3TFEB nuclear accumulation was measured using a high content screening assay (384 well). Approximately 2500 primary and immortalized human bronchial epithelial cells (BEAS-2B) stably expressing TFEB-EGFP in 25 μΐ^of HITES medium containing 10% FBS were dispensed into 384 well plates (black, glass bottom) and incubated for 8 hours. Compound serial dilutions were prepared using an automated liquid handler (DMEM low glucose medium with 2% FBS, 25 μΐ^volume). The compound solutions were then added to the cell plates and incubated for 18 hours. Cells were then fixed with 4% PFA and then DAPI stained. TFEB localization was imaged on the GFP channel using a Cytation 5 high content imager along with the DAPI signal. Images were processed by Biotek Gen5 software; specifically, the DAPI signal was used as a primary mask to quantify the nuclear TFEB-GFP signal. The TFEB-GFP signal of the cytoplasmic matrix was quantified by extending the primary mask. The TFEB nuclear / cytoplasmic ratio was calculated from the nuclear TFEB-GFP signal / cytoplasmic matrix TFEB-GFP signal, which determined the efficacy of the compound. The table shows the efficacy of the compound (with increasing compound concentration) in increasing the TFEB nuclear / cytoplasmic matrix ratio. Compound activity (μΜ) was determined by the minimum compound concentration required to increase the TFEB nuclear / cytoplasmic matrix ratio by 25%. Activity: “-” equals > 25 μΜ; “+” equals < 25 μΜ and > 10 μΜ; “++” equals < 10 μΜ and > 1 μΜ; and “+++” equals < 1 μΜ. N = 4.

[0038] Figure 4A B. Compound 178 (BC1834) and Compound 160 (BC18200) increase lysosome number. A. Beas2B cells were treated with Cmpd. 178, Cmpd. 160 or GSK3b inhibitor TWS119 (1 μΜ for 18 hours). Cells were then imaged by light microscopy. B. Beas2B cells were treated with Cmpd. 178 at the indicated concentrations for 18 hours. Cells were then stained with a lysosome red fluorescent probe (100 nM) for 30 minutes. Cells were then washed and imaged by confocal microscopy.

[0039] Figure 5A B. Compound 133 and Compound 115 increase lysosomal protein expression and secretion. A. Beas2B cells were treated with Cmpd. 133 at 10 μΜ for 24 hours. Cells were then harvested and analyzed for lysosomal protein gene expression. B. Beas2B cells were treated with Cmpd. 115 at the indicated concentrations for 18 hours. Secreted β-hexosaminidase activity (lysosomal enzyme) was then measured and normalized to cellular β-hexosaminidase activity.

[0040] Figure 6A B. Compound 178 reduces expression of the huntingtin gene. SH5Y cells stably transfected with GFP-72Q (huntingtin) were treated with the indicated amounts of Cmpd. 178 for 24 hours. Cells were then imaged using confocal microscopy or harvested and their protein expression was determined using a GFP-huntingtin immunoblot.

[0041] Figure 7 Compound 15 increases lysosomal activity in the liver. Female C57BL6 mice were injected intraperitoneally (i.p.) with Cmpd. 15 (50 mg / kg / d) for 4 days. The mice were then injected intravenously (i.v.) with dextran blue. 24 hours later, the mice were sacrificed, the livers were removed and imaged by confocal microscopy. The white fluorescent signal indicates dextran blue within lysosomes and provides a measure of the number and activity of lysosomes within the liver tissue (top panel). In another experiment, histological sections from the livers obtained from the above experiment were immunostained with a Lamp2 antibody (bottom panel) and show that treatment with Cmpd 15 enhances the signal. Scale bar: 50 microns. DETAILED DESCRIPTION

[0042] The present document provides methods and materials for increasing the level of a TFEB polypeptide. For example, the present document provides a therapeutic compound (e.g., a therapeutic organic compound) having the ability to increase the level of a TFEB polypeptide in a cell, a formulation comprising a therapeutic compound having the ability to increase the level of a TFEB polypeptide in a cell, a method of making a therapeutic compound having the ability to increase the level of a TFEB polypeptide in a cell, a method of making a formulation comprising a therapeutic compound having the ability to increase the level of a TFEB polypeptide in a cell, a method of increasing the level of a TFEB polypeptide in a cell, and a method for treating a mammal (e.g., a human) having a condition responsive to an increase in the level of a TFEB polypeptide in a cell nucleus. The present document also provides a therapeutic compound (e.g., an organic compound) having the ability to increase the level of a TFEB polypeptide in a cell nucleus, a formulation comprising a therapeutic compound having the ability to increase the level of a TFEB polypeptide in a cell nucleus, a method of making a therapeutic compound having the ability to increase the level of a TFEB polypeptide in a cell nucleus, a method of making a formulation comprising a therapeutic compound having the ability to increase the level of a TFEB polypeptide in a cell nucleus, a method of increasing the level of a TFEB polypeptide in a cell nucleus, and a method for treating a mammal (e.g., a human) having a condition responsive to an increase in the level of a TFEB polypeptide in a cell nucleus.

[0043] Therapeutic methods

[0044] Lysosomes are intracellular compartments responsible for the degradation of damaged proteins and organelles (e.g., mitochondria). Inside lysosomes, a very acidic pH is maintained and a variety of digestive enzymes exist that can efficiently degrade damaged or cellular no longer needed organelles and various biomolecules (e.g., proteins, lipids, and nucleic acids). Delivery of damaged contents to lysosomes can occur in a variety of ways, but one way that damaged delivered material reaches lysosomes is through the process of macroautophagy (herein "autophagy"). In this case, damaged biomolecules and organelles are wrapped in a double-membrane structure called an autophagosome, which then fuses with a lysosome. This process is responsible for homeostatic maintenance of cells and tissues. In the absence of autophagic flux and functional lysosomes, damaged biomolecules and organelles accumulate in cells. These damaged and dysfunctional components can exacerbate further cycles of damage. Failure of this system often leads to many pathological conditions. In rare genetic conditions known as lysosomal storage diseases (LSDs), children often inherit two copies of a defective lysosomal enzyme. LSDs are a collection of about 50 different genetic conditions that make patients' lysosomes unable to metabolize a particular molecule, the missing enzyme that normally degrades the particular molecule. This deficiency leads to accumulation of undegraded molecules within lysosomes and massive lysosomal distension. When lysosomes expand and fill with undegraded material, they eventually become dysfunctional, not only with respect to degradation of the particular molecule that is normally digested by the missing enzyme, but also with respect to their entire recycling capacity. Although there are now many replacement therapies available for the disease, where a child's "missing" enzyme is given back to the child to partially compensate for their genetic deficiency, there are currently no replacement therapies in many lysosomal storage diseases. Furthermore, even when replacement therapies exist, these protein-based therapies often only achieve a certain success because they often cannot treat conditions of the central nervous system (due to the blood-brain barrier) or cannot access certain cell types. In addition to LSDs, the process of autophagy and lysosomal degradation is also known to naturally slow with aging. The natural consequence is age-dependent accumulation of damaged contents in cells and tissues. This can be deleterious and can lead to a variety of age-related diseases. Enhancing autophagy and lysosomal function as described herein can be useful to reverse this damage. In other cases, it can be beneficial to stimulate autophagy and lysosomal function.This includes metabolic disorders (e.g., nonalcoholic steatohepatitis (NASH) or fatty liver), neurodegenerative disorders (e.g., Parkinson’s disease, ALS, Alzheimer’s disease, and Huntington’s disease), a range of other generally age-related other disorders (e.g., macular degeneration, muscle loss, and frailty), non- nervous system disorders of protein aggregation (e.g., alpha-1 antitrypsin, amyloidosis, and retinitis pigmentosa), or in disorders of impaired immunity (e.g., to help clear microbial pathogens, including intracellular pathogens (such as Mycobacterium tuberculosis) or disorders characterized by chronic bacterial colonization (such as cystic fibrosis)).

[0045] TFEB is a master regulator of lysosomal biogenesis. As described herein, increasing the level of a TFEB polypeptide within a cell and / or within a nucleus using a compound provided herein (e.g., a compound of Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) can result in one or more benefits to a cell and / or a mammal. For example, as described herein, increasing the level of a TFEB polypeptide within a cell and / or within a nucleus using a compound provided herein (e.g., a compound of Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) results in an increase in the number of lysosomes within a cell and / or an increase in lysosome function within a cell. In some cases, as described herein, increasing the level of a TFEB polypeptide within a cell and / or within a nucleus using a compound provided herein (e.g., a compound of Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) results in (a) an increase in the level of lysosomal exocytosis (a process by which lysosomal contents are expelled from a cell into the serum), (b) transcriptional enhancement of multiple factors that regulate autophagy, and / or (c) a coordinated increase in the ability of a cell to recycle and clear intracellular debris (e.g., enhanced autophagy, increased lysosome number, and increased lysosomal exocytosis). In some cases, as described herein, increasing the level of a TFEB polypeptide within a cell and / or within a nucleus using a compound provided herein (e.g., a compound of Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) can result in one or more of a reduction in symptoms of LSD, alpha-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 disorder (e.g., muscle loss).

[0046] In certain instances, the document provides methods of increasing the level of a TFEB polypeptide within a cell and / or within a nucleus by contacting the cell with one or more compounds provided herein (e.g., a compound of Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof). The increase in the level of the TFEB polypeptide can be compared to the level of the TFEB polypeptide prior to the contacting step. In some instances, the method of increasing the level of a TFEB polypeptide within a cell and / or within a nucleus can be performed in vivo. For example, one or more compounds provided herein (e.g., a compound of Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) can be administered to a mammal (e.g., a human) to increase the level of a TFEB polypeptide within a cell and / or within a nucleus in the mammal. In some instances, the method for increasing the level of a TFEB polypeptide within a cell and / or within a nucleus can be performed in vitro. For example, one or more compounds provided herein (e.g., a compound of 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 the level of a TFEB polypeptide within those cells and / or within those nuclei. In certain instances, such intervention can improve cell quality at the time of culture or subsequently. In certain instances, one or more compounds provided herein can be used during ex vivo expansion of genetically engineered T cells (e.g., CAR T cells) or tumor infiltrating T cells (e.g., TILs) to cause the treated T cells to exhibit improved in vivo persistence and / or efficacy. A range of other cell products that are ultimately infused into a mammal (e.g., a human) can be treated as described herein during their in vitro expansion.

[0047] In certain instances, the document provides a method of increasing lysosomal exocytosis in a cell by contacting the cell with one or more compounds provided herein (e.g., a compound of Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof). The increase in lysosomal exocytosis can be compared to the level of lysosomal exocytosis prior to the contacting step. In certain instances, the method of increasing lysosomal exocytosis in a cell can be performed in vivo. For example, one or more compounds provided herein (e.g., a compound of 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 cells of the mammal. In some instances involving LSD, one or more compounds provided herein can be administered to a mammal having LSD such that accumulated undegraded lysosomal material is released by exocytosis from the diseased cells, tissues, and / or organs. In certain instances, the method of increasing lysosomal exocytosis in a cell can be performed in vitro. For example, one or more compounds provided herein (e.g., a compound of 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 the cells.

[0048] In certain instances, the document provides a method of increasing autophagy in a cell by contacting the cell with one or more compounds provided herein (e.g., a compound of Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof). The increase in autophagy in the cell can be compared to the level of autophagy in the cell prior to the contacting step. In certain instances, the method of increasing autophagy in a cell can be performed in vivo. For example, one or more compounds provided herein (e.g., a compound of Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) can be administered to a mammal (e.g., a human) to increase autophagy in a cell of the mammal. In certain instances, the method of increasing autophagy in a cell can be performed in vitro. For example, one or more compounds provided herein (e.g., a compound of 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 autophagy in the cells.

[0049] In certain instances, the document provides methods of increasing nuclear localization of a TFEB polypeptide in a cell by contacting the cell with one or more compounds provided herein (e.g., a compound of Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof). The increase in nuclear localization of the TFEB polypeptide can be compared to the level of nuclear localization of the TFEB polypeptide prior to the contacting step. In certain instances, the method of increasing nuclear localization of a TFEB polypeptide in a cell can be performed in vivo. For example, one or more compounds provided herein (e.g., a compound of 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 a TFEB polypeptide in cells of the mammal. In certain instances, the method of increasing nuclear localization of a TFEB polypeptide in a cell can be performed in vitro. For example, one or more compounds provided herein (e.g., a compound of 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 a TFEB polypeptide in the cells.

[0050] The document also provides methods of treating a disease, disorder, and condition in a mammal by administering one or more compounds provided herein (e.g., a compound of Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) to a mammal in need thereof. In some instances, the disease, disorder, or condition treated can be a disease, disorder, or condition that responds to an increase in TFEB polypeptide levels in cells and / or in the nucleus of cells within the mammal. In some instances, the disease, disorder, or condition treated can be a disease, disorder, or condition associated with low TFEB polypeptide levels in cells and / or in 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 of Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) are as described herein, including but not limited to lysosomal storage disorders, acute or chronic inflammatory disorders, age-related functional decline, diseases associated with acute or chronic organ failure (e.g., kidney, lung, heart, or liver organ dysfunction), protein aggregation diseases, neurodegenerative diseases, and inherited or acquired muscle diseases. Examples of diseases, disorders, and conditions that can be treated with one or more compounds provided herein (e.g., a compound of Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) are as described herein, including but not limited to lysosomal storage disorders, acute or chronic inflammatory disorders, age-related functional decline, diseases associated with acute or chronic organ failure (e.g., kidney, lung, heart, or liver organ dysfunction), protein aggregation diseases, and neurodegenerative diseases.

[0051] Examples of lysosomal storage disorders that can be treated with one or more of the compounds provided herein (e.g., a compound of Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) are as described herein, including but not limited to, Krabbe disease, Sanfilippo syndrome, multiple sulfatase deficiency, alpha-mannosidosis, Fabry disease, Hunter syndrome, Scheie syndrome, Sanfilippo syndrome, Maroteaux-Lamy syndrome, hyaluronidase deficiency, sialidosis, mucolipidosis 1, neuronal ceroid lipofuscinosis (Batten disease), mucopolysaccharidoses types I, II, III, 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 types A, B, CI, and C2, Sandhoff disease, lysosomal acid lipase deficiency, GM2 gangliosidoses, Tay-Sachs disease, Gaucher disease, Salla disease, Pompe disease, Danon disease, Cholesterol ester storage disease, Aspartylglucosaminuria, Cystinosis, Lipoprotein disorders types I-IV, Schindler disease types I and II, Wolman disease, Fucosidosis, Pycnodysostosis, and Free sialic acid storage disease.

