RU2838857C2 - Methods and materials for increasing eb transcription factor polypeptide levels - Google Patents

Abstract

FIELD: biotechnology; medicine.

SUBSTANCE: invention relates to biotechnology and can be used in medicine. Disclosed are novel heterocyclic compounds suitable for increasing the levels of the polypeptide of the transcription factor EB in the cell nucleus in a mammal.

EFFECT: invention can be used for induction of lysosomal biogenesis, as well as in treatment of diseases accompanied by accumulation of pathological aggregates of complex molecules, for example glycosaminoglycans and some other proteins.

8 cl, 7 dwg, 7 tbl, 8 ex

Description

STATEMENT OF PRIORITY

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

RESEARCH WORKS FUNDED FROM THE FEDERAL BUDGET

This invention was made with federal support under grant numbers 1R35HL139860 and 1R01HL142777 awarded by the National Institutes of Health (NIH). The Government has certain rights in this invention.

AREA OF TECHNOLOGY

This document relates to methods and materials for increasing levels of transcription factor EB (TFEB) polypeptide. For example, this document provides compounds (e.g., organic compounds) having the ability to increase levels of TFEB polypeptide in cells, dosage forms containing compounds having the ability to increase levels of TFEB polypeptide, methods for producing compounds having the ability to increase levels of TFEB polypeptide in cells, methods for increasing levels of TFEB polypeptide in cells, and methods for treating mammals (e.g., humans) suffering from a pathological condition susceptible to an increase in levels of TFEB polypeptide.

LEVEL OF TECHNOLOGY

Lysosomes are membrane-bound cellular organelles that contain various degradative enzymes responsible for the metabolism and degradation of various biomolecules such as proteins, lipids, and nucleic acids that are damaged or no longer needed by the cell. In the absence of functional lysosomes, undigested molecules rapidly accumulate in the lysosome and then in the cytoplasm, leading to cellular damage and one of the causes of many pathological conditions.

TFEB is an important transcription factor that regulates the expression of hundreds of genes controlling 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 is translocated from the cell cytoplasm to the nucleus, it activates the expression of its target genes, which has been shown to induce lysosomal biogenesis and enhance the breakdown 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)). Some small molecule activators of TFEB have been shown to be useful for the treatment of metabolic and age-related disorders (Wang et al ., Nat. Commun. , 8:2270 (2017)).

ESSENCE OF THE INVENTION

Provided herein are methods and materials for increasing TFEB polypeptide levels. For example, provided herein are compounds (e.g., organic compounds) having the ability to increase TFEB polypeptide levels in cells, dosage forms comprising compounds having the ability to increase TFEB polypeptide levels, methods for producing compounds having the ability to increase TFEB polypeptide levels in cells, methods for producing dosage forms comprising compounds having the ability to increase TFEB polypeptide levels in cells, methods for increasing TFEB polypeptide levels in cells, and methods for treating mammals (e.g., humans) suffering from a pathological condition susceptible to an increase in TFEB polypeptide levels. The present document also provides compounds (e.g., organic compounds) having the ability to increase TFEB polypeptide levels in cell nuclei, dosage forms comprising compounds having the ability to increase TFEB polypeptide levels, methods for producing compounds having the ability to increase TFEB polypeptide levels in cell nuclei, methods for producing dosage forms comprising compounds having the ability to increase TFEB polypeptide levels in cell nuclei, methods for increasing TFEB polypeptide levels in cell nuclei, and methods for treating mammals (e.g., humans) suffering from a pathological condition susceptible to an increase in TFEB polypeptide levels in cell nuclei.

As described herein, the compounds provided herein can be used to increase TFEB polypeptide levels in cells in vitro or in vivo and/or in cell nuclei in vitro or in vivo . For example, the compounds provided herein can be used to increase nuclear polypeptide levels of endogenously produced TFEB polypeptide in mammalian (e.g., human) cells. Additionally, the compounds provided herein can be used to treat mammals (e.g., humans) suffering from a disease, disorder, or pathological condition associated with low cellular and/or nuclear levels of TFEB polypeptides. In some cases, the compounds provided herein can be used to treat mammals (e.g., humans) suffering from a disease, disorder, or pathological condition susceptible to an increase in TFEB polypeptide levels in cells and/or cell nuclei.

In some embodiments of this document, a method is provided for increasing the levels of a TFEB polypeptide in a cell and/or in the nucleus of a cell. The method includes (or consists essentially of, or consists of) administering to a mammal (e.g., a human) containing said cell, a compound of formula (I):

(I),

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

In some embodiments of the present document, there is provided a method of treating a disease, disorder or condition selected from the group consisting of lysosomal storage diseases (LSD), acute or chronic inflammatory disorders, neurological diseases and age-related functional decline conditions in mammals (e.g., humans). The proposed method comprises (or consists essentially of, or consists of) administering to a mammal (e.g., a human) suffering from said disease, disorder or condition, a compound of formula (I):

(I),

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

In some embodiments of this document, a compound of formula (IIa) is proposed:

(IIa),

or a pharmaceutically acceptable salt thereof, wherein X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ , ^RA , ^RB and Y are as described herein.

In some embodiments of this document, a compound of formula (IIb) is proposed:

(IIb),

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.

In some embodiments of this document, a compound selected from any of the following formulas is provided:

(IIc); (IId);

(IIe); (IIf);

(IIg); (IIh) and

(IIi),

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

In some embodiments of this document, a compound of formula (III) is proposed:

(III),

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

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

In some embodiments of the present document, a method for increasing the levels of a TFEB polypeptide in a cell and/or in the nucleus of a cell is provided. The proposed method comprises (or consists essentially of, or consists of) administering to a mammal (e.g., a human) containing said cell, a therapeutically effective amount of any one or more compounds described herein (or one or more pharmaceutically acceptable salts thereof).

In some embodiments of the present document, there is provided a method of treating a disease, disorder or pathological condition selected from the group consisting of lysosomal storage diseases (LSD), acute or chronic inflammatory disorders, neurological diseases and pathological conditions of age-related decline in functional abilities in mammals (e.g., humans), and congenital or acquired muscular diseases. The proposed method comprises (or consists essentially of, or consists of) administering to a mammal (e.g., a human) suffering from said disease, disorder or pathological condition, a therapeutically effective amount of any one or more compounds described herein (or one or more pharmaceutically acceptable salts thereof).

In some embodiments of the present document, there is provided a method of treating a disease, disorder or pathological condition selected from the group consisting of lysosomal storage diseases (LSD), acute or chronic inflammatory disorders, neurological diseases and pathological conditions of age-related functional decline in mammals (e.g., humans). The proposed method comprises (or consists essentially of, or consists of) administering to a mammal (e.g., a human) suffering from said disease, disorder or pathological condition, a therapeutically effective amount of any one or more compounds described herein (or one or more pharmaceutically acceptable salts thereof).

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

Other features and advantages of this application will become apparent from the following detailed description and drawings, as well as from the claims.

DESCRIPTION OF GRAPHIC MATERIALS

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

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

Fig. 3. Multiparameter screening assay (384 wells) to measure TFEB nuclear accumulation. About 2500 primary and immortalized human bronchial epithelial cells (BEAS-2B) stably expressing TFEB-EGFP in 25 μl HITE medium with 10% FBS were distributed in a 384-well plate (black with glass bottom) and incubated for 8 h. Serial dilutions of compounds (low glucose DMEM medium with 2% FBS, 25 μl volume) were prepared using a robotic liquid manipulator. The compound solutions were then added to the plate with the cells and incubated for 18 h. The cells were then fixed with 4% PFA, then stained with DAPI. TFEB localization was visualized on the GFP channel together with the DAPI signal using a Cytation 5 multiparameter imager. Images were processed using Biotek Gen5 software; specifically, the DAPI signal was used as a primary mask to quantify the nuclear TFEB-GFP signal. Cytosolic TFEB-GFP signal was quantified by expanding the primary mask. The nuclear/cytosolic TFEB ratio was calculated based on the ratio of the nuclear TFEB-GFP signal to the cytosolic TFEB-GFP signal, which determines the potency of the compound. The table shows the potency of the compound (at increasing compound concentrations) in increasing the nuclear/cytosolic TFEB ratio. Compound potencies (μM) were defined as the minimum concentration of the compound required to increase the nuclear/cytosolic TFEB ratio by 25%. Potency: “-” indicates > 25 μM; “+” indicates ≤25 μM to >10 μM; “++” means ≤10 μM to > 1 μM; and “+++” means ≤1 μM. N=4.

Fig. 4A-B. Compound 178 (BC1834) and compound 160 (BC 18200) increase lysosome abundance. A. Beas2B cells were treated with compound 178, compound 160, or the GSK3b inhibitor TWS119 (1 μM for 18 h). Cells were then imaged by light microscopy. B. Beas2B cells were treated with compound 178 for 18 h at the indicated concentrations. Cells were then stained with Lysotracker Red (100 nM) for 30 min. Cells were then washed and imaged by confocal microscopy.

Fig. 5A-B. Compound 133 and compound 115 increase lysosomal protein expression and secretion. A. Beas2B cells were treated with compound 133 at 10 μM for 24 h. The cells were then harvested and analyzed for lysosomal protein gene expression. B. Beas2B cells were treated with compound 115 at the indicated concentrations for 18 h. Secreted β-hexosaminidase (a lysosomal enzyme) activity was then measured and normalized to cellular β-hexosaminidase activity.

Fig. 6A-B. Compound 178 reduces Huntingtin gene expression. AB. SH5Y cells stably transfected with GFP-72Q (Huntingtin) were treated with the indicated amounts of compound 178 for 24 hours. Cells were then visualized using a confocal microscope or harvested and analyzed for protein expression using GFP-Huntingtin immunoblotting.

Fig. 7. Compound 15 increases lysosomal activity in the liver. Female C57BL6 mice were treated intraperitoneally (ip) with compound 15 (50 mg/kg/day) for 4 days. The mice were then treated intravenously (iv) with dextran blue. After 24 h, the mice were euthanized, the livers were removed, and they were imaged by confocal microscopy. The white fluorescent signal indicates dextran blue in lysosomes and allows measurement of the number and activity of lysosomes in liver tissue (upper panels). In another experiment, liver histology preparations from the above experiment were immunostained with Lamp2 antibody (lower panels) and showed enhanced signals upon treatment with compound 15. Scale bar: 50 μm.

DETAILED DESCRIPTION

Provided herein are methods and materials for increasing TFEB polypeptide levels. For example, provided herein are therapeutic compounds (e.g., therapeutic organic compounds) having the ability to increase TFEB polypeptide levels in cells, dosage forms comprising therapeutic compounds having the ability to increase TFEB polypeptide levels, methods for producing therapeutic compounds having the ability to increase TFEB polypeptide levels in cells, methods for producing dosage forms comprising therapeutic compounds having the ability to increase TFEB polypeptide levels in cells, methods for increasing TFEB polypeptide levels in cells, and methods for treating mammals (e.g., humans) suffering from a pathological condition susceptible to an increase in TFEB polypeptide levels. Also provided herein are therapeutic compounds (e.g., organic compounds) having the ability to increase TFEB polypeptide levels in cell nuclei, dosage forms comprising therapeutic compounds having the ability to increase TFEB polypeptide levels, methods for producing therapeutic compounds having the ability to increase TFEB polypeptide levels in cell nuclei, methods for producing dosage forms comprising therapeutic compounds having the ability to increase TFEB polypeptide levels in cell nuclei, methods for increasing TFEB polypeptide levels in cell nuclei, and methods for treating mammals (e.g., humans) suffering from a pathological condition susceptible to an increase in TFEB polypeptide levels in cell nuclei.

Treatment methods

The lysosome is a compartment within the cell that is responsible for the degradation of damaged proteins and organelles (such as mitochondria). The pH within the lysosome is maintained at a very acidic level and there are numerous degradative enzymes that can efficiently break down organelles and various biomolecules such as proteins, lipids, and nucleic acids that are either damaged or no longer needed by the cell. Delivery of damaged contents to the lysosome can occur in a variety of ways, but one way in which damaged cargo enters the lysosome is through the process of macroautophagy (in this context, “autophagy”). This involves wrapping damaged biomolecules and organelles in a double-membrane structure known as an autophagosome, which then fuses with the lysosome. This process is responsible for maintaining cellular and tissue homeostasis. In the absence of autophagic flux and functional lysosomes, damaged biomolecules and organelles accumulate within the cell. Such damaged and non-functional components can contribute to further damage. A disruption of this system typically results in a number of pathological conditions. In rare inherited conditions called lysosomal storage diseases (LSDs), a child often inherits two copies of a defective lysosomal enzyme. LSDs are a collection of about 50 different inherited conditions that make the patient’s lysosomes unable to metabolize a specific molecule that the missing enzyme normally breaks down. This deficiency causes undegraded molecules to accumulate in the lysosome, causing the lysosome to swell greatly. As the lysosome swells and fills with undegraded material, it eventually becomes dysfunctional not only in breaking down the specific molecule normally broken down by the missing enzyme, but also in its ability to recycle in general. Although a number of replacement therapies have recently become available for specific diseases in which the “missing” enzyme is given back to the child to partially compensate for the inherited defect, there are currently no replacement therapies available for many lysosomal storage diseases. Furthermore, even when replacement therapies exist, such protein-based therapies are often only moderately successful because they often cannot treat the pathological condition in the central nervous system (due to the blood-brain barrier) or penetrate certain cell types. In addition to LSD, the described process of autophagy and lysosomal degradation is known to naturally slow with age. A natural consequence of this is the age-related accumulation of damaged contents in cells and tissues. This can be detrimental and contribute to the development of a number of age-related diseases. Enhancement of autophagy and lysosomal function, as described herein, can be used to correct this impairment. In other circumstances, stimulation of autophagy and lysosomal function may be beneficial. These include metabolic conditions (eg, non-alcoholic steatohepatitis (NASH) or fatty liver disease), neurodegenerative conditions (eg, Parkinson's disease, ALS, Alzheimer's disease, and Huntington's disease), a number of other common age-related conditions (eg, macular degeneration, sarcopenia, and frailty), non-neurological disorders of protein aggregation (eg, β-1 antitrypsin deficiency, amyloidosis, and retinitis pigmentosa), or in immunocompromised conditions (eg, aiding in the clearance of microbiological pathogens, including intracellular pathogens such as Mycobacterium tuberculosis, or in conditions characterized by chronic bacterial colonization such as cystic fibrosis).

TFEB is a major regulator of lysosome biogenesis. Increasing the levels of TFEB polypeptide in cells and/or in the nucleus of cells using a compound provided herein (e.g., a compound represented by formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) as described herein can provide one or more benefits to a cell and/or mammal. For example, increasing the levels of TFEB polypeptide in cells and/or in the nucleus of cells using a compound provided herein (e.g., a compound represented by formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) as described herein can provide an increase in the number of lysosomes in cells and/or an enhancement of lysosomal function in cells. In some cases, increasing the levels of TFEB polypeptide in cells and/or in the nucleus of cells using a compound provided herein (e.g., a compound represented by formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof), as described herein, can provide (a) an increase in the level of lysosomal exocytosis (the process of releasing the contents of a lysosome from a cell into the serum), (b) a transcriptional increase in multiple factors regulating autophagy, and/or (c) a coordinated increase in the capacity for recycling within the cell and the removal of intracellular debris (e.g., an increase in autophagy, lysosome number, and lysosomal exocytosis). In some cases, increasing the levels of TFEB polypeptide in cells and/or in the nucleus of cells using a compound provided herein (e.g., a compound represented by formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof), as described herein, can provide a reduction in one or more symptoms associated with LSD, β-1-antitrypsin deficiency, a neurodegenerative disease (e.g., Alzheimer's disease, Parkinson's disease, ALS, or Huntington's disease), a metabolic disease (e.g., NASH), or an age-related condition (e.g., sarcopenia).

