WO2022032073A2 - Trpml modulators - Google Patents

Trpml modulators Download PDF

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Publication number
WO2022032073A2
WO2022032073A2 PCT/US2021/044911 US2021044911W WO2022032073A2 WO 2022032073 A2 WO2022032073 A2 WO 2022032073A2 US 2021044911 W US2021044911 W US 2021044911W WO 2022032073 A2 WO2022032073 A2 WO 2022032073A2
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optionally substituted
aliphatic
compound
alkylenyl
heteroatoms selected
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French (fr)
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WO2022032073A3 (en
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Andrew Thomas Maynard
Erik Lee MEREDITH
Jeffrey Owen SAUNDERS
Jian Lin
Jorge Garcia FORTANET
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Casma Therapeutics Inc
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Casma Therapeutics Inc
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Priority to CN202180057615.6A priority Critical patent/CN116113698A/zh
Priority to KR1020237007509A priority patent/KR20230050369A/ko
Priority to US18/019,638 priority patent/US20230416262A1/en
Priority to JP2023504748A priority patent/JP2023537274A/ja
Priority to EP21853420.4A priority patent/EP4192957A4/en
Publication of WO2022032073A2 publication Critical patent/WO2022032073A2/en
Publication of WO2022032073A3 publication Critical patent/WO2022032073A3/en
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D495/10—Spiro-condensed systems

Definitions

  • TRPML MODULATORS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] The present application claims priority to U.S. Provisional Application No. 63/062,943, filed August 7, 2020; U.S. Provisional Application No.63/119,915, filed December 1, 2020; and U.S. Provisional Application No.63/186,846, filed May 11, 2021, each of which is incorporated by reference in its entirety.
  • Transient Receptor Potential Mucolipin-1 also known as TRPML1 or ML1 is a Ca 2+ channel in the lysosome that regulates certain aspects of lysosome trafficking, including autophagy.
  • TRPML1 is an inwardly rectifying current channel that transports cations from the lumen of the lysosome to the cytosol. See Di Paolda, et al., Cell Calcium 69:112-121 (2016). Release of Ca 2+ from the lysosome via TRPML1 modulates transcription factor EB activity. See Medina, et al., Nat. Cell. Biol., 17(3):288-299 (2015). SUMMARY [0003] It has recently been discovered that upregulation of autophagy is beneficial to patients suffering from a number of diseases and disorders.
  • the present disclosure provides, among other things, technologies for regulating (e.g., up- regulating) autophagy.
  • the present disclosure demonstrates effectiveness of certain approaches to TRPML modulation (e.g., TRPML agonism, including agonism of TRPML1, TPRML2, and/or TRPML3) in enhancing autophagy.
  • TRPML agonism including agonism of TRPML1, TPRML2, and/or TRPML3
  • the present disclosure demonstrates that targeting a TRPML (e.g., TRPML1, TRPML2, and/or TRPML3) as described herein can enhance autophagy.
  • TRPML e.g., TRPML1, TRPML2, and/or TRPML3
  • the present disclosure also provides certrain technologies for use in medicine, and in particular for treating certain diseases, disorders or conditions and/or for identifying, characterizing, and/or manufacturing certain agents and/or compositions or that comprise or deliver them that are useful in treating such diseases, disorders or conditions.
  • modulating e.g., agonizing
  • a TRPML e.g., TRPML1, TRPML2, and/or TRPML3
  • enhancing autophagy is useful in the treatment of certain diseases, disorders or conditions.
  • TRPML e.g., TRPML1, TRPML2, and/or TRPML3 modulators useful for promoting autophagy and/or treating certain diseases, disorders, or conditions.
  • TRPML e.g., TRPML1, TRPML2, and/or TRPML3 modulators useful for promoting autophagy and/or treating certain diseases, disorders, or conditions.
  • the present application provides technologies useful for modulating a TRPML (e.g., TRPML1, TRPML2, and/or TRPML3).
  • TRMPL modulators that are small molecule compounds having a chemical structure as indicated below in Formula I: or a pharmaceutically acceptable salt thereof, wherein X is –NR 5 -, -C(R 5 ) 2, -C(O)-, - or –O-; each of Y 1 and Y 2 is independently selected from N and C; L is an optionally substituted group selected from -C 0 -C 6 alkylenyl–S(O) 2 -, –S(O) 2 -C 0 -C 6 alkylenyl, -S(O)-C 0 -C 6 alkylenyl, -C 0 -C 6 alkylenyl-S(O)-, -C(O)-C 0 -C 6 alkylenyl, -C(O)- O-C 0 -C 6 alkylenyl, -C(O)-
  • A is C 3 -C 12 cycloaliphatic or 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein A is substituted with (R 2 ) m ;
  • B is a fused optionally substituted C 5 -C 6 aryl or optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S;
  • R 1 is selected from C 1 -C 6 aliphatic, C 3 -C 12 cycloaliphatic, C 5 -C 12 aryl, 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and 3- to 12- membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein R 1 is substituted with (R 3 ) p ;
  • each R 2 is independently halo, oxo, -NR 2a R 2b , -C(O)
  • agonist generally refers to an agent whose presence or level correlates with elevated level or activity of a target, as compared with that observed absent the agent (or with the agent at a different level).
  • an agonist is one whose presence or level correlates with a target level or activity that is comparable to or greater than a particular reference level or activity (e.g., that observed under appropriate reference conditions, such as presence of a known agonist, e.g., a positive control).
  • an agonist may be a direct agonist in that it exerts its influence directly on (e.g., interacts directly with) the target; in some embodiments, an agonist may be an indirect agonist in that it exerts its influence indirectly (e.g., by acting on, such as interacting with, a regulator of the target, or with some other component or entity.
  • Aliphatic refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “cycloaliphatic”), that has a single point or more than one points of attachment to the rest of the molecule.
  • aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms (e.g., C 1-6 ).
  • aliphatic groups contain 1-5 aliphatic carbon atoms (e.g., C 1- 5 ). In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., C 1-4 ). In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (e.g., C 1-3 ), and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (e.g., C 1-2 ).
  • cycloaliphatic refers to a monocyclic C 3-8 hydrocarbon or a bicyclic C 7-10 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point or more than one points of attachment to the rest of the molecule.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, P 4 f 298
  • Alkyl refers to a saturated, optionally substituted straight or branched chain hydrocarbon group having (unless otherwise specified) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., C 1-12 , C 1-10 , C 1-8 , C 1-6 , C 1-4 , C 1- 3 , or C 1-2 ).
  • alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl.
  • Alkylene The terms “alkylene” and “alkylenyl” are used interchangeably and refer to a bivalent alkyl group. In some embodiments, “alkylene” is a bivalent straight or branched alkyl group. In some embodiments, an "alkylene chain" is a polymethylene group, i.e., -(CH 2 ) n -, wherein n is a positive integer, e.g., from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • An optionally substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms is optionally replaced with a substituent.
  • Suitable substituents include those described below for a substituted aliphatic group and also include those described in the specification herein. It will be appreciated that two substituents of the alkylene group may be taken together to form a ring system. In certain embodiments, two substituents can be taken together to form a 3- to 7-membered ring. The substituents can be on the same or different atoms.
  • the suffix “-ene” or “-enyl” when appended to certain groups herein are intended to refer to a bifunctional moiety of said group.
  • alkenyl when appended to “cyclopropyl” becomes “cyclopropylene” or “cyclopropylenyl” and is intended to refer to a bifunctional cyclopropyl group, e.g., .
  • Alkenyl used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain or cyclic hydrocarbon group having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms(e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3).
  • alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl.
  • cycloalkenyl refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms.
  • Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.
  • Alkenylene The term “alkenylene” and “alkenylenyl” are used interchangeably and refers to a bivalent alkenyl group. In some embodiments, “alkenylene” is a bivalent straight or branched alkenyl group.
  • Alkynyl The term “alkynyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C 2-12 , C 2-10 , C 2-8 , C 2-6 , C 2-4 , or C 2-3 ).
  • alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.
  • Alkynylene The term “alkynylene” and “alkynylenyl” are used interchangeably and refers to a bivalent alkynyl group. In some embodiments, “alkynylene” is a bivalent straight or branched alkynyl group.
  • Analog As used herein, the term “analog” refers to a substance that shares one or more particular structural features, elements, components, or moieties with a reference substance.
  • an “analog” shows significant structural similarity with the reference substance, for example sharing a core or consensus structure, but also differs in certain discrete ways.
  • an analog is a substance that can be generated from the reference substance, e.g., by chemical manipulation of the reference substance.
  • an analog is a substance that can be generated through performance of a synthetic process substantially similar to (e.g., sharing a plurality of steps with) one that generates the reference substance.
  • an analog is or can be generated through performance of a synthetic process different from that used to generate the reference substance.
  • Antagonist generally refers to an agent whose presence or level correlates with decreased level or activity of a target, as compared with that observed absent the agent (or with the agent at a different level).
  • an antagonist is one whose presence or level correlates with a target level or activity that is comparable to or less than a particular reference level or activity (e.g., that observed under appropriate reference conditions, such as presence of a known antagonist, e.g., a positive control).
  • an antagonist may be a direct antagonist in that it exerts its influence directly on (e.g., interacts directly with) the target; in some embodiments, an antagonist may be an indirect antagonist in that it exerts its influence indirectly (e.g., by acting on, such as interacting with, a regulator of the target, or with some other component or entity.
  • Aryl refers to monocyclic and bicyclic ring systems having a total of five to fourteen ring members (e.g., C 5 -C 14 ), wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. In some embodiments, an “aryl” group contains between six and twelve total ring members (e.g., C 6 -C 12 ). The term “aryl” may be used interchangeably with the term “aryl ring”.
  • aryl refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Unless otherwise specified, “aryl” groups are hydrocarbons. In some embodiments, an “aryl” ring system is an aromatic ring (e.g., phenyl) that is fused to a non-aromatic ring (e.g., cycloalkyl). Examples of aryl rings include that are fused include , , a .
  • Two events or entities are “associated” with one another, as that term is used herein, if the presence, level and/or form of one is correlated with that of the other.
  • a particular entity e.g., polypeptide, genetic signature, metabolite, microbe, etc
  • two or more entities are physically “associated” with one another if they interact, directly or indirectly, so that they are and/or remain in physical proximity with one another.
  • Biological sample typically refers to a sample obtained or derived from a biological source (e.g., a tissue or organism or cell culture) of interest, as described herein.
  • a source of interest comprises an organism, such as an animal or human.
  • a biological sample is or comprises biological tissue or fluid.
  • a biological sample may be or comprise bone marrow; blood; blood cells; ascites; tissue or fine needle biopsy samples; cell-containing body fluids; free floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washings P 7 f 298
  • a biological sample is or comprises cells obtained from an individual.
  • obtained cells are or include cells from an individual from whom the sample is obtained.
  • a sample is a “primary sample” obtained directly from a source of interest by any appropriate means.
  • a primary biological sample is obtained by methods selected from the group consisting of biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of body fluid (e.g., blood, lymph, feces etc.), etc.
  • sample refers to a preparation that is obtained by processing (e.g., by removing one or more components of and/or by adding one or more agents to) a primary sample. For example, filtering using a semi-permeable membrane.
  • Such a “processed sample” may comprise, for example, nucleic acids or proteins extracted from a sample or obtained by subjecting a primary sample to techniques such as amplification or reverse transcription of mRNA, isolation and/or purification of certain components, etc.
  • Biomarker The term “biomarker” is used herein, consistent with its use in the art, to refer to a to an entity (or form thereof) whose presence, or level, correlates with a particular biological event or state of interest, so that it is considered to be a “marker” of that event or state.
  • a biomarker may be or comprise a marker for a particular disease state, or for likelihood that a particular disease, disorder or condition may develop, occur, or reoccur.
  • a biomarker may be or comprise a marker for a particular disease or therapeutic outcome, or likelihood thereof.
  • a biomarker is predictive, in some embodiments, a biomarker is prognostic, in some embodiments, a biomarker is diagnostic, of the relevant biological event or state of interest.
  • Carrier refers to a diluent, adjuvant, excipient, or vehicle with which a composition is administered.