[0052] Examples of acute or chronic inflammatory diseases that can be treated with one or more compounds provided herein (e.g., a compound of Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) as described herein include, but are not limited to, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, lung inflammation (e.g., hypersensitivity pneumonitis or radiation pneumonitis), pulmonary inflammation, cystic fibrosis, psoriasis, arthritis / rheumatoid arthritis, rhinitis, pharyngitis, cystitis, prostatitis, dermatitis, allergies including hay fever, nephritis, conjunctivitis, encephalitis, meningitis, ophthalmia, uveitis, pleuritis, pericarditis, myocarditis, atherosclerosis, human immunodeficiency virus-associated inflammation, diabetes, osteoarthritis, psoriatic arthritis, inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis), colitis, sepsis, vasculitis, bursitis, connective tissue disease, autoimmune disease (e.g., systemic lupus erythematosus (SLE)), polymyalgia rheumatica, scleroderma, Wegener’s granulomatosis, temporal arteritis, vasculitis, cryoglobulinemia, multiple sclerosis, inflammation caused by viruses or influenza, chronic bacterial colonization or persistent intracellular pathogens, and impaired reactivity to antigen challenge or vaccination.

[0053] Examples of conditions associated with age-related functional decline that can be treated using one or more compounds provided herein (e.g., a compound of Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) as described herein include, but are not limited to, neurodegenerative diseases (e.g., Alzheimer’s disease, 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 genetic or acquired retinal degenerative diseases, age-related hearing loss, early cognitive decline, osteoporosis, age-related immune dysfunction (e.g., impaired reactivity to vaccination or immunosenescence), and other non-neurological disorders of protein aggregation (e.g., amyloidosis or alpha-1 antitrypsin deficiency).

[0054] Examples of genetic or acquired muscle diseases that can be treated with one or more compounds provided herein (e.g., a compound of Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) include, but are not limited to, myofibrillar myopathy, sporadic inclusion body myositis, inclusion body myopathy in frontotemporal dementia (IBMFTD), and cardiomyopathy (e.g., dilated cardiomyopathy or protein toxic cardiomyopathy such as late protein toxic cardiomyopathy).

[0055] In some cases, one or more of the compounds provided herein (e.g., a compound of Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) can be used as the only active ingredient (e.g., for increasing the level of a TFEB polypeptide in the nucleus of a cell and / or treating a disease, disorder, or condition described herein) as described herein. For example, a composition comprising a compound of Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof, can lack any other active ingredient that increases the level of a TFEB polypeptide in the nucleus of a cell. In certain cases, a composition comprising a compound of Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof, can lack any other active ingredient that is effective for treating a disease, disorder, or condition described herein.

[0056] Therapeutic compounds

[0057] As described herein, any one or more of the compounds provided herein can be used to increase the level of a TFEB polypeptide in a cell and / or in the nucleus of a cell, to increase lysosomal exocytosis in a cell, to increase autophagy in a cell, to increase the nuclear localization of a TFEB polypeptide in a cell, and / or to treat a disease, disorder, and condition described herein in a mammal.

[0058] In some embodiments, the file provides a compound of Formula (I):

[0059]

[0060] or a pharmaceutically acceptable salt thereof, wherein:

[0061] each L is independently selected from O, S, S(=0)2, C 1-3 alkylene, C(=0) and N(R N ), wherein the C 1-3 alkylene is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO2, OH, C 1-3 alkoxy, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino;

[0062] each R N is independently selected from H and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO2, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NRc1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 S(O)2R b1 , S(O)2R b1 and S(O)2NR c1 R d1 ;

[0063] n is an integer selected from 1, 2 and 3;

[0064] X 1 is selected from N, N + –O - and CR 1 ;

[0065] X 2 is selected from N, N + –O - and CR 2 ;

[0066] X 3 is selected from N, N + –O - and CR 3 ;

[0067] X 4 is selected from N, N + –O - and CR 4 ;

[0068] X 5 is selected from N, N + –O - and CR 5 ;

[0069] X 6 is selected from N, N + –O - and CR 6 ;

[0070] provided that no more than four of X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are N;

[0071] each R 1 , R 2 , R 3 , R 4 , R 5 and R6 each independently selected from H, halogen, CN, NO2, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 S(O)2R b1 , S(O)2R b1 and S(O)2NR c1 R d1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from CN, NO2, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 S(O)2R b1 , S(O)2R b1 and S(O)2NR c1 R d1 ;

[0072] R A is selected from Cy A1 , O-Cy A1 and N(R N )-Cy A1 ;

[0073] Cy A1 is selected from C 6-10 aryl, C 3-10 cycloalkyl, 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 ;

[0074] R B selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl and Cy 1 , wherein the C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 , CN, NO2, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 S(O)2R b1 , S(O)2R b1 and S(O)2NR c1 R d1 ;

[0075] or, when R B is attached to L, L is N(R N ), R B and R N together with the N atom to which they are attached form a 4-14 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 , halo, CN, NO2, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 S(O)2R b1 , S(O)2R b1and S(O)2NR c1 R d1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 , CN, NO2, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 S(O)2R b1 , S(O)2R b1 , and S(O)2NR c1 R d1 ;

[0076] each Cy 1 is independently selected from C 6-10 aryl, C 3-14 cycloalkyl, 5-10 membered heteroaryl, and 4-14 membered heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Cy2 ;

[0077] R Cy1 and R Cy2 are each independently selected from oxo, halogen, CN, NO2, Cy 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 S(O)2R b2 , S(O)2R b2 , and S(O)2NR c2 Rd2 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy 2 , halo, CN, NO2, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 S(O)2R b2 , S(O)2R b2 , and S(O)2NR c2 R d2 ;

[0078] each Cy 2 is selected from C 6-10 aryl, C 3-10 cycloalkyl, 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 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 S(O)2R b2 , S(O)2R b2 , and S(O)2NR c2 R d2 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl 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 c2 R d2 , C(O)OR a2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 S(O)2R b2 , S(O)2R b2 and S(O)2NR c2 R d2 ;

[0079] each R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 and R d2 is each independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkylene, C 3-10 cycloalkyl-C 1-4 alkylene, (5-10 membered heteroaryl)-C 1-4 alkylene and (4-10 membered heterocycloalkyl)-C 1-4 alkylene, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkylene, C 3-10 cycloalkyl-C 1-4 alkylene, (5-10 membered heteroaryl)-C 1-4 alkylene and (4-10 membered heterocycloalkyl)-C 1-4 alkylene is each optionally substituted with 1, 2, 3, 4, or 5 substituents selected independently from R g ;

[0080] or any R c1 and Rd1 with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group, which is optionally substituted with 1, 2, or 3 substituents independently selected from R g with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group, which is optionally substituted with 1, 2, or 3 substituents independently selected from R

[0081] or any R c2 and R d2 with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group, which is optionally substituted with 1, 2, or 3 substituents independently selected from R g with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group, which is optionally substituted with 1, 2, or 3 substituents independently selected from R

[0082] each R g is independently selected from OH, NO2, CN, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano-C 1-3 alkylene, HO-C 1-3 alkylene, C 6-10 aryl, C 6-10 aryloxy, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkylene, C 3-10 cycloalkyl-C 1-4 alkylene, (5-10 membered heteroaryl)-C 1-4 alkylene, (4-10 membered heterocycloalkyl)-C 1-4 alkylene, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamoyl, C 1-6 alkylcarbamoyl, di(C 1-6 alkyl)carbamoyl, carboxyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)sulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino and di(C1-6 Alkyl)aminocarbonylamino.

[0083] In some embodiments:

[0084] R B and R N Together with the N atom to which they are attached, they form 4-7 membered heterocyclic alkyl groups, which are optionally substituted with 1, 2, or 3 substituents, the substituents being independently selected from Cy. 1 Halogens, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, OR a1 C(O)R b1 C(O)NR c1 R d1 C(O)OR a1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 S(O)2R b1 S(O)2R b1 and S(O)2NR c1 R d1 ; wherein C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Each alkynyl group is optionally substituted by one, two, or three substituents, which are independently selected from Cy 1 CN, NO2, OR a1 C(O)R b1 C(O)NR c1 R d1 C(O)OR a1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 S(O)2R b1 S(O)2R b1 and S(O)2NR c1 R d1 ;and

[0085] Each Cy 1 Selected independently from C 6-10 Aryl, 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

[0086] In some embodiments:

[0087] R A is selected from C 6-10 aryl, C 3-10 cycloalkyl, 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

[0088] R Cy1 and R Cy2 are each independently selected from halogen, CN, NO2, Cy 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 S(O)2R b2 , S(O)2R b2 , and S(O)2NR c2 R d2 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy 2 , halogen, CN, NO2, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 S(O)2R​b2 S(O)2R b2 and S(O)2NR c2 R d2 .

[0089] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0090] In some embodiments, L is independently selected from C 1-3 alkylene, C(=O), and N(R N ), wherein the C 1-3 alkylene is optionally substituted with OH.

[0091] In some embodiments, L is C 1-3 alkylene, which is optionally substituted with halogen, CN, NO2, OH, C 1-3 alkoxy, or amino.

[0092] In some embodiments, L is C 1-3 alkylene, which is optionally substituted with OH.

[0093] In some embodiments, L is C(=O).

[0094] In some embodiments, L is N(R N ).

[0095] In some embodiments, R N is selected from H and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from halogen, CN, NO2, and C 1-3 alkoxy.

[0096] In some embodiments, R N is selected from H and C 1-6 alkyl. In some embodiments, R N is H. In some embodiments, R N is C 1-6 alkyl, which is optionally substituted with halogen, CN, NO2, or C 1-3 alkoxy.

[0097] In some embodiments, L is NH.

[0098] In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from H, halogen, CN, C 1-6alkyl, C 1-6 haloalkyl, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 S(O)2R b1 , S(O)2R b1 , and S(O)2NR c1 R d1 .

[0099] In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from H, halogen, CN, C 1-6 alkyl, OR a1 , NR c1 R d1 , and S(O)2R b1 .

[0100] In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 S(O)2R b1 , S(O)2R b1 , and S(O)2NR c1 R d1 .

[0101] In some embodiments, R 1 , R 2 , R 3 , R 4 , R5 and R 6 each independently is selected from H, halogen, C 1-6 alkyl and C 1-6 alkoxy.

[0102] In some embodiments, the compound of Formula (I) has the formula:

[0103]

[0104] or a pharmaceutically acceptable salt thereof.

[0105] In some embodiments, R 3 , R 4 , R 5 and R 6 each independently is selected from H, halogen, C 1-6 alkyl and C 1-6 alkoxy. In some embodiments, R 3 , R 4 , R 5 and R 6 each is H.

[0106] In some embodiments, the compound of Formula (I) has the formula:

[0107]

[0108] or a pharmaceutically acceptable salt thereof.

[0109] In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 each independently is selected from H, halogen, C 1-6 alkyl and C 1-6 alkoxy. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 each is H.

[0110] In some embodiments, the compound of Formula (I) has the formula:

[0111]

[0112] or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, R 1 , R 3 , R 4R 5 R 6 each independently is selected from H, halogen, C 1-6 alkyl, and C 1-6 alkoxy. In some embodiments, R 1 , R 3 , R 4 , R 5 , and R 6 each is H.

[0114] In some embodiments, the compound of Formula (I) has the formula:

[0115]

[0116] or a pharmaceutically acceptable salt thereof.

[0117] In some embodiments, R 2 , R 3 , R 4 , R 5 , and R 6 each independently is selected from H, halogen, C 1-6 alkyl, and C 1-6 alkoxy. In some embodiments, R 2 , R 3 , R 4 , R 5 , and R 6 each is H.

[0118] In some embodiments, the compound of Formula (I) has the formula:

[0119]

[0120] or a pharmaceutically acceptable salt thereof.

[0121] In some embodiments, R 3 , R 4 , and R 5 each independently is selected from H, halogen, C 1-6 alkyl, and C 1-6 alkoxy. In some embodiments, R 3 , R 4 , and R 5 each is H.

[0122] In some embodiments, the compound of Formula (I) has the formula:

[0123]

[0124] or a pharmaceutically acceptable salt thereof.

[0125] In some embodiments, R 4, R 5 , R 6 each is independently selected from H, halogen, C 1-6 alkyl, and C 1-6 alkoxy. In some embodiments, R 4 , R 5 , and R 6 each is H.

[0126] In some embodiments, the compound of Formula (I) has Formula:

[0127]

[0128] or a pharmaceutically acceptable salt thereof.

[0129] In some embodiments, R 3 , R 5 , and R 6 each is independently selected from H, halogen, C 1-6 alkyl, and C 1-6 alkoxy. In some embodiments, R 3 , R 5 , and R 6 each is H.

[0130] In some embodiments of the compound of Formula (IIg), the compound of Formula (IIg) is not:

[0131]

[0132] In some embodiments, in the compound of Formula (IIg), R B is 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 .

[0133] In some embodiments, in the compound of Formula (IIg), R B is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R Cy2 . In some embodiments of Formula (IIg), R B is not C 6-10 aryl substituted with one halogen.

[0134] In some embodiments, the compound of Formula (I) has Formula (IIh):

[0135]

[0136] or a pharmaceutically acceptable salt thereof.

[0137] In some embodiments, in the compound of Formula (IIh), RB is 5-10 membered heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R Cy2

[0138] In some embodiments, the compound of Formula (IIh) has the formula:

[0139]

[0140] or a pharmaceutically acceptable salt thereof.

[0141] In some embodiments of Formula (IIh), R 1 , R 3 , R 4 , and R 5 are each independently selected from H, halogen, CN, C 1-6 alkyl, OR a1 , NR c1 R d1 , and S(O)2R b1 .

[0142] In some embodiments of Formula (IIh), R 3 is selected from H, halogen, CN, OR a1 , NR c1 R d1 , and S(O)2R b1 . In some embodiments of Formula (IIh), R 1 is selected from H, halogen, and C 1-6 alkyl.

[0143] In some embodiments, the compound of Formula (I) has the formula (IIi):

[0144]

[0145] or a pharmaceutically acceptable salt thereof.

[0146] In some embodiments, in the compound of Formula (IIi), R B is 5-10 membered heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R Cy2 . In some embodiments, in the compound of Formula (IIi), R A is 5-10 membered heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R Cy1 . In some embodiments, in the compound of Formula (IIi), R 1 , R 3 , R 4 , and R 6 are each H.

[0147] ​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.

[0148] In some embodiments, R A is selected from C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Cy1 .

[0149] In some embodiments, R A is selected from C 6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted with 1, 2, or 3 substituents independently selected from R Cy1 .

[0150] In some embodiments, R A is Cy A1 .

[0151] In some embodiments, R A is O-Cy A1 .

[0152] In some embodiments, R A is NH-Cy A1 .

[0153] In some embodiments, Cy A1 is selected from C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Cy1 .

[0154] In some embodiments, Cy A1 is selected from C 6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Cy1 .

[0155] In some embodiments, Cy A1 is 5-10 membered heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R Cy1 .