In some cases, provided herein are methods for increasing the levels of a TFEB polypeptide in cells and/or in the nucleus of cells by contacting a cell with one or more compounds provided herein (e.g., a compound represented by formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof). The increase in the levels of the TFEB polypeptide can be compared to the levels of the TFEB polypeptide prior to the contacting step. In some cases, the methods for increasing the levels of a TFEB polypeptide in cells and/or in the nucleus of cells can be performed in vivo . For example, one or more compounds provided herein (e.g., a compound represented by 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 levels of the TFEB polypeptide in cells and/or in the nucleus of cells of said mammal. In some cases, methods for increasing the levels of TFEB polypeptide in cells and/or in the nucleus of cells can be performed in vitro . For example, one or more compounds provided herein (e.g., a compound represented by 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 levels of TFEB polypeptide in the cells and/or in the nucleus of said cells. In some cases, such intervention can provide for improved cell quality while the cell is in culture or later. In some cases, one or more compounds provided herein can be used during ex vivo expansion of 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 number of other cell products that are ultimately to be administered to a mammal (e.g., a human) can be processed as described herein during their in vitro propagation.

In some cases, provided herein are methods of enhancing lysosomal exocytosis in a cell by contacting the cell with one or more compounds provided herein (e.g., a compound represented by formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof). The enhancement of lysosomal exocytosis can be compared to the level of lysosomal exocytosis before the contacting step. In some cases, the methods of enhancing lysosomal exocytosis in a cell can be performed in vivo . For example, one or more compounds provided herein (e.g., a compound represented by formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) can be administered to a mammal (e.g., a human) to enhance lysosomal exocytosis in a cell located in the body of said mammal. In some cases involving LSD, one or more compounds provided herein can be administered to a mammal suffering from LSD, thereby allowing the release of accumulated undigested lysosomal material via exocytosis from the affected cell, tissue, and/or organ. In some cases, methods for enhancing lysosomal exocytosis in a cell can be performed in vitro . For example, one or more compounds provided herein (e.g., a compound represented by formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) can be added to a cell culture comprising cells (e.g., human cells) to enhance lysosomal exocytosis in said cells.

In some cases, provided herein are methods of enhancing cellular autophagy in a cell by contacting the cell with one or more compounds provided herein (e.g., a compound represented by formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof). The enhancement of cellular autophagy can be compared to the level of cellular autophagy prior to the contacting step. In some cases, the methods of enhancing cellular autophagy in a cell can be performed in vivo . For example, one or more compounds provided herein (e.g., a compound represented by formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) can be administered to a mammal (e.g., a human) to enhance cellular autophagy in a cell located in the body of said mammal. In some cases, the methods of enhancing cellular autophagy in a cell can be performed in vitro . For example, one or more compounds provided herein (e.g., a compound represented by 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 enhance cellular autophagy in said cells.

In some cases, provided herein are methods of increasing the nuclear localization of TFEB polypeptides in a cell by contacting the cell with one or more compounds provided herein (e.g., a compound represented by formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof). The increase in nuclear localization of the TFEB polypeptides can be compared to the level of nuclear localization of the TFEB polypeptides prior to the contacting step. In some cases, the methods of increasing the nuclear localization of TFEB polypeptides in a cell can be performed in vivo . For example, one or more compounds provided herein (e.g., a compound represented by 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 nuclear localization of the TFEB polypeptides in a cell located in the mammal. In some cases, the methods of increasing the nuclear localization of TFEB polypeptides in a cell can be performed in vitro . For example, one or more compounds provided herein (e.g., a compound represented by 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 nuclear localization of TFEB polypeptides in said cells.

This document also provides methods for treating diseases, disorders and pathological conditions in a mammal by administering one or more compounds provided herein (e.g., a compound represented by formula (I), (IIa-IIi) or (III), or a pharmaceutically acceptable salt thereof) to a mammal in need thereof. In some cases, the disease, disorder, or condition being treated may be a disease, disorder, or condition that is susceptible to increased levels of TFEB polypeptides in cells and/or in the nucleus of cells in a mammal. In some cases, the disease, disorder, or condition being treated may be a disease, disorder, or condition that is associated with low levels of TFEB polypeptides in cells and/or in the nucleus of cells in a mammal. Examples of diseases, disorders, and pathological conditions that can be treated with one or more compounds provided herein (e.g., a compound represented by formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) as described herein include, but are not limited to, lysosomal storage diseases, acute and chronic inflammatory disorders, conditions associated with age-related functional decline, acute or chronic organ failure (e.g., renal, pulmonary, cardiac, or hepatic dysfunction), protein aggregation disorders, neurodegenerative conditions, and congenital or acquired muscle diseases. Examples of diseases, disorders, and pathological conditions that can be treated with one or more compounds provided herein (e.g., a compound represented by formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) as described herein include, but are not limited to, lysosomal storage diseases, acute and chronic inflammatory disorders, conditions associated with age-related functional decline, acute or chronic organ failure (e.g., renal, pulmonary, cardiac, or hepatic dysfunction), protein aggregation disorders, and neurodegenerative conditions.

Examples of lysosomal storage diseases that can be treated with one or more compounds provided herein (e.g., a compound represented by formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) as described herein include, but are 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, mucolipidin 1 deficiency, neuronal ceroid lipofuscinosis (Batten disease), mucopolysaccharidoses types I, II, III, IV, VI, VII, and IX, Hurler-Scheie syndrome, Morquio syndrome, glycoproteinosis, glycogen storage disease, metachromatic leukodystrophy, Sly syndrome, I-cell disease, Danon disease, Niemann-Pick disease types A, B, C1 and C2, Sandhoff disease, lysosomal acid lipase deficiency, GM2 gangliosidosis, Tay-Sachs disease, Gaucher disease, Salla disease, Pompe disease, Danon disease, cholesteryl ester storage disease, aspartylglucosaminuria, cystinosis, mucolipidosis types I-IV, Schindler disease types I and II, Wolman disease, fucosidosis, pycnodysostosis and free sialic acid storage disease.

Examples of acute or chronic inflammatory disorders that can be treated with one or more compounds provided herein (e.g., a compound represented by 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, pneumonitis (e.g., hypersensitivity pneumonitis or radiation pneumonitis), pneumonia, cystic fibrosis, psoriasis, arthritis/rheumatoid arthritis, rhinitis, pharyngitis, cystitis, prostatitis, dermatitis, allergies including hay fever, nephritis, conjunctivitis, encephalitis, meningitis, ophthalmitis, uveitis, pleurisy, pericarditis, myocarditis, atherosclerosis, human immunodeficiency virus-associated inflammation, diabetes, osteoarthritis, psoriatic arthritis, inflammatory bowel disease (eg, Crohn's disease or ulcerative colitis), colitis, sepsis, vasculitis, bursitis, connective tissue disease, autoimmune diseases (eg, systemic lupus erythematosus (SLE)), polymyalgia rheumatica, scleroderma, Wegener's granulomatosis, temporal arteritis, vasculitis, cryoglobulinemia, multiple sclerosis, viral or influenza-induced inflammation, chronic bacterial colonization or persistent intracellular pathogen, and impaired response to antigen challenge or vaccine administration.

Examples of pathological conditions associated with age-related functional decline that can be treated with one or more compounds provided herein (e.g., a compound represented by formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt) 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 inherited or acquired degenerative retinal diseases, age-related hearing loss, early cognitive decline, osteoporosis, acute or age-related organ dysfunction (e.g., cardiac and/or renal dysfunction), age-related immune dysfunction (e.g., impaired response to vaccination or immune senescence), and other non-neurological protein aggregation disorders (e.g., amyloidosis or α-1-antitrypsin deficiency).

Examples of inherited or acquired muscle diseases that can be treated with one or more compounds provided herein (e.g., a compound represented by 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 with frontotemporal dementia (IBMFTD), and cardiomyopathy (e.g., dilated cardiomyopathy or proteotoxic cardiomyopathy, such as disseminated proteotoxic cardiomyopathy).

In some cases, one or more compounds provided herein (e.g., a compound represented by formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) can be used as described herein (e.g., to increase TFEB polypeptide levels in the nucleus of cells and/or to treat a disease, disorder, or condition described herein) as the sole active ingredient(s). For example, a composition comprising a compound represented by formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof, may not contain other active ingredients that increase the levels of TFEB polypeptides in the nucleus of cells. In some cases, a composition comprising a compound represented by formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof, may not contain other active ingredients that are effective for treating a disease, disorder, or pathological condition described herein.

Therapeutic compounds

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

In some embodiments of this document, a compound of formula (I) is provided:

(I),

or a pharmaceutically acceptable salt thereof, wherein:

each L is independently selected from O, S, S(=O) ₂ , _C1-3alkylene , C(=O) and N(R ^N ), wherein said _C1-3alkylene is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, CN, _NO2 , OH, _C1-3alkoxy , amino, _{C1-3alkylamino} and di( _C1-3alkyl )amino;

each R ^N is independently 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 halogen, CN, NO ₂ , 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) ₂ R ^b1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 ;

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

X ¹ is selected from N, N ⁺ -O ^- and CR ¹ ;

X ² is selected from N, N ⁺ -O ^- and CR ² ;

X ³ is selected from N, N ⁺ -O ^- and CR ³ ;

X ⁴ is selected from N, N ⁺ -O ^- and CR ⁴ ;

X ⁵ is selected from N, N ^{+ -O-} and CR ⁵ ;

X ⁶ is selected from N, N ^{+ -O-} and CR ⁶ ;

provided that no more than four of X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ represent N;

each R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from H, halogen, CN, NO ₂ , 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) ₂ R ^b1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 ; wherein each 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 CN, NO ₂ , 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) ₂ R ^b1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 ;

R ^A is selected from Cy ^A1 , O-Cy ^A1 and N(R ^N )-Cy ^A1 ;

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 ;

R ^B is selected from C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl and Cy ¹ , each of said C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl being optionally substituted with 1, 2 or 3 substituents independently selected from Cy ¹ , CN, NO ₂ , 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) ₂ R ^b1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 ;

or if R ^B is attached to L which is N(R ^N ), then R ^B and R ^N together with the N atom to which they are attached form a 4- to 14-membered heterocycloalkyl which is optionally substituted with 1, 2 or 3 substituents independently selected from Cy ¹ , halogen, CN, NO ₂ , 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) ₂ R ^b1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 ; wherein each 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, NO ₂ , 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) ₂ R ^b1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 ;

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 ;

each R ^Cy1 and R ^Cy2 is independently selected from oxo, halogen, CN, NO ₂ , 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) ₂ R ^b2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 ; wherein each 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 ² , halogen, CN, NO ₂ , 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) ₂ R ^b2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 ;

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 halogen, CN, NO 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) ₂ R ^b2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 ; wherein each 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 halogen, CN, NO ₂ , 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) ₂ R ^b2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 ;

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 _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 each said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, _C6-10 aryl, _C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, _C6-10 aryl- _C1-4 alkylene, _C3-10 cycloalkyl- _C1-4 alkylene, (5-10 membered heteroaryl) _-C1-4 alkylene and (4-10 membered heterocycloalkyl) _-C1-4 alkylene are optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ^g ;

or any of 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 ;

or any of R ^c2 and R ^d2 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 ; and

each R ^g is independently selected from OH, NO ₂ , 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, carbamyl, C _1-6 alkylcarbamyl, di(C _1-6 alkyl)carbamyl, carboxy, 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.

In some embodiments:

R ^B and R ^N together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl which is optionally substituted with 1, 2 or 3 substituents independently selected from Cy ¹ , halogen, CN, NO ₂ , 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) ₂ R ^b1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 ; wherein each 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, NO ₂ , 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) ₂ R ^b1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 ; and

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 .

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 of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ^Cy1 ; and

each R ^Cy1 and R ^Cy2 are independently selected from halogen, CN, NO ₂ , 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) ₂ R ^b2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 ; wherein each 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 ² , halogen, CN, NO ₂ , 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) ₂ R ^b2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 .

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

In some embodiments, L is independently selected from C _1-3 alkylene, C(=O), and N(R ^N ), wherein said C _1-3 alkylene is optionally substituted with an OH group.

In some embodiments, L is C _1-3 alkylene that is optionally substituted with halogen, CN, NO ₂ , OH, C _1-3 alkoxy, or amino.

In some embodiments, L is C _1-3 alkylene that is optionally substituted with an OH group.

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

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

In some embodiments, R ^N 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 halogen, CN, NO ₂ , and C _1-3 alkoxy.

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 optionally substituted with halogen, CN, NO ₂ , or C _1-3 alkoxy.

In some embodiments, L is NH.

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, 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) ₂ R ^b1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 .

In some embodiments, each R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from H, halogen, CN, C _1-6 alkyl, OR ^a1 , NR ^c1 R ^d1 and S(O) ₂ R ^b1 .

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) ₂ R ^b1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 .

In some embodiments, each R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from H, halogen, C _1-6 alkyl and C _1-6 alkoxy.

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

,

or a pharmaceutically acceptable salt thereof.

In some embodiments, each R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from H, halogen, C _1-6 alkyl and C _1-6 alkoxy. In some embodiments, each R ³ , R ⁴ , R ⁵ and R ⁶ is H.

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

,

or a pharmaceutically acceptable salt thereof.

In some embodiments, each R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from H, halogen, C _1-6 alkyl and C _1-6 alkoxy. In some embodiments, each R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is H.

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

(IIc),

or a pharmaceutically acceptable salt thereof.

In some embodiments, each R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from H, halogen, C _1-6 alkyl and C _1-6 alkoxy. In some embodiments, each R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ is H.

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

(IId),

or a pharmaceutically acceptable salt thereof.

In some embodiments, each R2, ^R3 , ^R4 , ^R5 , and ^R6 is independently selected from H, halogen, _C1-6 alkyl, and _C1-6 alkoxy. In some embodiments, each R2, ^R3 , ^R4 , ^R5 , and ^R6 is H.

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

(IIe),

or a pharmaceutically acceptable salt thereof.

In some embodiments, each R ³ , R ⁴ and R ⁵ is independently selected from H, halogen, C _1-6 alkyl and C _1-6 alkoxy. In some embodiments, each R ³ , R ⁴ and R ⁵ is H.

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

(IIf),

or a pharmaceutically acceptable salt thereof.

In some embodiments, each R ⁴ , R ⁵ and R ⁶ is independently selected from H, halogen, C _1-6 alkyl and C _1-6 alkoxy. In some embodiments, each R ⁴ , R ⁵ and R ⁶ is H.

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

(IIg),

or a pharmaceutically acceptable salt thereof.

In some embodiments, each R ³ , R ⁵ and R ⁶ is independently selected from H, halogen, C _1-6 alkyl and C _1-6 alkoxy. In some embodiments, each R ³ , R ⁵ and R ⁶ is H.

In some embodiments of a compound of formula (IIg), said compound of formula (IIg) is not:

.

In some embodiments of 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 .

In some embodiments of the compound of formula (IIg), R ^B is a 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.

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

(IIh),

or a pharmaceutically acceptable salt thereof.

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

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

,

or a pharmaceutically acceptable salt thereof.

In some embodiments of formula (IIh), each R ¹ , R ³ , R ⁴ and R ⁵ is independently selected from H, halogen, CN, C _1-6 alkyl, OR ^a1 , NR ^c1 R ^d1 and S(O) ₂ R ^b1 .

In some embodiments of formula (IIh), R ³ is selected from H, halogen, CN, OR ^a1 , NR ^c1 R ^d1 , and S(O) ₂ R ^b1 . In some embodiments of formula (IIh), R ¹ is selected from H, halogen, and C _1-6 alkyl.

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

(IIi),

or a pharmaceutically acceptable salt thereof.

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

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

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 of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ^Cy1 .

In some embodiments, 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 .

In some embodiments, R ^A is Cy ^A1 .

In some embodiments, R ^A is O-Cy ^A1 .

In some embodiments, R ^A is NH-Cy ^A1 .

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 of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ^Cy1 .

In some embodiments, 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, 3, 4, or 5 substituents independently selected from R ^Cy1 .

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

In some embodiments, Cy ^A1 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 has the formula:

.

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

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

; ; ; ; ; ; ; ; ; ; ; ; ; And .