  • carriers can include sterile liquids, such as, for example, water and oils, including oils of petroleum, animal, vegetable or synthetic origin, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil and the like. In some embodiments, carriers are or include one or more solid components.
  • Combination therapy refers to those situations in which a subject is simultaneously exposed to two or more therapeutic regimens (e.g., P 8 f 298 two or more therapeutic agents or modality(ies)).
  • the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens.
  • “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination.
  • combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition, or even in a combination compound (e.g., as part of a single chemical complex or covalent entity).
  • Comparable refers to two or more agents, entities, situations, sets of conditions, etc., that may not be identical to one another but that are sufficiently similar to permit comparison therebetween so that one skilled in the art will appreciate that conclusions may reasonably be drawn based on differences or similarities observed.
  • comparable sets of conditions, circumstances, individuals, or populations are characterized by a plurality of substantially identical features and one or a small number of varied features.
  • Those of ordinary skill in the art will understand, in context, what degree of identity is required in any given circumstance for two or more such agents, entities, situations, sets of conditions, etc. to be considered comparable.
  • sets of circumstances, individuals, or populations are comparable to one another when characterized by a sufficient number and type of substantially identical features to warrant a reasonable conclusion that differences in results obtained or phenomena observed under or with different sets of circumstances, individuals, or populations are caused by or indicative of the variation in those features that are varied.
  • composition may be used to refer to a discrete physical entity that comprises one or more specified components. In general, unless otherwise specified, a composition may be of any form – e.g., gas, gel, liquid, solid, etc.
  • Cycloaliphatic As used herein, the term “cycloaliphatic” refers to a monocyclic C 3-8 hydrocarbon or a bicyclic C 7-10 hydrocarbon that is completely saturated or that contains one or P 9 f 298 more units of unsaturation, but which is not aromatic, that has a single point or more than one points of attachment to the rest of the molecule.
  • Cycloalkyl refers to an optionally substituted saturated ring monocyclic or polycyclic system of about 3 to about 10 ring carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • Dosage form or unit dosage form Those skilled in the art will appreciate that the term “dosage form” may be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent.
  • an active agent e.g., a therapeutic or diagnostic agent
  • such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., with a therapeutic dosing regimen).
  • a dosing regimen or a whole fraction thereof
  • the total amount of a therapeutic composition or agent administered to a particular subject is determined by one or more attending physicians and may involve administration of multiple dosage forms.
  • Dosing regimen or therapeutic regimen Those skilled in the art will appreciate that the terms “dosing regimen” and “therapeutic regimen” may be used to refer to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time.
  • a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses.
  • a dosing regimen comprises a plurality of doses each of which is separated in time from other doses.
  • individual doses are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses.
  • all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts.
  • a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first P 10 f 298 dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic dosing regimen). [0032] Engineered: In general, the term “engineered” refers to the aspect of having been manipulated by the hand of man.
  • a small molecule may be considered to be engineered if its structure and/or production is designed and/or implemented by the hand to man.
  • a polynucleotide may be considered to be “engineered” when two or more sequences, that are not linked together in that order in nature, are manipulated by the hand of man to be directly linked to one another in the engineered polynucleotide.
  • an engineered polynucleotide comprises a regulatory sequence that is found in nature in operative association with a first coding sequence but not in operative association with a second coding sequence, is linked by the hand of man so that it is operatively associated with the second coding sequence.
  • a cell or organism is considered to be “engineered” if it has been manipulated so that its genetic information is altered (e.g., new genetic material not previously present has been introduced, for example by transformation, mating, somatic hybridization, transfection, transduction, or other mechanism, or previously present genetic material is altered or removed, for example by substitution or deletion mutation, or by mating protocols).
  • new genetic material not previously present has been introduced, for example by transformation, mating, somatic hybridization, transfection, transduction, or other mechanism, or previously present genetic material is altered or removed, for example by substitution or deletion mutation, or by mating protocols.
  • expression products of an engineered polynucleotide, and/or progency of an engineered polynucleotide or cell are typically still referred to as “engineered” even though the actual manipulation was performed on a prior entity.
  • Excipient refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired consistency or stabilizing effect.
  • suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • Heteroaliphatic denotes an optionally substituted hydrocarbon moiety having, in addition to carbon atoms, from one to five heteroatoms, that may be straight–chain (i.e., unbranched), branched, or cyclic (“heterocyclic”) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic.
  • heteroatom refers to nitrogen, oxygen, or P 11 f 298 sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • nitrogen also includes a substituted nitrogen.
  • heteroaliphatic groups contain 1–10 carbon atoms wherein 1–3 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, heteroaliphatic groups contain 1–4 carbon atoms, wherein 1–2 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In yet other embodiments, heteroaliphatic groups contain 1–3 carbon atoms, wherein 1 carbon atom is optionally and independently replaced with a heteroatom selected from oxygen, nitrogen, and sulfur. Suitable heteroaliphatic groups include, but are not limited to, linear or branched, heteroalkyl, heteroalkenyl, and heteroalkynyl groups.
  • a 1- to 10 atom heteroaliphatic group includes the following exemplary groups: -O-CH 3 , -CH 2 -O-CH 3 , -O-CH 2 - CH 2 -O-CH 2 -CH 2 -O-CH 3 , and the like.
  • Heteroaryl The terms “heteroaryl” and “heteroar—”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to monocyclic or bicyclic ring groups having 5 to 12 ring atoms (e.g., 5- to 6- membered monocyclic heteroaryl or 9- to 12-membered bicyclic heteroaryl); having 6, 10, or 14 ⁇ -electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • heteroaryl and “heteroar—”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to monocyclic or bicyclic ring groups having 5 to 12 ring atoms (e.g., 5- to 6- membered monocyclic heteroaryl or 9- to 12-membered bicyclic heteroaryl); having 6,
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyridyl, imidazo[4,5-b]pyridyl, imidazo[4,5-c]pyridyl, pyrrol
  • heteroaryl and “heteroar—”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms).
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzotriazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3–b]–1,4–oxazin–3(4H)–one, and P 12 f 298 benzoisoxazolyl.
  • heteroaryl group may be mono– or bicyclic.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted.
  • heteroarylkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
  • Heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • Heterocycle As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclic radical”, and “heterocyclic ring” are used interchangeably and refer to a stable 3- to 8-membered monocyclic, a 7- to 12-membered bicyclic, or a 10- to 16-membered polycyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, such as one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl.
  • a heterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic.
  • the term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • a bicyclic heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl rings. Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3- , , P 13 f 298 , , , , .
  • a bicyclic heterocyclic ring can also be a spirocyclic ring system (e.g., 7- to 11-membered spirocyclic fused heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)).
  • a bicyclic heterocyclic ring can also be a bridged ring system (e.g., 7- to 11-membered bridged heterocyclic ring having one, two, or three bridging atoms.
  • Exemplary bridged ring systems include .
  • Exemplary polycyclic heterocyclic ring systems that are spirocyclic include .
  • Modulator refers to a compound (e.g., a small molecule) that can alter the activity of another molecule (e.g., a protein).
  • a modulator can cause an increase or decrease in the magnitude of a certain activity of a type of molecule as compared to the magnitude of the activity in the absence of the modulator.
  • a modulator can be an agonist or an antagonist of a particular target, as those terms are defined herein.
  • a modulator is an agonist.
  • a modulator is an antagonist.
  • Oral The phrases “oral administration” and “administered orally” as used herein have their art-understood meaning referring to administration by mouth of a compound or composition.
  • Parenteral The phrases “parenteral administration” and “administered parenterally” as used herein have their art-understood meaning referring to modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.
  • Partially unsaturated refers to a ring moiety that includes at least one double or triple bond between ring atoms.
  • the term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties, as herein defined.
  • Patient or subject refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, P 14 f 298 prophylactic, cosmetic, and/or therapeutic purposes.
  • Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans).
  • a patient is a human.
  • a patient or a subject is suffering from or susceptible to one or more disorders or conditions.
  • a patient or subject displays one or more symptoms of a disorder or condition.
  • a patient or subject has been diagnosed with one or more disorders or conditions.
  • a patient or a subject is receiving or has received certain therapy to diagnose and/or to treat a disease, disorder, or condition.
  • Pharmaceutical composition refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers.
  • the active agent is present in unit dose amount appropriate for administration in a therapeutic or dosing regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population.
  • pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream,
  • compositions or vehicles which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or P 15 f 298
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl o
  • compositions that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).
  • pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts, which are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • nontoxic acid addition salts which are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palm
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
  • Polycyclic refers to a saturated or unsaturated ring system having two or more rings (for example, heterocyclyl rings, heteroaryl rings, cycloalkyl rings, or aryl rings), having between 7 and 20 atoms, in which one or more carbon atoms are common to two adjacent rings.
  • a polycyclic ring system refers to a saturated or unsaturated ring system having three or more rings (for example, heterocyclyl rings, heteroaryl rings, cycloalkyl rings, or aryl rings), having between 14 and 20 atoms, in which one or more carbon atoms are common to two adjacent rings.
  • the rings in a polycyclic ring system may be fused (i.e., bicyclic or tricyclic), spirocyclic, or a combination thereof.
  • Prevent or prevention when used in connection with the occurrence of a disease, disorder, and/or condition, refer to reducing the risk of developing the disease, disorder and/or condition and/or to delaying onset of one or more characteristics or symptoms of the disease, disorder or condition. Prevention may be considered complete when onset of a disease, disorder or condition has been delayed for a predefined period of time.
  • Reference As used herein describes a standard or control relative to which a comparison is performed. For example, in some embodiments, an agent, animal, individual, population, sample, sequence or value of interest is compared with a reference or control agent, animal, individual, population, sample, sequence or value.
  • a reference or control is tested and/or determined substantially simultaneously with the testing or determination of interest.
  • a reference or control is a historical reference or control, optionally embodied in a tangible medium.
  • a reference or control is determined or characterized under comparable conditions or circumstances P 17 f 298
  • sample typically refers to an aliquot of material obtained or derived from a source of interest.
  • a source of interest is a biological or environmental source.
  • a source of interest may be or comprise a cell, tissue, or organism, such as a microbe, a plant, or an animal (e.g., a human).
  • a source of interest is or comprises biological tissue or fluid.
  • a source of interest may be or comprise a preparation generated in a production run.
  • a sample is a “primary sample” obtained directly from a source of interest by any appropriate means.
  • sample refers to a preparation that is obtained by processing (e.g., by removing one or more components of and/or by adding one or more agents to) a primary sample.
  • specific when used herein with reference to an agent having an activity, is understood by those skilled in the art to mean that the agent discriminates between potential target entities or states. For example, in some embodiments, an agent is said to bind “specifically” to its target if it binds preferentially with that target in the presence of one or more competing alternative targets.
  • specific interaction is dependent upon the presence of a particular structural feature of the target entity (e.g., an epitope, a cleft, a binding site). It is to be understood that specificity need not be absolute. In some embodiments, specificity may be evaluated relative to that of the binding agent for one or more other potential target entities (e.g., competitors). In some embodiments, specificity is evaluated relative to that of a reference specific binding agent. In some embodiments, specificity is evaluated relative to that of a reference non-specific binding agent. In some embodiments, the agent or entity does not detectably bind to the competing alternative target under conditions of binding to its target entity.
  • a particular structural feature of the target entity e.g., an epitope, a cleft, a binding site. It is to be understood that specificity need not be absolute. In some embodiments, specificity may be evaluated relative to that of the binding agent for one or more other potential target entities (e.g., competitors). In some embodiments, specificity is evaluated relative to that of a reference specific binding agent
  • a binding agent binds with higher on-rate, lower off-rate, increased affinity, decreased dissociation, and/or increased stability to its target entity as compared with the competing alternative target(s).
  • Substituted or optionally substituted As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or more hydrogens P 18 f 298
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes provided herein.
  • Groups described as being “substituted” preferably have between 1 and 4 substituents, more preferably 1 or 2 substituents. Groups described as being “optionally substituted” may be unsubstituted or be “substituted” as described above.