[0156] In some embodiments, CyA1 is C 6-10 aryl optionally substituted with 1, 2, or 3 substituents independently selected from R Cy1 In some embodiments, C 6-10 aryl is of the formula:

[0157]

[0158] In some embodiments, Cy A1 is 5-10 membered heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R Cy1 .

[0159] In some embodiments, the 5-10 membered heteroaryl is of the formula selected from the group consisting of:

[0160]

[0161] In some embodiments, the 5-10 membered heteroaryl is of the formula selected from the group consisting of:

[0162]

[0163]

[0164] In some embodiments, Cy A1 is 4-10 membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from R Cy1 .

[0165] In some embodiments, the 4-10 membered heterocycloalkyl is of the formula selected from the group consisting of:

[0166]

[0167] In some embodiments, the 4-10 membered heterocycloalkyl is of the formula selected from the group consisting of:

[0168]

[0169] In some embodiments, each R Cy1 is independently selected from the group consisting of halogen, CN, NO2, Cy 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 Rd2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 S(O)2R b2 , S(O)2R b2 and S(O)2NR c2 R d2 ; wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy 2 , halo, CN, NO2, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 S(O)2R b2 , S(O)2R b2 and S(O)2NR c2 R d2 .

[0170] In some embodiments, each R Cy1 is independently selected from halo, NO2, C 1-6 alkyl, C 1-6 haloalkyl, OR a2 , C(O)OR a2 , C(O)R b2 , C(O)NR c2 R d2 , NR c2 R d2 , and S(O)2R b2 , wherein the C 1-6 alkyl is optionally substituted with OR a2 .

[0171] In some embodiments, each R Cy1 is independently selected from halo, NO2, C 1-6 alkyl, OR a2 , and C(O)OR a2 .

[0172] In some embodiments, each R Cy1independently selected from halogen, NO2, C 1-6 alkyl, OH, C 1-6 alkoxy and C(O)(C 1-6 alkoxy).

[0173] In some embodiments, each R Cy1 is independently selected from halogen, NO2, C 1-6 alkyl, C 1-6 alkoxy and C(O)(C 1-6 alkoxy).

[0174] In some embodiments, R Cy1 is selected from Cl and F. In some embodiments, R Cy1 is NO2. In some embodiments, R Cy1 is C 1-6 alkyl or C 1-6 alkoxy.

[0175] In some embodiments, R B is selected from C 1-6 alkyl and Cy 1 , wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 , CN, OR a1 , S(O)2R b1 , and S(O)2NR c1 R d1 .

[0176] In some embodiments, R B is C 1-6 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 , CN, OR a1 , S(O)2R b1 , and S(O)2NR c1 R d1 .

[0177] In some embodiments, R B is C 1-6 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 , CN, OH, S(O)2CH3, and S(O)2NH2.

[0178] In some embodiments, R B is Cy 1 .

[0179] In some embodiments, Cy 1 is C 6-10aryl, which is optionally substituted with 1, 2, or 3 substituents independently selected from R Cy2 In some embodiments, C 6-10 aryl has the formula:

[0180]

[0181] In some embodiments, Cy 1 is C 3-14 cycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from R Cy2

[0182] In some embodiments, Cy 1 is C 3-14 cycloalkyl having the formula:

[0183]

[0184] and

[0185] In some embodiments, Cy 1 is C 3-10 cycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from R Cy2 In some embodiments, C 3-10 cycloalkyl has a formula selected from:

[0186]

[0187] In some embodiments, Cy 1 is a 4-14 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from R Cy2

[0188] In some embodiments, Cy 1 is a 4-14 membered heterocycloalkyl having a formula selected from:

[0189]

[0190] In some embodiments, Cy 1 is a 4-10 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from R Cy2 In some embodiments, the 4-10 membered heterocycloalkyl has a formula selected from:

[0191]

[0192] In some embodiments, Cy 1 is a 5-10 membered heteroaryl, which is optionally substituted with 1, 2, or 3 substituents independently selected from R​​Cy2 Substituents are substituted.

[0193] In some embodiments, the 5-10 member heteroaryl group has a formula selected from the following:

[0194]

[0195]

[0196] In some embodiments, the 5-10 member heteroaryl group has a formula selected from the following:

[0197]

[0198] In some embodiments, each R Cy2 Independently selected from halogens, CN, NO2, Cy 2 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, OR a2 C(O)R b2 C(O)NR c2 R d2 C(O)OR a2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 S(O)2R b2 S(O)2R b2 and S(O)2NR c2 R d2 ; wherein, the C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Each alkynyl group is optionally substituted by one, two, or three substituents, which are independently selected from Cy 2 Halogen, CN, NO2, OR a2 C(O)R b2 C(O)NR c2 R d2 C(O)OR a2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 S(O)2R b2, S(O)2R b2 , and S(O)2NR c2 R d2 .

[0199] In some embodiments, each R Cy2 is independently selected from halogen, Cy 2 , C 1-6 1-6 alkyl, C 1-6 1-6 haloalkyl, OR a2 , C(O)R c2 , C(O)NR d2 R c2 , NR d2 R c2 , NR b2 C(O)R b2 , and S(O)2R Cy2 .

[0200] In some embodiments, each R 3-10 is independently selected from halogen, CN, C 1-6 3-6 cycloalkyl, C 1-6 1-6 alkyl, C a2 1-6 haloalkyl, OR b2 , C(O)R c2 , C(O)NR d2 R c2 , and NR d2 R Cy2 .

[0201] In some embodiments, each R 3-10 is independently selected from halogen, CN, C 1-6 3-6 cycloalkyl, C 1-6 1-6 alkyl, C 1-6 1-6 haloalkyl, C 1-6 1-6 alkoxy, C(O)(C Cy2 1-6 alkyl), C(O)NH2, and NH2.

[0202] In some embodiments, R Cy2 is halogen.

[0203] In some embodiments, R 1-6 is C 1-6 1-6 alkyl, C 1-6 1-6 haloalkyl, or C Cy2 1-6 alkoxy.

[0204] In some embodiments, R a1 is NH2.

[0205] In some embodiments, each R b1 , R c1 , R d1 , R a2R b2 R c2 and R d2 are independently selected from H and C 1-6 alkyl.

[0206] In some embodiments, R B is C 6-10 aryl optionally substituted with 1, 2, or 3 substituents independently selected from R Cy2 ; R A is C 6-10 aryl optionally substituted with 1, 2, or 3 substituents independently selected from R Cy1 .

[0207] In some embodiments, R B is 5-10 membered heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R Cy2 ; R A is C 6-10 aryl optionally substituted with 1, 2, or 3 substituents independently selected from R Cy1 .

[0208] In some embodiments, R B is 5-10 membered heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R Cy2 ; R A is 5-10 membered heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R Cy1 .

[0209] In some embodiments, R B is C 6-10 aryl optionally substituted with 1, 2, or 3 substituents independently selected from R Cy2 ; R A is 5-10 membered heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R Cy1 .

[0210] In some embodiments:

[0211] n is 1;

[0212] L is selected from C 1-3 alkylene, C(=O) and N(R N ), wherein said C 1-3 alkylene is optionally substituted with OH;

[0213] R N is selected from H and C 1-6 alkyl;

[0214] R 1 , R2 R 3 R 4 R 5 and R 6 are each independently selected from H, halogen, CN, C 1-6 alkyl, OR a1 , NR c1 R d1 and S(O)2R b1 ;

[0215] R A is selected from Cy A1 , O-Cy A1 and NH-Cy A1 ;

[0216] each Cy A1 is selected from C 6-10 aryl, 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 ;

[0217] R B is selected from C 1-6 alkyl and Cy 1 , wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 , CN, OR a1 , S(O)2R b1 and S(O)2NR c1 R d1 ;

[0218] or, when R B is attached to N(R N ), R B and R N together with the N atom to which they are attached form a 4-14 membered heterocycloalkyl group, which is optionally substituted with Cy 1 , C 1-6 alkyl, OR a1 and halogen;

[0219] each R Cy1 is independently selected from halogen, NO2, C 1-6 alkyl, C 1-6 haloalkyl, OR a2 , C(O)OR a2 , C(O)R b2 , C(O)NR c2 R d2 , NR c2 R d2 and S(O)2R b2wherein the C 1-6 alkyl is optionally substituted with OR a2 ;

[0220] each Cy 1 is independently selected from C 6-10 aryl, C 3-14 cycloalkyl, 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 ;

[0221] each R Cy2 is independently selected from halogen, Cy 2 , C 1-6 alkyl, C 1-6 haloalkyl, OR a2 , C(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , and S(O)2R b2 ; and

[0222] each R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , and R d2 is each independently selected from H and C 1-6 alkyl.

[0223] In some embodiments:

[0224] n is 1;

[0225] L is selected from C 1-3 alkylene, C(=O), and N(R N ), wherein the C 1-3 alkylene is optionally substituted with OH;

[0226] R N is selected from H and C 1-6 alkyl;

[0227] R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from H, halogen, CN, C 1-6 alkyl, OR a1 , NRc1 R d1 and S(O)2R b1 ;

[0228] R A is selected from Cy A1 , O-Cy A1 , and NH-Cy A1 ;

[0229] each Cy A1 is selected from C 6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted with 1, 2, or 3 substituents independently selected from R Cy1 ;

[0230] R B is selected from C 1-6 alkyl and Cy 1 , wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 , CN, OR a1 , S(O)2R b1 , and S(O)2NR c1 R d1 ;

[0231] or, when R B is attached to N(R N ), R B and R N , together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group, optionally substituted with OR a1 ;

[0232] each R Cy1 is independently selected from halogen, NO2, C 1-6 alkyl, C 1-6 haloalkyl, OR a2 , C(O)OR a2 , C(O)R b2 , C(O)NR c2 R d2 , NR c2 R d2 , and S(O)2R b2 , wherein said C 1-6 alkyl is optionally substituted with OR a2 ;

[0233] each R Cy2 is independently selected from halogen, CN, C 3-10 cycloalkyl, C 1-6 alkyl, C 1-6 haloalkyl, ORa2 C(O)R b2 C(O)NR c2 R d2 and NR c2 R d ; and

[0234] each R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 and R d2 is each independently selected from H and C 1-6 alkyl.

[0235] In some embodiments:

[0236] n is 1 ;

[0237] L is selected from C 1-3 alkylene, C(=O) and N(R N ), wherein the C 1-3 alkylene is optionally substituted with OH;

[0238] R N is selected from H and C 1-6 alkyl;

[0239] R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from H, halogen, C 1-6 alkyl and OR a1 ;

[0240] R A is selected from C 6-10 aryl, 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 ;

[0241] R B is selected from C 1-6 alkyl and Cy 1 , wherein the C 1-6 alkyl is optionally substituted with 1, 2 or 3 substituents independently selected from Cy 1 , CN, OR a1 , S(O)2R b1 and S(O)2NR c1 R d1 ;

[0242] or, when R B is attached to N(R N ), R B and R N together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group, which is optionally substituted with OR a1 ;

[0243] each R Cy1 is independently selected from halo, NO2, C 1-6 alkyl, OR a2 , and C(O)OR a2 ;

[0244] each R Cy2 is independently selected from halo, CN, C 3-10 cycloalkyl, C 1-6 alkyl, C 1-6 haloalkyl, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , and NR c2 R d ; and

[0245] each R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , and R d2 is each independently H and C 1-6 alkyl.

[0246] In some embodiments, the compound of Formula (I) is selected from any one of Table 1, Table la, Table 2, Table 3, Table 5, Table 5a, and Table 6, or a pharmaceutically acceptable salt thereof.

[0247] In some embodiments, the compound of Formula (I) is selected from any one of Table 1, Table la, Table 2, Table 3, Table 5, and Table 6, or a pharmaceutically acceptable salt thereof.

[0248] In some embodiments, the compound of Formula (I) is selected from any one of Table 1, Table 2, or Table 3, or a pharmaceutically acceptable salt thereof.

[0249] 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 la, 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.

[0250] In some embodiments, the compound of Formula (I) is selected from any one of Formulae (lie)-(IIi).

[0251] In some embodiments, the compound of Formula (I) is selected from any one of the following compounds:

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262] or a pharmaceutically acceptable salt thereof.

[0263] In some embodiments, the compound of Formula (I) is selected from any one of the following compounds:

[0264]

[0265]

[0266] or a pharmaceutically acceptable salt thereof.

[0267] In some embodiments, the compound of any one of Formulae (IIc)-(IIi) is selected from any one of the following compounds:

[0268]

[0269]

[0270]

[0271]

[0272] or a pharmaceutically acceptable salt thereof.

[0273] In some embodiments, the compound of any one of Formulae (IIc)-(IIi) is selected from any one of the following compounds:

[0274]

[0275]

[0276]

[0277]

[0278] or a pharmaceutically acceptable salt thereof.

[0279] 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.

[0280] 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.

[0281] 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.

[0282] 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.