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

; ; ; ; And .

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

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

; ; ; ; And .

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

; ; ; And .

In some embodiments, each R ^Cy1 is independently selected from halogen, CN, NO ₂ , 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) ₂ R ^b2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 ; wherein each 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 ² , halogen, CN, NO ₂ , 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) ₂ R ^b2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 .

In some embodiments, each R ^Cy1 is independently selected from halogen, NO ₂ , 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) ₂ R ^b2 , wherein said C _1-6 alkyl is optionally substituted with an OR ^a2 group.

In some embodiments, each R ^Cy1 is independently selected from halogen, NO ₂ , C _1-6 alkyl, OR ^a2 , and C(O)OR ^a2 .

In some embodiments, each R ^Cy1 is independently selected from halogen, NO ₂ , C _1-6 alkyl, OH, C _1-6 alkoxy, and C(O)(C _1-6 alkoxy).

In some embodiments, each R ^Cy1 is independently selected from halogen, NO ₂ , C _1-6 alkyl, C _1-6 alkoxy, and C(O)(C _1-6 alkoxy).

In some embodiments, R ^Cy1 is selected from Cl and F. In some embodiments, R ^Cy1 is NO ₂ . In some embodiments, R ^Cy1 is C _1-6 alkyl or C _1-6 alkoxy.

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) ₂ R ^b1 , and S(O) ₂ NR ^c1 R ^d1 .

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) ₂ R ^b1 , and S(O) ₂ NR ^c1 R ^d1 .

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) ₂ CH ₃ , and S(O) ₂ NH ₂ .

In some embodiments, R ^B is Cy ¹ .

In some embodiments, Cy ¹ is C _6-10 aryl optionally substituted with 1, 2, or 3 substituents independently selected from R ^Cy2 . In some embodiments, C _6-10 aryl has the formula:

.

In some embodiments, Cy ¹ is C _3-14 cycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from R ^Cy2 .

In some embodiments, Cy ¹ is C _3-14 cycloalkyl having a formula selected from:

; ; ;

; And .

In some embodiments, Cy ¹ is C _3-10 cycloalkyl 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:

; ; ; And .

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

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

; ; ; ; ; ; ; ; ; ; And .

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

; ; ; ; ; ; ; ; ; And .

In some embodiments, Cy ¹ is a 5-10 membered heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R ^Cy2 .

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

; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; And .

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

; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; And .

In some embodiments, each R ^Cy2 is independently selected from halogen, CN, NO ₂ , 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) ₂ R ^b2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 ; wherein each 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 ² , halogen, CN, NO ₂ , 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) ₂ R ^b2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 .

In some embodiments, 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) ₂ R ^b2 .

In some embodiments, 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 ^d2 .

In some embodiments, each R ^Cy2 is independently selected from halogen, CN, C _3-10 cycloalkyl, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C(O)(C _1-6 alkyl), C(O)NH ₂ , and NH ₂ .

In some embodiments, R ^Cy2 is a halogen.

In some embodiments, R ^Cy2 is C _1-6 alkyl, C _1-6 haloalkyl, or C _1-6 alkoxy.

In some embodiments, R ^Cy2 is NH ₂ .

In some embodiments, each R ^a1 , R ^b1 , R ^c1 , R ^d1 , R ^a2 , R ^b2 , R ^c2 and R ^d2 is independently selected from H and C _1-6 alkyl.

In some embodiments, R ^B is C _6-10 aryl optionally substituted with 1, 2, or 3 substituents independently selected from R ^Cy2 ; and R ^A is C _6-10 aryl optionally substituted with 1, 2, or 3 substituents independently selected from R ^Cy1 .

In some embodiments, R ^B is a 5-10 membered heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R ^Cy2 ; and R ^A is C _6-10 aryl optionally substituted with 1, 2, or 3 substituents independently selected from R ^Cy1 .

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

In some embodiments, R ^B is C _6-10 aryl optionally substituted with 1, 2, or 3 substituents independently selected from R ^Cy2 ; and R ^A is 5-10 membered heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from R ^Cy1 .

In some embodiments:

n is equal to 1;

L is selected from C _1-3 alkylene, C(=O) and N(R ^N ), wherein said C _1-3 alkylene is optionally substituted with an OH group;

R ^N is selected from H and C _1-6 alkyl;

each R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from H, halogen, CN, C _1-6 alkyl, OR ^a1 , NR ^c1 R ^d1 and S(O) ₂ R ^b1 ;

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

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 ;

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) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 ;

or if R ^B is attached to N(R ^N ), then R ^B and R ^N together with the N atom to which they are attached form a 4- to 14-membered heterocycloalkyl which is optionally substituted by a Cy ¹ group, C _1-6 alkyl, OR ^a1 and halogen;

each R ^Cy1 is independently selected from halogen, NO ₂ , 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) ₂ R ^b2 , wherein said C _1-6 alkyl is optionally substituted with an OR ^a2 group;

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 ;

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) ₂ R ^b2 ; and

each R ^a1 , R ^b1 , R ^c1 , R ^d1 , R ^a2 , R ^b2 , R ^c2 and R ^d2 is independently selected from H and C _1-6 alkyl.

In some embodiments:

n is equal to 1;

L is selected from C _1-3 alkylene, C(=O) and N(R ^N ), wherein said C _1-3 alkylene is optionally substituted with an OH group;

R ^N is selected from H and C _1-6 alkyl;

each R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from H, halogen, CN, C _1-6 alkyl, OR ^a1 , NR ^c1 R ^d1 and S(O) ₂ R ^b1 ;

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

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 ;

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) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 ;

or if R ^B is attached to N(R ^N ), then R ^B and R ^N together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl which is optionally substituted with an OR ^a1 group;

each R ^Cy1 is independently selected from halogen, NO ₂ , 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) ₂ R ^b2 , wherein said C _1-6 alkyl is optionally substituted with an OR ^a2 group;

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 ^d2 ; and

each R ^a1 , R ^b1 , R ^c1 , R ^d1 , R ^a2 , R ^b2 , R ^c2 and R ^d2 is independently selected from H and C _1-6 alkyl.

In some embodiments:

n is equal to 1;

L is selected from C _1-3 alkylene, C(=O) and N(R ^N ), wherein said C _1-3 alkylene is optionally substituted with an OH group;

R ^N is selected from H and C _1-6 alkyl;

each R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from H, halogen, C _1-6 alkyl and OR ^a1 ;

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 ;

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) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 ;

or if R ^B is attached to N(R ^N ), then R ^B and R ^N together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl which is optionally substituted with an OR ^a1 group;

each R ^Cy1 is independently selected from halogen, NO ₂ , C _1-6 alkyl, OR ^a2 and C(O)OR ^a2 ;

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 ^d2 ; and

each R ^a1 , R ^b1 , R ^c1 , R ^d1 , R ^a2 , R ^b2 , R ^c2 and R ^d2 is independently selected from H and C _1-6 alkyl.

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

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

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

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

In some embodiments, the compound of formula (I) is selected from any of formulas (IIc)-(IIi).

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

BC18618 BC18664 BC18666 BC18670 BC18702 BC18703 BC18704 BC18705 BC18706 BC18720 BC18722 BC18738 BC18740 BC18742 BC18853 BC18854 BC191107 BC191108 BC191109 BC191110 BC191111 BC191112 BC191113 BC191114 BC191115 BC191116 BC191117 BC191118 BC191119 BC191120 BC191121 BC191122 BC191123 BC191124 BC191125 BC191126 BC191127 BC191128 BC191129 BC191130 BC191131 BC191132 BC191133 BC191134 BC191135 BC191136 BC191137 BC191138 BC191139 BC191140 BC191142 BC191143 BC191144 BC191145 BC191146 BC191147 BC191148 BC191149 BC191150 BC191151 BC191152 BC191155 BC191156 BC191157 BC191158 BC191159 BC191160 BC191161 BC191162 BC191163 BC191164 BC191165 BC191166 BC191167 BC191168 BC191169 BC191170 BC191171 BC191172 BC191173 BC191185 BC191186 BC191187 BC191188 BC191189 BC191190 BC191191 BC191192 BC191193 BC191194 BC191195 BC191196 BC191197 BC191198 BC191199 BC191200 BC191201 BC191202 BC18829 BC18830 BC18831 BC18832 BC18833 BC18834 BC18835 BC18836 BC18838 BC18839 BC18840 BC18841 BC18845

or a pharmaceutically acceptable salt thereof.

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

BC18618 BC18664 BC18666 BC18670 BC18702 BC18703 BC18704 BC18705 BC18706 BC18720 BC18722 BC18738 BC18740 BC18742

or a pharmaceutically acceptable salt thereof.

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

BC18663 BC18668 BC18669 BC18687 BC18688 BC18689 BC18707 BC18708 BC18709 BC18711 BC18713 BC18714 BC18755 BC18756 BC18757 BC18758 BC18759 BC18760 BC18761 BC18762 BC18763 BC18764 BC18765 BC18766 BC18767 BC18768 BC18769 BC18770 BC18771 BC18772 BC18773 BC18774 BC18775 BC18776 BC18778 BC18783 BC18785 BC18796 BC18799 BC18801 BC18806 BC18808 BC18821 BC18829 BC18830 BC18831 BC18832 BC18837 BC18845

or a pharmaceutically acceptable salt thereof.

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

BC18663 BC18668 BC18669 BC18687 BC18688 BC18689 BC18707 BC18708 BC18709 BC18711 BC18713 BC18714 BC18755 BC18756 BC18757 BC18758 BC18759 BC18760 BC18761 BC18762 BC18763 BC18764 BC18765 BC18766 BC18767 BC18768 BC18769 BC18770 BC18771 BC18772 BC18773 BC18774 BC18775 BC18776 BC18778 BC18783 BC18785 BC18796

or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

(IIa),

or a pharmaceutically acceptable salt thereof, wherein:

Y is selected from C(=O) and C(R ⁷ )(R ⁸ );

each R ⁷ and R ⁸ is independently selected from H, halogen, CN, NO ₂ , OH, C _1-3 alkoxy, amino, C _1-3 alkylamino and di(C _1-3 alkyl)amino;

X ¹ is selected from N, N ⁺ -O ^- and CR ¹ ;

X ² is selected from N, N ⁺ -O ^- and CR ² ;

X ³ is selected from N, N ⁺ -O ^- and CR ³ ;

X ⁴ is selected from N, N ⁺ -O ^- and CR ⁴ ;

X ⁵ is selected from N, N ^{+ -O-} and CR ⁵ ;

X ⁶ is selected from N, N ^{+ -O-} and CR ⁶ ;

provided that no more than four of X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ represent N;

each R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from H, halogen, CN, NO ₂ , 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) ₂ R ^b1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 ; wherein each 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 CN, NO ₂ , 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) ₂ R ^b1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 ;

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 ;

R ^B is selected from C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl and Cy ¹ , each of said C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl being optionally substituted with 1, 2 or 3 substituents independently selected from Cy ¹ , CN, NO ₂ , 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) ₂ R ^b1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 ;

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 ;

each R ^Cy1 and R ^Cy2 are independently selected from halogen, CN, NO ₂ , 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) ₂ R ^b2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 ; wherein each 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 ² , halogen, CN, NO ₂ , 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) ₂ R ^b2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 ;

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 halogen, CN, NO 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) ₂ R ^b2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 ; wherein each 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 halogen, CN, NO ₂ , 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) ₂ R ^b2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 ;

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 _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 each said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, _C6-10 aryl, _C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, _C6-10 aryl- _C1-4 alkylene, _C3-10 cycloalkyl- _C1-4 alkylene, (5-10 membered heteroaryl) _-C1-4 alkylene and (4-10 membered heterocycloalkyl) _-C1-4 alkylene are optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ^g ;

or any of 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 ;

or any of R ^c2 and R ^d2 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 ; and

each R ^g is independently selected from OH, NO ₂ , 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, carbamyl, C _1-6 alkylcarbamyl, di(C _1-6 alkyl)carbamyl, carboxy, 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.

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

,

or a pharmaceutically acceptable salt thereof.

In some embodiments, R ⁷ is H, and R ⁸ is selected from H, halogen, CN, NO ₂ , OH, and C _1-3 alkoxy. In some embodiments, R ⁷ is H, and R ⁸ is selected from H and OH.

In some embodiments, Y is CH ₂ .

In some embodiments, Y is CH(OH).

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

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

,

or a pharmaceutically acceptable salt thereof.

In some embodiments of formula (IIa), each R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from H, halogen, C _1-6 alkyl and C _1-6 alkoxy. In some embodiments, each R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from H, halogen, C _1-6 alkyl and C _1-6 alkoxy. In some embodiments, each R ³ , R ⁴ , R ⁵ and R ⁶ is H.

In some embodiments of formula (IIa), R ^B 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, or 3 substituents independently selected from R ^Cy2 .

In some embodiments of formula (IIa), R ^B is C _6-10 aryl optionally substituted with halogen.

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 .

In some embodiments of formula (IIa), R ^A is 5-10 membered heteroaryl optionally substituted with halogen, NO ₂ , C _1-6 alkyl, or C _1-6 alkoxy.

In some embodiments of formula (IIa):

R ⁷ is H; and R ⁸ is selected from H and OH;

each R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from H, halogen, C _1-6 alkyl and C _1-6 alkoxy;

R ^B is C _6-10 aryl optionally substituted with halogen; and

R ^A is 5-10 membered heteroaryl optionally substituted with halogen, NO ₂ , C _1-6 alkyl or C _1-6 alkoxy.

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

BC18615 BC18616 BC18617

or a pharmaceutically acceptable salt thereof.

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

(IIb),

or a pharmaceutically acceptable salt thereof, wherein:

each L is independently selected from O, S, S(=O) ₂ , _C1-3alkylene , C(=O) and N(R ^N ), wherein said _C1-3alkylene is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, CN, _NO2 , OH, _C1-3alkoxy , amino, _{C1-3alkylamino} and di( _C1-3alkyl )amino;

each R ^N is independently 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 halogen, CN, NO ₂ , 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) ₂ R ^b1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 ;

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

X ¹ is selected from N, N ⁺ -O ^- and CR ¹ ;

X ² is selected from N, N ⁺ -O ^- and CR ² ;

X ³ is selected from N, N ⁺ -O ^- and CR ³ ;

X ⁴ is selected from N, N ⁺ -O ^- and CR ⁴ ;

X ⁵ is selected from N, N ^{+ -O-} and CR ⁵ ;

X ⁶ is selected from N, N ^{+ -O-} and CR ⁶ ;

provided that no more than four of X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ represent N;

each R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from H, halogen, CN, NO ₂ , 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) ₂ R ^b1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 ; wherein each 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 CN, NO ₂ , 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) ₂ R ^b1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 ;

R ^C selected from:

4-10 membered heterocycloalkyl optionally substituted with 1, 2 or 3 substituents independently selected from R ^Cy1 ; and

a group selected from O-Cy ^A1 , N(R ^N )-Cy ^A1 ; and Cy ^A1 ;

each Cy ^A1 represents a 5- to 10-membered heteroaryl group having a formula selected from:

; ; ; ; ; ; ; ; ; ; ; ; And ;

R ^B is selected from C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl and Cy ¹ , each of said C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl being optionally substituted with 1, 2 or 3 substituents independently selected from Cy ¹ , CN, NO ₂ , 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) ₂ R ^b1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 ;

or if R ^B is attached to N(R ^N ), then R ^B and R ^N together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl which is optionally substituted with 1, 2 or 3 substituents independently selected from Cy ¹ , halogen, CN, NO ₂ , 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) ₂ R ^b1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 ; wherein each 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, NO ₂ , 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) ₂ R ^b1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 ;

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 ;

each R ^Cy1 and R ^Cy2 are independently selected from halogen, CN, NO ₂ , 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) ₂ R ^b2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 ; wherein each 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 ² , halogen, CN, NO ₂ , 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) ₂ R ^b2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 ;

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 halogen, CN, NO 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) ₂ R ^b2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 ; wherein each 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 halogen, CN, NO ₂ , 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) ₂ R ^b2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 ;

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 _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 each said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, _C6-10 aryl, _C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, _C6-10 aryl- _C1-4 alkylene, _C3-10 cycloalkyl- _C1-4 alkylene, (5-10 membered heteroaryl) _-C1-4 alkylene and (4-10 membered heterocycloalkyl) _-C1-4 alkylene are optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ^g ;

or any of 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 ;

or any of R ^c2 and R ^d2 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 ; and

each R ^g is independently selected from OH, NO ₂ , 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, carbamyl, C _1-6 alkylcarbamyl, di(C _1-6 alkyl)carbamyl, carboxy, 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.