  • each Rq may be substituted as defined below and is independently hydrogen, C 1–6 aliphatic, –CH 2 Ph, –O(CH 2 ) 0– 1 Ph, -CH 2 -(5- to 6-membered heteroaryl ring), or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of Rq, taken together with their intervening atom(s), form a 3- to 12-membered saturated, partially unsaturated, or ary
  • Suitable monovalent substituents on Rq are independently halogen, —(CH 2 ) 0–2 R z , –(haloR z ), –(CH 2 ) 0–2 OH, –(CH 2 ) 0–2 OR z , –(CH 2 ) 0–2 CH(OR z ) 2 , -O(haloR z ), –CN, –N 3 , –(CH 2 ) 0– 2 C(O)R z , –(CH 2 ) 0–2 C(O)OH, –(CH 2 ) 0–2 C(O)OR z , –(CH 2 ) 0–2 SR z , –(CH 2 ) 0–2 SH, –(CH 2 ) 0–2 NH 2 , – (CH 2 ) 0
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR * 2) 2–3 O–, wherein each independent occurrence of R * is selected from hydrogen, C 1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R * is selected from hydrogen, C 1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R * include halogen, –R z , -(haloR z ), -OH, – OR z , –O(haloR z ), –CN, –C(O)OH, –C(O)OR z , –NH 2 , –NHR z , –NR z 2, or –NO 2 , wherein each R z is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include ⁇ , – C(O)CH ; wherein each R ⁇ is independently hydrogen, C 1–6 aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ⁇ , taken together with their intervening atom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, – R z , -(haloR z ), –OH, –OR z , –O(haloR z ), –CN, –C(O)OH, –C(O)OR z , –NH 2 , –NHR z , –NR z 2, or -NO 2 , wherein each R z is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Small molecule means a low molecular weight organic and/or inorganic compound.
  • a “small molecule” is a molecule that is less than about 5 kilodaltons (kD) in size.
  • a small molecule is less than about 4 kD, 3 kD, about 2 kD, or about 1 kD.
  • the small molecule is less than about 800 daltons (D), about 600 D, about 500 D, about 400 D, about 300 D, about 200 D, or about 100 D.
  • a small molecule is less than about 2000 g/mol, less than about 1500 g/mol, less than about 1000 g/mol, less than about 800 g/mol, or less than about 500 g/mol. In some embodiments, a small molecule is not a polymer.
  • a small molecule does not include a polymeric moiety.
  • a small molecule is not and/or does not comprise a protein or polypeptide (e.g., is not an oligopeptide or peptide).
  • a small molecule is not and/or does not comprise a polynucleotide (e.g., is not an oligonucleotide).
  • a small molecule is not and/or does not comprise a polysaccharide; for example, in some embodiments, a small molecule is not a glycoprotein, proteoglycan, glycolipid, etc.). In some embodiments, a small molecule is not a lipid.
  • a small molecule is a modulating agent (e.g., is an inhibiting agent or an activating agent).
  • a small molecule is biologically active.
  • a small molecule is detectable (e.g., comprises at least one detectable moiety).
  • a small molecule is a therapeutic agent.
  • such a small molecule may be utilized in accordance with the present disclosure in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers; in some embodiments, such a small molecule may be utilized in accordance with the present disclosure in a racemic mixture form.
  • certain small molecule compounds have structures that can exist in one or more tautomeric forms. In some embodiments, such a small molecule may be utilized in accoradance with the present disclosure in the form of an individual tautomer, or in a form that interconverts between tautomeric forms.
  • reference to a particular small molecule compound may relate to a specific form of that compound.
  • a particular small molecule compound may be provided and/or utilized in a salt form (e.g., in an acid-addition or base-addition salt form, depending on the compound); in some such embodiments, the salt form may be a pharmaceutically acceptable salt form.
  • a small molecule compound is one that exists or is found in nature, that compound may be provided and/or utilized in accordance in the present disclosure in a form different from that in which it exists or is found in nature.
  • a preparation of a particular small molecule compound that contains an absolute or relative amount of the compound, or of a particular form thereof, that is different from the absolute or relative (with respect to another component of the preparation including, for example, another form of the compound) amount of the compound or form that is present in a reference preparation of interest is distinct from the compound as it exists in the reference preparation or source.
  • a preparation of a single stereoisomer of a small molecule compound may be considered to be a different form of the compound than a racemic mixture of the compound; a particular salt of a small molecule compound may be considered to be a different form from another salt form of the compound; a preparation that contains only a form of the compound that contains one conformational isomer ((Z) or (E)) of a double bond may be considered to be a different form of the compound from one that contains the other conformational isomer ((E) or (Z)) of the double bond; a preparation in which one or more atoms is a different isotope than is present in a reference preparation may be considered to be a different form; etc.
  • a bond designated as in a small molecule structure refers to a bond that, in some embodiments, is a single (e.g., saturated) bond, and in some embodiments, is a double (e.g., unsaturated) bond.
  • a bond that, in some embodiments, is a single (e.g., saturated) bond, and in some embodiments, is a double (e.g., unsaturated) bond.
  • therapeutic agent in general refers to any agent that elicits a desired pharmacological effect when administered to an organism.
  • an agent is considered to be a therapeutic agent if it demonstrates a statistically significant effect across an appropriate population.
  • the appropriate population may be a population of model organisms.
  • an appropriate population may be defined by various criteria, such as a certain age group, gender, genetic background, preexisting clinical conditions, etc.
  • a therapeutic agent is a substance that can be used to alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and/or reduce incidence of one or more symptoms or features of a disease, disorder, and/or condition.
  • a “therapeutic agent” is an agent that has been or is required to be approved by a government agency before it can be marketed for administration to humans.
  • a “therapeutic agent” is an agent for which a medical prescription is required for administration to humans.
  • Treat refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and/or reduce incidence of one or more symptoms or features of a disease, disorder, and/or condition.
  • Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition.
  • treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and/or condition, for example, for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and/or condition.
  • Autophagy is a mechanism of the cell that degrades cytoplasmic material and organelles.
  • autophagy There are multiple types of autophagy: (1) macroautophagy (generally referred to as autophagy); (2) microautophagy; and (3) chaperone-mediateed autophagy. See Eskelinen & Saftig, Biochimica et Biophysica Acta – Mol. Cell Res., 1793(4):664-673 (2009).
  • macroautophagy the autophagosome engulfs waste materials in the cytoplasm and fuses to the lysosome, where materials are delivered for degradation.
  • the lysosome is as a subcellular organelle containing more than 50 soluble acid hydrolases useful for digesting cellular components. Fusion of the lysosome to the autophagosome is activated, in part, by release of ions through ion channels in the membrane of the lysome, including Ca 2+ . See Cao, et al., J. Bio. Chem., 292(20)8424-8435 (2017).
  • Transient Receptor Potential Mucolipin-1 also known as TRPML1 or ML1 is a Ca 2+ channel in the lysosome that regulates autophagy. See Wang, et al., PNAS, E1373-E1381 (March 2, 2015).
  • TRPML1 is an inwardly rectifying current channel that transports cations from the lumen of the lysosome to the cytosol.
  • TRPML1 is an inwardly rectifying current channel that transports cations from the lumen of the lysosome to the cytosol.
  • Release of Ca 2+ from the lysosome via TRPML1 modulates transcription factor EB activity via local calcineurin activation, which ultimately induces autophagy and lysosomal biogenesis.
  • Medina et al., Nat. C0ell. Biol., 17(3):288-299 (2015).
  • upregulation of autophagy is beneficial to patients suffering from a number of diseases and disorders.
  • TRPML1 modulators useful for promoting autophagy and/or treating certain diseases, disorders, or conditions.
  • TRMPL modulators e.g., TRPML1, TPRML2, and/or TPRML3
  • TRMPL modulators e.g., TRPML1, TPRML2, and/or TPRML3
  • TRMPL modulators e.g., TRPML1, TPRML2, and/or TPRML3
  • TRPML1, TPRML2, and/or TPRML3 small molecule compounds having a chemical structure as indicated below in Formula I: I or a pharmaceutically acceptable salt thereof, wherein X is –NR 5 -, -C(R 5 ) 2 -, -C(O)-, or –O-; each of Y 1 and Y 2 is independently selected from N and C; L is an optionally substituted group selected from -C 0 -C 6 alkylenyl–S(O) 2 -, –S(O) 2 -C 1 -C 6 alkylenyl, -S(O)-C 0 -C 6 alkyl
  • X is –NR 5 -, -C(R 5 ) 2 -, - C(O)-, or –O-.
  • X is –NR 5 -.
  • X is —NH-.
  • X is –C(R 5 ) 2 -.
  • X is –CH(R 5 )-.
  • X is P 27 f 298
  • X is -CH(CH 3 )-. In some embodiments, X is –O-. In some embodiments, X is -C(O)-. [0078] As defined generally above, Y 1 and Y 2 are each independently N or C. In some embodiments, Y 1 and Y 2 are each N. In some embodiments, Y 1 and Y 2 are each C. In some embodiments, Y 1 is N and Y 2 is C. In some embodiments, Y 1 is C and Y 2 is N.
  • L is an optionally substituted group selected from –C 0 -C 6 alkylenyl–S(O) 2 -, –S(O) 2 -C 1 -C 6 alkylenyl, -S(O)-C 0 -C 6 alkylenyl, -C 0 -C 6 alkylenyl-S(O)-, -C(O)- C 0 -C 6 alkylenyl, , -C(O)-O-C 0 -C 6 alkylenyl, -C(O)-N(R 8 )-C 0 -C 6 alkylenyl, -C 1 -C 6 alkylenyl, and C 3 -C 6 cycloalkylenyl.
  • L is optionally substituted –C 0 -C 6 alkylenyl–S(O) 2 -. In some embodiments, L is –S(O) 2 -. In some embodiments, L is optionally substituted –C 1 -C 6 alkylenyl- S(O) 2 -. In some embodiments, L is–C 1 -C 6 alkylenyl-S(O) 2 - substituted with halogen, –(CH 2 ) 0– 4 Rq ⁇ –(CH 2 ) 0–4 ORq, or -O(CH 2 ) 0-4 R o .
  • L is optionally substituted –C 1 -C 3 alkylenyl-S(O) 2 -. In some embodiments, L is–C 1 -C 3 alkylenyl-S(O) 2 - substituted with halogen, – (CH 2 ) 0–4 Rq ⁇ –(CH 2 ) 0–4 ORq, or -O(CH 2 ) 0-4 R o . In some embodiments, L is –CH 2 -S(O) 2 -. In some embodiments, L is –CH(CH 3 )-S(O) 2 -. In some embodiments, L is –CH(R°)-S(O) 2 -.
  • L is optionally substituted –S(O) 2 -C 1 -C 6 alkylenyl.
  • L is–S(O) 2 -C 1 -C 6 alkylenyl substituted with halogen, –(CH 2 ) 0–4 Rq ⁇ –(CH 2 ) 0–4 ORq, or -O(CH 2 ) 0-4 R o .
  • L is optionally substituted –S(O) 2 -C 1 -C 3 alkylenyl.
  • L is–S(O) 2 -C 1 -C 3 alkylenyl substituted with halogen, –(CH 2 ) 0–4 Rq ⁇ –(CH 2 ) 0– 4 ORq, or -O(CH 2 ) 0-4 R o .
  • L is –S(O) 2 -CH 2 -.
  • L is – S(O) 2 -CH(CH 3 )-.
  • L is –S(O) 2 -CH(R°)-.
  • L is . [0082]
  • L is optionally substituted -S(O)-C 1 -C 6 alkylenyl.
  • L is–S(O)-C 1 -C 6 alkylenyl substituted with halogen, –(CH 2 ) 0–4 Rq ⁇ –(CH 2 ) 0–4 ORq, or -O(CH 2 ) 0-4 R o .
  • L is optionally substituted –S(O)-C 1 -C 3 alkylenyl.
  • L is–S(O)-C1-C3 alkylenyl substituted with halogen, –(CH2)0–4Rq ⁇ –(CH2)0– 4 ORq, or -O(CH 2 ) 0-4 R o .
  • L is –S(O)-CH 2 -.
  • L is – S(O)-CH(CH 3 )-.