[0283] In some embodiments, the compound of Formula (I) has Formula (IIa):

[0284]

[0285] or a pharmaceutically acceptable salt thereof, wherein:

[0286] Y is selected from C(=0) and C(R7 ) (R 8 );

[0287] R 7 and R 8 are each independently selected from the group consisting of H, halogen, CN, NO2, OH, C 1-3 alkoxy, amino, C 1-3 alkylamino and di(C 1-3 alkyl)amino;

[0288] X 1 is selected from the group consisting of N, N + -O - and CR 1 ;

[0289] X 2 is selected from the group consisting of N, N + -O - and CR 2 ;

[0290] X 3 is selected from the group consisting of N, N + -O - and CR 3 ;

[0291] X 4 is selected from the group consisting of N, N + -O - and CR 4 ;

[0292] X 5 is selected from the group consisting of N, N + -O - and CR 5 ;

[0293] X 6 is selected from the group consisting of N, N + -O - and CR 6 ;

[0294] with the proviso that not more than four of X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are N;

[0295] R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from the group consisting of H, halogen, CN, NO2, C 1-6 alkyl, C 1-6haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 S(O)2R b1 , S(O)2R b1 and S(O)2NR c1 R d1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of CN, NO2, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 S(O)2R b1 , S(O)2R b1 and S(O)2NR c1 R d1 ;

[0296] R A is selected from C 6-10 aryl, C 3-10 cycloalkyl, 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 ;

[0297] R B is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl and Cy 1 , wherein said C 1-6 alkyl, C 2-6 alkenyl and C2-6 each alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 , CN, NO2, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 S(O)2R b1 , S(O)2R b1 , and S(O)2NR c1 R d1 ;

[0298] each Cy 1 is independently selected from C 6-10 e, 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 3-10 ;

[0299] each R Cy1 and R Cy2 is independently selected from halo, CN, NO2, Cy 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 S(O)2R b2 , S(O)2R b2 , and S(O)2NR c2 R d2 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy 2 ;each alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 2 , halo, CN, NO2, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 S(O)2R b2 , S(O)2R b2 , and S(O)2NR c2 R d2 ;

[0300] each Cy 2 is independently selected from C 6-10 aryl, C 3-10 cycloalkyl, 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 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 S(O)2R b2 , S(O)2R b2 , and S(O)2NR c2 R d2 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO2, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)ORa2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 S(O)2R b2 S(O)2R b2 and S(O)2NR c2 R d2 ;

[0301] each R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 and R d2 is each independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkylene, C 3-10 cycloalkyl-C 1-4 alkylene, (5-10 membered heteroaryl)-C 1-4 alkylene and (4-10 membered heterocycloalkyl)-C 1-4 alkylene, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkylene, C 3-10 cycloalkyl-C 1-4 alkylene, (5-10 membered heteroaryl)-C 1-4 alkylene and (4-10 membered heterocycloalkyl)-C 1-4 alkylene is each optionally substituted with 1, 2, 3, 4, or 5 substituents selected independently from R g ;

[0302] or any R c1 and R d1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents selected independently from Rg The substituents are replaced;

[0303] Or any R c2 and R d2 Together with the N atoms to which they are attached, they form 4-7 membered heterocyclic alkyl groups, which are optionally composed of 1, 2, or 3 independently selected from R. g The substituents are replaced by; and

[0304] Each R g Independently selected from OH, NO2, CN, halogens, and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-4 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, cyano-C 1-3 Alkylene, HO-C 1-3 Alkylene, C 6-10 Aryl, C 6-10 aryloxy group, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkylene, C 3-10 cycloalkyl-C 1-4 Alkylene, (5-10-membered heteroaryl)-C 1-4 Alkylene, (4-10 membered heterocyclic alkyl)-C 1-4 Alkylene, amino, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, thio, C 1-6 Alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamoyl, C 1-6 Alkyl carbamoyl, di(C 1-6 Alkyl) carbamoyl, carboxyl, C 1-6 alkyl carbonyl, C 1-6 alkoxycarbonyl, C 1-6 Alkyl carbonyl amino, C 1-6 Alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 Alkylaminosulfonylamino, di(C 1-6 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 Alkylaminocarbonylamino and di(C) 1-6 Alkyl)aminocarbonylamino.

[0305] In some embodiments, the compound of Formula (IIa) has the formula:

[0306]

[0307] or a pharmaceutically acceptable salt thereof.

[0308] In some embodiments, R 7 is H, and R 8 is selected from H, halo, CN, NO2, OH, and C 1-3 alkoxy. In some embodiments, R 7 is H and R 8 is selected from H and OH.

[0309] In some embodiments, Y is CH2.

[0310] In some embodiments, Y is CH(OH).

[0311] In some embodiments, Y is C(=O).

[0312] In some embodiments, the compound of Formula (IIa) has the formula:

[0313]

[0314] or a pharmaceutically acceptable salt thereof.

[0315] In some embodiments of Formula (IIa), R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from H, halo, C 1-6 alkyl, and C 1-6 alkoxy. In some embodiments, R 3 , R 4 , R 5 , and R 6 are each independently selected from H, halo, C 1-6 alkyl, and C 1-6 alkoxy. In some embodiments, R 3 , R 4 , R 5 , and R 6 are each H.

[0316] In some embodiments of Formula (IIa), R B is selected from C 6-10 ary!, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 R Cy2substituted with 1, 2, or 3 substituents independently selected from R

[0317] In some embodiments of formula (IIa), R B is C 6-10 aryl optionally substituted with halo.

[0318] In some embodiments of formula (IIa), R A is selected from C 6-10 aryl, 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 substituents.

[0319] In some embodiments of formula (IIa), R A is 5-10 membered heteroaryl optionally substituted with halo, NO2, C 1-6 alkyl, or C 1-6 alkoxy.

[0320] In some embodiments of formula (IIa):

[0321] R 7 is H; R 8 is selected from H and OH;

[0322] R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from H, halo, C 1-6 alkyl, and C 1-6 alkoxy;

[0323] R B is C 6-10 aryl optionally substituted with halo; and

[0324] R A is 5-10 membered heteroaryl optionally substituted with halo, NO2, C 1-6 alkyl, or C 1-6 alkoxy.

[0325] In some embodiments, the compound of formula (IIa) is selected from any one of the following compounds:

[0326]

[0327]

[0328] or a pharmaceutically acceptable salt thereof.

[0329] In some embodiments, the compound of formula (I) is of formula (IIb):

[0330]

[0331] or pharmaceutically acceptable salts thereof, wherein:

[0332] each L is independently selected from O, S, S(=0)2, C 1-3 alkylene, C(=0) and N(R N ), wherein the C 1-3 alkylene is optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, NO2, OH, C 1-3 alkoxy, amino, C 1-3 alkylamino and di(C 1-3 alkyl)amino;

[0333] each R N is independently selected from H and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, NO2, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 S(O)2R b1 , S(O)2R b1 and S(O)2NR c1 R d1 ;

[0334] n is an integer selected from 1, 2 and 3;

[0335] X 1 is selected from N, N + -O - and CR 1 ;

[0336] X 2 is selected from N, N + -O - and CR 2 ;

[0337] X 3 is selected from N, N + -O - and CR 3 ;

[0338] X 4 selected from N, N + -O - and CR 4 ;

[0339] X 5 selected from N, N + -O - and CR 5 ;

[0340] X 6 selected from N, N + -O - and CR 6 ;

[0341] provided that no more than four of X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are N;

[0342] each R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is independently selected from H, halogen, CN, NO2, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 S(O)2R b1 , S(O)2R b1 and S(O)2NR c1 R d1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from CN, NO2, OR a1 , C(O)R b1 ;, C(O)OR c1 R d1 , C(O)OR a1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 S(O)2R b1 , S(O)2R b1 , and S(O)2NR c1 R d1 ;

[0343] R C is selected from:

[0344] (i) 4-10 membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from R Cy1 ; and

[0345] (ii) a group selected from O-Cy A1 , N(R N )-Cy A1 ; and Cy A1 ;

[0346] each Cy A1 is a 5-10 membered heteroaryl selected from the following:

[0347]

[0348] R B is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, and Cy 1 , wherein each of said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 , CN, NO2, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1S(O)2R b1 , S(O)2R b1 , and S(O)2NR c1 R d1 ;

[0349] or, when R B is attached to N(R N ), R B and R N together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 , halo, CN, NO2, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 S(O)2R b1 , S(O)2R b1 , and S(O)2NR c1 R d1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 , CN, NO2, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 S(O)2R b1 , S(O)2R b1 , and S(O)2NR c1 R d1 ;

[0350] each Cy 1 is independently selected from C 6-10 aryl, C 3-10 cycloalkyl, 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 ;

[0351] R Cy1 and R Cy2 are each independently selected from halogen, CN, NO2, Cy 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 S(O)2R b2 , S(O)2R b2 , and S(O)2NR c2 R d2 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy 2 , halogen, CN, NO2, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 S(O)2R b2 , S(O)2R b2 , and S(O)2NR c2 R d2 ;

[0352] each Cy 2 is independently selected from C6-10 aryl, C 3-10 cycloalkyl, 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 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 S(O)2R b2 , S(O)2R b2 , and S(O)2NR c2 R d2 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO2, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 S(O)2R b2 , S(O)2R b2 , and S(O)2NR c2 R d2 ;

[0353] each R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , and R d2 is each independently selected from H, C 1-6 alkyl, C 1-4haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkylene, C 3-10 cycloalkyl-C 1-4 alkylene, (5-10 membered heteroaryl)-C 1-4 alkylene and (4-10 membered heterocycloalkyl)-C 1-4 alkylene, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkylene, C 3-10 cycloalkyl-C 1-4 alkylene, (5-10 membered heteroaryl)-C 1-4 alkylene and (4-10 membered heterocycloalkyl)-C 1-4 each R g is independently selected from the group consisting of OH, NO2, CN, halogen, C

[0354] or any R c1 and R d1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from R g ;

[0355] or any R c2 and R d2 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group, optionally substituted with 1, 2, or 3 substituents independently selected from R g ; and

[0356] each R g is independently selected from the group consisting of OH, NO2, CN, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano-C 1-3 alkylene, HO-C 1-3 alkylene, C 6-10 aryl, C 6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkylene, C 3-10 cycloalkyl-C 1-4 alkylene, (5-10 membered heteroaryl)-C 1-4 alkylene, (4-10 membered heterocycloalkyl)-C 1-4 alkylene, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfmyl, C 1-6 alkylsulfonyl, carbamoyl, C 1-6 alkylcarbamoyl, di(C 1-6 alkyl)carbamoyl, carboxyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)sulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino and di(C 1-6 alkyl)aminocarbonylamino.

[0357] In some embodiments, R C is selected from 4-10 membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from R Cy1 ; and 5-10 membered heteroaryl of the formula:

[0358]

[0359] In some embodiments of the compound of formula (IIb), R C is 4-10 membered heterocycloalkyl having a formula selected from:

[0360]

[0361] In some embodiments of the compound of formula (IIb), R C is 4-10 membered heterocycloalkyl having a formula selected from:

[0362]

[0363] In some embodiments of the compound of formula (IIb):

[0364] n is 1 ;

[0365] L is selected from C 1-3 alkylene, C(=0) and N(R N ), wherein the C 1-3 alkylene is optionally substituted with OH;

[0366] R N is selected from H and C 1-6 alkyl;

[0367] R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from H, halogen, CN, C 1-6 alkyl, OR a1 , NR c1 R d1 and S(0)2R b1 ;

[0368] R C is selected from:

[0369] (i) 4-10 membered heterocycloalkyl selected from:

[0370]

[0371] (ii) a group selected from O-Cy A1 , N(R N )-Cy A1 ; and Cy A1 , wherein each Cy A1 is a 5-10 membered heteroaryl selected from the following:

[0372] and

[0373] R B is selected from C 1-6 alkyl and Cy 1 , wherein the C 1-6 alkyl is optionally substituted with 1, 2 or 3 substituents independently selected from Cy 1 , CN, OR a1 , S(0)2R b1 and S(0)2NR c1 R d1 ;

[0374] or, when R B is attached to N(R N ), R B and R N together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group, which is optionally substituted with OR a1 ;

[0375] each R Cy1 is independently selected from halogen, NO2, C 1-6 alkyl, C 1-6 haloalkyl, OR a2 , C(O)OR a2 , C(O)R b2 , C(O)NR c2 R d2 , NR c2 R d2 , and S(O)2R b2 , wherein said C 1-6 alkyl is optionally substituted with OR a2 ;

[0376] each R Cy2 is independently selected from halogen, CN, C 3-10 cycloalkyl, C 1-6 alkyl, C 1-6 haloalkyl, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , and NR c2 R d ; and

[0377] each R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , and R d2 is each independently selected from H and C 1-6 alkyl.

[0378] In some embodiments of the compound of formula (IIb):

[0379] n is 1 ;

[0380] L is selected from C 1-3 alkylene, C(=O), and N(R N ), wherein said C 1-3 alkylene is optionally substituted with OH;

[0381] R N is H and C1-6 alkyl is selected;

[0382] R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from H, halo, C 1-6 alkyl and OR a1 ;

[0383] R C is selected from:

[0384]

[0385] R B is selected from C 1-6 alkyl and Cy 1 , wherein said C 1-6 alkyl is optionally substituted with 1, 2 or 3 substituents independently selected from Cy 1 , CN, OR a1 , S(O)2R b1 and S(O)2NR c1 R d1 ;

[0386] or, when R B is attached to L, L is N(R N ), R B and R N together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group, which is optionally substituted with OR a1 ;

[0387] each R Cy1 is independently selected from halo, NO2, C 1-6 alkyl, OR a2 and C(O)OR a2 ;

[0388] each R Cy2 is independently selected from halo, CN, C 3-10 cycloalkyl, C 1-6 alkyl, C 1-6 haloalkyl, OR a2 , C(O)R b2 , C(O)NR c2 R d2 and NR c2 R d ; and

[0389] each R a1 , R b1 , R c1R d1 R a2 R b2 R c2 and R d2 are each independently selected from H and C 1-6 alkyl.

[0390] In some embodiments, the compound of Formula (IIb) is selected from any one of the following compounds:

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402] or a pharmaceutically acceptable salt thereof.

[0403] In some embodiments, the compound of Formula (IIb) is selected from any one of the following compounds:

[0404]

[0405]

[0406] or a pharmaceutically acceptable salt thereof.

[0407] In some embodiments, the document provides a compound of Formula (III):

[0408]

[0409] or a pharmaceutically acceptable salt thereof, wherein:

[0410] R 1 is selected from C 1-6 alkyl, C 1-6haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl and Cy 1 wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 , CN, NO2, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 S(O)2R b1 , S(O)2R b1 and S(O)2NR c1 R d1 ;

[0411] R 2 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl and Cy 1 wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 , CN, NO2, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 S(O)2R b1 , S(O)2R b1 and S(O)2NR c1 R d1 ;

[0412] R 3 , R4 R 5 and R 6 are each independently selected from H, halogen, CN, NO2, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 S(O)2R b1 , S(O)2R b1 , and S(O)2NR c1 R d1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from CN, NO2, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 S(O)2R b1 , S(O)2R b1 , and S(O)2NR c1 R d1 ;

[0413] each Cy 1 is independently selected from C 6-10 aryl, C 3-10 cycloalkyl, 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 ;

[0414] each R Cy2 is independently selected from halogen, CN, NO2, C 1-6 alkyl, C1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, OR a2 C(O)R b2 C(O)NR c2 R d2 C(O)OR a2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 S(O)2R b2 S(O)2R b2 and S(O)2NR c2 R d2 ; wherein, the C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Each alkynyl group is optionally substituted by one, two, or three substituents, which are independently selected from halogens, CN, NO2, and OR. a2 and C(O)R b2 C(O)NR c2 R d2 ;

[0415] Each R a1 R b1 R c1 R d1 R a2 R b2 R c2 and R d2 Each is independently selected from H and C. 1-6 Alkyl, C 1-4 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkylene, C 3-10 cycloalkyl-C 1-4 Alkylene, (5-10-membered heteroaryl)-C 1-4 Alkylene and (4-10 membered heterocyclic alkyl)-C 1-4 Alkylene, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkylene, C 3-10 cycloalkyl-C 1-4 alkylene, (5-10 membered heteroaryl)-C 1-4 alkylene and (4-10 membered heterocycloalkyl)-C 1-4 each of the alkylene groups is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R g ;

[0416] or any R c1 and R d1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group, which is optionally substituted with 1, 2, or 3 substituents independently selected from R g ;

[0417] or any R c2 and R d2 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group, which is optionally substituted with 1, 2, or 3 substituents independently selected from R g ; and

[0418] each R g is independently selected from OH, NO2, CN, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano-C 1-3 alkylene, HO-C 1-3 alkylene, C 6-10 aryl, C 6-10 aryloxy, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkylene, C 3-10 cycloalkyl-C 1-4 alkylene, (5-10 membered heteroaryl)-C 1-4 alkylene, (4-10 membered heterocycloalkyl)-C 1-4 alkylene, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamoyl, C 1-6 alkylcarbamoyl, di(C 1-6alkyl)carbonyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino and di(C 1-6 alkyl)aminocarbonylamino.