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

; ; ; And .

In some embodiments of the compound of formula (IIb), said 4-10 membered heterocycloalkyl for R ^C has a formula selected from:

; ; ; ; And .

In some embodiments of the compound of formula (IIb), said 4-10 membered heterocycloalkyl for R ^C has a formula selected from:

; ; ; And .

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

n is equal to 1;

L is selected from C _1-3 alkylene, C(=O) and N(R ^N ), wherein said C _1-3 alkylene is optionally substituted with an OH group;

R ^N is selected from H and C _1-6 alkyl;

each R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from H, halogen, CN, C _1-6 alkyl, OR ^a1 , NR ^c1 R ^d1 and S(O) ₂ R ^b1 ;

R ^C selected from:

4-10 membered heterocycloalkyl selected from:

; ; ;

; And ; And

a group selected from O-Cy ^A1 , N(R ^N )-Cy ^A1 ; and Cy ^A1 , wherein each Cy ^A1 is a 5- to 10-membered heteroaryl group having a formula selected from:

; ; ; ; ; ; ; ; ; ; ;

; And ;

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) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 ;

or if R ^B is attached to N(R ^N ), then R ^B and R ^N together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl which is optionally substituted with an OR ^a1 group;

each R ^Cy1 is independently selected from halogen, NO ₂ , 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) ₂ R ^b2 , wherein said C _1-6 alkyl is optionally substituted with an OR ^a2 group;

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 ^d2 ; and

each R ^a1 , R ^b1 , R ^c1 , R ^d1 , R ^a2 , R ^b2 , R ^c2 and R ^d2 is independently selected from H and C _1-6 alkyl.

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

n is equal to 1;

L is selected from C _1-3 alkylene, C(=O) and N(R ^N ), wherein said C _1-3 alkylene is optionally substituted with an OH group;

R ^N is selected from H and C _1-6 alkyl;

each R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from H, halogen, C _1-6 alkyl and OR ^a1 ;

R ^C selected from:

; ; ; ; ; ; ; And ;

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) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 ;

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

each R ^Cy1 is independently selected from halogen, NO ₂ , C _1-6 alkyl, OR ^a2 and C(O)OR ^a2 ;

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 ^d2 ; and

each R ^a1 , R ^b1 , R ^c1 , R ^d1 , R ^a2 , R ^b2 , R ^c2 and R ^d2 is independently selected from H and C _1-6 alkyl.

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

BC18618 BC18664 BC18666 BC18670 BC18702 BC18703 BC18704 BC18705 BC18706 BC18720 BC18722 BC18738 BC18740 BC18742 BC18853 BC18854 BC191107 BC191108 BC191109 BC191110 BC191111 BC191112 BC191113 BC191114 BC191115 BC191116 BC191117 BC191118 BC191119 BC191120 BC191121 BC191122 BC191123 BC191124 BC191125 BC191126 BC191127 BC191128 BC191129 BC191130 BC191131 BC191132 BC191133 BC191134 BC191135 BC191136 BC191137 BC191138 BC191139 BC191140 BC191142 BC191143 BC191144 BC191145 BC191146 BC191147 BC191148 BC191149 BC191150 BC191151 BC191152 BC191155 BC191156 BC191157 BC191158 BC191159 BC191160 BC191161 BC191162 BC191163 BC191164 BC191165 BC191166 BC191167 BC191168 BC191169 BC191170 BC191171 BC191172 BC191173 BC191185 BC191186 BC191187 BC191188 BC191189 BC191190 BC191191 BC191192 BC191193 BC191194 BC191195 BC191196 BC191197 BC191198 BC191199 BC191200 BC191201 BC191202 BC18829 BC18830 BC18831 BC18832 BC18833 BC18834 BC18835 BC18836 BC18838 BC18839 BC18840 BC18841 BC18845

or a pharmaceutically acceptable salt thereof.

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

BC18618 BC18664 BC18666 BC18670 BC18702 BC18703 BC18704 BC18705 BC18706 BC18720 BC18722 BC18738 BC18740 BC18742

or a pharmaceutically acceptable salt thereof.

In some embodiments of this document, a compound of formula (III) is proposed:

(III),

or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is selected from C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl and Cy ¹ , each of said C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl being optionally substituted with 1, 2 or 3 substituents independently selected from Cy ¹ , CN, NO ₂ , 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) ₂ R ^b1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 ;

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 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, NO ₂ , 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) ₂ R ^b1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 ;

each R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from H, halogen, CN, NO ₂ , 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) ₂ R ^b1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 ; wherein each 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 CN, NO ₂ , 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) ₂ R ^b1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 ;

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 ;

each R ^Cy2 is independently selected from halogen, CN, NO 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) ₂ R ^b2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 ; wherein each 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 halogen, CN, NO ₂ , OR ^a2 and C(O)R ^b2 , C(O)NR ^c2 R ^d2 ;

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 _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 each said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, _C6-10 aryl, _C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, _C6-10 aryl- _C1-4 alkylene, _C3-10 cycloalkyl- _C1-4 alkylene, (5-10 membered heteroaryl) _-C1-4 alkylene and (4-10 membered heterocycloalkyl) _-C1-4 alkylene are optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ^g ;

or any of 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 ;

or any of R ^c2 and R ^d2 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 ; and

each R ^g is independently selected from OH, NO ₂ , 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, carbamyl, C _1-6 alkylcarbamyl, di(C _1-6 alkyl)carbamyl, carboxy, 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.

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 .

In some embodiments, R ¹ is C _1-6 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from Cy ¹ .

In some embodiments, R ¹ is Cy ¹ .

In some embodiments, R ¹ is C _2-6 alkenyl.

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 .

In some embodiments, R ² is H.

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)NR ^c1 R ^d1 , and NR ^c1 R ^d1 .

In some embodiments, R ² is C _1-6 alkyl optionally substituted with a Cy ¹ group.

In some embodiments, R ² is C _1-6 alkyl optionally substituted with a C(O)NR ^c1 R ^d1 or NR ^c1 R ^d1 group.

In some embodiments, R ² is C _1-6 alkyl optionally substituted with a C(O)NR ^c1 R ^d1 group.

In some embodiments, R ² is C _1-6 alkyl optionally substituted with a NR ^c1 R ^d1 group. In some embodiments, each R ^c1 and R ^d1 is H. In some embodiments, each R ^c1 and R ^d1 is 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 .

In some embodiments, each R ³ , R ⁴ , R ⁵ , and R ⁶ is independently selected from H and C(O)NR ^c1 R ^d1 .

In some embodiments, each R ³ and R ⁶ is H.

In some embodiments, R ⁴ is C(O)NR ^c1 R ^d1 . In some embodiments, each of R ³ , R ⁵ , and R ⁶ is H. In some embodiments, R ⁵ is C(O)NR ^c1 R ^d1 . In some embodiments, each of R ³ , R ⁴ , and R ⁶ is H. In some embodiments, R ^c1 is H, and R ^d1 is selected from C _6-10 aryl-C _1-4 alkylene and (5-10 membered heteroaryl)-C _1-4 alkylene.

In some embodiments, each 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 .

In some embodiments, Cy ¹ is C _6-10 aryl (e.g., phenyl) optionally substituted with 1, 2, or 3 substituents independently selected from R ^Cy2 .

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

In some embodiments, each R ^Cy2 is independently selected from halogen, CN, C _1-6 alkyl, OR ^a2 ; wherein said C _1-6 alkyl is optionally substituted with a C(O)NR ^c2 R ^d2 group.

In some embodiments, R ^Cy2 is a halogen.

In some embodiments, R ^Cy2 is CN, C _1-6 alkyl, or C _1-6 alkoxy.

In some embodiments, R ^Cy2 is C _1-6 alkyl optionally substituted with a C(O)NR ^c2 R ^d2 group. In 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 of which is optionally substituted with 1, 2, or 3 substituents independently selected from R ^g .

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 each of 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 is optionally substituted with 1, 2 or 3 substituents independently selected from R ^g .

In some embodiments, each R ^g is independently selected from halogen, C _1-6 alkyl, and C _1-6 alkoxy.

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 ;

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 ;

each R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from H and C(O)NR ^c1 R ^d1 ;

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 ;

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 a C(O)NR ^c2 R ^d2 group;

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, each 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 optionally substituted with 1, 2 or 3 substituents independently selected from R ^g ; And

each R ^g is independently selected from halogen, C _1-6 alkyl and C _1-6 alkoxy.

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

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

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

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

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

In some embodiments, a compound of any of the formulas described herein, or a pharmaceutically acceptable salt thereof, may have the ability to increase the levels of a TFEB polypeptide in a cell and/or in the nucleus of a cell. Such cells may be in vitro or in vivo. For example, a compound of any of the formulas described herein, or a pharmaceutically acceptable salt thereof, may have the ability to increase the levels of a TFEB polypeptide in the nucleus of cells located in a mammal (e.g., a human) after administration to said mammal.

Methods for obtaining therapeutic compounds

Compounds of any of the formulae described herein, including salts thereof, may be prepared by known methods of organic synthesis and may be synthesized according to any of a variety of possible synthetic routes. For example, the compounds described herein may be prepared by methods and techniques similar to those described in Examples 1a-1p herein. Those skilled in the art will know how to select and carry out appropriate synthetic protocols and will appreciate that the methods described are not the only possible method for synthesizing the compounds provided herein and that a wide range of synthetic organic reactions may potentially be used to synthesize the compounds provided herein.

Suitable synthetic routes for the starting materials, intermediates, and products can be found by reference to literature sources, including the following references: Advances in Heterocyclic Chemistry , volumes 1–107 (Elsevier, 1963–2012); Journal of Heterocyclic Chemistry , volumes V 1–49 ( J. Heterocyclic Chemistry , 1964–2012); Carreira et al ., (Ed.) Science of Synthesis , volumes 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 ., (eds.) Comprehensive Organic Functional Group Transformations II (Elsevier, ^2nd ed., 2004); Katritzky et al ., (eds.) 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 , ^6th ed. (Wiley, 2007); Trost et al. (ed.) Comprehensive Organic Synthesis (Pergamon Press, 1991).

The reactions for obtaining the compounds proposed in this document can be carried out in suitable solvents, which can be easily selected by a person skilled in the art of organic synthesis. Suitable solvents can be solvents that do not substantially react with the starting materials (reagents), intermediates or products at the temperatures of the reaction, for example, at temperatures that can vary from the freezing point of the solvent to the boiling point of the solvent. This reaction can be carried out in one solvent or in a mixture of more than one solvent. Depending on the specific reaction step, suitable solvents for a specific reaction step can be selected by a person skilled in the art.

The preparation of the compounds disclosed herein may involve the protection and deprotection of various chemical groups. The need for protection or deprotection, as well as the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups is presented, for example, in P. G. M. Wuts and T. W. Greene, Protective Groups in Organic Synthesis , ^4th ed., Wiley & Sons, Inc., New York (2006).

Pharmaceutical compositions and dosage forms

Also provided herein are pharmaceutical compositions comprising an effective amount of a compound of any of the formulae (I)-(III) described herein, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. The pharmaceutical composition may also contain any of the additional therapeutic agents and/or therapeutic molecules described herein. The carrier(s) are "acceptable" in the sense that they are compatible with the other ingredients of the dosage form and, in the case of a pharmaceutically acceptable carrier, are not deleterious to the recipient thereof in the amount in which they are used in the medicament.

Pharmaceutically acceptable carriers, adjuvants, and vehicles that can be used in the pharmaceutical compositions provided herein include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffering agents such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

The compositions or dosage forms may contain any one or more compounds or therapeutic agents described herein in an amount from 0.005 percent to 100 percent, with the balance being suitable pharmaceutically acceptable carriers or excipients. The provided compositions may contain from about 0.001 percent to about 100 percent (e.g., from about 0.1 percent to about 95 percent, from about 75 percent to about 85 percent, or from about 20 percent to about 80 percent) of any one or more compounds or therapeutic agents provided herein, with the balance being any pharmaceutically acceptable carrier or excipient described herein, or any combination of such carriers or excipients.

Routes of administration and dosage forms

Therapeutic compounds and/or pharmaceutical compositions provided herein (e.g., a composition comprising one or more compounds represented by formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) may include those suitable for any suitable route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intralingual, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intranasal, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, preenteric, transdermal, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, vaginal, intravitreal, subretinal or other intraocular routes of administration.

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

In some embodiments, any one or more of the compounds or therapeutic agents described herein can be administered orally. The compositions described herein that are suitable for oral administration can be presented as discrete units such as capsules, sachets, granules, or tablets, each containing a predetermined amount (e.g., an effective amount) of the active ingredient(s); as powders or granules; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; as an oil-in-water liquid emulsion; as a water-in-oil liquid emulsion; can be packaged in liposomes; or as a bolus. Soft gelatin capsules can be suitable for incorporating such suspensions, which can advantageously increase the rate of absorption of the compound. In the case of tablets for oral use, commonly used carriers include, but are not limited to, lactose, sucrose, glucose, mannitol, silicic acid, and starches. Other suitable excipients may include, but are not limited to, (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose and gum arabic, (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) dissolution 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 capsule form, useful diluents include, but are not limited to, lactose and dried corn starch. For oral administration of aqueous suspensions, the active ingredient(s) can be combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents can be added. Compositions suitable for oral administration include, but are not limited to, lozenges comprising the ingredients in a flavor base, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient(s) in an inert base such as gelatin and glycerol, or sucrose and acacia.

Compositions suitable for parenteral administration include, but are not limited to, aqueous and non-aqueous sterile injection or infusion solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the dosage form isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickening agents. The dosage forms may be presented in unit dose form or in multi-dose containers such as sealed ampoules and vials and may be stored in a freeze-dried (lyophilized) state requiring only the addition of a sterile liquid carrier such as water for injection, saline (e.g., 0.9% saline) or 5% dextrose solution immediately before use. Injectable solutions and suspensions for immediate administration may be prepared from sterile powders, granules and tablets. Injectable solutions can be in the form of, for example, a sterile aqueous or oleaginous injection suspension. Such a suspension can be formulated by methods known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injection solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils can be used as a solvent or suspending medium. Any tasteless fixed oils can be used for this purpose, including, without limitation, synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives can be used to obtain injectable preparations. In some cases, natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in the form of their polyoxyethylated derivatives, may be used to prepare injectable preparations. Such oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.

In some cases, the therapeutic compound and/or pharmaceutical composition provided herein may be administered in the form of a suppository for rectal administration. Such compositions may be prepared by mixing a compound described herein (e.g., a compound represented by formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) with a suitable non-irritating excipient that is solid at room temperature but liquid at the rectal temperature and therefore melts in the rectum to release the active component(s). Such materials include, but are not limited to, cocoa butter, beeswax, and polyethyleneglycols.

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

In some cases, the therapeutic compounds and/or pharmaceutical compositions provided herein may be formulated as a topical composition and used in the form of an aerosol spray, cream, emulsion, solid, liquid, dispersion, foam, oil, gel, hydrogel, lotion, mousse, ointment, powder, patch, pomade, solution, dispenser spray, stick, wipe, soap or other forms commonly used for topical administration and/or in cosmetics and skin care products. The topical compositions may be in the form of an emulsion. Topical administration of the therapeutic compounds and/or pharmaceutical compositions provided herein may be convenient if the desired treatment involves treatment of areas or organs that are easily accessible by topical application. In some cases, the topical composition may comprise a combination of any one or more compounds or therapeutic agents described herein (e.g., a compound represented by formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof), and one or more additional ingredients, carriers, excipients, or diluents, including, but not limited to, absorbents, anti-irritants, anti-acne agents, preservatives, antioxidants, coloring agents/pigments, emollients (humidifiers), emulsifiers, film-forming/retention agents, fragrances, leave-on exfoliants, prescription drugs, preservatives, scrubs, silicones, skin identical/restorative agents, glidants, sunscreens, surfactants/detergents, penetration enhancers, and thickeners.