  • L is optionally substituted -C 0 -C 6 alkylenyl-S(O)-. In some embodiments, L is –S(O)-. In some embodiments, L is optionally substituted –C 1 -C 6 alkylenyl- S(O)-. In some embodiments, L is–C 1 -C 6 alkylenyl-S(O)- substituted with halogen, –(CH 2 ) 0–4 Rq ⁇ –(CH 2 ) 0–4 ORq, or -O(CH 2 ) 0-4 R o .
  • L is optionally substituted –C 1 -C 3 alkylenyl-S(O)-. In some embodiments, L is–C 1 -C 3 alkylenyl-S(O)- substituted with halogen, – (CH 2 ) 0–4 Rq ⁇ –(CH 2 ) 0–4 ORq, or -O(CH 2 ) 0-4 R o . In some embodiments, L is –CH 2 -S(O)-. In some embodiments, L is –CH(CH 3 )-S(O)-. In some embodiments, L is –CH(R°)-S(O)-.
  • L is optionally substituted -C(O)-C 0 -C 6 alkylenyl. In some embodiments, L is –C(O)-. In some embodiments, L is–C(O)-C 1 -C 6 alkylenyl substituted with halogen, –(CH 2 ) 0–4 ORq, or -O(CH 2 ) 0-4 R o . In some embodiments, L is optionally substituted –C(O)-C 1 -C 3 alkylenyl.
  • L is–C(O)-C 1 -C 3 alkylenyl substituted with halogen, –(CH 2 ) 0–4 Rq ⁇ –(CH 2 ) 0–4 ORq, or -O(CH 2 ) 0-4 R o .
  • L is –C(O)- CH 2 -.
  • L is –C(O)-CH(CH 3 )-.
  • L is optionally substituted -C(O)-O-C 0 -C 6 alkylenyl.
  • L is -C(O)-O-.
  • L is optionally substituted -C(O)-N(R 8 )-C 0 -C 6 alkylenyl. In some embodiments, L is optionally substituted -C(O)-N(H)-C 0 -C 6 alkylenyl. In some embodiments,L is optionally substituted -C(O)-N(C 1 -C 6 aliphatic)-C 0 -C 6 alkylenyl. In some embodiments, L is optionally substituted -C(O)-N(R 8 )-. In some embodiments, L is -C(O)-NH-. In some embodiments, L is –C(O)-N(CH 3 )-.
  • L is optionally substituted -C 1 -C 6 alkylenyl. In some embodiments, L is optionally substituted –C 1 -C 3 alkylenyl. In some embodiments, L is -C 1 -C 6 alkylenyl. In some embodiments, L is –C 1 -C 6 alkylenyl substituted with halogen, –(CH 2 ) 0–4 Rq ⁇ –(CH 2 ) 0–4 ORq, or -O(CH 2 ) 0-4 R o .
  • L is –C 1 -C 3 alkylenyl substituted with halogen, –(CH 2 ) 0– 4 Rq ⁇ –(CH 2 ) 0–4 ORq, or -O(CH 2 ) 0-4 R o .
  • L is –CH 2 -.
  • L is –CH 2 -CH 2 -.
  • L is –CH(CH 3 )-.
  • L is optionally substituted C 3 -C 6 cycloalkylenyl.
  • L is optionally substituted C 3 cycloalkylenyl.
  • L is optionally substituted cyclopropylenyl. In some embodiments, L is optionally substituted C 4 cycloalkylenyl. In some embodiments, L is optionally substituted cyclobutylenyl. In some embodiments, L is optionally substituted C 5 cycloalkylenyl. In some embodiments, L is optionally substituted P 29 f 298
  • L is optionally substituted C 6 cycloalkylenyl. In some embodiments, L is optionally substituted cyclohexylenyl. In some embodiments, L is . [0089] In some embodiments, L is selected from –S(O) 2 -, –S(O) 2 -CH 2 -, –S(O) 2 -CH(CH 3 )-, -CH 2 - S .
  • A is C 3 -C 12 cycloaliphatic or 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein A is substituted with (R 2 ) m .
  • A is C 3 -C 12 cycloaliphatic.
  • A is C 3 -C 10 cycloaliphatic.
  • A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
  • A is cyclopentyl or cyclohexyl.
  • A is: , .
  • A is . [0091] In some embodiments, A is 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, A is 4- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, A is 4-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, A azetidinyl. In some embodiments, A is 5-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, A is pyrrolidinyl.
  • A is 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • A is piperidinyl or tetrahydropyranyl.
  • A is pyrrolidinyl, piperidinyl, tetrahydropyranyl, or tetrahyrothiopyranyl.
  • A is pyrrolidinyl or piperidinyl.
  • A is P 30 f 298 [ [0093]
  • A is substituted with (R 2 ) m .
  • A is substituted with 0, 1, 2, 3, or 4 instances of R 2 .
  • A is substituted with 0 instances of R 2 (i.e., A is unsubstituted). In some embodiments, A is substituted with 1 R 2 . In some embodiments, A is substituted with 2 R 2 . In some embodiments, A is substituted with 3 R 2 . In some embodiments, A is substituted with 4 R 2 . [0094] As defined generally above, B is a fused optionally substituted C 5 -C 6 aryl or optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • B is a fused C 5 -C 6 aryl or 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, substituted with one or more instances of halogen, CN, – (CH 2 ) 0–4 Rq ⁇ –(CH 2 ) 0–4 ORq, or -O(CH 2 ) 0-4 R o .
  • B is a fused optionally substituted C 5 -C 6 aryl.
  • B is a fused C 5 -C 6 aryl.
  • B is a fused C 5 -C 6 aryl substituted with one or more instances of halogen, CN, –(CH 2 ) 0–4 Rq ⁇ –(CH 2 ) 0– 4 ORq, or -O(CH 2 ) 0-4 R o .
  • B is a fused C 5 -C 6 aryl substituted with one or more instances of halogen, CN, or OCH 3 .
  • B is a fused phenyl.
  • B is a fused phenyl substituted with one or more instances of halogen, CN, or OCH 3 .
  • B is fused optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, B is fused 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, B is fused 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with one or more instances of halogen, CN, –(CH 2 ) 0–4 Rq ⁇ –(CH 2 ) 0–4 ORq, P 31 f 298 or -O(CH 2 ) 0-4 R o .
  • B is fused 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with one or more instances of halogen, CN, or OCH 3 .
  • B is fused thienyl.
  • B is a fused thienyl substituted with one or more instances of halogen, CN, or OCH 3 .
  • B is fused pyridyl.
  • B is fused pyridyl substituted with one or more instances of , –(CH 2 ) 0–4 Rq ⁇
  • B is fused pyridyl substituted with C 1 -C 6 aliphatic.
  • B is fused pyridyl substituted with methyl. In some embodiments, B is fused pyrazolyl. In some embodiments, B is fused pyrazolyl substituted with one or more instances of , –(CH 2 ) 0–4 Rq. In some embodiments, B is fused pyrazolyl substituted with C 1 -C 6 aliphatic. In some embodiments, B is fused pyrazolyl substituted with methyl.
  • R 1 is selected from C 1 -C 6 aliphatic, C 3 -C 12 cycloaliphatic, C 5 - C 12 aryl, 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein R 1 is substituted with (R 3 ) p .
  • R 1 is C 5 -C 12 aryl substituted with (R 3 ) p , 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R 3 ) p , or 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R 3 ) p .
  • R 1 is C 1 -C 6 aliphatic substituted with (R 3 ) p .
  • R 1 is C 1 -C 6 aliphatic, wherein p is 0.
  • R 1 is C 1 -C 6 alkyl substituted with (R 3 ) p . In some embodiments, R 1 is C 1 -C 3 alkyl substituted with (R 3 ) p . In some embodiments, R 1 is methyl, ethyl, propyl (e.g., n-propyl and iso-propyl), butyl (e.g., n-butyl, iso-butyl, sec-butyl, and tert-butyl), pentyl, or hexyl, optionally substituted with (R 3 ) p .
  • propyl e.g., n-propyl and iso-propyl
  • butyl e.g., n-butyl, iso-butyl, sec-butyl, and tert-butyl
  • pentyl or hexyl, optionally substituted with (R 3 ) p .
  • R 1 is C 3 -C 12 cycloaliphatic substituted with (R 3 ) p . In some embodiments, R 1 is C 3 -C 12 cycloalkyl substituted with (R 3 ) p . In some embodiments, R 1 is C 3 -C 6 cycloalkyl substituted with (R 3 ) p . In some embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl substituted with (R 3 ) p .
  • R 1 is C 5 -C 12 aryl substituted with 1 In some embodiments, R is C 5 -C 6 aryl substituted with (R 3 ) p . In some embodiments, R 1 is phenyl substituted with (R 3 ) p . [0101] In some embodiments, R 1 is monocyclic or bicyclic 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R 3 ) p . In some
  • R 1 is monocyclic 3- to 7-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R 3 ) p .
  • R 1 is 4- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R 3 ) p .
  • R 1 is 4-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R 3 ) p .
  • R 1 is 5-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R 3 ) p .
  • R 1 is 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R 3 ) p .
  • R 1 is bicyclic 10- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R 3 ) p .
  • R 1 is bicyclic 10- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, substituted with ( where one ring of said bicyclic heterocyclyl is a fused aryl ring.
  • R 1 is bicyclic 10-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R 3 ) p .
  • R 1 is bicyclic 11-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R 3 ) p .
  • R 1 is bicyclic 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R 3 ) p .
  • R 1 is 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R 3 ) p .
  • R 1 is 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R 3 ) p . In some embodiments, R 1 is 5-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R 3 ) p . In some embodiments, R 1 is 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with 1 In some embodiments, R is pyrrolyl, imidazolyl, pyrrazolyl, thiophenyl, pyridinyl, or pyrazinyl substituted with (R 3 ) p .
  • R 1 is pyrrazolyl or thiophenyl substituted with (R 3 ) p .
  • R 1 is substituted with p-instances of R 3 (i.e., (R 3 ) p ).
  • p is 0 to 4 (i.e., 0, 1, 2, 3, or 4).
  • p is 0 (i.e., R 1 is unsubstituted).
  • p is 1.
  • p is 2.
  • p is 3.
  • p is 4.
  • each R 3 is independently halo, –S(O) 2 -NR 3a R 3b , –S(O) 2 -R 3b , - S(NR 3c )(O)-NR 3a R 3b , -S(O)(NR 3c )-R 3b , -S(O)-R 3b , -NR 3a –S(O) 2 -R 3b , -O-R 3a , -C(O)-R 3a , - P 33 f 298
  • each R 3 is halo, oxo, –S(O) 2 -NR 3a R 3b , or an optionally substituted group selected from C 1 -C 6 aliphatic or C 3 -C 12 cycloaliphatic.
  • R 3 is oxo. [0108] In some embodiments, R 3 is halo. In some embodiments, R 3 is F, Cl, Br, or I. In some embodiments, R 3 is F. In some embodiments, R 3 is Cl. In some embodiments, R 3 is Br. In some embodiments, R 3 is I. [0109] In some embodiments, R 3 is –S(O) 2 -NR 3a R 3b . In some embodiments, R 3 is –S(O) 2 -NH 2 . In some embodiments, R 3 is –S(O) 2 -NH(C 1 -C 6 aliphatic).
  • R 3 is –S(O) 2 - N(C 1 -C 6 aliphatic) 2 . In some embodiments, R 3 is –S(O) 2 -N(CH 3 ) 2 . [0110] In some embodiments, R 3 is –S(O) 2 -R 3b . In some embodiments, R 3 is –S(O) 2 -C 1 -C 6 aliphatic. In some embodiments, R 3 is –S(O) 2 -CH 3 . In some embodiments, R 3 is –S(O) 2 -CHF 2 .
  • R 3 is –S(O) 2 -(3- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S). In some embodiments, R 3 is –S(O) 2 -(azetidinyl). [0111] In some embodiments, R 3 is -S(NH)(O)-NR 3a R 3b . In some embodiments, R 3 is -S(NH)(O)- N(C 1-6 aliphatic) 2 . In some embodiments, R 3 is -S(NH)(O)-N(CH 3 ) 2 . In some embodiments, R 3 is -S(NH)(O)-NH(CH 3 ) .