[0419] In some embodiments, R 1 is selected from C 1-6 alkyl, C 2-6 alkenyl and Cy 1 , wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 .

[0420] In some embodiments, R 1 is C 1-6 alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 .

[0421] In some embodiments, R 1 is Cy 1 .

[0422] In some embodiments, R 1 is C 2-6 alkenyl.

[0423] In some embodiments, R 2 is selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 , C(O)NR c1 R d1 and NR c1 R d1 .

[0424] In some embodiments, R 2 is H.

[0425] In some embodiments, R 2 is C 1-6 alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 , C(O)NRc1 R d1 and NR c1 R d1 substituted.

[0426] In some embodiments, R 2 is C 1-6 alkyl optionally substituted with Cy 1 .

[0427] In some embodiments, R 2 is C 1-6 alkyl optionally substituted with C(O)NR c1 R d1 or NR c1 R d1 .

[0428] In some embodiments, R 2 is C 1-6 alkyl optionally substituted with C(O)NR c1 R d1 .

[0429] In some embodiments, R 2 is C 1-6 alkyl optionally substituted with NR c1 R d1 . In some embodiments, R c1 and R d1 are each H. In some embodiments, R c1 and R d1 are each C 1-6 alkyl. In some embodiments, R c1 and R d1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from R g .

[0430] In some embodiments, R 3 , R 4 , R 5 , and R 6 are each independently selected from H and C(O)NR c1 R d1 .

[0431] In some embodiments, R 3 and R 6 are each H.

[0432] In some embodiments, R 4 is C(O)NR c1 R d1 . In some embodiments, R 3R 5 and R 6 Each is H. In some embodiments, R 5 For C(O)NR c1 R d1 In some embodiments, R 3 R 4 and R 6 Each is H. In some embodiments, R c1 For H and R d1 Selected from C 6-10 Aryl-C 1-4 Alkylene and (5-10-membered heteroaryl)-C 1-4 Alkylene.

[0433] In some embodiments, each Cy 1 Selected independently from C 6-10 Aryl and 4-10 membered heterocyclic alkyl groups, each optionally composed of 1, 2 or 3 independently selected from R Cy2 Substituents are substituted.

[0434] In some embodiments, Cy 1 It is C 6-10 aryl (e.g., phenyl), which is optionally composed of 1, 2 or 3 independently selected from R Cy2 Substituents are substituted.

[0435] In some embodiments, Cy 1 It is a 4-10 membered heterocyclic alkyl group (e.g., pyrrolidinyl, morpholinyl), which is optionally composed of 1, 2 or 3 independently selected from R Cy2 Substituents are substituted.

[0436] In some embodiments, each R Cy2 Independently selected from halogens, CN, C 1-6 Alkyl or OR a2 ; wherein C 1-6 Alkyl groups are optionally surrounded by C(O)NR c2 R d2 replace.

[0437] In some embodiments, R Cy2 It is a halogen.

[0438] In some embodiments, R Cy2 For CN, C 1-6 Alkyl or C 1-6 Alkyl group.

[0439] In some embodiments, R Cy2 C 1-6 Alkyl, optionally substituted C(O)NR c2 R d2In some embodiments, R c2 is H, and R d2 is selected from C 6-10 aryl, 5-10 membered heteroaryl, C 6-10 aryl-C 1-4 alkylene, and (5-10 membered heteroaryl)-C 1-4 alkylene, each alkylene being optionally substituted with 1, 2, or 3 substituents independently selected from R g .

[0440] In some embodiments, R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , and R d2 are each independently selected from H, C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 6-10 aryl-C 1-4 alkylene, and (5-10 membered heteroaryl)-C 1-4 alkylene, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 6-10 aryl-C 1-4 alkylene, and (5-10 membered heteroaryl)-C 1-4 alkylene are each optionally substituted with 1, 2, or 3 substituents independently selected from R g .

[0441] In some embodiments, each R g is independently selected from halogen, C 1-6 alkyl, and C 1-6 alkoxy.

[0442] In some embodiments:

[0443] R 1 is selected from C 1-6 alkyl, C 2-6 alkenyl, and Cy 1 , wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 .

[0444] R 2 is selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 , C(O)NR c1 Rd1 and NR c1 R d1 substituted;

[0445] R 3 , R 4 , R 5 and R 6 are each independently selected from H and C(O)NR c1 R d1 ;

[0446] Cy 1 is independently selected from C 6-10 aryl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R Cy2 ;

[0447] R Cy2 is independently selected from halogen, CN, C 1-6 alkyl, and OR a2 ; wherein said C 1-6 alkyl is optionally substituted with C(O)NR c2 R d2 ;

[0448] each R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , and R d2 is independently selected from H, C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 6-10 aryl-C 1-4 alkylene, and (5-10 membered heteroaryl)-C 1-4 alkylene, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 6-10 aryl-C 1-4 alkylene, and (5-10 membered heteroaryl)-C 1-4 alkylene are each optionally substituted with 1, 2, or 3 substituents independently selected from R g ; and

[0449] each R g is independently selected from halogen, C 1-6 alkyl, and C 1-6 alkoxy.

[0450] In some embodiments, the compound of Formula (III) is any one of the compounds provided in Table 4, or a pharmaceutically acceptable salt thereof.

[0451] In some embodiments, salts of the compounds of any of the formulae disclosed herein are formed between acids and basic groups of the compounds (e.g., amino functional groups) or between bases and acidic groups of the compounds (e.g., carboxyl functional groups). According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt.

[0452] In some embodiments, acids commonly used to form pharmaceutically acceptable salts of the compounds of any of the formulae disclosed herein include inorganic acids (such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid) and organic acids (such as p-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, benzenesulfonic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid) and 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, 1,4-butanedienyl butylate, 1,6-hexanedienyl hexylate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, beta-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 inorganic acids (such as hydrochloric acid and hydrobromic acid) and with organic acids (such as maleic acid).

[0453] In some embodiments, bases commonly used to form pharmaceutically acceptable salts of the compounds of any of the formulae disclosed herein include hydroxides of alkali metals, including sodium, potassium, and lithium; hydroxides of alkaline earth metal, such as calcium, magnesium, and the like; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines, such as unsubstituted or hydroxy-substituted mono-, di- or trialkylamines, dicyclohexylamines; tributyl amines; pyridines; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis- or tris-(2-hydroxy-(Ci-C6)-alkylamines), such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tris-(2-hydroxyethyl)amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; amino acids, such as arginine, lysine, and the like.

[0454] In some embodiments, the compounds of any of the formulae disclosed herein, or pharmaceutically acceptable salts thereof, are substantially isolated.

[0455] In some embodiments, the compounds of any of the formulae disclosed herein, or pharmaceutically acceptable salts thereof, can have the ability to increase the level of a TFEB polypeptide within a cell and / or within a nucleus of a cell. Such a cell can be in vitro or in vivo. For example, upon administration to a mammal, the compounds of any of the formulae disclosed herein, or pharmaceutically acceptable salts thereof, can have the ability to increase the level of a TFEB polypeptide within a nucleus of a cell present within the mammal (e.g., a human).

[0456] Methods of making therapeutic compounds

[0457] The compounds of any of the formulae disclosed herein, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes. For example, the compounds described herein can be prepared using methods and procedures similar to those described in Examples la-lp herein. Those skilled in the art know how to choose and implement appropriate synthetic protocols, and understand that the described methods are not the only methods by which the compounds provided herein can be synthesized, and that a wide array of libraries of synthetic organic reactions are available to potentially be used to synthesize the compounds provided herein.

[0458] Suitable synthetic methods for starting materials, intermediates, and products can be identified by reference to the literature, including reference works 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, 2003); Katritzky et al., (Ed.) Handbook of nd Synthetic Organic Chemistry (Wiley, 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, 6thEd. (Wiley, 2007); Trost et al. (Ed.) Comprehensive Organic Synthesis (Pergamon Press, 1991). th

[0459] ​The reactions to prepare the compounds provided herein can be carried out in suitable solvents which can be readily selected by one of ordinary skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials, intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which 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. The choice of a suitable solvent will depend on the particular reaction step or steps involved in preparing the compound.

[0460] The preparation of the compounds provided herein can involve 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 th Ed., Wiley & Sons, Inc., New York (2006).

[0461] Pharmaceutical compositions and formulations

[0462] The document also provides a pharmaceutical composition, comprising an effective amount of a compound of any one of Formulas (I)-(III) disclosed herein, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. The pharmaceutical composition can also include any other therapeutic agent and / or therapeutic molecule described herein. The carrier is "acceptable" in the sense of being compatible with the other ingredients of the formulation, and in the case of a pharmaceutically acceptable carrier, its use in

[0463] Pharmaceutically acceptable carriers, adjuvants and vehicles that can be employed in the pharmaceutical compositions provided herein include, but are not limited to, 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.

[0464] The compositions or dosage forms can include in the range of 0.005% to 100% of any one or more compounds or therapeutic agents described herein, with the remainder consisting of suitable pharmaceutically acceptable carriers or excipients. Contemplated compositions can include about 0.001% to about 100% (e.g., about 0.1% to about 95%, about 75% to about 85%, or about 20% to about 80%) of any one or more compounds or therapeutic agents provided herein, with the remainder consisting of any pharmaceutically acceptable carriers or excipients described herein or any combination of these carriers or excipients.

[0465] Routes of administration and dosage forms

[0466] The therapeutic compounds and / or pharmaceutical compositions provided herein (e.g., compositions comprising one or more compounds of Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) can include those suitable for any of the accepted modes of administration. Accepted modes of administration include, but are not limited to, buccal, dermal, intra-cervical, paranasal, intratracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intracatheter, intraduodenal, intradural, intradermal, intraesophageal, intragastric, intragingival, intrailieal, intralymphatic, intramedullary, intramembranous, intramuscular, intranasal, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinus, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, intranasal, nasogastric, oral, parenteral, percutaneous, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, vaginal, intravitreal, subretinal, or other intraocular routes of administration.

[0467] The compositions and formulations described herein can conveniently be presented in unit dosage form, e.g., tablets, sustained release capsules, and liposomes, and can be prepared by any methods well known in the art of pharmacy. See, e.g., Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (20th ed. 2000). Such preparative methods include, but are not limited to, those involving the step of bringing into association with the molecule of interest (e.g., a carrier which constitutes one or more accessory ingredients) the carrier which 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.

[0468] In some embodiments, any one or more of the compounds or therapeutic agents described herein can be administered orally. Compositions described herein suitable for oral administration can be presented as discrete units, such as capsules, sachets, granules, or tablets, each containing a predetermined amount (e.g., an effective amount) of the active ingredient; powders or granules; solutions or suspensions in an aqueous or non-aqueous liquid; oil-in-water emulsions; water-in-oil emulsions; contained in liposomes; or large-dose preparations. Soft gelatin capsules can be useful in holding such suspensions, which can advantageously increase the rate of absorption of the compounds. For tablets, carriers which are often used include, but are not limited to, lactose, sucrose, dextrose, mannitol, sorbitol, dicalcium phosphate, magnesium stearate, sodium chloride, and starch. Other acceptable excipients can include, but are not limited to, (a) fillers or extenders, such as starches, lactose, sucrose, dextrose, mannitol, and silicic acids; (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, but are not limited to, lactose and dried cornstarch. When aqueous suspensions are administered orally, one or more active ingredients 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, but are not limited to, tablets containing the active ingredient in a

[0469] Compositions suitable for parenteral administration include, but are not limited to, aqueous and non-aqueous sterile injection solutions or infusion solutions, which can contain anti-oxidants, buffers, bactericides, and solutes, which render the formulation isotonic with the blood of the intended recipient; aqueous and non-aqueous sterile suspensions, which can 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 can be stored in a freeze-dried (lyophilized) condition, requiring only the addition of the sterile liquid carrier, for example, water, 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. Injection solutions can be in the form of, for example, sterile injectable aqueous or oleaginous suspensions. This suspension can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be aqueous or oleaginous solutions or suspensions containing a non-toxic parenterally acceptable diluent or solvent, for example, solutions in 1,3-butanediol. Among the acceptable excipients and solvents that can be used are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils can be employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including, but not limited to, synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables. In certain cases, natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions, can be useful in the preparation of injectables. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants.

[0470] In certain instances, the therapeutic compounds and / or pharmaceutical compositions provided herein can be in the form of a suppository for rectal administration. These compositions can be prepared by mixing a compound described herein (e.g., a compound of Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active component. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

[0471] In certain instances, the therapeutic compounds and / or pharmaceutical compositions provided herein can be administered by nasal spray 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 known solubilizing or dispersing agents. See, e.g., U.S. Patent No. 6,803,031. Other 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).

[0472] In certain instances, the therapeutic compounds and / or pharmaceutical compositions provided herein can be prepared as a topical composition and used in the form of an aerosol, cream, lotion, solid, liquid, dispersion, foam, oil, gel, hydrogel, lotion, mousse, ointment, powder, patch, pomade, solution, pump spray, stick, towelette, soap, or other form of topical administration and / or cosmetic and skin care formulation commonly used in the art. The topical composition can be in the form of an emulsion. Topical administration of the therapeutic compounds and / or pharmaceutical compositions provided herein can be useful when the desired treatment involves areas or organs readily accessible by topical application. In certain instances, the topical composition can include any one or more compounds or combinations of therapeutic agents described herein (e.g., a compound of Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof), along with one or more other ingredients, carriers, excipients, or diluents, including but not limited to, absorbents, anti-irritants, anti-acne agents, preservatives, antioxidants, colorants / pigments, emollients (moisturizers), emulsifiers, film-forming / retention agents, fragrances, leave-on exfoliants, prescription drugs, preservatives, abrasives, silicones, skin-identical / restoring agents, slip agents, sunscreen active agents, surfactants / detergent cleansers, penetration enhancers, and thickening agents.

[0473] In some cases, one or more compounds or therapeutic agents described herein (e.g., a compound of 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, a prosthetic valve, a vascular graft, a stent, or a catheter. General methods of preparing suitable coatings and coated implantable devices are known in the art and are set forth in U.S. Patent No. 6,099,562; U.S. Patent No. 5,886,026; and U.S. Patent No. 5,304,121. The coating can be a biocompatible polymeric material, such as a hydrogel polymer, a polymethyldisiloxane, a polycaprolactone, a polyethylene glycol, a polylactic acid, an ethylene vinyl acetate, or mixtures thereof. In some cases, the coating can optionally be further covered by a suitable overcoat of a fluorosilicone, a polysaccharide, a polyethylene glycol, a phospholipid, or a combination thereof to impart controlled release properties to the composition.