In some cases, one or more compounds or therapeutic agents described herein (e.g., a compound represented by 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, an artificial valve, a vascular graft, a stent, or a catheter. Suitable coatings and general methods for producing coated implantable devices are known in the art and are exemplified in U.S. Patent Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings can be biocompatible polymeric materials, such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, or a mixture thereof. In some cases, said coating may be further coated with a suitable surface coating of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to provide controlled release properties of the proposed composition.

In some cases, provided herein is an implantable drug release device impregnated with or containing one or more compounds or therapeutic agents described herein (e.g., a compound represented by formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof), such that said compound(s) or therapeutic agent(s) are released from said device and are therapeutically active.

Doses and administration schedules

A composition (e.g., pharmaceutical compositions provided herein) comprising a compound provided herein (e.g., a compound represented by formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) may comprise said compound in an effective amount (e.g., in a therapeutically effective amount).

Effective doses may vary depending on the disease being treated, the severity of the disease, the route of administration, the sex, age and general health of the subject, the excipient used, the possibility of co-use with other therapeutic agents, for example, the possibility of use with other agents, and the judgment of the treating physician.

In some embodiments, an effective amount of a compound of any of Formulas (I)-(III), or a pharmaceutically acceptable salt thereof, can be, for example, from about 0.1 mg to about 1000 mg. In some cases, an effective amount can be from about 0.5 mg to about 500 mg of a compound described herein, or any amount in between, such as 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, disorder, or condition being treated as described herein.

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

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

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

Sets

Also provided herein are pharmaceutical kits useful for, for example, increasing the levels of a TFEB polypeptide in cells and/or in the nucleus of cells in a mammal (e.g., a human). In some cases, provided herein are pharmaceutical kits useful for, for example, treating the diseases, disorders, and pathological conditions mentioned herein. Such pharmaceutical kits may comprise one or more containers containing a pharmaceutical composition that comprises a therapeutically effective amount of a compound provided herein (e.g., a compound represented by formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof). In some cases, such kits may further comprise, if desired, one or more different standard components of pharmaceutical kits, such as containers with one or more pharmaceutically acceptable carriers. A kit provided herein may also include instructions in the form of inserts or labels that specify amounts of the components to be administered, instructions for administration, and/or directions for mixing the components.

Combination therapy

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) may be combined with one or more therapeutic molecules. Examples of therapeutic molecules that may be used in combination with one or more compounds provided herein (e.g., a compound represented by formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) include, but are not limited to, enzyme replacement therapy (e.g., an approved enzyme therapy) for LSD (e.g., fabrazyme or cerezime). In such cases, the addition of one or more such compounds may facilitate the treatment of a central nervous system disorder that is inaccessible to enzyme replacement therapy due to the limitations of the blood-brain barrier on serum proteins. In some cases, the addition of one or more such compounds may enhance cellular uptake of the therapeutic protein intended to replace the lysosomal enzyme in the periphery by enhancing the expression of the mannose-6-phosphate receptor, a transcriptional target of TFEB, and the receptor-mediated mechanism by which the enzyme replacement therapeutic agent enters the affected cell or tissue. Additional examples of therapeutic molecules that can be used in combination with one or more compounds provided herein (e.g., a compound represented by formula (I), (IIa-IIi), or (III), or a pharmaceutically acceptable salt thereof) include, but are not limited to, anti-inflammatory agents (e.g., steroids and antibodies against IL-6 or TNF-alpha), antimicrobial agents (e.g., antibiotics, antimycobacterial drugs, and antiviral agents), anticancer agents (e.g., chemotherapeutic agents and cellular products such as engineered T cells), anti-aging agents (e.g., nicotinamide riboside or rapamycin), neurological agents (e.g., L-DOPA, memantine, and riluzole), therapeutic agents for the treatment of neurodegenerative diseases (e.g., edaravone or tetrabenazine), and agents used to treat chronic organ dysfunction (e.g., an ACE inhibitor and lactulose).

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 may be administered in any order or simultaneously. When administered simultaneously, they may be presented in a single combined form or in multiple forms (e.g., in the form of a single pill or in the form of two separate pills). One of the agents may be presented in multiple doses, or both agents may be presented in multiple doses. When administered non-simultaneously, the time between multiple doses may vary from greater than zero weeks to less than four weeks.

Definitions

In this context, the term "about" means "approximately" (e.g. plus or minus approximately 10% of the stated value).

At various points in this document, substituents of compounds provided herein are described in groups or ranges. Such groups and ranges are specifically intended to include each and every distinct subcombination of members of such groups and ranges. For example, the term "C _1-6 alkyl" is specifically intended to separately describe methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, and C ₆ alkyl.

Various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described at various points in this document. Unless otherwise noted, these rings may be attached to the rest of the molecule at any member of the ring, as long as valence permits. For example, the term "pyridine ring" or "pyridinyl" may refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.

It should further be understood that some features described herein, which for clarity are described in the context of separate embodiments, may also be provided in combination as part of a single embodiment. Conversely, some features described herein, which for brevity are described in the context of a single embodiment, may also be provided individually or in any suitable subcombination.

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

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

In this context, the expression "optionally substituted" means unsubstituted or substituted. The substituents are independently selected and the substitution may be at any chemically permissible position. In this context, the term "substituted" means that a hydrogen atom is removed and replaced by a substituent. One divalent substituent, such as oxo, may replace two hydrogen atoms. It should be understood that the substitution at a given atom is limited by valence.

In the context of definitions, the term "C _nm " means a range that includes the extreme values, where n and m are integers and indicate the number of carbon atoms. Examples include C _1-4 , C _1-6 , etc.

As used herein, the term "C _nm alkyl" used alone or in combination with other terms refers to a saturated hydrocarbon group, which may be straight or branched, containing from n to m carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n -propyl, isopropyl, n -butyl, tert -butyl, isobutyl, sec -butyl; higher homologues such as 2-methyl-1-butyl, n- pentyl, 3-pentyl, n- hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or from 1 to 2 carbon atoms.

As used herein, the term "C _nm haloalkyl", used alone or in combination with other terms, refers to an alkyl group containing from one halogen atom to 2s+1 halogen atoms, which may be the same or different, wherein "s" represents the number of carbon atoms in the alkyl group, and said alkyl group contains from n to m carbon atoms. In some embodiments, the haloalkyl group is only fluorinated. In some embodiments, the alkyl group contains from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

As used herein, the term " _Cnm alkenyl" refers to an alkyl group containing one or more carbon-carbon double bonds and containing n to m carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, n -propenyl, isopropenyl, n -butenyl, sec -butenyl, and the like. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, the term " _Cnm alkynyl" refers to an alkyl group containing one or more carbon-carbon triple bonds and containing n to m carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, the term "C _nm alkylene," used alone or in combination with other terms, refers to a divalent alkyl linking group having n to m carbon atoms. 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, butane-1,3-diyl, butane-1,2-diyl, 2-methylpropane-1,3-diyl, and the like. In some embodiments, the alkylene moiety has 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or 1 to 2 carbon atoms.

As used herein, the term " _Cnm alkoxy," used alone or in combination with other terms, refers to a group of the formula -O-alkyl, wherein the alkyl group contains from n to m carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n -propoxy and isopropoxy), butoxy (e.g., n- butoxy and tert -butoxy), and the like. In some embodiments, the alkyl group contains from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

As used herein, "C _nm haloalkoxy" refers to a group of the formula -O-haloalkoxy containing from n to m carbon atoms. An example of a haloalkoxy group is _OCF3 . In some embodiments, the haloalkoxy group is only fluorinated. In some embodiments, the alkyl group contains from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

In this context, the term "amino" refers to a group of the formula -NH ₂ .

As used herein, the term "C _nm alkylamino" refers to a group of the formula -NH(alkyl) wherein the alkyl group contains from n to m carbon atoms. In some embodiments, the alkyl group contains from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms. Examples of alkylamino groups 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-( tert -butyl)amino), and the like.

As used herein, the term "di( _Cnm -alkyl)amino" refers to a group of the formula -N(alkyl) ₂ in which the two alkyl groups each independently contain from n to m carbon atoms. In some embodiments, each alkyl group independently contains from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

As used herein, the term " _Cnm alkoxycarbonyl" refers to a group of the formula -C(O)O-alkyl, wherein the alkyl group contains from n to m carbon atoms. In some embodiments, the alkyl group contains from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms. Examples of alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl (e.g., n -propoxycarbonyl and isopropoxycarbonyl), butoxycarbonyl (e.g., n -butoxycarbonyl and tert -butoxycarbonyl), and the like.

As used herein, the term " _Cnm alkylcarbonyl" refers to a group of the formula -C(O)-alkyl, wherein the alkyl group contains from n to m carbon atoms. In some embodiments, the alkyl group contains from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms. Examples of alkylcarbonyl groups include, but are not limited to, methylcarbonyl, ethylcarbonyl, propylcarbonyl (e.g., n -propylcarbonyl and isopropylcarbonyl), butylcarbonyl (e.g., n -butylcarbonyl and tert -butylcarbonyl), and the like.

As used herein, the term "C _nm alkylcarbonylamino" refers to a group of the formula -NHC(O)-alkyl, wherein the alkyl group contains from n to m carbon atoms. In some embodiments, the alkyl group contains from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

As used herein, the term "C _nm alkylsulfonylamino" refers to a group of the formula -NHS(O) ₂ -alkyl, wherein the alkyl group contains from n to m carbon atoms. In some embodiments, the alkyl group contains from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

As used herein, the term "aminosulfonyl" refers to a group of the formula -S(O) ₂ NH ₂ .

As used herein, the term "C _nm alkylaminosulfonyl" refers to a group of the formula -S(O) ₂ NH(alkyl), wherein the alkyl group contains from n to m carbon atoms. In some embodiments, the alkyl group contains from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

As used herein, the term "di( _Cnm alkyl)aminosulfonyl" refers to a group of the formula -S(O) _2N (alkyl) ₂ , wherein each alkyl group independently contains n to m carbon atoms. In some embodiments, each alkyl group independently contains 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term "aminosulfonylamino" refers to a group of the formula -NHS(O) ₂ NH ₂ .

As used herein, the term "C _nm alkylaminosulfonylamino" refers to a group of the formula -NHS(O) ₂ NH(alkyl), wherein the alkyl group contains from n to m carbon atoms. In some embodiments, the alkyl group contains from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

As used herein, the term "di( _Cnm alkyl)aminosulfonylamino" refers to a group of the formula -NHS(O) _2N (alkyl) ₂ , wherein each alkyl group independently contains n to m carbon atoms. In some embodiments, each alkyl group independently contains 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

In this context, the term "aminocarbonylamino", used alone or in combination with other terms, refers to a group of the formula -NHC(O)NH ₂ .

As used herein, the term "C _nm alkylaminocarbonylamino" refers to a group of the formula -NHC(O)NH(alkyl) in which the alkyl group contains from n to m carbon atoms. In some embodiments, the alkyl group contains from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

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

As used herein, the term "carbamyl" refers to a group of the formula -C(O)NH ₂ .

As used herein, the term "C _nm alkylcarbamyl" refers to a group of the formula -C(O)-NH(alkyl), wherein the alkyl group contains from n to m carbon atoms. In some embodiments, the alkyl group contains from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

As used herein, the term "di( _Cnm -alkyl)carbamyl" refers to a group of the formula -C(O)N(alkyl) ₂ in which the two alkyl groups each independently contain from n to m carbon atoms. In some embodiments, each alkyl group independently contains from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

In this context, the term "thio" refers to a group of formula -SH.

As used herein, the term "C _nm alkylthio" refers to a group of the formula -S-alkyl, wherein the alkyl group contains from n to m carbon atoms. In some embodiments, the alkyl group contains from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

As used herein, the term "C _nm alkylsulfinyl" refers to a group of the formula -S(O)-alkyl, wherein the alkyl group contains from n to m carbon atoms. In some embodiments, the alkyl group contains from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

As used herein, the term "C _nm alkylsulfonyl" refers to a group of the formula -S(O) ₂ -alkyl, wherein the alkyl group contains from n to m carbon atoms. In some embodiments, the alkyl group contains from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

In this context, the term "carbonyl", used alone or in combination with other terms, refers to the group -C(=O)-, which can also be written as C(O).

In this context, the term "carboxy" refers to a -C(O)OH group. In some embodiments, the "carboxy" group also refers to a bioisosteric substituent group selected from the group consisting of:

and the like, where R refers to hydrogen, (C ₁ -C ₈ ) alkyl or C ₆ aryl.

In this context, the term "cyano-C _1-3 alkyl" refers to a group of the formula -(C _1-3 alkylene)-CN.

In this context, the term "HO-C _1-3 alkyl" refers to a group of the formula -(C _1-3 alkylene)-OH.

In this context, “halogen” refers to F, Cl, Br, or I. In some embodiments, the halogen is F, Cl, or Br.

As used herein, the term "aryl" used alone or in combination with other terms refers to an aromatic hydrocarbon group that may be monocyclic or polycyclic (e.g., containing 2, 3, or 4 fused rings). The term "C _nm aryl" refers to an aryl group containing n to m ring carbon atoms. Aryl groups include, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups may contain 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl.

As used herein, "cycloalkyl" refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and/or alkenyl groups. Cycloalkyl groups may include mono- or polycyclic (e.g., containing 2, 3, or 4 fused rings) groups and spirocycles. The ring-forming carbon atoms of a cycloalkyl group may be optionally substituted with 1 or 2 independently selected oxo or sulfide groups (e.g., C(O) or C(S)). Also included within the definition of cycloalkyl are moieties that contain one or more aromatic or non-aromatic rings fused (i.e., sharing a common bond) to the cycloalkyl ring, such as benzo- or thienyl derivatives of cyclopentane, cyclohexane, and the like. A cycloalkyl group containing a fused aromatic ring may be attached through any ring-forming atom, including a ring atom of the fused aromatic ring. A cycloalkyl group may comprise a fused heterocycloalkyl ring, which itself may be fused to another ring, such as an aromatic ring. In such a case, the cycloalkyl group may be attached through any ring-forming atom, including ring-forming atoms of the heterocycloalkyl ring or the aromatic ring. Cycloalkyl groups may contain 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbon atoms (C _3-10 ). Cycloalkyl groups may also contain 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 _3-14 cycloalkyl). In some embodiments, the cycloalkyl is a C _3-10 monocyclic or bicyclic cycloalkyl. In some embodiments, the cycloalkyl is a _C3-7 monocyclic cycloalkyl. In some embodiments, the cycloalkyl is a _C3-14 bicyclic or tricyclic cycloalkyl. Examples of cycloalkyl groups 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.