  • R 3 is -S(O)(NH)-R 3b . In some embodiments, R 3 is -S(O)(NH)-C 1-6 aliphatic. In some embodiments, R 3 is -S(O)(NH)-CH 3 . In some embodiments, R 3 is -S(O)(NH)- CHF 2 . [0113] In some embodiments, R 3 is -S(O)-R 3b . In some embodiments, R 3 is -S(O)-C 1-6 aliphatic. In some embodiments, R 3 is -S(O)-CH 3 .
  • R 3 is -NR 3a –S(O) 2 -R 3b . In some embodiments, R 3 is -NH–S(O) 2 - C 1 -C 6 aliphatic. In some embodiments, R 3 is -NH–S(O) 2 -CH 3 . In some embodiments, R 3 is – N(C 1 -C 6 aliphatic)–S(O) 2 -C 1 -C 6 aliphatic. In some embodiments, R 3 is –N(CH 3 )–S(O) 2 -CH 3 . [0115] In some embodiments, R 3 is -O-R 3a . In some embodiments, R 3 is OH.
  • R 3 is O-C 1 -C 6 aliphatic, wherein C 1 -C 6 aliphatic is optionally substituted with halo. In some embodiments, R 3 is O-C 1 -C 6 alkyl, wherein C 1 -C 6 alkyl is optionally substituted with halo. P 34 f 298
  • R 3 is O-CH 3 . In some embodiments, R 3 is O-CH 2 F. In some embodiments, R 3 is O-CHF 2 . In some embodiments, R 3 is O-CF 3 . [0116] In some embodiments, R 3 is C(O)-R 3a . In some embodiments, R 3 is C(O)-C 1- C 6 aliphatic. In some embodiments, R 3 is C(O)-C 1 -C 6 alkyl. In some embodiments, R 3 is C(O)-CH 3 . [0117] In some embodiments, R 3 is C(O)NH-R 3a . In some embodiments, R 3 is C(O)NH-C 1- C 6 aliphatic.
  • R 3 is C(O)NH-C 1 -C 6 alkyl. In some embodiments, R 3 is C(O)NH-CH 3 . [0118] In some embodiments, R 3 is optionally substituted C 1 -C 6 aliphatic. In some embodiments, R 3 is C 1 -C 6 aliphatic. In some embodiments, R 3 is C 1 -C 6 aliphatic substituted with substituted with one or more instances of halogen, –(CH 2 ) 0–4 Rq ⁇ –(CH 2 ) 0–4 ORq, or -O(CH 2 ) 0-4 R o .
  • R 3 is C 1 -C 6 alkyl substituted with substituted with one or more instances of halogen, –(CH 2 ) 0–4 Rq ⁇ –(CH 2 ) 0–4 ORq, or -O(CH 2 ) 0-4 R o .
  • R 3 is C 1 -C 6 aliphatic substituted with substituted with one or more instances of halogen, –(CH 2 ) 0–4 Rq ⁇ –(CH 2 ) 0–4 ORq, or -O(CH 2 ) 0-4 R o , wherein each R o is independently, halo, C 1 -C 6 aliphatic, C(O)-C 1 -C 6 aliphatic, C(O)O-C 1 -C 6 aliphatic or OH.
  • R 3 methyl, ethyl, propyl, or butyl.
  • R 3 is CH 2 F.
  • R 3 is CHF 2 .
  • R 3 is CF 3 . In some embodiments, R 3 is C(CH 3 ) 2 -O-CH 3 . In some embodiments, R 3 is C(CH 3 ) 2 -OH. In some embodiments, R 3 is C(CH 3 ) 2 -C(O)-CH 3 . [0119] In some embodiments, R 3 is optionally substituted C 5 -C 12 aryl. In some embodiments, R 3 is C 5 -C 12 aryl. In some embodiments, R 3 is C 5 -C 12 aryl substituted with –(CH 2 ) 0–4 Rq ⁇ –(CH 2 ) 0– 4 ORq, or -O(CH 2 ) 0-4 R o .
  • R 3 is optionally substituted phenyl. In some embodiments, R 3 is phenyl substituted with C 1 -C 6 aliphatic. In some embodiments, R 3 is phenyl substituted with CH 3 . [0120] In some embodiments, R 3 is optionally substituted C 3 -C 12 cycloaliphatic. In some embodiments, R 3 is C 3 -C 12 cycloaliphatic optionally substituted with halogen or C 1 -C 6 aliphatic. In some embodiments, R 3 is C 3 -C 6 cycloaliphatic optionally substituted with halogen or C 1 -C 6 aliphatic.
  • R 3 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl optionally substituted with halogen or C 1 -C 6 aliphatic. In some embodiments, R 3 is cyclopropyl. In some embodiments, R 3 is cyclopropyl substituted with halogen. [0121] In some embodiments, R 3 is optionally substituted 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 3 is optionally P 35 f 298
  • R 3 is 5- to 6-membered heteroaryl. In some embodiments, R 3 is 5- to 6-membered heteroaryl optionally substituted with –(CH 2 ) 0–4 Rq ⁇ –(CH 2 ) 0–4 ORq, or -O(CH 2 ) 0-4 R o .
  • R 3 is 5- to 6-membered heteroaryl optionally substituted with with –(CH 2 ) 0–4 Rq ⁇ –(CH 2 ) 0–4 ORq, or -O(CH 2 ) 0-4 R o , wherein R° is C 1–6 aliphatic or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0122] In some embodiments, R 3 is optionally substituted 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 3 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 3 is monocyclic 3- to 7-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with halogen, – (CH 2 ) 0–4 Rq ⁇ –(CH 2 ) 0–4 ORq, or -O(CH 2 ) 0-4 R o .
  • R 3 is monocyclic 3- to 7- membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with halogen, –(CH 2 ) 0–4 Rq ⁇ –(CH 2 ) 0–4 ORq, or -O(CH 2 ) 0-4 R o .
  • R 3 is monocyclic 3- to 7-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with halogen, –(CH 2 ) 0–4 Rq ⁇ –(CH 2 ) 0–4 ORq, or -O(CH 2 ) 0-4 R o , where R° is C 1 -C 6 aliphatic.
  • R 3 is optionally substituted monocyclic 3-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 3 is optionally substituted monocyclic 4-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 3 is optionally substituted monocyclic 5- membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 3 is optionally substituted monocyclic 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 3 is optionally substituted monocyclic 7-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 3 is dioxolanyl. [0123] In some embodiments, R 3 is optionally substituted 10- to 12-membered bicyclic heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 3 is optionally substituted 10- to 12-membered bicyclic heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with halogen, oxo, –(CH 2 ) 0–4 Rq ⁇ –(CH 2 ) 0–4 ORq, or -O(CH 2 ) 0-4 R o .
  • R 3 is optionally substituted 10- to 12-membered bicyclic heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with P 36 f 298
  • R 3 is optionally substituted 10-membered bicyclic heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with halogen, oxo, –(CH 2 ) 0–4 Rq ⁇ – (CH 2 ) 0–4 ORq, or -O(CH 2 ) 0-4 R o , where R° is C 1 -C 6 aliphatic.
  • R 3 is optionally substituted 11-membered bicyclic heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with halogen, oxo, –(CH 2 ) 0–4 Rq ⁇ –(CH 2 ) 0–4 ORq, or - O(CH 2 ) 0-4 R o , where R° is C 1 -C 6 aliphatic.
  • R 3 is optionally substituted 12- membered bicyclic heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with halogen, oxo, –(CH2)0–4Rq ⁇ –(CH2)0–4ORq, or -O(CH2)0-4R o , where R° is C 1 -C 6 aliphatic.
  • R 3a and R 3b are each independently selected from H and optionally substituted C 1 -C 6 aliphatic, or R 3a and R 3b come together with the atoms to which they are attached to form optionally substituted C 3 -C 12 cycloaliphatic or 3- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • R 3a and R 3b are each independently selected from H and optionally substituted C 1 -C 6 aliphatic.
  • R 3a and R 3b come together with the atoms to which they are attached to form optionally substituted C 3 -C 12 cycloaliphatic or 3- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • each R 3c is independently selected from H, OH, and optionally substituted C 1 -C 6 aliphatic.
  • R 3c is H.
  • R 3c is OH.
  • R 3c is optionally substituted C 1 -C 6 aliphatic.
  • R 3c is CH 3 .
  • R 1 is selected from: -CH(CH 3 ) 2 , , , P 37 f 298
  • each R 2 is independently halo, oxo, -NR 2a R 2b , -C(O)O-R 2a , - O-C(O)R 2a , -S(O) 2 , -S(O) 2 -R 2a , -C(O)-NR 2a R 2b , -N(R 2a )-C(O)-R 2b , -C(O)-R 2a , -O-R 2a , -O-C(O)- NR 2a R 2b , -NH-C(O)-NR 2a R 2b , -NH-C(O)-OR 2a , -NH-S(O) 2 -R 2a , -C 1 -C 6 alkylenyl-C(O)-NR 2a R 2b
  • each R 2 is independently halo, oxo, -NR 2a R 2b , -C(O)O-R 2a , -C(O)- NR 2a R 2b , -N(R 2a )-C(O)-R 2b , -C(O)-R 2a , -O-R 2a , or an optionally substituted group selected from C 1 -C 6 aliphatic, C 5 -C 12 aryl, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 2 is halo.
  • R 2 is F, Br, Cl, or I. In some embodiments, R 2 is F. In some embodiments, R 2 is Br. In some embodiments, R 2 is Cl. [0130] In some embodiments, R 2 is oxo. [0131] In some embodiments, R 2 is -N(R 2a )(R 2b ). In some embodiments, R 2 is -NH(R 2b ). In some embodiments, R 2 is -NH(R 2a ). In some embodiments, R 2 is –NH 2 . [0132] In some embodiments, R 2 is –C(O)O-R 2a . In some embodiments, R 2 is –C(O)OH.
  • R 2 is –C(O)O-C 1 -C 6 aliphatic. In some embodiments, R 2 is –C(O)O-C 1 -C 6 aliphatic optionally substituted with –(CH 2 ) 0–4 Rq ⁇ –(CH 2 ) 0–4 ORq, or -O(CH 2 ) 0-4 R o . In some embodiments, R 2 is –C(O)O-C 1 -C 6 aliphatic optionally substituted with –(CH 2 ) 0–4 Rq.
  • R 2 is –C(O)O-C 1 -C 6 aliphatic optionally substituted with –(CH 2 ) 0–4 Rq ⁇ where Rq ⁇ is an optionally substituted C 1–6 aliphatic or an optionally substituted 3- to 6-membered saturated, partially P 39 f 298
  • R 2 is –C(O)O-C 1 -C 6 aliphatic optionally substituted with –(CH 2 ) 0– 4 Rq ⁇ where Rq ⁇ is C 1–6 aliphatic or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, where Rq ⁇ is substituted with –(CH 2 ) 0–2 R z , where R z is C 1 -C 6 aliphatic.
  • R 2 is –C(O)O- C 1 -C 6 aliphatic optionally substituted with phenyl. In some embodiments, R 2 is –C(O)O-C 1 -C 6 aliphatic optionally substituted with pyridyl. In some embodiments, R 2 is –C(O)O-C 1 -C 6 aliphatic optionally substituted with pyrazolyl. In some embodiments, R 2 is –C(O)O-C 1 -C 6 aliphatic optionally substituted with pyrazolyl substituted with –(CH 2 ) 0–2 R z .
  • R 2 is –C(O)O-C 1 -C 6 aliphatic optionally substituted with imidazolyl. In some embodiments, R 2 is – C(O)O-C 1 -C 6 aliphatic optionally substituted with imidazolyl substituted with –(CH 2 ) 0–2 R z . In some embodiments, R 2 is –C(O)O-C 1 -C 6 aliphatic optionally substituted with isoxazolyl. In some embodiments, R 2 is –C(O)O-C 1 -C 6 aliphatic optionally substituted with C 3 -C 6 cycloalkyl.