[0474] In certain cases, the document provides an implantable drug release device impregnated or comprising one or more compounds or therapeutic agents described herein (e.g., a compound of Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt), such that the compound or therapeutic agent is released from the device and is therapeutically active.

[0475] Dosage and treatment regimen

[0476] A composition (e.g., a pharmaceutical composition provided herein) comprising a compound provided herein (e.g., a compound of Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) can include an effective amount of the compound (e.g., a therapeutically effective amount).

[0477] The effective dose can vary depending on the disease to be treated, the severity of the disease, the route of administration, the gender, age and general health condition of the subject, the use of excipients, the possibility of co-use with other therapeutic methods, such as the use of other drugs, and the judgment of the attending physician.

[0478] 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, an effective amount can be about 0.5 mg to about 500 mg of a compound disclosed herein, or any amount 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. An effective amount can be an amount sufficient to alleviate or reduce one or more symptoms associated with a disease, condition, or disorder being treated as described herein.

[0479] In some cases, an effective amount of a compound of any one of Formulas (I)-(III), or a pharmaceutically acceptable salt thereof, can range from, e.g., about 0.001 mg / kg to about 500 mg / kg (e.g., about 0.001 mg / kg to about 200 mg / kg; about 0.01 mg / kg to about 200 mg / kg; about 0.01 mg / kg to about 150 mg / kg; about 0.01 mg / kg to about 100 mg / kg; about 0.01 mg / kg to about 50 mg / kg; about 0.01 mg / kg to about 10 mg / kg; about 0.01 mg / kg to about 5 mg / kg; about 0.01 mg / kg to about 1 mg / kg; about 0.01 mg / kg to about 0.5 mg / kg; about 0.01 mg / kg to about 0.1 mg / kg; about 0.1 mg / kg to about 200 mg / kg; from about 0.1 mg / kg to about 150 mg / kg; from 0.1 mg / kg to about 100 mg / kg; from about 0.1 mg / kg to about 50 mg / kg; from 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; about 0.1 mg / kg to about 0.5 mg / kg, or about 0.5 mg / kg to about 500 mg / kg).

[0480] In some cases, an effective amount of a compound of any one of Formulas (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.

[0481] The foregoing doses can be administered once per day (e.g., as a single dose or in two or more divided doses, e.g., once per day, twice per day, three times per day) or non-daily (e.g., every other day, every two days, every three days, once per week, twice per week, once every two weeks, or once per month). In some cases, a dose can be administered every 4 hours, 6 hours, 8 hours, 12 hours, or 24 hours.

[0482] Kit

[0483] The document also provides, e.g., pharmaceutical kits for increasing the level of a TFEB polypeptide within a cell and / or within the nucleus of a cell within a mammal (e.g., a human). In certain instances, the document provides pharmaceutical kits that can be used, e.g., to treat the diseases, disorders, and conditions referred to herein. Such pharmaceutical kits can include one or more containers comprising a pharmaceutical composition including a therapeutically effective amount of a compound provided herein (e.g., a compound of Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof). In certain instances, such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers. Instructions, in the form of an insert or label, can also be included in the kits provided herein, indicating quantities of the components to be administered, guidelines for administration, and / or guidelines for mixing the components.

[0484] Combination therapy

[0485] In some cases, one or more compounds provided herein (e.g., a compound of 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 of Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) include, but are not limited to, enzyme replacement therapies (e.g., approved enzyme therapies) for LSD (e.g., fabrazyme or cerezyme). In such cases, due to the blood brain barrier restriction on serum proteins, the addition of one or more such compounds can help treat central nervous system diseases that cannot be treated by enzyme replacement therapy. In certain cases, the addition of one or more such compounds can increase cellular uptake of a given lysosomal enzyme replacement therapy protein in the periphery by increasing the expression of mannose 6 phosphate receptors, a TFEB transcriptional target, through which enzyme replacement therapies enter disease cells or tissues. Other examples of therapeutic molecules that can be used in combination with one or more compounds provided herein (e.g., a compound of Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) include, but are not limited to, anti-inflammatory drugs (e.g., steroids and antibodies against IL-6 or TNF-a), antimicrobial drugs (e.g., antibiotics, anti-mycobacterial drugs, and antiviral drugs), anticancer drugs (e.g., chemotherapeutic agents and cellular products such as engineered T cells), anti-aging agents (e.g., nicotinamide riboside or rapamycin), nervous system drugs (e.g., L-DOPA, memantine, and riluzole), therapies for neurodegenerative diseases (e.g., edaravone or benserazide), and drugs for treating chronic organ dysfunction (e.g., ACE inhibitors and lactulose).

[0486] One or more compounds provided herein (e.g., a compound of Formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) and one or more therapeutic molecules can be administered in any order or simultaneously. If administered simultaneously, they can be provided in a single, unified form or in multiple forms (e.g., as a single pill or as two separate pills). Either one or both can be administered multiple times. If not simultaneously, the time interval between multiple administrations can vary from greater than zero weeks to less than four weeks.

[0487] Definitions

[0488] As used herein, the term“about” means“approximately” (e.g., about 10% of the indicated value, either positively or negatively).

[0489] At various places in the present document, substituents of the compounds provided herein are disclosed in groups or ranges. It is specifically intended that these groups and ranges include every individual subcombination of the members of these groups and ranges. For example, the term "C 1-6 alkyl" is specifically intended to individually disclose methyl, ethyl, C3alkyl, C4alkyl, C5alkyl, and C6alkyl.

[0490] At various places in the present 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 for which valence allows. For example, the term "pyridine ring" or "pyridyl" can refer to a pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl ring.

[0491] It is also to be understood that certain features that are, for clarity, described in the context of separate embodiments can also be provided in combination in a single embodiment. Conversely, various features that are, for brevity, described in the context of a single embodiment can also be provided separately or in any suitable subcombination.

[0492] The term "aromatic" refers to a carbocyclic or heterocyclic ring having one or more polyunsaturated rings having aromatic character (i.e., having (4n+2) delocalized pi (π) electrons, where n is an integer).

[0493] The term "n-membered", where n is an integer, generally describes the number of ring-forming atoms in a moiety in which 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.

[0494] As used herein, the phrase "optionally substituted" means unsubstituted or substituted. 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 with a substituent. A single bivalent substituent, such as oxo, can replace two hydrogen atoms. It will be appreciated that substitution on a given atom is limited by valency.

[0495] In all definitions, the term "C n-m " indicates a range inclusive of the endpoints, where n and m are integers and represent the number of carbons. Examples include C 1-4 , C 1-6 , etc.

[0496] As used herein, the term "C n-m“Alkyl” refers to a saturated hydrocarbon radical that can be straight-chain or branched, having n to m carbons. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, sec-butyl; higher homologs such as 2-methyl-l-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, an alkyl group comprises 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

[0497] The term “C nm “Haloalkyl” refers to an alkyl group having one halogen atom to 2s+1halogen atoms, 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, haloalkyl is only fluorinated. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0498] As used herein, “C n-m “Alkenyl” refers to an alkyl group having one or more double carbon-carbon bonds and having n to m carbons. Examples of alkenyl groups include, but are not limited to, ethenyl, n-propenyl, i-propenyl, n-butenyl, sec-butenyl, and the like. In some embodiments, an alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0499] As used herein, “C n-m “Alkynyl” refers to an alkyl group having one or more triple carbon-carbon bonds and having n to m carbons. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl-1-yl, propynyl-2-yl, and the like. In some embodiments, an alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0500] The term “C nm “Alkylene” refers to a divalent alkyl linking group having n to m carbons. Examples of alkylene groups include, but are not limited to, ethane-1,1-diyl, ethane 1,2-diyl, propane-1,1-diyl, propane-1,3-diyl, propane 1,2-diyl, butane-1,4-diyl, but-1,3-diyl, but-1,2-diyl, 2-methyl-propane-1,3-diyl, and the like. In some embodiments, an alkylene moiety comprises 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or 1 to 2 carbon atoms.

[0501] The term “C nm“Alkoxy” refers to a radical of the formula -O-alkyl, wherein the alkyl group has n to m carbons. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and t-butoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0502] As used herein, “C n-m “Haloalkoxy” refers to a radical of the formula -O-haloalkyl having n to m carbon atoms. An example of haloalkoxy is OCF3. In some embodiments, the haloalkoxy is only fluorinated. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0503] As used herein, the term “amino” refers to a radical of the formula -NH2.

[0504] As used herein, the term “C n-m “Alkylamino” refers to a radical of the 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 include, but are not limited to, 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-(t-butyl)amino), and the like.

[0505] As used herein, the term “di(C n-m “Di(C

[0506] As used herein, the term “C n-m “Alkoxycarbonyl” refers to a radical of the 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 include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl (e.g., n-propoxycarbonyl and isopropoxycarbonyl), butoxycarbonyl (e.g., n-butoxycarbonyl and t-butoxycarbonyl), and the like.

[0507] As used herein, the term “C n-m “Alkylcarbonyl” refers to a radical of the 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 include, but are not limited to, methylcarbonyl, ethylcarbonyl, propyl (e.g., n-propylcarbonyl and isopropylcarbonyl), butylcarbonyl (e.g., n-butylcarbonyl and t-butylcarbonyl), and the like.

[0508] As used herein, the term "C n-m "Alkylcarbonylamino" refers to a group of the 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.

[0509] As used herein, the term "C n–m "Alkylsulfonylamino" refers to a group of the 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.

[0510] As used herein, the term "Aminosulfonyl" refers to a group of the formula -S(O)2NH2.

[0511] As used herein, the term "C n-m "Alkylsulfonylamino" refers to a group of the 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.

[0512] As used herein, the term "Di(C n-m "Alkylsulfonylamino" refers to a group of the 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.

[0513] As used herein, the term "Aminosulfonylamino" refers to a group of the formula -NHS(O)2NH2.

[0514] As used herein, the term "C n-m "Alkylsulfonylamino" refers to a group of the 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.

[0515] As used herein, the term "Di(C n-m "Alkylsulfonylamino" refers to a group of the 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.

[0516] As used herein, the term "Aminocarbonylamino" alone or in combination with other terminology means a group of the formula -NHC(O)NH2.

[0517] As used herein, the term "C n-m"Aryloxy" refers to a group of the formula -O-aryl, wherein aryl has n to m carbon atoms. In some embodiments, aryl has 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms.

[0518] As used herein, the term "di(C n-m "Arylamino" refers to a group of the formula -N(aryl)2, wherein each aryl group independently has n to m carbon atoms. In some embodiments, each aryl group independently has 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms.

[0519] As used herein, the term "carbamoyl" is a group of the formula -C(O)NH2.

[0520] As used herein, the term "C nm "Arylamino" refers to a group of the formula -N(aryl)2, wherein each aryl group independently has n to m carbon atoms. In some embodiments, each aryl group independently has 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms.

[0521] As used herein, the term "di(C n-m "Arylamino" refers to a group of the formula -N(aryl)2, wherein each aryl group independently has n to m carbon atoms. In some embodiments, each aryl group independently has 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms.

[0522] As used herein, the term "thio" refers to a group of the formula -SH.

[0523] As used herein, the term "C n-m "Arylamino" refers to a group of the formula -N(aryl)2, wherein each aryl group independently has n to m carbon atoms. In some embodiments, each aryl group independently has 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms.

[0524] As used herein, the term "C n-m "Arylamino" refers to a group of the formula -N(aryl)2, wherein each aryl group independently has n to m carbon atoms. In some embodiments, each aryl group independently has 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms.

[0525] As used herein, the term "C n-m "Arylamino" refers to a group of the formula -N(aryl)2, wherein each aryl group independently has n to m carbon atoms. In some embodiments, each aryl group independently has 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms.

[0526] As used herein, the term "carbonyl," used alone or in combination with other terms, refers to a -C(=O)- group, which can also be written as C(O).

[0527] As used herein, the term "carboxyl" refers to a -C(O)OH group. In some embodiments, a "carboxyl" group also refers to a bioisosteric substituent selected from the following:

[0528]

[0529] and the like, where R is hydrogen, (Ci-C8)alkyl, or C6 aryl, etc.

[0530] As used herein, the term "cyano-C 1-3 alkyl" refers to a group of formula -(C 1-3 alkylene)-CN.

[0531] As used herein, the term "HO-C 1-3 alkyl" refers to a group of formula -(C 1-3 alkylene)-OH.

[0532] As used herein, "halogen" refers to F, Cl, Br, or I. In some embodiments, halogen is F, Cl, or Br.

[0533] As used herein, the term "aryl," used alone or in combination with other terms, refers to an aromatic hydrocarbon group that can be monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings). The term "C n-m aryl" refers to an aryl group having n to m ring carbon atoms. Aryl groups include, for example, phenyl, naphthyl, anthryl, phenanthryl, indanyl, indenyl, and the like. In some embodiments, aryl groups can have 6 to 10 carbon atoms. In some embodiments, aryl is phenyl or naphthyl.