As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic heterocycle comprising at least one ring heteroatom selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring comprises 1, 2, 3, or 4 ring heteroatoms independently selected from nitrogen, sulfur, and oxygen. In some embodiments, any ring-forming N atom in the heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl is a 5- to 10-membered monocyclic or bicyclic heteroaryl comprising 1, 2, 3, or 4 ring heteroatoms independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a 5- to 14-membered monocyclic, bicyclic, or tricyclic heteroaryl comprising 1, 2, 3, or 4 ring heteroatoms independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl ring is a 5-6-membered monocyclic heteroaryl containing 1 or 2 ring heteroatoms independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a five-membered or six-membered heteroaryl ring. A five-membered heteroaryl ring is a heteroaryl with a ring containing five ring atoms, wherein one or more (e.g., 1, 2, or 3) of the ring atoms are independently selected from N, O, and S. Exemplary five-membered ring heteroaryls include, but are not limited to, thienyl, furyl, 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 with a ring containing six ring atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Illustrative six-membered ring heteroaryls include, but are not limited to, pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

As used herein, "heterocycloalkyl" refers to non-aromatic monocyclic or polycyclic heterocycles containing one or more ring-forming heteroatoms selected from O, N or S. Included within the term "heterocycloalkyl" are monocyclic 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl groups. Included within the term "heterocycloalkyl" are mono-, bi-, tri- and tetracyclic 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13- or 14-membered heterocycloalkyl groups. Heterocycloalkyl groups may also contain spirocycles. Examples of heterocycloalkyl groups include, but are not limited to, pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, and the like. The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group may be optionally substituted with 1 or 2 independently selected oxo or sulfido groups (e.g., C(O), S(O), C(S) or S(O) ₂ , etc.). A heterocycloalkyl group may be attached through a ring carbon atom or a ring heteroatom. In some embodiments, a heterocycloalkyl group contains from 0 to 3 double bonds. In some embodiments, a heterocycloalkyl group contains from 0 to 2 double bonds. Also included within the definition of heterocycloalkyl are moieties that contain one or more aromatic or nonaromatic rings fused (i.e., sharing a bond) with the heterocycloalkyl ring, such as benzo- or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring may be attached through any atom forming the ring, including a ring atom of the fused aromatic ring. In some embodiments, heterocycloalkyl is a monocyclic 4-6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur and containing one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 4-10 membered heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and containing one or more oxidized ring members.

In some cases, the specified definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise specified, the specified rings may be attached to any member of the ring, provided that the valency of the specified atom is not exceeded. For example, an azetidine ring may be attached at any position on the ring, while a pyridin-3-yl ring is attached at the 3-position.

In this context, the term "oxo" refers to an oxygen atom as a divalent substituent that forms a carbonyl group when attached to a carbon atom (e.g., C=O) or when attached to a heteroatom to form a sulfoxide or sulfone group.

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

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

The compounds provided herein also include tautomeric forms. Tautomeric forms arise from the exchange of a single bond with an adjacent double bond, with the attendant 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, ketone-enol pairs, amide-imide acid pairs, lactam-lactim pairs, enamine-imine pairs, and ring 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 may be in equilibrium or sterically locked into one form by appropriate substitution. For example, in aqueous solution, pyrazoles may have the following isomeric forms, which are called tautomers of each other:

As will be appreciated by those skilled in the art, tautomerism can be exhibited by a wide variety of functional groups and other structures, and all tautomers of the compounds described herein are within the scope of this disclosure.

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

In this context, the term "contacting" refers to bringing said moieties or elements into interaction in an in vitro system, in an ex vivo system, or in an in vivo system. For example, "contacting" a cell with a compound provided herein includes the act of administering said compound to a mammal (e.g., a human) containing said cell, as well as, for example, introducing said compound into a cell culture containing said cell.

In this context, the term "mammal" includes, without limitation, mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, elephants, deer, lower primates (e.g., monkeys and apes), domestic pets, and humans.

As used herein, the expression "effective amount" or "therapeutically effective amount" refers to that amount of an active compound or pharmaceutical agent that produces the biological or medical response desired by the researcher, veterinarian, physician or other clinician in a tissue, system, organism, mammal or human.

In this context, "treat" or "treatment" refers to (a) slowing down a disease, disorder or condition, such as slowing down a disease, disorder or condition in a mammal (e.g. a human) that is experiencing or exhibiting the pathology or symptomatology of said disease, disorder or condition (e.g. stopping the further development of the pathology and/or symptomatology), or (b) alleviating a disease, disorder or condition, such as alleviating a disease, disorder or condition in a mammal (e.g. a human) that is experiencing or exhibiting the pathology or symptomatology of said disease, disorder or condition (e.g. reversing the pathology and/or symptomatology).

In this context, the term "prevent" or "prevention" of a disease, disorder or pathological condition refers to a reduction in the risk of occurrence of the disease, disorder or pathological condition in a mammal or group of mammals (e.g., a mammal or group of mammals predisposed or susceptible to said disease, disorder or pathological condition). In some embodiments, preventing a disease, disorder or pathological condition refers to a reduction in the likelihood of acquiring the disease, disorder or pathological condition and/or the symptoms associated therewith. In some embodiments, preventing a disease, disorder or pathological condition refers to a complete or nearly complete cessation of the occurrence of the disease, disorder or pathological condition.

EXAMPLES

Materials and methods

All nonaqueous reactions were carried out under nitrogen in oven-dried or flame-dried glassware unless otherwise noted. Anhydrous tetrahydrofuran and diethyl ether were distilled from sodium benzophenone ketyl solutions; anhydrous dichloromethane and toluene were distilled over CaH ₂ ; alternatively, the same solvents were prepared on a solvent purification system using alumina columns. All other solvents and reagents were used as purchased from commercial suppliers without further purification unless otherwise noted. The reaction progress was monitored by TLC using 250 µm silica gel 60 F254 pre-coated plates visualized under UV light at 254 nm and/or 365 nm and stained with KMnO ₄ (1.5 g KMnO ₄ , 10 g K ₂ CO ₃ , and 1.25 ml 10% NaOH in 200 ml water), cerium molybdate (0.5 g Ce(NH ₄ ) ₂ (NO ₃ ) ₆ , 12 g (NH ₄ ) ₆ Mo ₇ O ₂₄ •4H ₂ O, and 28 ml conc. H ₂ SO ₄ in 235 ml water), or vanillin (6 g vanillin and 1.5 ml conc. H ₂ SO ₄ in 100 ml EtOH). Flash chromatography was performed on SiliCycle 60 silica gel (230-400 mesh) or an ISCO MPLC system. ¹ H and ¹³ C NMR spectra were recorded on Bruker Avance 300, 400 or 500 MHz spectrometers using residual solvent as an internal standard. IR spectra were recorded on a Smiths IdentifyIR or PerkinElmer Spectrum 100 instrument. HRMS data were recorded on a Thermo Scientific Exactive HRMS instrument coupled to a Thermo Scientific Accela HPLC system using a C18 Waters XTerra 2.1 x 50 mm, 3.5 μm column, eluting with MeCN/H ₂ O containing 0.1% formic acid. Compound purity was assessed on the same HPLC system using either a photodiode array detector (PDA) or an Agilent 385 evaporative light scattering detector (ELSD). All final screening samples were quality controlled to be >95% pure by LC/MS/ELSD analysis.

General scheme of synthesis

For example, to prepare compounds of formula (I) where n is 1 and L is NH (1), equimolar amounts of the 4-chloroquinazoline analog (2) and the amine (3) are mixed in a suitable solvent (e.g., isopropanol). The resulting reaction mixture is stirred and refluxed, e.g., for 4 hours. The progress of the reaction is monitored by methods known in the art. After consumption of the starting material, the reaction mixture is concentrated and the desired compound is purified by preparative TLC or flash chromatography. The products can be further purified by crystallization by methods known in the art. In the general scheme shown, X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ , ^RA and ^RB are as described herein and LG is a leaving group (e.g., Cl, Br, I or OTf). Compounds of formula (I) wherein L is other than NH can be prepared from analogous starting materials using reactions and synthetic methods known in the art. The skilled artisan can select and practice appropriate reaction protocols and conditions.

Example 1a. Synthesis of compound 8 (BC18618)

Getting a connection 3 :

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

Preparation of compound 8 (BC18618)

To a solution of 3 (273 mg, 1 mmol, 1 equiv.) in dioxane/ _H2O (1:1, 15 mL) was added 4 (248 mg, 2 mmol, 2 equiv.), _K2CO3 (276 mg, ₂ mmol, 2 equiv.) and Pd( _PPh3 ) ₄ (124 mg, 0.1 mmol, 0.1 equiv.) under _N2 . The mixture was stirred at 115°C overnight. The mixture was then filtered and the filter cake was washed with MeOH to yield 205 mg of BC18618 (compound 8) (off-white solid, 52%).

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

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).

Example 1b. Synthesis of compound 76 (BC18703)

General method for obtaining compound 3:

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

General method for obtaining compound 5

To a solution of 3 (0.4 g, 1.36 mmol, 1 equiv) in dioxane/ _H2O (2:1, 1.5 mL) was added 4 (632 mg, 2.04 mmol, 1.5 equiv), _K2CO3 (844 mg, 6.12 mmol, _4.5 equiv), and _PdCl2 (dppf) (95 mg, 0.13 mmol, 0.1 equiv) 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 column chromatography on silica (PE/EA, 5:1) to give 0.4 g of 5 (yellow solid, 70%). MS (ESI) m/z: 443 [M+H]+.

General method for obtaining compound 6

To a solution of 5 (0.2 g, 0.45 mmol, 1 equiv.) in MeOH (5 mL) was added Pd(OH) ₂ (30 mg, 15% w/w) under _N2 . The system was evacuated three times and filled with _H2 . After stirring at room temperature overnight, the mixture was filtered and the filtrate was concentrated to give 0.16 g of 6 (colorless oily substance, 80%). MS (ESI) m/z: 445 [M+H]+.

General method for preparing compound BC18703

To a solution of 6 (160 mg) in MeOH (2 mL) was added 3 M HCl/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 [MH]-

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 (dd, J=8.2, 5.3, 2.6 Hz, 1H), 7.75 (dd, J=9.0, 1.6 Hz, 1H), 7.65 (d, J=9.0 Hz, 1H), 3.36-3.33 (m, 1H), 3.29 (d, J=11.7 Hz, 2H), 2.94 (dd, J=21.0, 11.0 Hz, 2H), 2.11 (d, J=13.0 Hz, 2H), 2.05-1.92 (m, 2H).

Example 1c. Synthesis of Compound 78 (BC18705)

General method for obtaining compound 3

To the solution1(200 mg, 1.0 mmol, 1 equiv.) ini-PrOH (3 ml) was added DIEA (284 mg, 2.0 mmol, 2 equiv.) And 2(146 mg, 1.1 mmol, 1.1 equiv). The reaction mixture was stirred at 85°C overnight. The solution was concentrated and the residue was purified by column chromatography on silica (PE/EA, 2:1) to give 150 mg3(yellow solid, 76%). MS (ESI) m/z: 295 [M+H]+

General method for preparing compound BC18705

To a solution of 3 (100 mg, 0.339 mmol, 1 equiv.) in dioxane/H ₂ O (1:1, 3 mL) was added 4 (215 mg, 1.02 mmol, 3 equiv.), K ₂ CO ₃ (210 mg, 1.5 mmol, 4.5 equiv.) and Pd(dppf)Cl ₂ (25 mg, 0.034 mmol, 0.1 equiv.) under N ₂ atmosphere. The mixture was stirred at 95 °C overnight. The mixture was concentrated and 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 [MH]-

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

Example 1d. Synthesis of compound 383 (BC18829)

General method for preparing compound 3-1

To a solution of 1 (0.2 g, 1.01 mmol, 1 equiv) in i -PrOH (3 mL) were added 2 (148 mg, 1.11 mmol, 1.1 equiv) and DIEA (260 mg, 2.02 mmol, 2 equiv). The reaction mixture was stirred at 85 °C overnight. The reaction mixture 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]+.

General method for preparing compound BC18829

To a solution of 3-1 (50 mg, 0.17 mmol, 1 equiv.) in dioxane/ _H2O (4:1, 5 mL) was added 4-1 (40 mg, 0.19 mmol, 1.1 equiv.), _K2CO3 (47 mg, 0.34 _mmol , 2 equiv.) and _PdCl2 (dppf) (25 mg, 0.03 mmol, 0.2 equiv.) 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 preparative TLC (DCM/MeOH, 10:1) to give 5 mg of BC18829 (brown solid, 9%). MS (IER) m/z: 346 [M+H]+, 344 [MH]-

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

Example 1e. Synthesis of Compound 384 (BC18830)

General method for obtaining compound 3-2

To a solution of 1 (0.2 g, 1.01 mmol, 1 equiv) in i -PrOH (3 mL) were added 2 (167 mg, 1.11 mmol, 1.1 equiv) and DIEA (260 mg, 2.02 mmol, 2 equiv). The reaction mixture was stirred at 85 °C overnight. The reaction mixture 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]+

General method for obtaining compound BC18830

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

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

Example 1f. Synthesis of compound 385 (BC18831)

General method for obtaining compound 3-3

To a solution of 3-2 (prepared in Example 1e) (150 mg, 0.48 mmol, 1 equiv) in dioxane/ _H2O (4:1, 5 mL) were added 2-3 (185 mg, 0.53 mmol, 1.1 equiv), _K2CO3 ( ₁₃₃ mg, 0.96 mmol, 2 equiv) and Pd(dppf) _Cl2 (37 mg, 0.05 mmol, 0.1 equiv) 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 to give 245 mg of 3-3 (yellow solid, 100%). MS (IER) m/z: 483 [M+H]+

General method for preparing compound BC18831

To a solution of 3-3 (245 mg, crude, 0.51 mmol, 1 equiv) in THF (2 mL) was added 1 M TBAF in THF (1.02 mL, 1.02 mmol, 2 equiv). The reaction mixture 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 [MH]-

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).

Example 1g. Synthesis of compound 43 (BC18663)

General method for obtaining compound 3

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

General method for obtaining compound 4

To a solution of compound 3 (220 mg, 1.0 mmol, 1 equiv.) in DMSO (0.6 mL) was added phosphorus oxychloride (465 mL, 5.0 mmol, 5 equiv.). The mixture was stirred at 80 °C for 3.5 h. After completion of the reaction, 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]+

General method for obtaining compound BC18663

To a solution of 4 (83 mg, 0.35 mmol, 1.0 equiv.) in 4 M HCl/dioxane (2 mL) was added 5 (58 mg, 0.53 mmol, 1.5 equiv.). The reaction mixture 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 [MH]-

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 (dd, J=8.2, 6.9, 1.3 Hz, 1H), 7.39 (dd, J=15.3, 8.2 Hz, 1H), 6.82 (td, J=8.1, 1.9 Hz, 1H).

Example 1h. Synthesis of compound 48 (BC18668)

General method for obtaining compound BC18668

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

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

Example 1i. Synthesis of Compound 69 (BC18689)

General method for preparing compound BC18689

To the solution2(111 mg, 1.0 mmol, 1.2 equiv.) in DMF (4 ml) was added 60% NaH (100 mg, 2.49 mmol, 3 equiv) at 0°C and stirred the mixture for 15 min, then added to the resulting solution1(prepared according to the same literature, 0.2 g, 0.83 mmol, 1 equiv). The mixture was heated to 80°C for 3 h. After cooling to room temperature, H₂O (5 mL). The mixture was extracted with EA (10 mL×2) and the organic phase was concentrated. The residue was purified by preparative TLC to yield 187 mgBC18689(white solid, 72%). MS (ESI) m/z: 316 [M+H]+

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 (dd, J=8.3, 6.8, 1.2 Hz, 1H), 7.61 (s, 1H), 7.58 (ddd, J=8.2, 7.0, 1.2 Hz, 1H), 7.47-7.40 (m, 1H), 7.29 (dd, J=7.7, 2.3 Hz, 1H), 7.24 (dt, J=11.1, 2.3 Hz, 1H), 6.93 (td, J=8.5, 2.4 Hz, 1H).