  • R 2 is –C(O)O-C 1 -C 6 aliphatic optionally substituted with cyclopropyl. In some embodiments, R 2 is –C(O)O-CH(CH 3 ) 2 . In some embodiments, R 2 is –C(O)O-C(CH 3 ) 3 . In some embodiments, R 2 is –C(O)O-R 2a , where R 2a is optionally substituted C 5 -C 14 aryl. In some embodiments, R 2 is –C(O)O-phenyl. [0133] In some embodiments, R 2 is -C(O)-N(R 2a )(R 2b ).
  • R 2 is -C(O)- N(H)(R 2b ). In some embodiments, R 2 is -C(O)-N(C 1 -C 6 aliphatic)(R 2b ). In some embodiments, R 2 is -C(O)-N(R 2a )(R 2b ), where R 2b is optionally substituted C 1 -C 6 aliphatic.
  • R 2 is -C(O)-N(R 2a )(R 2b ), where R 2b is C 1 -C 6 aliphatic optionally substituted with halogen, – (CH 2 ) 0–4 Rq ⁇ or –(CH 2 ) 0–4 ORq ⁇ In some embodiments R 2 is -C(O)-N(R 2a )(R 2b ), where R 2b is C 1 -C 6 aliphatic optionally substituted with –(CH 2 ) 0–4 Rq ⁇ where Rq ⁇ is selected from hydrogen and 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 2 is -C(O)-N(R 2a )(R 2b ) where R 2b is C 1 -C 6 aliphatic optionally substituted with a group selected from cyclopropyl, phenyl, tetrahydrofuranyl, pyrazolyl, isoxazolyl, tetrahydropyranyl, and pyridyl.
  • R 2 is -C(O)-N(R 2a )(R 2b ), where R 2b is C 1 -C 6 aliphatic optionally substituted with –(CH 2 ) 0– 4 ORq ⁇ where Rq ⁇ is C 1-6 aliphatic.
  • R 2 is –C(O)-N(H)(CH 2 CHF 2 ). In some embodiments, R 2 is –C(O)-N(H)(CH 2 CF 3 ). In some embodiments, R 2 is –C(O)- N(H)(CH 2 CH 2 CF 3 ). In some embodiments, R 2 is –C(O)-N(H)(CH(CH 3 ) 2 ). In some embodiments P 40 f 298
  • R 2 is -C(O)-N(R 2a )(R 2b ), where R 2b is optionally substituted C 3 -C 12 cycloaliphatic. In some embodiments R 2 is -C(O)-N(R 2a )(R 2b ), where R 2b is optionally substituted C 3 -C 6 cycloaliphatic. In some embodiments of R 2 , R 2b is optionally substituted cyclopropyl.
  • R 2 is - C(O)-N(R 2a )(R 2b ), where R 2b is phenyl optionally substituted with –(CH 2 ) 0–4 Rq or –(CH 2 ) 0–4 ORq ⁇
  • R 2 is -C(O)-N(R 2a )(R 2b ), where R 2b is optionally substituted 5- to 12- membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • R 2 is -C(O)-N(R 2a )(R 2b ), where R 2b is optionally substituted 5- to 6-membered heteroaryl comprising 1 to 2 heteroatoms selected from N, O, and S
  • R 2 is - C(O)-N(R 2a )(R 2b ), where R 2b is selected from pyridinyl, pyrrolyl, pyrazolyl, imidazolyl, isothiazolyl, and isoxazolyl optionally substituted with halogen, –(CH 2 ) 0–4 Rq ⁇ or –(CH 2 ) 0–4 ORq.
  • R 2 is -C(O)-N(R 2a )(R 2b ), where R 2b is optionally substituted 3- to 12- membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 2 is -C(O)-N(R 2a )(R 2b ), where R 2b is optionally substituted tetrahydrofuranyl or tetrahydropyranyl.
  • R 2 is -C(O)-N(R 2a )(R 2b ), where R 2b is an optionally substituted 9- to 10-membered bicyclic heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 2 is -N(R 2a )-C(O)-R 2b . [0135] In some embodiments, R 2 is –O-C(O)R 2a . [0136] In some embodiments, R 2 is –S(O) 2 . [0137] In some embodiments, R 2 is –S(O) 2 -R 2a . [0138] In some embodimments, R 2 is –O-C(O)-NR 2a R 2b . [0139] In some embodiments, R 2 is –NH-C(O)-NR 2a R 2b . [0140] In some embodiments, R 2 is –NH-C(O)-OR 2a .
  • R 2 is –C 1 -C 6 alkylenyl-C(O)-NR 2a R 2b .
  • R 2 is -NH-S(O) 2 -R 2a .
  • R 2 is –C(O)R 2a .
  • R 2 is –C(O)-C 1 -C 6 aliphatic.
  • R 2 is –C(O)-C 1 -C 6 aliphatic optionally substituted with halogen, –(CH 2 ) 0– 4 Rq ⁇ –(CH 2 ) 0–4 ORq, or -O(CH 2 ) 0-4 R o .
  • R 2 is –C(O)-C 1 -C 6 aliphatic P 41 f 298
  • R 2 is –C(O)-C(CH 3 ) 3 .
  • R 2 is –C(O)- C 3 -C 12 cycloaliphatic.
  • R 2 is –C(O)- C 3 -C 12 cyclopropyl.
  • R 2 is –C(O)-C 5 -C 14 aryl.
  • R 2 is –C(O)-phenyl. In some embodiments, R 2 is –C(O)R 2a , where R 2a is a 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 2 is –C(O)R 2a , where R 2a is selected from optionally substituted pyrrolidinyl, piperidinyl, and morpholinyl. In some embodiments, R 2 is –C(O)R 2a , where R 2a is a 7- to 11-membered spirocyclic ring system spirocyclic ring system comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 2 is -O-R 2a .
  • R 2 is –OH.
  • R 2 is –O-C 1 -C 6 aliphatic.
  • R 2 is –O-C 1 -C 6 aliphatic, optionally substituted with –(CH 2 ) 0–4 Rq ⁇ –(CH 2 ) 0–4 ORq, or -O(CH 2 ) 0-4 R o .
  • R 2 is –OCH 3 .
  • R 2 is optionally substituted C 1 -C 6 aliphatic.
  • R 2 is optionally substituted C 1 -C 6 alkyl. In some embodiments, R 2 is C 1 -C 6 aliphatic optionally substituted with halo, –(CH 2 ) 0–4 Rq ⁇ –(CH 2 ) 0–4 ORq, -O(CH 2 ) 0-4 R o , or -(CH 2 ) 0–4 N(Rq) 2 . In some embodiments, R 2 is methyl, ethyl, propyl, or butyl. In some embodiments, R 2 is –CH 3 . In some embodiments, R 2 is –(CH 2 ) 0–6 -CF 3 .
  • R 2 is –CH 2 -CF 3 .
  • R 2 is C 1 -C 6 aliphatic substituted with -OR o , where R° is C 1–6 aliphatic or a 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 2 is -CH 2 -O-CH 3 .
  • R 2 is -CH 2 -O-CH 2 CH 3
  • R 2 is -CH 2 -CF 2 -CH 3 .
  • R 2 is C 1 -C 6 aliphatic optionally substituted with -(CH 2 ) 0–4 N(Rq) 2 . In some embodiments, R 2 is C 1 -C 6 aliphatic optionally substituted with -(CH 2 ) 0–4 N(Rq) 2 , where R° is hydrogen, C 1–6 aliphatic or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur..
  • R 2 is C 1 -C 6 aliphatic optionally substituted with R°, where R° is C 1–6 aliphatic or a 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 2 is C1-C6 aliphatic optionally substituted with R°, where R° is 3- to 6-membered saturated, partially unsaturated, or aryl ring P 42 f 298
  • R 2 is C 1 -C 6 aliphatic optionally substituted with R°, where R° is phenyl. [0146] In some embodiments, R 2 is optionally substituted C 5 -C 12 aryl. In some embodiments, R 2 is optionally substituted C 5 -C 6 aryl. In some embodiments, R 2 is C 5 -C 6 aryl optionally substituted with halo, –(CH 2 ) 0–4 Rq ⁇ –(CH 2 ) 0–4 ORq, or -O(CH 2 ) 0-4 R o .
  • R 2 is C 5 -C 6 aryl substituted with halo. In some embodiments, R 2 is phenyl. In some embodiments, R 2 is phenyl substituted with halo. [0147] In some embodiments, R 2 is 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 2 is optionally substituted 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 2 is optionally substituted monocyclic 3- to 7-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 2 is monocyclic 3- to 7-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with halogen, – (CH 2 ) 0–4 Rq ⁇ –(CH 2 ) 0–4 ORq, or -O(CH 2 ) 0-4 R o .
  • R 2 is monocyclic 3- to 7- membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with halogen, –(CH 2 ) 0–4 Rq ⁇ –(CH o 2 –4 ORq, or -O(CH 2 ) 0-4 R .
  • R is optionally substituted monocyclic 3-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 2 is optionally substituted monocyclic 4- membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 2 is optionally substituted monocyclic 5-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 2 is optionally substituted monocyclic 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 2 is optionally substituted monocyclic 7-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • each R 2 is selected from F, Br, Cl, CN, –OCH 3 , -CH 2 -CF 3 , -CF 3 , - NH 2 , -CH 2 -O-CH 3 , -CH 2 -O-CH 2 CH 3 , -CH 2 -CF 2 -CH 3 , -CH 3 , -OH, oxo, P 43 f 298
  • each R 2a and each R 2b are independently selected from H and an optionally substituted group selected from C 1 -C 6 aliphatic, C 3 -C 12 cycloaliphatic, C 5 -C 14 aryl, 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • each R 5 is independently selected from hydrogen, halo, CN, and optionally substituted C 1 -C 6 aliphatic. In some embodiments, R 5 is hydrogen. In some P 45 f 298
  • R 5 is halo. In some embodiments, R 5 is CN. In some embodiments, R 5 is optionally substituted C 1 -C 6 aliphatic. In some embodiments, R 5 is C 1 -C 6 aliphatic optionally substituted with halogen, –(CH 2 ) 0–4 Rq, –(CH 2 ) 0–4 ORq, or -O(CH 2 ) 0-4 R o . In some embodiments, R 5 is methyl, ethyl, propyl, or butyl. In some embodiments, R 5 is methyl. [0151] As defined generally above, R 8 is selected from H and optionally substituted C 1 -C 6 aliphatic.
  • R 8 is H. In some embodiments, R 8 is C 1 -C 6 aliphatic. In some embodiments, R 8 is methyl.
  • n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1.
  • m is 0 to 4. In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. [0154] As defined generally above, p is 0 to 4. In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0.
  • p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. [0155] As defined generally above, q is 1 or 2. In some embodiments, q is 1. In some embodiments, q is 2. [0156] In some embodiments, q is 1 and n is 0 or 1. In some embodiments, q is 1 and n is 0, and a compound of formula I is: wherein R 1 , L, Y 1 , Y 2 , A, and B are as defined herein and above.
  • q is 1 and n is 1, and a compound of formula I is: wherein R 1 , L, Y 1 , Y 2 , X, A, and B are as defined herein and above.
  • q is 2, and n is 0, and a compound of formula I is: P 46 f 298
  • TRMPL1 modulators that are small molecule compounds having a chemical structure as indicated below in Formula Ia: or a pharmaceutically acceptable salt thereof, wherein X, n, A, L, and R 1 are as defined generally herein, and each of X a , X b , X c , and X d are independently selected from N and CR 6 ; and each R 6 is H, halo, CN, O-C 1 -C 6 aliphatic, or an optionally substituted C 1 -C 6 aliphatic.
  • the present disclosure provides and/or utilizes TRMPL1 modulators that are small molecule compounds having a chemical structure as indicated below in Formula Ia: or a pharmaceutically acceptable salt thereof, wherein X is –NR 5 -, -C(R 5 ) 2 -, -C(O)-, or –O-; each of X a , X b , X c , and X d are independently selected from N and CR 6 ; L is an optionally substituted group selected from -C 0 -C 6 alkylenyl–S(O) 2 -, –S(O) 2 -C 0 -C 6 alkylenyl, -S(O)-C 0 -C 6 alkylenyl, -C 0 -C 6 alkylenyl-S(O)-, -C(O)-C 0 -C 6 alkylenyl, , - P 47 f
  • A is C 3 -C 12 cycloaliphatic or 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein A is substituted with (R 2 ) m ;
  • R 1 is selected from C 1 -C 6 aliphatic, C 3 -C 12 cycloaliphatic, C 5 -C 12 aryl, 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and 3- to 12- membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein R 1 is substituted with (R 3 ) p ; each R 2 is independently
  • each R 6 is H, halo, CN, O-C 1 -C 6 aliphatic, or an optionally substituted C 1 -C 6 aliphatic; n is 0 or 1; m is 0 to 4; and p is 0 to 4.