[0534] As used herein, "cycloalkyl" refers to non-aromatic cyclic hydrocarbons including cycloalkyl and / or alkenyl groups. Cycloalkyl groups can include single rings or multiple rings (e.g., having 2, 3, or 4 fused rings) and spiro rings. The ring-forming carbon atoms of a cycloalkyl group can optionally be substituted with 1 or 2 independently selected oxo or thia groups (e.g., C(O) or C(S)). Also included within the definition of cycloalkyl are moieties having one or more aromatic or non-aromatic rings fused to (i.e., sharing a bond with) a cycloalkyl ring, such as benzene or thiophene derivatives of cyclopentane, cyclohexane, and the like. Cycloalkyl groups comprising fused aromatic rings can be attached through any of the ring-forming atoms that comprise the fused aromatic rings. Cycloalkyl groups can comprise fused heterocycloalkyl rings, which themselves can be fused to another ring (such as an aromatic ring). In such cases, the cycloalkyl group can be attached through any of the ring-forming atoms, including those of the heterocycloalkyl ring or the aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbon (C 3-10 ) atoms. 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 to a heterocycloalkyl ring) (C 3-14Cycloalkyl). In some embodiments, the cycloalkyl is C 3-10 Monocyclic or bicyclic cycloalkyl. In some embodiments, the cycloalkyl is C 3-7 Monocyclic cycloalkyl. In some embodiments, the cycloalkyl is C 3-14 Bicyclic or tricyclic cycloalkyl. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like. In some embodiments, the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0535] As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic heterocycle having at least one ring member that is a heteroatom selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 ring members that are heteroatoms 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 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 ring members that are heteroatoms independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a 5-14 membered monocyclic, bicyclic, or tricyclic heteroaryl having 1, 2, 3, or 4 ring members that are heteroatoms independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a 5-6 membered monocyclic heteroaryl having 1 or 2 ring members that are heteroatoms independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a five- or six-membered heteroaryl ring. A five-membered heteroaryl ring is a heteroaryl having a ring with five ring atoms, one or more (e.g., 1, 2, or 3) of which are independently selected from N, O, and S. Exemplary five-membered ring heteroaryls include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 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 having a ring with six ring atoms, one or more (e.g., 1, 2, or 3) of which are independently selected from N, O, and S. Exemplary six-membered ring heteroaryls include, but are not limited to, pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

[0536] As used herein, "heterocycloalkyl" refers to a non-aromatic monocyclic or polycyclic heterocycle having one or more ring-forming heteroatoms selected from O, N, or S. Included among heterocycloalkyl groups are monocyclic 4, 5, 6, 7, 8, 9, or 10-membered heterocycloalkyl groups. Included among heterocycloalkyl groups are mono-, bi-, tri-, and tetra-cyclic 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14-membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocyclic rings. Examples of heterocycloalkyl groups include, but are not limited to, pyrrolidin-2-one, 1,3- isoxazolidin-2-one, pyranyl, tetrahydropyranyl, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, pyrrolidinyl, isoxazolinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepinyl, benzazepinyl, and the like. The ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can optionally be substituted with 1 or 2 independently selected oxo or thioxo groups (e.g., C(O), S(O), C(S), or S(O)2, etc.). A heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, a heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, a heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties having one or more aromatic or non-aromatic rings fused (i.e., sharing a bond) to the heterocycloalkyl ring, such as piperidine, morpholine, benz or thienyl derivatives of azepine, a heterocycloalkyl containing a fused aromatic ring can be attached through any ring-forming atom including the fused aromatic ring. In some embodiments, a 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, a 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.

[0537] In certain places, a definition or embodiment refers to a particular ring (e.g., azetidine ring, pyridine ring, etc.). Unless otherwise specified, such rings can be attached at any ring member, so long as the valency of the atom is not exceeded. For example, an azetidine ring can be attached at any position on the ring, while a pyridine-3-yl ring is attached at the 3-position.

[0538] 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 a sulfoxide or sulfone group when attached to a heteroatom.

[0539] As used herein, the term "compound" refers to all stereoisomers, geometric isomers, tautomers, and isotopologues that include the depicted structure. Unless otherwise specified, a compound identified herein by name or structure as a particular tautomer is intended to include other tautomeric forms.

[0540] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). Unless otherwise stated, all stereoisomers, e.g., enantiomers and diastereomers, are intended. Compounds provided herein that include asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. The optically active forms can be prepared using any suitable method, e.g., from optically active starting materials. For example, techniques such as chiral separation of racemic mixtures or stereoselective synthesis can be used to prepare optically active forms of the compounds provided herein. Many geometric isomers of olefins, C=N double bonds, N=N double bonds, and the like can also exist and are contemplated herein. Cis and trans geometric isomers of the compounds provided herein are described and can be isolated as a mixture of isomers or as isolated isomers. In some embodiments, the compounds provided herein have the (R)-configuration. In some embodiments, the compounds provided herein have the (S)-configuration.

[0541] The compounds provided herein also include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond and the concomitant migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states having the same empirical formula and overall charge. Examples of prototropic tautomers include, but are not limited to, keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which a proton can occupy two or more positions of a heterocyclic system, such as 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 spatially 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 one another:

[0542]

[0543] As will be readily understood by those skilled in the art, a variety of functional groups and other structures can exhibit tautomerism, and all tautomers of the compounds described herein are within the scope provided herein.

[0544] As used herein, the term “cell” refers to a cell 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, e.g., a mammal (e.g., a human).

[0545] As used herein, the term "contacting" refers to bringing the indicated moieties or items together in an in vitro system, ex vivo system, or in vivo system. For example, "contacting" a cell with a compound provided herein includes the act of administering the compound to a mammal (e.g., a human) containing the cell as well as, for example, introducing the compound into a cell culture containing the cell.

[0546] As used herein, the term "mammal" includes, but is not limited to, mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, elephants, deer, non-human primates (e.g., monkeys and apes), domesticated pets, and humans.

[0547] 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 medical response of a tissue, system, mammal, or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician.

[0548] As used herein, the term "treatment" refers to (a) inhibiting the disease, disorder, or condition, e.g., arresting the further development of the pathology and / or symptomology of the 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., preventing the disease, disorder, or condition from worsening), or (b) ameliorating the disease, disorder, or condition, e.g., reversing the pathology and / or symptomology of the 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 disease, disorder, or condition).

[0549] As used herein, the term "preventing" or "prevention" of a disease, disorder, or condition refers to reducing the risk of developing a disease, disorder, or condition in a mammal or group of mammals (e.g., a mammal or group of mammals predisposed or susceptible to the disease, disorder, or condition). In some embodiments, preventing a disease, disorder, or condition refers to reducing the likelihood 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 occurrence of the disease, disorder, or condition.

[0550] EMBODIMENTS

[0551] MATERIALS AND METHODS

[0552] Unless otherwise specified, all non-aqueous reactions were carried out in oven-dried or flame-dried glassware under a nitrogen atmosphere. Anhydrous tetrahydrofuran and diethyl ether were distilled from sodium benzophenone solution; anhydrous dichloromethane and toluene were distilled from CaH2; or the same solvents were obtained from a solvent purification system using an alumina column. Unless otherwise specified, all other solvents and reagents were commercially available and could be used without further purification. Reactions were monitored by TLC using 250 μm pre-coated silica gel 60F254 plates, observed under UV light at 254 nm and / or 365 nm, and with potassium permanganate (1.5 g potassium permanganate, 10 g K2CO3 and 1.25 mL 10% sodium hydroxide dissolved in 200 mL water), cerium molybdate (0.5 g Ce(NH4)2(NO3)6, 12 g (NH4)6Mo7O) 24 Staining was performed using either 4H₂O and 28 mL concentrated sulfuric acid dissolved in 235 mL water, or vanillin (6 g vanillin and 1.5 mL concentrated sulfuric acid dissolved in 100 mL ethanol). Rapid liquid chromatography was performed using SiliCycle silica gel 60 (230-400 mesh) or ISCOM PLC. Residual solvents were used as internal standards, and staining was recorded on a Bruker Avance 300, 400, or 500 MHz spectrometer. 1 H and 13 CNMR spectroscopy. Infrared spectra were obtained on a Smiths IdentifyIR or PerkinElmerSpectrum 100. HRMS data were obtained using a 2.1 x 50 mm 3.5 μm Waters XTerra C18 column eluted with 0.1% formic acid and a ThermoScientificExactive HRMS column connected to a ThermoScientificAccela HPLC system. The purity of the compounds was assessed using the same HPLC system with a PDA or Agilent 385ELSD. All final-screened samples passed QC with a purity >95% by LC / MS / ELSD analysis.

[0553] General synthesis scheme

[0554]

[0555] For example, to prepare a compound of formula (I) where n is 1 and L is NH (1), equimolar amounts of a 4-chloroquinazoline analog (2) and an amine group (3) are mixed in a suitable solvent (e.g., isopropanol). The resulting reaction mixture is stirred and refluxed for, e.g., 4 hours. The progress of the reaction is monitored by techniques known in the art. Upon consumption of starting materials, the reaction mixture is concentrated and the target compound is purified by preparative TLC or flash chromatography. The product can be further purified by crystallization as is routine in the art. Referring to the general scheme, X 1 2 3 4 5 6 A B As described herein, and LG is a leaving group (e.g., CI, Br, I, or OTf). Compounds of formula (I) where L is not NH can be prepared from similar starting materials using reactions and synthetic routes well known in the art. The skilled chemist will be able to select and implement the appropriate reaction scheme and conditions.

[0556] Example la - Synthesis of compound 8 (BC18618)

[0557]

[0558] Preparation of compound 3:

[0559] 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 gel column chromatography (PE / EA, 2:1) to give 1.2 g of 3 (yellow oil, 87%). MS (ESI) m / z: 274 [M+H]+

[0560] Preparation of compound 8 (BC18618)

[0561] 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 with MeOH to give 205 mg of BC18618 (compound 8) (off-white solid, 52%).

[0562] ​​​​​​​MS (ESI) m / z: 318 [M+H]+, 316 [M-H]-

[0563] 1 H 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).

[0564] Example 1b - Synthesis of compound 76 (BC18703)

[0565]

[0566] General procedure for the preparation of compound 3:

[0567] 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 gel column chromatography (PE / EA, 2:1) to give 0.45 g of 3 (yellow oil, 61 %). MS (ESI) m / z: 296 [M+H]+

[0568] General procedure for the preparation of compound 5

[0569] To a solution of 3 (0.4 g, 1.36 mmol, 1 eq) in dioxane / H2O (1:1, 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 with EA. The organic phase was washed with brine, then dried and concentrated. The residue was purified by silica gel column chromatography (PE / EA, 5:1) to give 0.4 g of 5 (yellow solid, 70 %). MS (ESI) m / z: 443 [M+H]+.

[0570] General procedure for the preparation of compound 6

[0571] 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 stirring at room temperature overnight, the mixture was filtered and the filtrate was concentrated to give 0.16 g of 6 (colorless oil, 80%). MS (ESI) m / z: 445 [M+H]+.

[0572] General procedure for the preparation of compound BC18703

[0573] To a solution of 6 (160 mg) in MeOH (2 mL) was added 3M HC1 / EA (4 mL). After stirring at room temperature 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]-

[0574] 1 H NMR (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).

[0575] Example 1c - Synthesis of compound 78 (BC18705)

[0576]

[0577] General procedure for the preparation of compound 3

[0578] 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 gel column chromatography (PE / EA, 2: 1) to give 150 mg of 3 (yellow solid, 76%). MS (ESI) m / z: 295 [M+H]+

[0579] General procedure for the preparation of compound BC18705

[0580] To a solution of 3 (100 mg, 0.339 mmol, 1 eq) in dioxane / H20 (1 : 1, 3 mL) was added 4 (215 mg, 1.02 mmol, 3 eq), K2C03(210 mg), 1.5 mmol, 4.5 eq) and Pd(dppf)C12(25 mg, 0.034 mmol, 0.1 eq) under N2. The mixture was stirred at 95 °C overnight. The mixture was concentrated, the residue was purified by preparative HPLC to give 5 mg of BC18705 (off-white solid, 4%). MS (ESI) m / z: 344 [M+H]+, 342 [M-H]-

[0581] 1 H NMR (400 MHz, DMSO) d 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).

[0582] Example Id - Synthesis of compound 383 (BC18829)

[0583]

[0584] General procedure for the preparation of compound 3-1

[0585] 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 filter cake was dried to give 0.29 g of 3-1 (yellow solid, 97%). MS (ESI) m / z: 297 [M+H]+.

[0586] General procedure for the preparation of BC18829

[0587] To a solution of 3-1 (50 mg, 0.17 mmol, 1 eq) in dioxane / H20 (4: 1, 5 mL) was added 4-1 (40 mg, 0.19 mmol, 1.1 eq), K2C03(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 with EA, and the organic phase was dried and concentrated. The residue was purified by Prep-TLC (DCM / MeOH, 10: 1) to give 5 mg of BC18829 (brown solid, 9%). MS (ESI) m / z: 346 [M+H]+, 344 [M-H]-

[0588] 1 H NMR (400 MHz, DMSO) d 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).

[0589] Example 1e - Synthesis of compound 384 (BC18830)

[0590]

[0591] General procedure for preparing compound 3-2

[0592] 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 filter cake was dried to give 0.3 g of 3-2 (yellow solid, 96%). MS (ESI) m / z: 314 [M+H]+

[0593] General procedure for preparing BC18830

[0594] 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 x 2). The organic phase was dried and concentrated. The residue was purified by Prep-TLC to give 49 mg of BC18830 (yellow solid, 42%). MS (ESI) m / z: 365 [M+H]+, 363 [M-H].

[0595] 1 H 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).

[0596] Example If - Synthesis of compound 385 (BC18831)

[0597]

[0598] General procedure for the preparation of 3-3

[0599] To a solution of 3-2 (as prepared in Example le) (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 hours. The mixture was filtered. The filter cake was washed with EA, the organic phase was dried and concentrated to give 245 mg of 3-3 (yellow solid, 100%). MS (ESI) m / z: 483 [M+H]+

[0600] General procedure for the preparation of compound BC18831

[0601] 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 room temperature for 4 h. The mixture was concentrated and the residue was purified by preparative HPLC to give 44 mg of BC18831 (yellow solid, 25%). MS (ESI) m / z: 345 [M+H]+, 343 [M-H]-

[0602] 1 H NMR (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).

[0603] Example 1g - Synthesis of compound 43 (BC18663)

[0604]

[0605] General procedure for the preparation of compound 3

[0606] 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 precipitated solid was collected and dried to give 1.3 g of 3 (grey solid, 96%). MS (ESI) m / z: 223 [M+H]+

[0607] General procedure for the preparation of compound 4

[0608] 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. Upon completion, the mixture was poured into ice (~ 1 g). The solid was collected and dried to give 200 mg of 4 (yellow solid, 84%). MS (ESI) m / z: 241 [M+H]+

[0609] General procedure for the preparation of compound BC18663

[0610] To a solution of 4 (83 mg, 0.35 mmol, 1.0 eq) in 4 M HC1 / 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 preparative HPLC to give 19 mg of BC18663 (yellow solid, 18 %). MS (ESI) m / z: 316 [M+H]+, 314 [M-H]-

[0611] 1 H 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).

[0612] Example 1h - Synthesis of compound 48 (BC18668)

[0613]

[0614] General procedure for the preparation of BC18668

[0615] 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, then 4 (as prepared in Example Ig) (103 mg, 0.43 mmol, 1 eq) was added. The mixture was stirred at 80 °C for 3 h. Water (10 mL) was added. The precipitated solid was collected and purified by preparative HPLC to give 31 mg of BC18668 (white solid, 22 %). MS (ESI) m / z: 338 [M+H]+

[0616] 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).

[0617] Example 1i - Synthesis of compound 69 (BC18689)

[0618]

[0619] General procedure for the preparation of compound BC18689

[0620] 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 from the same literature, 0.2 g, 0.83 mmol, 1 eq) was added to the above solution. The mixture was heated to 80 °C for 3 h. After cooling to room temperature, H2O (5 mL) was added slowly. The mixture was extracted with EA (10 mL x 2) and the organic phase was concentrated. The residue was purified by Prep-TLC to give 187 mg of BC18689 (white solid, 72%). MS (ESI) m / z: 316 [M+H]+

[0621] 1 H 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).