Example 1j. Synthesis of compound 126 (BC18763)

General method for obtaining compound 3

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

General method for obtaining compound 4

A solution of 3 (2 g, 8.26 mmol, 1.0 equiv.) in KOH (1 N, 20 mL) was heated to 100 °C and stirred for 3 h. TLC showed that 3 remained. The pH of the mixture was adjusted to 7 with aqueous HCl (4 M). The mixture was filtered. The solid that precipitated was collected and dried to give 1.4 g of 4 (white solid, 70%). MS (ESI) m/z: 225 [M+H]+

General method for obtaining compound 5

A solution of 4 (1.4 g, 6.3 mmol, 1.0 equiv.) in POCl ₃ (10 mL) was stirred at 100 °C overnight. The reaction mixture was concentrated and the residue was adjusted to pH 9~10 with saturated Na ₂ CO ₃ solution. The mixture was extracted with CHCl ₃ (15 mL×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]+

General method for preparing compound BC18763

To a solution of 5 (50 mg, 0.21 mmol, 1 equiv.) in i -PrOH (3 mL) was added 6-1 (33 mg, 0.23 mmol, 1.1 equiv.). The reaction mixture 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 [MH]-

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

Example 1k. Synthesis of compound 127 (BC18764)

General method for obtaining compound BC18764

To a solution of 5 (prepared in Example 1j) (100 mg, 0.21 mmol, 1 equiv) in i -PrOH (3 mL) was added 6-2 (33 mg, 0.23 mmol, 1.1 equiv). The reaction mixture was stirred at 85 °C overnight. The reaction mixture was concentrated and 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 [MH]-

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).

Example 1l. Synthesis of compound 120 (BC18757)

General method for preparing compound BC18757

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

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).

Example 1m. Synthesis of compound 83 (BC18711)

General method for obtaining compound 3

To a solution of 1 (1.0 g, 5.0 mmol, 1 equiv.) in i -PrOH (15 mL) were added 2 (726 mg, 5.5 mmol, 1.1 equiv.) and DIEA (1.29 g, 10.0 mmol, 2 equiv.). The reaction mixture 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]+

General method for preparing compound BC18711

To a solution of 3 (700 mg, 2.36 mmol, 1 equiv) in dioxane/ _H2O (4:1, 10 mL) was added 4 (348 mg, 2.83 mmol, 1.2 equiv), _K2CO3 (651 mg, 4.72 mmol, ₂ equiv), and _PdCl2 (dppf) (176 mg, 0.24 mmol, 0.1 equiv) 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 preparative HPLC to give 34 mg of BC18711 (gray solid, 5%). MS (IER) m/z: 339 [M+H]+, 337 [MH]-

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 (dd, J=11.0, 6.8, 1.8 Hz, 4H), 9.09 (dd, J=8.5, 4.2 Hz, 1H), 8.89 (dd, J=8.7, 1.9 Hz, 1H), 8.65 (d, J=8.7 Hz, 1H), 8.56 (t, J=2.7 Hz, 1H), 7.68 (s, 1H).

Example 1n. Synthesis of intermediate 8 (suitable for the preparation of compound BC18847)

General method for obtaining compound 6

Compound 5 (44 g, 225 mmol, 1 equiv), tert- butyl nitrite (45 mL, 375 mmol, 1.67 equiv) and _CuBr2 (60 g, 270 mmol, 1.2 equiv) were suspended in acetonitrile (500 mL, 10 vol) and stirred at room temperature for 1-2 h. The reaction progress was monitored by TLC (PE:EA 5:1). The resulting reaction mixture was quenched with 1 N aqueous HCl (3 L) and extracted with _CH2Cl2 (3× _{2 L). The combined organic layers were dried over Na2SO4 and} concentrated to give compound 6 (66.4 g, 99%) as a yellow powder, which was used in the next step without further purification. MS (ESI) m/z: 259 [M+H]+.

General method for obtaining compound 7

To a solution of 6 (50.0 g, 194 mmol, 1.0 equiv) in toluene/ _H2O (v/v=2:1, 2 L) were added 6-1 (50 g, 581 mmol, 3.0 equiv), _Cs2CO3 (126 _g , 389 mmol, 2.0 equiv), and Pd(dppf) _Cl2 (14.2 g, 19.4 mmol, 0.1 equiv). The mixture was evacuated three times and filled with Ar, and then stirred at 100 °C overnight. The mixture was filtered through a pad of celite and washed with ethyl acetate (mL). The organic layers were washed with water and brine, and dried over sodium sulfate. The residue was concentrated and purified by column chromatography on silica (PE/EA, 10:1) to give 19.1 g of 7 (off-white solid, 45%).

General method for obtaining compound 8

To a solution of compound 7 (20.0 g, 90.9 mmol, 1.0 equiv.) in MeOH (200 mL) was added 10% Pd-C (6 g, 20% w/w) and stirred under H ₂ at room temperature for 3~4 h. TLC showed that compound 7 remained, another portion of Pd-C (6 g, 20% w/w) was added and the reaction mixture was continued to stir at room temperature for 4~6 h. TLC showed no compound 7 but two spots by TLC. Another portion of Pd-C (6 g, 20% w/w) was added and the reaction mixture 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]+

Example 1o. Synthesis of compound 241 (BC18847)

General method for obtaining compound 2

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

General method for obtaining compound 3

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

General method for obtaining compound 4

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

General method for preparing compound BC18847

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

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).

Example 1p. Synthesis of compound 244 (BC18850)

General method for obtaining BC18850 compound

To a solution of 3 (prepared in Example 1o) (0.12 g, 0.50 mmol, 1 equiv) and 9 (0.17 g, 1.0 mmol, 2 equiv) in NMP (1.5 mL) was added 4 M HCl/dioxane solution (0.13 mL, 0.50 mmol, 1 equiv) 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]+.

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).

Example 1. Connection structures

The compounds in Table 1 were prepared as shown in the general scheme, based on available starting materials.

Table 1

No. Code BC Structure 1 BC18607 2 BC18608 3 BC18612 4 BC18614 5 BC18615 6 BC18616 7 BC18617 8 BC18618 9 BC18619 10 BC18625 11 BC18626 12 BC18627 13 BC18628 14 BC18629 15 BC18630 16 BC18630 salt with HCl 17 BC18631 18 BC18633 19 BC18634 20 BC18635 21 BC18636 22 BC18637 23 BC18639 24 BC18640 25 BC18641 26 BC18642 27 BC18643 28 BC18644 29 BC18645 30 BC18646 31 BC18647 32 BC18648 33 BC18649 34 BC18652 35 BC18653 36 BC18654 37 BC18655 38 BC18656 39 BC18657 40 BC18658 41 BC18659 42 BC18660 43 BC18663 44 BC18664 45 BC18665 46 BC18666 47 BC18667 48 BC18668 49 BC18669 50 BC18670 51 BC18671 52 BC18672 53 BC18673 54 BC18674 55 BC18675 56 BC18676 57 BC18677 58 BC18678 59 BC18679 60 BC18680 61 BC18681 62 BC18682 63 BC18683 64 BC18684 65 BC18685 66 BC18686 67 BC18687 68 BC18688 69 BC18689 70 BC18690 71 BC18693 72 BC18695 73 BC18697 74 BC18698 75 BC18702 76 BC18703 77 BC18704 78 BC18705 79 BC18706 80 BC18707 81 BC18708 82 BC18709 83 BC18711 84 BC18713 85 BC18714 86 BC18717 87 BC18718 88 BC18720 89 BC18722 90 BC18724 91 BC18725 92 BC18726 93 BC18727 94 BC18728 95 BC18729 96 BC18730 97 BC18731 98 BC18732 99 BC18733 100 BC18734 101 BC18735 102 BC18736 103 BC18737 104 BC18738 105 BC18739 106 BC18740 107 BC18742 108 BC18743 109 BC18744 110 BC18745 111 BC18746 112 BC18747 113 BC18748 114 BC18749 115 BC18750 116 BC18752 117 BC18754 118 BC18755 119 BC18756 120 BC18757 121 BC18758 122 BC18759 123 BC18760 124 BC18761 125 BC18762 126 BC18763 127 BC18764 128 BC18765 129 BC18766 130 BC18767 131 BC18768 132 BC18769 133 BC18770 134 BC18771 135 BC18772 136 BC18773 137 BC18774 138 BC18775 139 BC18776 140 BC18778 141 BC18779 142 BC18780 143 BC18782 144 BC18783 145 BC18784 146 BC18785 147 BC18786 148 BC18787 149 BC18788 150 BC18789 151 BC18790 152 BC18791 153 BC18792 154 BC18793 155 BC18794 156 BC18816 157 BC18813 158 BC18815

Note : Compound 35 was isolated and tested in the TFA salt form. Compounds 42, 51, 59, 63, 64, and 65 were isolated and tested in the HCl salt form. Compounds 82, 83, 89, 106, 107, 108, 113, 115, 116, 117, 119, 120, and 121 were isolated and tested in the formate salt form.

The following compounds, presented in Table 1a, can be prepared using synthetic methods understood by those skilled in the art from available starting materials.

Table 1a

No. Code BC Structure 352 BC18795 353 BC18796 354 BC18797 355 BC18798 356 BC18799 357 BC18800 358 BC18801 359 BC18802 360 BC18803 361 BC18804 362 BC18805 363 BC18806 364 BC18807 365 BC18808 366 BC18809 367 BC18810 368 BC18811 369 BC18812 370 BC18814 371 BC18817 372 BC18818 373 BC18819 374 BC18820 375 BC18821 376 BC18822 377 BC18823 378 BC18824 379 BC18825 380 BC18826 381 BC18827 382 BC18828 383 BC18829 384 BC18830 385 BC18831 386 BC18832 387 BC18833 388 BC18834 389 BC18835 390 BC18836 391 BC18837 392 BC18838 393 BC18839 394 BC18840 395 BC18841 396 BC18845

Note : Compounds 353, 364 and 376 were isolated and tested in the form of the HCOOH salt.

The following compounds (free bases) presented in Table 2 were purchased from commercial sources (ChemDIV, Inc. and Molport, Inc.):

Table 2

No. Code BC Structure 159 BC1820 160 BC18200 161 BC18201 162 BC18202 163 BC18203 164 BC18204 165 BC18205 166 BC18206 167 BC18207 168 BC18208 169 BC18209 170 BC18210 171 BC18211 172 BC18212 173 BC18213 174 BC18214 175 BC18215 176 BC18216 177 BC18217 178 BC1834 179 BC18601 180 BC18602 181 BC18603 182 BC18604 183 BC18605 184 BC18606 185 BC18609 186 BC18610 187 BC18611 188 BC18613 189 BC18623 190 BC18624 191 BC18632 192 BC18651 193 BC18661 194 BC18715

The following compounds, presented in Table 3, can be prepared using synthetic methods understood by those skilled in the art from available starting materials.

Table 3

No. Code BC Structure 195 BC1816 196 BC1835 197 BC1836 198 BC1837 199 BC1838 200 BC1839 201 BC1840 202 BC1841 203 204 205 206 207 208 209 210 211 212 213

Note : Compounds 197 and 199 were isolated and tested in the HCl salt form.

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

Table 4

No. Code BC Structure 214 BC1770 215 BC1771 216 BC1772 217 BC1773 218 BC1774 219 BC1775 220 BC1776 221 BC1777 222 BC1753 223 BC1780 224 BC1781 225 BC1782 226 BC1783 227 BC1784 228 BC1785 229 BC1786 230 BC1787 231 BC1811 232 BC1812 233 BC1813 234 BC1814 235 BC1815 236 BC1817 237 BC1818 238 BC1819

The following compounds, presented in Table 5, can be prepared using synthetic methods understood by those skilled in the art from available starting materials.

Table 5

No. Code BC Structure 239 BC18842 240 BC18846 241 BC18847 242 BC18848 243 BC18849 244 BC18850 245 BC18851 246 BC18852 247 BC18853 248 BC18854 249 BC191100 250 BC191101 251 BC191102 252 BC191103 253 BC191104 254 BC191105 255 BC191106 256 BC191107 257 BC191108 258 BC191109 259 BC191110 260 BC191111 261 BC191112 262 BC191113 263 BC191114 264 BC191115 265 BC191116 266 BC191117 267 BC191118 268 BC191119 269 BC191120 270 BC191121 271 BC191122 272 BC191123 273 BC191124 274 BC191125 275 BC191126 276 BC191127 277 BC191128 278 BC191129 279 BC191130 280 BC191131 281 BC191132 282 BC191133 283 BC191134 284 BC191135 285 BC191136 286 BC191137 287 BC191138 288 BC191139 289 BC191140 290 BC191141 291 BC191142 292 BC191143 293 BC191144 294 BC191145 295 BC191146 296 BC191147 297 BC191148 298 BC191149 299 BC191150 300 BC191151 301 BC191152 302 BC191153 303 BC191154 304 BC191155 305 BC191156 306 BC191157 307 BC191158 308 BC191159 309 BC191160 310 BC191161 311 BC191162 312 BC191163 313 BC191164 314 BC191165 315 BC191166 316 BC191167 317 BC191168 318 BC191169 319 BC191170 320 BC191171 321 BC191172 322 BC191173 323 BC191174 324 BC191175 325 BC191176 326 BC191177 327 BC191178 328 BC191179 329 BC191180 330 BC191181 331 BC191182 332 BC191183 333 BC191184 334 BC191185 335 BC191186 336 BC191187 337 BC191188 338 BC191189 339 BC191190 340 BC191191 341 BC191192 342 BC191193 343 BC191194 344 BC191195 345 BC191196 346 BC191197 347 BC191198 348 BC191199 349 BC191200 350 BC191201 351 BC191202

Note : Compounds 239, 240, 242, and 243 were isolated and tested in the HCOOH salt form; compounds 246, 247, and 248 were isolated and tested in the HCl salt form.

The following compounds, presented in Table 5a, can be prepared using synthetic methods understood by those skilled in the art from available starting materials.

Table 5a

No. Code BC Structure 400 BC18858 401 BC18859 402 BC18860 BC191500 BC191501 BC191502 BC191503 BC191504 BC191505 BC191507 BC191508 BC191509 BC191510 BC191511 BC191512 BC191513 BC191514 BC191515 BC191516 BC191517 BC191518 BC191519 BC191520 BC191521 BC191522 BC191524 BC191525 BC191526 BC191527 BC191528 BC191529 BC191530 BC191531 BC191532 BC191533 BC191534 BC191535 BC191536 BC191537 BC191538 BC191539 BC191540 BC191541 BC191542 BC191543 BC191544

The following compounds, presented in Table 6, can be prepared using synthetic methods understood by those skilled in the art from available starting materials.

Table 6

No. Code BC Structure 397 BC18855 398 BC18856 399 BC18857

Note : Compounds 397, 398 and 399 were isolated and tested in the HCl salt form.

Example 2. Analysis results

Analysis protocol

Approximately 2500 primary and immortalized human bronchial epithelial cells (BEAS-2B) stably expressing TFEB-EGFP were distributed in 25 μl of HITE medium with 10% FBS in a 384-well plate (black with glass bottom) and incubated for 8 h. Serial dilutions of compound (low glucose DMEM medium with 2% FBS, 25 μl volume) were prepared using a robotic liquid handler. Compound solution was then added to the cell plate and incubated for 18 h. Cells were then fixed with 4% PFA and then stained with DAPI. TFEB localization was visualized on the GFP channel along with the DAPI signal using a Cytation 5 multiparameter imager. Images were processed in Biotek Gen5 software. Specifically, the DAPI signal was used as a primary mask to quantify the nuclear TFEB-GFP signal. The cytosolic TFEB-GFP signal was quantified by expanding the primary mask. The nuclear/cytosolic TFEB ratio was calculated based on the ratio of the nuclear TFEB-GFP signal to the cytosolic TFEB-GFP signal, which determines the efficiency of the compound.

Compound potency (μM) was defined as the minimum compound concentration required to increase the nuclear/cytosolic TFEB ratio by 25%. Potency: “+” means >25 μM; “++” means ≤25 μM to >1 μM; and “+++” means ≤1 μM.

Toxicity was determined by measuring the concentration of compound required to induce greater than 50 percent cell loss. To describe toxicity, greater than 50 percent cell loss at a concentration of equal to or greater than 25 μM was designated as “+”; greater than 50 percent cell loss at a concentration of less than 25 μM and greater than 1 μM was designated as “++”; and greater than 50 percent cell loss at a concentration of equal to or less than 1 μM was designated as “+++”. The results of the analysis of compounds 1-202, 214-248, 332, 333, and 352-402 are presented in Table A.