  • each of X a , X b , X c , and X d are independently selected from N and CR 6 .
  • X a , X b , X c , and X d are each CR 6 .
  • X a , X b , X c , and X d are each CH.
  • X a , X b , and X c are each CR 6 , and X d is N. In some embodiments, X a , X b , and X d are each CR 6 , and X c is N. In some embodiments, X a , X c , and X d are each CR 6 , and X b is N. In some embodiments, X b , X c , and X d are each CR 6 , and X a is N. In some embodiments, X a and X b , are each CR 6 , and X c and X d are each N.
  • X a and X c are each CR 6 , and X b and X d are each N. In some embodiments, X a and X d , are each CR 6 , and X b and X c are each N. In some embodiments, X b and X c , are each CR 6 , and X a and X d are each N. In some embodiments, X c and X d , are each CR 6 , and X a and X b are each N.
  • each R 6 is H, halo, CN, O-C 1 -C 6 aliphatic, or an optionally substituted C 1 -C 6 aliphatic.
  • R 6 is H or halo.
  • R 6 is H.
  • R 6 is halo (e.g., fluoro, chloro, bromo, iodo).
  • R 6 is CN.
  • R 6 is O-C 1 -C 6 aliphatic.
  • R 6 is –OCH 3 .
  • R 6 is optionally substituted C 1 -C 6 aliphatic.
  • R 6 is C 1 -C 6 aliphatic optionally substituted with halo. In some embodiments, R 6 is CH 3 or CF 3 . In some embodiments, R 6 is CH 3 . In some embodiments, R 6 is CF 3 . [0163] As provided herein, the present disclosure provides and/or utilizes TRMPL1 modulators that are small molecule compounds having a chemical structure as indicated below in Formula Ib: Ib or a pharmaceutically acceptable salt thereof, wherein P 49 f 298
  • X, n, A, L, R 1 , Y 1 , and Y 2 are as defined generally herein, and each of X e , X f , and X g are independently selected from S, N, O, and CR 7 ; and each R 7 is H, halo, CN, O-C 1 -C 6 aliphatic, or an optionally substituted group selected from C 1 - C 6 aliphatic and C 3 -C 6 cycloaliphatic.
  • the present disclosure provides and/or utilizes TRMPL1 modulators that are small molecule compounds having a chemical structure as indicated below in Formula Ib: Ib or a pharmaceutically acceptable salt thereof, wherein X is –NR 5 -, -C(R 5 )2-, -C(O)-, or –O-; each of X e , X f , and X g are independently selected from S, N, O, and CR 7 ; each of Y 1 and Y 2 is independently selected from N and C; L is an optionally substituted group selected from -C 0 -C 6 alkylenyl–S(O) 2 -, –S(O) 2 -C 0 -C 6 alkylenyl, -S(O)-C 0 -C 6 alkylenyl, -C 0 -C 6 alkylenyl-S(O)-, -C(O)-C 0 -C -C -C 0
  • each R 2a and each R 2b are independently selected from H and an optionally substituted group selected from C 1 -C 6 aliphatic, C 3 -C 12 cycloaliphatic, C 5 -C 14 aryl, 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and 3- to 12- membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; each R 3 is independently halo, –S(O) 2 -NR 3a R 3b , –S(O) 2 -R 3b , -S(NR 3c )(O)-NR 3a R 3b , - S(O)(NR 3c )-R 3b , –S(O)-R 3b , -NR 3a –S(O) 2 -R 3b , -O-R 3a , -C(O)-R 3a , -C(O)NH-R 3a
  • each of X e , X f , and X g are independently selected from S, N, O, and CR 7 .
  • each of X e , X f , and X g are CR 7 .
  • each of X e , X f , and X g are independently selected from S and CR 7 .
  • each of X e , X f , and X g are independently selected from N and CR 7 .
  • each R 7 is H, halo, CN, O-C 1 -C 6 aliphatic, or an optionally substituted C 1 -C 6 aliphatic.
  • R 7 is H or halo.
  • R 7 is H.
  • R 7 is halo (e.g., fluoro, chloro, bromo, iodo).
  • R 7 is CN.
  • R 7 is O-C 1 -C 6 aliphatic. In some P 51 f 298
  • R 7 is –OCH 3 .
  • R 7 is an optionally substituted group selected from C 1 -C 6 aliphatic and C 3 -C 6 cycloaliphatic.
  • R 7 is optionally substituted C 1 -C 6 aliphatic.
  • R 7 is C 1 -C 6 aliphatic optionally substituted with halo.
  • R 7 is CH 3 or CF 3 .
  • R 7 is CH 3 .
  • R 7 is CF 3 .
  • R 7 is optionally substituted C 3 -C 6 cycloaliphatic.
  • the present disclosure provides compounds of Formula Ic: Ic or a pharmaceutically acceptable salt thereof, wherein: each of X a , X b , X c , and X d are independently selected from N and CR 6 ; L is an optionally substituted group selected from -C 0 -C 6 alkylenyl–S(O) 2 -, –S(O) 2 -C 0 -C 6 alkylenyl, -S(O)-C 0 -C 6 alkylenyl, -C 0 -C 6 alkylenyl-S(O)-, -C(O)-C 0 -C 6 alkylenyl, , - C(O)-O-C 0 -C 6 alkylenyl, -C(O)-N(R 8 )-C 0 -C 6 alkylenyl, -C 1 -C 6 alkylen
  • each R 2a and each R 2b are independently selected from H and an optionally substituted group selected from C 1 -C 6 aliphatic, C 3 -C 12 cycloaliphatic, C 5 -C 14 aryl, 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and 3- to 12- membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; each R 3 is independently halo, –S(O) 2 -NR 3a R 3b , –S(O) 2 -R 3b , –S(O)(NR 3c )-R 3b , -S(NR 3c )(O)- NR 3a R 3b , –S(O)-R 3b , -NR 3a –S(O) 2 -R 3b , -O-R 3a , -C(O)-R 3a , -C(O)NH-R 3a
  • the present disclosure provides compounds of Formula II: or a pharmaceutically acceptable salt thereof, wherein L, R 1 , and A are as defined generally and herein. [0169] In some embodiments, the present disclosure provides compounds of Formula IIIa: P 53 f 298
  • the present disclosure provides compounds of Formula IIIa: IIIa or a pharmaceutically acceptable salt thereof, wherein L is an optionally substituted group selected from -C 0 -C 6 alkylenyl–S(O) 2 -, –S(O) 2 -C 0 -C 6 alkylenyl, -S(O)-C0-C6 alkylenyl, -C0-C6 alkylenyl-S(O)-, -C(O)-C0-C6 alkylenyl, -C(O)- O-C 0 -C 6 alkylenyl, -C(O)-N(R 8 )-C 0 -C 6 alkylenyl,-C 1 -C 6 alkylenyl, and C 3 -C 6 cycloalky
  • each R 3 is independently halo, –S(O) 2 -NR 3a R 3b , –S(O) 2 -R 3b , -S(NR 3c )(O)-NR 3a R 3b , - S(O)(NR 3c )-R 3b , –S(O)-R 3b , -NR 3a –S(O) 2 -R 3b , -O-R 3a , -C(O)-R 3a , -C(O)NH-R 3a , oxo, or an optionally substituted group selected from C 1 -C 6 aliphatic, C 5 -C 12 aryl, C 3 -C 12 cycloaliphatic, 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; R 3a and R 3b are
  • the present disclosure provides compounds of Formula IIIb: or a pharmaceutically acceptable salt thereof, wherein L, R 1 , R 2 , and m are as defined generally and herein. [0172] In some embodiments, the present disclosure provides compounds of Formula IIIb: or a pharmaceutically acceptable salt thereof, wherein P 55 f 298
  • L is an optionally substituted group selected from -C 0 -C 6 alkylenyl–S(O) 2 -, –S(O) 2 -C 0 -C 6 alkylenyl, -S(O)-C 0 -C 6 alkylenyl, -C 0 -C 6 alkylenyl-S(O)-, -C(O)-C 0 -C 6 alkylenyl, -C(O)- O-C 0 -C 6 alkylenyl, -C(O)-N(R 8 )-C 0 -C 6 alkylenyl, -C 1 -C 6 alkylenyl, and C 3 -C 6 cycloalkylenyl; R 1 is selected from C 3 -C 12 cycloaliphatic, 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and 3- to 12-membere
  • the present disclosure provides compounds of Formula IVa: IVa or a pharmaceutically acceptable salt thereof, wherein A, L, R 3 , and p are as defined generally and herein. [0174] In some embodiments, the present disclosure provides compounds of Formula IVa: IVa or a pharmaceutically acceptable salt thereof, wherein L is an optionally substituted group selected from -C 0 -C 6 alkylenyl–S(O) 2 -, –S(O) 2 -C 0 -C 6 alkylenyl, -S(O)-C0-C6 alkylenyl, -C0-C6 alkylenyl-S(O)-, -C(O)-C0-C6 alkylenyl, - C(O)-O-C 0 -C 6 alkylenyl, -C(O)-N(R 8 )-C 0 -C 6 alkylenyl, -C 1 -C 6 alkylenyl, -
  • each R 2a and each R 2b are independently selected from H and an optionally substituted group selected from C 1 -C 6 aliphatic, C 3 -C 12 cycloaliphatic, C 5 -C 14 aryl, 5- to 12- membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and 3- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; each R 3 is independently halo, –S(O) 2 -NR 3a R 3b , –S(O) 2 -R 3b , -S(NR 3c )(O)-NR 3a R 3b , - S(O)(NR 3c )-R 3b , -S(O)-R 3b , -NR 3a –S(O) 2 -R 3b , -O-R 3a , -C(O)-R 3a , -C(O)NH-R 3a
  • the present disclosure provides compounds of Formula IVb: or a pharmaceutically acceptable salt thereof, wherein A, L, R 3 , and p are as defined generally and herein. [0176] In some embodiments, the present disclosure provides compounds of Formula IVb: P 58 f 298
  • L is an optionally substituted group selected from -C 0 -C 6 alkylenyl–S(O) 2 -, –S(O) 2 -C 0 -C 6 alkylenyl, -S(O)-C 0 -C 6 alkylenyl, -C 0 -C 6 alkylenyl-S(O)-, -C(O)-C 0 -C 6 alkylenyl, - C(O)-O-C 0 -C 6 alkylenyl, -C(O)-N(R 8 )-C 0 -C 6 alkylenyl, -C 1 -C 6 alkylenyl, and C 3 -C 6 cycloalkylenyl;
  • A is C 3 -C 12 cycloaliphatic or 3- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O
  • the present disclosure provides a compound, or a pharmaceutically acceptable salt thereof, selected from Table 1: Table 1 P 60 f 298
  • the present disclosure provides a compound, or a pharmaceutically acceptable salt thereof, selected from Table 2: Table 2 P 93 f 298
  • the present disclosure describes one or more characteristics of certain TRPML (e.g., TRPML1, TRPML2, and/or TRPML3) modulators provided by and/or useful in the practice of the present disclosure.
  • TRPML e.g., TRPML1, TRPML2, and/or TRPML3 modulators
  • the present disclosure provides technologies for assessing one or more relevant characteristics and/or for identifying, selecting, prioritizing, and/or characterizing one or more useful TRPML (e.g., TRPML1, TRPML2, and/or TRPML3) modulators.
  • the present disclosure provides certain biological and/or chemical assays (e.g., that facilitate and/or permit assessment of one or more feature(s) of TRMPL (e.g., TRPML1, TRPML2, and/or TRPML3) expression and/or activity, and/or of impact of TRPML (e.g., TRPML1, TRPML2, and/or TRPML3) modulator(s) on such expression and/or activity.