[0622] Example 1j - Synthesis of compound 126 (BC18763)

[0623]

[0624] General procedure for the preparation of compound 3

[0625] 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 room temperature overnight. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (DCM / MeOH, 50:1) to give 11.5 g of 3 (yellow solid, 85%). MS (ESI) m / z: 243 [M+H]+

[0626] General procedure for the preparation of compound 4

[0627] A solution of 3 (2 g, 8.26 mmol, 1.0 eq) in KOH (1 N, 20 mL) was heated to 100 °C and stirred for 3 h. TLC showed no 3. The pH of the mixture was adjusted to 7 with aqueous HC1 (4 M). The mixture was filtered. The precipitated solid was collected and dried to give 1.4 g of 4 (white solid, 70%). MS (ESI) m / z: 225 [M+H]+

[0628] General procedure for the preparation of compound 5

[0629] 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 pH of the residue was adjusted to 9-10 with saturated Na2CO3. The mixture was extracted with CHCl3 (15 mL x 3) and the organic phase was dried and concentrated to give 750 mg of 5 (yellow solid, 50%). MS (ESI) m / z: 243 [M+H]+

[0630] General procedure for the preparation of BC18763

[0631] 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 filter cake was washed with i-PrOH and dried to give 30.1 mg of BC18763 (brown solid, 41%). MS (ESI) m / z: 353 [M+H]+, 351 [M-H]-

[0632] 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)

[0633] Example 1k - Synthesis of compound 127 (BC18764)

[0634]

[0635] General procedure for the preparation of BC18764

[0636] To a solution of 5 (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, the residue was purified by preparative HPLC to give 10.6 mg of BC18764 (brown solid, 8%). MS (ESI) m / z: 351 [M+H]+, 349 [M-H]-

[0637] 1 H 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).

[0638] Example 1l - Synthesis of compound 120 (BC18757)

[0639]

[0640] General procedure for the preparation of BC18757

[0641] To a solution of 5 (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, the residue was purified by preparative HPLC to give 20 mg of BC18757 (yellow solid, 11%). MS (ESI) m / z: 399 [M+H]+, 397 [M-H]-

[0642] 1 H 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).

[0643] Example Im - Synthesis of compound 83 (BC18711)

[0644]

[0645] General procedure for the preparation of compound 3

[0646] 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 filter cake was washed with i-PrOH and dried to give 1.2 g of 3 (yellow solid, 81%). MS (ESI) m / z: 296 [M+H]+

[0647] General procedure for the preparation of BC18711

[0648] 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 with EA, and the organic phase was dried and concentrated. The residue was purified by prep-HPLC to give 34 mg of BC18711 (gray solid, 5%). MS (ESI) m / z: 339 [M+H]+, 337 [M-H]-

[0649] 1 H 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).

[0650] Example In - Synthesis of intermediate 8 (for preparation of compound BC18847)

[0651]

[0652] General procedure for preparation of compound 6

[0653] 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) were suspended in acetonitrile (500 mL, 10 V) and stirred at room temperature for 1-2 hours. The progress of the reaction was monitored by TLC (PE:EA 5:1). The resulting reaction mixture was quenched with 1 N aqueous HC1 (3 L) and extracted with CH2Cl2(3 x 2 L). The combined organic layers were dried over Na2SO4, concentrated to give compound 6 (66.4 g, 99%) as a yellow powder which was used for the next step without further purification. MS (ESI) m / z: 259 [M+H]+.

[0654] General procedure for preparation of compound 7

[0655] To a solution of 6 (50.0 g, 194 mmol, 1.0 eq) in toluene / H20 (V / V = 2: 1, 2 L) was added 6-1 (50 g, 581 mmol, 3.0 eq), Cs2C03(126 g, 389 mmol, 2.0 eq) and Pd(dppf)Cl2(14.2 g, 19.4 mmol, 0.1 eq). The mixture was vacuumed and backfilled with Ar for 3 times, then stirred at 100 °C overnight. The mixture was filtered through a pad of celite and washed with ethyl acetate (mL). The organic layer was washed with water and brine, and dried over sodium sulfate. Concentration, the residue was purified by silica gel column chromatography (PE / EA, 10: 1) to give 19.1 g of 7 (off-white solid, 45%).

[0656] General procedure for the preparation of compound 8

[0657] 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 at room temperature under H2for 3-4 h. TLC showed remaining 7, another batch of Pd-C (6 g, 20% W / W) was added, and the reaction was continued to stir at room temperature for 4-6 h. TLC showed no 7, but two spots on TLC. Another batch of Pd-C (6 g, 20% W / W) was added, and the reaction was continued to stir at room temperature for 3-5 h. The reaction progress 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 product, which was recrystallized from EA to give 12.1 g of 8 (gray solid, 73%). MS (ESI) m / z: 191 [M+H]+

[0658] Example 10 - Synthesis of compound 241 (BC18847)

[0659]

[0660] General procedure for the preparation of compound 2

[0661] To a solution of 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) iodide (13.8 g, 9.6 mmol, 0.1 eq) in N,N-dimethylformamide (750 mL) was 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 in the next step without further purification.

[0662] General procedure for the preparation of compound 3

[0663] A solution of compound 2 (175.2 g) in phosphorus oxychloride (500 mL) was stirred at 110 °C overnight and the reaction progress was checked by LCMS. The excess phosphorus oxychloride was distilled off under reduced pressure. EA (400 mL) and water (200 mL) were added to the system. The pH of the mixture was adjusted to 7 with saturated aqueous NaHC03solution. The aqueous phase was extracted with EA (500 mL x 3). The organic phase was washed with brine and dried over anhydrous sodium sulfate, concentrated to give the crude product which was purified by column chromatography on silica gel (EA: PE = 10: 1 to 1: 1) to give 14.5 g of 3 (yellow solid, 7%, 2 steps). MS (ESI) m / z: 242 [M+H]+

[0664] General procedure for the preparation of compound 4

[0665] To a suspension of NaH (2.4 g, 100 mmol, 3 eq) in DMF (65 mL) was added amine base 8 (5.3 g, 33.7 mmol, 1.01 eq) at 0 °C. The mixture was stirred at room temperature for 30 minutes. To the above mixture was added compound 3 (8.0 g, 33.2 mmol, 1 eq). The mixture was stirred at 80 °C for 16 hours. Upon completion, the mixture was cooled to room temperature and water (350 mL) was added slowly. The collected solid was triturated with EA, dried to give 9.7 g of 4 (yellow solid, 74%). MS (ESI) m / z: 396 [M+H]+, 394 [M-H]-

[0666] General procedure for the preparation of BC18847

[0667] To a solution of compound 4 (30 g, 75.9 mmol, 1 eq) in ACN (60 mL) was added 1 N HC1 (114 mL, 113.9 mmol, 1.5 eq). The mixture was stirred for 0.5 hours. Then the mixture was lyophilized to give 32 g of BC18847 (red solid, 97%). MS (ESI) m / z: 396 [M+H]+, 394 [M-H]-

[0668] 1 H 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).

[0669] Example Ip - Synthesis of compound 244 (BC18850)

[0670]

[0671] General procedure for the preparation of BC18850

[0672] To a solution of 3 (prepared from example lo) (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 4M HC1 / dioxane (0.13 mL, 0.50 mmol, 1 eq) and the mixture was stirred at 100 °C overnight. After cooling to room temperature, the mixture was directly purified by preparative HPLC to give 17 mg of BC18850 (yellow solid, 9%). MS (ESI) m / z: 378 [M+H]+.

[0673] 1 H 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).

[0674] Example 1 - Compound Structures

[0675] As shown in the general scheme, the compounds in Table 1 were prepared from readily available starting materials.

[0676] Table 1

[0677]

[0678]

[0679]

[0680]

[0681]

[0682]

[0683]

[0684]

[0685]

[0686]

[0687]

[0688]

[0689]

[0690] Note Compounds 35 was isolated and tested as a TFA salt. Compounds 42, 51, 59, 63, 64, and 65 were isolated and tested as HC1 salts, respectively. Compounds 82, 83, 89, 106, 107, 108, 113, 115, 116, 117, 119, 120, and 121 were isolated and tested as formic acid salts, respectively.

[0691] The following compounds shown in Table 1a can be prepared from readily available starting materials using chemical routes readily understood by one of ordinary skill in the art.

[0692] Table 1a

[0693]

[0694]

[0695]

[0696]

[0697] Note Compounds 353, 364, and 376 were isolated and tested as HCOOH salts.

[0698] The following compounds (free base) provided in Table 2 were obtained from commercial sources (Chem DIV, Inc. and Molport, Inc.):

[0699] Table 2

[0700]

[0701]

[0702]

[0703]

[0704] The following compounds shown in Table 3 can be prepared from readily available starting materials using chemical routes readily understood by those of ordinary skill in the art.

[0705] Table 3

[0706]

[0707]

[0708] Note Compounds 197 and 199 were isolated and tested as HC1 salts.

[0709] The following compounds shown in Table 4 were purchased from Chem DIV, Inc.

[0710] Table 4

[0711]

[0712]

[0713] The following compounds shown in Table 5 can be prepared from readily available starting materials using chemical routes readily understood by those of ordinary skill in the art.

[0714] Table 5

[0715]

[0716]

[0717]

[0718]

[0719]

[0720]

[0721]

[0722]

[0723]

[0724]

[0725] NoteCompounds 239, 240, 242 and 243 were isolated and tested as HCOOH salts; compounds 246, 247 and 248 were isolated and tested as HC1 salts.

[0726] The following compounds shown in Table 5a can be prepared from readily available starting materials using chemical routes that will be readily understood by those of ordinary skill in the art.

[0727] Table 5a

[0728]

[0729]

[0730]

[0731]

[0732]

[0733] The following compounds shown in Table 6 can be prepared from readily available starting materials using chemical routes that will be readily understood by those of ordinary skill in the art.

[0734] Table 6

[0735]

[0736] Note Compounds 397, 398 and 399 were isolated and tested as HC1 salts.

[0737] Example 2 - Assay Results

[0738] Assay protocol

[0739] Approximately 2500 primary and immortalized human bronchial epithelial cells (BEAS-2B) stably expressing TFEB-EGFP in 25 μL of HITES medium containing 10% FBS were dispensed into 384-well plates (black, glass bottom) and incubated for 8 hours. Compound serial dilutions were prepared using an automated liquid handler (DMEM low glucose medium with 2% FBS, 25 μL volume). The compound solutions were then added to the cell plates and incubated for 18 hours. The cells were then fixed with 4% PFA and then DAPI stained. TFEB localization was imaged on the GFP channel along with the DAPI signal using a Cytation 5 high content imager. Images were processed by Biotek Gen5 software. Specifically, the DAPI signal was used as a primary mask to quantify the nuclear TFEB-GFP signal. The TFEB-GFP signal of the cytoplasmic matrix was quantified by extending the primary mask. The TFEB nuclear / cytoplasmic matrix ratio was calculated from the nuclear TFEB-GFP signal / cytoplasmic matrix TFEB-GFP signal, which determined the efficacy of the compounds.

[0740] Compound efficacy (μM) was determined from the minimum compound concentration required to increase the TFEB nuclear / cytoplasmic matrix ratio by 25%. Activity: “+” equals > 25 μM; “++” equals ≤ 25 μM and > 1 μM; and “+++” equals ≤ 1 μM.

[0741] Toxicity was determined by determining the compound concentration required to induce greater than 50% cell loss. For toxicity, greater than 50% cell loss at concentrations equal to or greater than 25 μM was indicated as “+”; greater than 50% cell loss at concentrations less than 25 μM and greater than 1 μM was indicated as “++”; and greater than 50% cell loss at concentrations equal to or less than 1 μM was indicated as “+++”. The assay results for compounds 1-202, 214-248, 332, 333, and 352-402 are shown in Table A.

[0742] Table A. Compound efficacy and toxicity results.

[0743]

[0744]

[0745]

[0746]

[0747]

[0748] Example 3 - Use of BC1753 to Increase TFEB Polypeptide Levels

[0749] BC1753 was tested. Figure 2A The ability to increase TFEB peptide levels was investigated. In short, mouse 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 TFEB-GFP protein levels were determined by Western blotting. Figure 2B Mouse lung epithelial cells (MLE12) stably expressing TFEB-EGFP were treated with BC1753 in a dose-dependent manner for 18 hours. Cells were then fixed with 4% PFA and stained with DAPI. TFEB localization along with the DAPI signal was imaged on the GFP channel using a Nikon A1 confocal microscope. Figure 2C BC1753 significantly increased the intracellular total TFEB peptide level. Figure 2B ) and increased the accumulation of nuclear TFEB peptides ( Figure 2C ).

[0750] Example 4 - Compounds for Increasing TFEB Polypeptide Levels

[0751] Within the nucleus

[0752] High-content imaging screening was performed using Beas2B cells stably expressing GFP-TFEB. This method demonstrated a robust and accurate measurement of the TFEB nucleus / cytoplasmic matrix ratio after treatment with various compounds. Figure 3 ).

[0753] Example 5 - Increasing the Number of Lysosomes, Increasing Expression of Lysosomal Proteins,

[0754] and Increasing Secretion of Lysosomal Enzymes

[0755] Compounds 178 (BC1834) and / or 160 (BC18200) at specified concentrations were found to increase lysosomal mass. Figure 4A -B), increases lysosomal protein expression ( Figure 5A and increases the secretion of the lysosomal enzyme β-hexosaminease. Figure 5B ).

[0756] Example 6 - Use of Compounds Provided Herein to Decrease Huntingtin Polypeptide Levels

[0757] The ability of compound 178 (BC1834) to reduce intracellular huntingtin protein levels was tested. Briefly, compound 178 was administered to SH5Y cells stably expressing GFP-huntingtin protein (72Q). Figure 6A As shown in Figure B, compound 178 dose-dependently reduced the level of GFP-huntington protein. These results demonstrate that the compounds presented herein may be used to treat neurological disorders such as Huntington's disease.

[0758] Example 7 - In Vivo Effects

[0759] Female C57BL6 mice were injected intraperitoneally with compound 15 (50 mg / kg / day) for 4 days. The mice were then injected intravenously with dextran blue. After 24 hours, the mice were sacrificed, liver samples were removed and imaged by confocal microscopy. As shown in Figure 7 Figure 18, compound 15 treatment significantly increased lysosomal dextran blue signal and lamp2 staining (pseudocolor white). These results demonstrate that the compounds provided herein can increase lysosome number and activity in vivo.

[0760] Other Embodiments

[0761] It is to be understood that while the application has been described in conjunction with the specific embodiments thereof, the foregoing description is intended to illustrate and not limit the scope of the application. Other aspects, advantages and modifications are within the scope of the following claims.

Claims

1. A compound, said compound being selected from the group consisting of: Or its pharmaceutically acceptable salt.

2. A compound, said compound being selected from the group consisting of: Or its pharmaceutically acceptable salt.

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