Table A . Efficacy and toxicity results of compounds

No. Code BC efficiency toxicity 1 BC18607 +++ + 2 BC18608 +++ + 3 BC18612 +++ + 4 BC18614 +++ +++ 5 BC18615 + + 6 BC18616 + + 7 BC18617 + + 8 BC18618 + + 9 BC18619 + + 10 BC18625 + + 11 BC18626 +++ + 12 BC18627 +++ + 13 BC18628 + + 14 BC18629 + + 15 BC18630 +++ + 16 BC18630, HCl salt +++ + 17 BC18631 + + 18 BC18633 + + 19 BC18634 + + 20 BC18635 ++ + 21 BC18636 + + 22 BC18637 + + 23 BC18639 +++ + 24 BC18640 +++ + 25 BC18641 +++ ++ 26 BC18642 +++ +++ 27 BC18643 +++ + 28 BC18644 + + 29 BC18645 ++ + 30 BC18646 +++ +++ 31 BC18647 +++ +++ 32 BC18648 +++ +++ 33 BC18649 + + 34 BC18652 +++ + 35 BC18653 +++ ++ 36 BC18654 + + 37 BC18655 ++ + 38 BC18656 + + 39 BC18657 + + 40 BC18658 ++ + 41 BC18659 ++ ++ 42 BC18660 +++ + 43 BC18663 ++ + 44 BC18664 +++ + 45 BC18665 + + 46 BC18666 + + 47 BC18667 +++ +++ 48 BC18668 + + 49 BC18669 + + 50 BC18670 + + 51 BC18671 + + 52 BC18672 + + 53 BC18673 + + 54 BC18674 + + 55 BC18675 + + 56 BC18676 ++ + 57 BC18677 +++ + 58 BC18678 ++ + 59 BC18679 ++ + 60 BC18680 + + 61 BC18681 +++ ++ 62 BC18682 +++ +++ 63 BC18683 + + 64 BC18684 ++ ++ 65 BC18685 + + 66 BC18686 + + 67 BC18687 + + 68 BC18688 + + 69 BC18689 + + 70 BC18690 +++ + 71 BC18693 +++ + 72 BC18695 +++ +++ 73 BC18697 +++ +++ 74 BC18698 +++ ++ 75 BC18702 + + 76 BC18703 + + 77 BC18704 +++ + 78 BC18705 ++ + 79 BC18706 + + 80 BC18707 ++ + 81 BC18708 +++ ++ 82 BC18709 +++ + 83 BC18711 ++ + 84 BC18713 +++ + 85 BC18714 +++ + 86 BC18717 +++ +++ 87 BC18718 + + 88 BC18720 + + 89 BC18722 ++ ++ 90 BC18724 +++ + 91 BC18725 +++ + 92 BC18726 ++ + 93 BC18727 + + 94 BC18728 +++ + 95 BC18729 + + 96 BC18730 + + 97 BC18731 +++ + 98 BC18732 +++ + 99 BC18733 +++ + 100 BC18734 + + 101 BC18735 + + 102 BC18736 +++ + 103 BC18737 +++ + 104 BC18738 +++ + 105 BC18739 + + 106 BC18740 + + 107 BC18742 + + 108 BC18743 +++ + 109 BC18744 +++ + 110 BC18745 +++ + 111 BC18746 + + 112 BC18747 +++ + 113 BC18748 +++ ++ 114 BC18749 +++ ++ 115 BC18750 + + 116 BC18752 +++ + 117 BC18754 +++ + 118 BC18755 ++ + 119 BC18756 + + 120 BC18757 + + 121 BC18758 + + 122 BC18759 + + 123 BC18760 ++ + 124 BC18761 +++ + 125 BC18762 ++ + 126 BC18763 ++ + 127 BC18764 ++ + 128 BC18765 +++ + 129 BC18766 +++ + 130 BC18767 +++ + 131 BC18768 +++ + 132 BC18769 +++ + 133 BC18770 +++ + 134 BC18771 +++ + 135 BC18772 ++ + 136 BC18773 +++ + 137 BC18774 +++ + 138 BC18775 +++ + 139 BC18776 + + 140 BC18778 + + 141 BC18779 +++ ++ 142 BC18780 +++ + 143 BC18782 +++ + 144 BC18783 + + 145 BC18784 +++ + 146 BC18785 +++ + 147 BC18786 ++ + 148 BC18787 +++ + 149 BC18788 ++ ++ 150 BC18789 +++ ++ 151 BC18790 +++ + 152 BC18791 ++ + 153 BC18792 ++ + 154 BC18793 +++ + 155 BC18794 +++ + 156 BC18795 +++ + 157 BC18796 +++ ++ 158 BC18797 +++ + 159 BC1820 + + 160 BC18200 +++ ++ 161 BC18201 + + 162 BC18202 + + 163 BC18203 + + 164 BC18204 + + 165 BC18205 + + 166 BC18206 + + 167 BC18207 ++ + 168 BC18208 + + 169 BC18209 + + 170 BC18210 + + 171 BC18211 + + 172 BC18212 + + 173 BC18213 + + 174 BC18214 + + 175 BC18215 + + 176 BC18216 ++ + 177 BC18217 + + 178 BC1834 +++ + 179 BC18601 ++ + 180 BC18602 + + 181 BC18603 +++ + 182 BC18604 + + 183 BC18605 ++ + 184 BC18606 ++ + 185 BC18609 +++ + 186 BC18610 +++ + 187 BC18611 +++ + 188 BC18613 + + 189 BC18623 ++ + 190 BC18624 ++ + 191 BC18632 +++ + 192 BC18651 +++ + 193 BC18661 ++ ++ 194 BC18715 +++ + 195 BC1816 + + 196 BC1835 + + 197 BC1836 + + 198 BC1837 + + 199 BC1838 + + 200 BC1839 ++ + 201 BC1840 + + 202 BC1841 + + 214 BC1770 + + 215 BC1771 ++ ++ 216 BC1772 + + 217 BC1773 + + 218 BC1774 + + 219 BC1775 + + 220 BC1776 + + 221 BC1777 + + 222 BC1753 ++ ++ 223 BC1780 + + 224 BC1781 + + 225 BC1782 + + 226 BC1783 + + 227 BC1784 + + 228 BC1785 + + 229 BC1786 + + 230 BC1787 + + 231 BC1811 ++ + 232 BC1812 + + 233 BC1813 + + 234 BC1814 ++ + 235 BC1815 ++ + 236 BC1817 ++ + 237 BC1818 ++ + 238 BC1819 + + 239 BC18842 ++ + 240 BC18846 +++ + 241 BC18847 +++ + 242 BC18848 +++ + 243 BC18849 +++ + 244 BC18850 +++ + 245 BC18851 +++ + 246 BC18852 +++ + 247 BC18853 ++ + 248 BC18854 ++ + 332 BC191183/ BC18861 +++ + 333 BC191184/ BC18862 +++ + 352 BC18795 ++ + 353 BC18796 ++ + 354 BC18797 + + 355 BC18798 ++ + 356 BC18799 +++ + 357 BC18800 + + 358 BC18801 ++ + 359 BC18802 + + 360 BC18803 + + 361 BC18804 ++ + 362 BC18805 + + 363 BC18806 +++ + 364 BC18807 + + 365 BC18808 +++ + 366 BC18809 + + 367 BC18810 ++ + 368 BC18811 ++ + 369 BC18812 + + 370 BC18814 +++ + 371 BC18817 +++ + 372 BC18818 +++ + 373 BC18819 ++ + 374 BC18820 ++ + 375 BC18821 +++ + 376 BC18822 +++ + 377 BC18823 ++ + 378 BC18824 +++ + 379 BC18825 +++ + 380 BC18826 ++ + 381 BC18827 +++ + 382 BC18828 + + 383 BC18829 ++ + 384 BC18830 +++ + 385 BC18831 ++ + 386 BC18832 +++ + 387 BC18833 + + 388 BC18834 + + 389 BC18835 + + 390 BC18836 + + 391 BC18837 +++ + 392 BC18838 + + 393 BC18839 ++ + 394 BC18840 + + 395 BC18841 +++ + 396 BC18845 +++ + 397 BC18855 ++ + 398 BC18856 +++ + 399 BC18857 +++ + 400 BC18858 +++ + 401 BC18859 +++ + 402 BC18860 +++ +

Example 3. Use of BC1753 to Increase TFEB Polypeptide Levels

BC1753 (Fig. 2A) was tested for its ability to increase TFEB polypeptide levels. Briefly, mouse lung epithelial cells (MLE12) stably expressing TFEB-EGFP were treated with BC1753 in a dose-dependent manner for 18 h. The cells were then harvested and analyzed by immunoblotting to determine TFEB-GFP protein levels (Fig. 2B). Mouse lung epithelial cells (MLE12) stably expressing TFEB-EGFP were treated with BC1753 in a dose-dependent manner for 18 h. The cells were then fixed with 4% PFA and then stained with DAPI. TFEB localization was visualized on the GFP channel along with the DAPI signal using a Nikon A1 confocal microscope (Fig. 2C). Compound BC1753 provides a dramatic increase in total TFEB polypeptide levels in cells (Fig. 2B) and enhanced nuclear accumulation of TFEB polypeptide (Fig. 2C).

Example 4. Compounds for increasing TFEB polypeptide levels in the cell nucleus

Multiparametric imaging screening was performed using Beas2B cells stably expressing GFP-TFEB. This approach demonstrated robust and accurate measurement of the nuclear/cytosolic TFEB ratio upon treatment with different compounds (Fig. 3).

Example 5. Increased number of lysosomes, lysosomal protein expression and secretion of lysosomal enzymes

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

Example 6. Use of the compounds provided herein to reduce levels of Huntingtin polypeptides

Compound 178 (BC1834) was tested for its ability to reduce Huntington's polypeptide levels in cells. Briefly, compound 178 was administered to SH5Y cells stably expressing GFP-Huntington's (72Q). As shown in Fig. 6A-B, compound 178 reduced GFP-Huntington's polypeptide levels in a dose-dependent manner. These results demonstrate that the compounds provided herein may be useful for the treatment of neurological conditions such as Huntington's disease.

Example 7. In vivo effect

Female C57BL6 mice were given i.p. injections of compound 15 (50 mg/kg/day) for 4 days. The mice were then given i.v. injections of dextran blue. After 24 hours, the mice were euthanized and liver samples were collected and visualized by confocal microscopy. As shown in Fig. 7, administration of compound 15 dramatically increased the lysosomal dextran blue signal and LAMP2 (pseudo-stained white) staining. These results demonstrate that the compounds provided herein can increase the number and activity of lysosomes in vivo.

OTHER IMPLEMENTATION OPTIONS

It should be understood that although this application is presented together with the detailed description thereof, the foregoing description is intended to illustrate and not to limit the scope of this application, which should be defined by the scope of the appended claims. Other aspects, advantages and modifications are within the scope of the following claims.

--->

SEQUENCE LIST

<110> University of Pittsburgh - Higher Education System

British Commonwealth

<120> METHODS AND MATERIALS FOR INCREASING POLYPEPTIDE LEVELS

TRANSCRIPTION FACTORS EB

<130> 45049-0021WO1

<140> PCT/US2020/012268

<141> 2020-01-03

<150> 62/879,374

<151> 2019-07-26

<150> 62/788,049

<151> 2019-01-03

<160> 1

<170> PatentIn, version 3.5

<210> 1

<211> 419

<212> PRT

<213> Homo sapiens

<400> 1

Met Ala Ser Arg Ile Gly Leu Arg Met Gln Leu Met Arg Glu Gln Ala

1 5 10 15

Gln Gln Glu Glu Gln Arg Glu Arg Met Gln Gln Gln Ala Val Met His

20 25 30

Tyr Met Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Leu Gly Gly Pro

35 40 45

Pro Thr Pro Ala Ile Asn Thr Pro Val His Gln Ser Pro Pro Pro Val

50 55 60

Pro Gly Glu Val Leu Lys Val Gln Ser Tyr Leu Glu Asn Pro Thr Ser

65 70 75 80

Tyr His Leu Gln Gln Ser Gln His Gln Lys Val Arg Glu Tyr Leu Ser

85 90 95

Glu Thr Tyr Gly Asn Lys Phe Ala Ala His Ile Ser Pro Ala Gln Gly

100 105 110

Ser Pro Lys Pro Pro Pro Ala Ala Ser Pro Gly Val Arg Ala Gly His

115 120 125

Val Leu Ser Ser Ser Ala Gly Asn Ser Ala Pro Asn Ser Pro Met Ala

130 135 140

Met Leu His Ile Gly Ser Asn Pro Glu Arg Glu Leu Asp Asp Val Ile

145 150 155 160

Asp Asn Ile Met Arg Leu Asp Asp Val Leu Gly Tyr Ile Asn Pro Glu

165 170 175

Met Gln Met Pro Asn Thr Leu Pro Leu Ser Ser Ser His Leu Asn Val

180 185 190

Tyr Ser Ser Asp Pro Gln Val Thr Ala Ser Leu Val Gly Val Thr Ser

195 200 205

Ser Ser Cys Pro Ala Asp Leu Thr Gln Lys Arg Glu Leu Thr Asp Ala

210 215 220

Glu Ser Arg Ala Leu Ala Lys Glu Arg Gln Lys Lys Asp Asn His Asn

225 230 235 240

Leu Ile Glu Arg Arg Arg Arg Phe Asn Ile Asn Asp Arg Ile Lys Glu

245 250 255

Leu Gly Met Leu Ile Pro Lys Ala Asn Asp Leu Asp Val Arg Trp Asn

260 265 270

Lys Gly Thr Ile Leu Lys Ala Ser Val Asp Tyr Ile Arg Arg Met Gln

275 280 285

Lys Asp Leu Gln Lys Ser Arg Glu Leu Glu Asn His Ser Arg Arg Leu

290 295 300

Glu Met Thr Asn Lys Gln Leu Trp Leu Arg Ile Gln Glu Leu Glu Met

305 310 315 320

Gln Ala Arg Val His Gly Leu Pro Thr Thr Ser Pro Ser Gly Met Asn

325 330 335

Met Ala Glu Leu Ala Gln Gln Val Val Lys Gln Glu Leu Pro Ser Glu

340 345 350

Glu Gly Pro Gly Glu Ala Leu Met Leu Gly Ala Glu Val Pro Asp Pro

355 360 365

Glu Pro Leu Pro Ala Leu Pro Pro Gln Ala Pro Leu Pro Leu Pro Thr

370 375 380

Gln Pro Pro Ser Pro Phe His His Leu Asp Phe Ser His Ser Leu Ser

385 390 395 400

Phe Gly Gly Arg Glu Asp Glu Gly Pro Pro Gly Tyr Pro Glu Pro Leu

405 410 415

Ala Pro Gly

<---

Claims (36)

1. Compound of formula (IIh) or a pharmaceutically acceptable salt thereof, where L is N(R ^N ); R ^N is H; n is equal to 1; each R ¹ , R ³ , R ⁴ and R ⁵ is independently selected from H, halogen and C _1-6 alkyl; R ^A is ; R ^B is Cy ¹ ; each Cy ¹ is independently selected from C _6-10 aryl or 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ^Cy2 ; each R ^Cy2 is independently halogen, Cy ² , C _1-6 alkyl, OR ^a2 and NR ^c2 C(O)R ^b2 ; each Cy ² is C _3-10 cycloalkyl; each R ^a2 , R ^b2 and R ^c2 is independently selected from H and C _1-6 alkyl. 2. The compound according to claim 1, characterized in that R ^B is selected from the group consisting of 3. A compound according to claim 1, wherein R ^B is a 5-10 membered heteroaryl, optionally substituted with 1, 2 or 3 substituents independently selected from R ^Cy2 . 4. The compound according to claim 1, having the formula or a pharmaceutically acceptable salt thereof. 5. A compound according to claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof. 6. A compound according to claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof. 7. A pharmaceutical composition for increasing the levels of the transcription factor EB polypeptide in the cell nucleus in a mammal, comprising an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 8. A method for increasing the levels of the transcription factor EB polypeptide in the nucleus of a cell in the body of a mammal, comprising administering to said mammal a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

Images