  • TRMPL e.g., TRPML1, TRPML2, and/or TRPML3
  • the present disclosure provides technologies for identifying and/or characterizing one or more aspects of biological pathway(s) (e.g., autophagy pathway(s)) involving TRMPL (e.g., TRPML1, TRPML2, and/or TRPML3), and thus permits identification and/or characterization of additional useful targets within such pathway(s) and/or of modulator(s) that impact such pathway(s) (whether or not targeting TRPML (e.g., TRPML1, TRPML2, and/or TRPML3) itself).
  • TRMPL e.g., TRPML1, TRPML2, and/or TRPML3
  • Compositions e.g., TRPML1, TRPML2, and/or TRPML3
  • the present disclosure provides and/or utilizes a composition that comprises and/or delivers a compound as described herein (e.g., together with one or more other components).
  • compositions that comprise and/or deliver compounds reported herein (e.g., compounds of Formula I-IVb), or an intermediate, degradant, or an active metabolite thereof, e.g., when contacted with or otherwise administered to a system or environment e.g., which system or environment may include TRPML (e.g., TRPML1, TRPML2, and/or TRPML3) activity; in some embodiments, administration of such a composition to the system or environment achieves the regulation of autophagy and lysosomal biogenesis as described herein.
  • compounds reported herein e.g., compounds of Formula I-IVb
  • an intermediate, degradant, or an active metabolite thereof e.g., when contacted with or otherwise administered to a system or environment e.g., which system or environment may include TRPML (e.g., TRPML1, TRPML2, and/or TRPML3) activity
  • TRPML e.g., TRPML1, TRPML2, and/or TRP
  • a provided composition as described herein may be a pharmaceutical composition in that it comprises an active agent (e.g., compounds of Formula I- P 106 f 298 IVb) and one or more pharmaceutically acceptable excipients (e.g., one or more pharmaceutically acceptable adjuvants, carriers, excipients, and/or vehicles); in some such embodiments, a provided pharmaceutical composition comprises and/or delivers a compound described herein (e.g., compounds of Formula I-IVb), or an active metabolite thereof to a relevant system or environment (e.g., to a subject in need thereof) as described herein.
  • an active agent e.g., compounds of Formula I- P 106 f 298 IVb
  • pharmaceutically acceptable excipients e.g., one or more pharmaceutically acceptable adjuvants, carriers, excipients, and/or vehicles
  • a provided pharmaceutical composition comprises and/or delivers a compound described herein (e.g., compounds of Formula I-IVb), or an active metabolite thereof
  • a provided composition (e.g., a pharmaceutical composition) includes a compound (e.g., as described herein) in a salt form such as a pharmaceutically acceptable salt form.
  • a provided composition (e.g., a pharmaceutical composition) may be formulated for administration to a subject (e.g., a human) according to a particular route (e.g., orally, parenterally, by inhalation or nasal spray, topically (e.g., as by powders, ointments, or drops), rectally, buccally, intravaginally, intraperitoneally, intracisternally or via an implanted reservoir, etc).
  • a particular route e.g., orally, parenterally, by inhalation or nasal spray, topically (e.g., as by powders, ointments, or drops), rectally, buccally, intravaginally, intraperitoneally, intracisternally or via an implanted reservoir, etc).
  • a provided composition (e.g., a pharmaceutical composition) comprises or delivers an amount of a compound as described herein (or an active metabolite thereof) that is effective to measurably modulate TRPML (e.g., TRPML1, TRPML2, and/or TRPML3) activity, and/or to induce autophagy and/or lysosomal biogenesis in a biological sample or in a subject, when administered in accordance with a therapeutic regimen.
  • TRPML e.g., TRPML1, TRPML2, and/or TRPML3
  • a provided compound or composition is formulated for administration to a patient in need of such composition.
  • a compound or composition as described herein may be administered in a dose amount and/or by a route of administration effective for treating or lessening the severity of a disease or disorder described herein.
  • a composition e.g., a pharmaceutical composition
  • a route of administration effective for treating or lessening the severity of a disease or disorder described herein.
  • a composition e.g., a pharmaceutical composition
  • an appropriate dosage level may be within a range of about 0.01 mg/kg to about 50 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • the present application provides a variety of uses and applications for compounds and/or compositions as described herein, for example in light of their activities and/or characteristics as described herein.
  • such uses may include therapeutic and/or diagnostic uses.
  • such uses may include research, production, and/or other technological uses.
  • the present disclosure provides technologies for modulating TRPML activity (e.g., TRPML1, TRPML2, TRPML3, or combinations thereof).
  • the present application relates to a method of modulating TRPML activty (e.g., TRPML1, TRPML2, TRPML3, or combinations thereof) in a subject comprising administering to the subject a provided compound, or a composition as described herein.
  • TRPML1 activty in a subject comprising administering to the subject a provided compound, or a composition as described herein.
  • the present application relates to a method of modulating TRPML2 activty in a subject comprising administering to the subject a provided compound, or a composition as described herein.
  • the present application relates to a method of modulating TRPML3 activty in a subject comprising administering to the subject a provided compound, or a composition as described herein. In some embodiments, the present application relates to a method of modulating TRPML1, TRPML2, and/or TRPML3 activty in a subject comprising administering to the subject a provided compound, or a composition as described herein.
  • P 108 f 298 Diseases, Disorders, and Conditions The present disclosure demonstrates that compounds and/or compositions as described herein may be useful in medicine (e.g., in the treatment of one or more diseases, disorders, or conditions).
  • a disease, disorder or condition that may be treated as described herein may be or comprise a disease, disorder or condition associated with TRPML (e.g., TRPML1, TRPML2, TRPML3, or combinations thereof) deficiency.
  • the present disclosure identifies that TRMPL (e.g., TRPML1, TRPML2, TRPML3, or combinations thereof) deficiency is associated with particular diseases, disorders or conditions, some or all of which may be treated in accordance with the present disclosure.
  • treatment provided herein involves administration of a TRMPL1 modulator as described herein in an amount effective to modulate TRMPL (e.g., TRPML1, TRPML2, TRPML3, or combinations thereof) activity in a lysosome and/or increase autophagy.
  • a disease, disorder, or condition amenable to treatment as described herein is or comprises a liver disease, a neurodegenerative disorder, cancer, or a heart disease.
  • a disease, disorder, or condition amenable to treatment as described herein is or comprises a lysosomal storage disease, such as Niemann-Pick C (NPC) disease, Gaucher disease, and Pompe disease.
  • a disease, disorder, or condition amenable to treatment as described herein is an age-related common neurodegenerative disease, such as Alzheimer’s Disease, Parkinson’s Disease, and Huntington’s Disease.
  • a disease, disorder, or condition amenable to treatment as described herein is a type IV Mucolipidosis (ML4) neurodegenerative lysosomal storage disease caused by mutations in TRPML (e.g., TRPML1, TRPML2, TRPML3, or combinations thereof).
  • ML4 Mucolipidosis
  • a disease, disorder, or condition amenable to treatment as described herein is related to reactive oxygen species or oxidative stress.
  • the present application relates to use of a compound and/or composition described herein for use in the manufacture of a medicament e.g., for modulation of TRPML (e.g., TRPML1, TRPML2, TRPML3, or combinations thereof) activity.
  • TRPML e.g., TRPML1, TRPML2, TRPML3, or combinations thereof
  • the present application relates to use of a compound and/or composition described herein for use in the manufacture of a medicament for treating a disease, disorder or condition, e.g., through modulation of TRPML (e.g., TRPML1, TRPML2, TRPML3, or combinations thereof) activity; in some emebodiments, the disease, disorder, or condition is a liver disease, a neurodegenerative disorder, cancer, or a heart disease.
  • a disease, disorder, or condition is a muscular disease, a liver disease, a metabolic disease, an atherosclerotic disease, an inflammatory bowel disease, an atherosclerotic disease, a neurodegenerative disease, or an oncological disease.
  • a disease, disorder, or condition is a muscular disease.
  • a muscular disease is a muscular dystrophy.
  • a muscular dystrophy is Duchenne muscular dystrophy.
  • a disease, disorder, or condition is an infectious disease.
  • an infectious disease is an infection of Heliobacter pylori or Mycobacterium tuberculosis.
  • a disease, disorder, or condition is tuberculosis.
  • L is an optionally substituted group selected from -C 0 -C 6 alkylenyl–S(O) 2 -, –S(O) 2 -C 0 -C 6 alkylenyl, -S(O)-C 0 -C 6 alkylenyl, -C 0 -C 6 alkylenyl-S(O)-, -C(O)-C 0 -C 6 alkylenyl, - C(O)-O-C 0 -C 6 alkylenyl, -C(O)-N(R 8 )-C 0 -C 6 alkylenyl, -C 1 -C 6 alkylenyl, and C 3 -C 6 cycloalkylenyl;
  • A is C 3 -C
  • Embodiment 2 The compound of Embodiment 1, wherein n is 0. Embodiment 3. The compound of Embodiments 1 or 2, wherein q is 1. Embodiment 4. The compound of any one of Embodiments 1-3, wherein L is optionally substituted –S(O) 2 -C 0 -C 6 alkylenyl. Embodiment 5. The compound of Embodiment 4, wherein L is –S(O) 2 -. Embodiment 6. The compound of Embodiment 4, wherein L is optionally substituted – S(O) 2 -C 1 -C 6 alkylenyl. Embodiment 7. The compound of Embodiment 6, wherein L is –S(O) 2 -CH 2 -.
  • Embodiment 8 The compound of Embodiment 1, wherein L is selected from –S(O) 2 -, – S(O) 2 -CH 2 -, P 112 f 298 , a .
  • Embodiment 9 The compound of any one of Embodiments 1-8, wherein A is 3- to 12- membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • Embodiment 10 The compound of any one of Embodiments 1-9, wherein A is 4- to 6- membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • Embodiment 11 The compound of any one of Embodiments 1-10, wherein A is pyrrolidinyl or piperidinyl.
  • Embodiment 12 The compound of any one of Embodiments 1-8, wherein A is C3-C12 cycloaliphatic.
  • Embodiment 13 The compound of any one of Embodiments 1-8 or 12, wherein A is C 5 -C 10 cycloaliphatic.
  • Embodiment 14 The compound of any one of Embodiments 1-8 or 12-13, wherein A is cyclopentyl or cyclohexyl.
  • Embodiment 15. The compound of Embodiment 1, wherein A is selected from: , a P 113 f 298 Embodiment 16.
  • Embodiment 18 The compound of any one of Embodiments 1-16, wherein B is a fused optionally substituted C 5 -C 6 aryl.
  • Embodiment 18 The compound of any one of Embodiments 1-16, wherein B is a fused optionally substituted 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • Embodiment 19 The compound of Embodiment 18, wherein B is a fused optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • Embodiment 20 The compound of any one of Embodiments 1-16, wherein B is a fused optionally substituted C 5 -C 6 aryl.
  • Embodiment 21 wherein R 1 is phenyl substituted with (R 3 ) p .
  • Embodiment 23 The compound of any one of Embodiments 1-22, wherein R 1 is 3- to 12- membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R 3 ) p .
  • P 114 f 298 Embodiment 24 The compound of Embodiment 23, wherein R 1 is bicyclic 10- to 12- membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R 3 ) p .
  • Embodiment 25 Embodiment 25.
  • Embodiment 26 The compound of Embodiment 25, wherein R 1 is 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R 3 ) p .
  • Embodiment 27 The compound of Embodiment 1, wherein R 1 is selected from -CH(CH 3 ) 2 , , , , , , , P 115 f 298 , P 116 f 298 .
  • Embodiment 28 The compound of any one of Embodiments 1-22, wherein R 1 is 5- to 12- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R 3 ) p .
  • Embodiment 26 The compound of Embodiment 25, wherein R 1 is 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S substituted with (R 3 ) p .
  • Embodiment 27 The compound of Embodiment 1, wherein
  • Embodiment 29 The compound of any one of Embodiments 1-27, wherein m is 0.
  • Embodiment 30 The compound of any one of Embodiments 1-27 or 29, wherein each R 2 is halo, -C(O)O-R 2a or an optionally substituted group selected from C 1 -C 6 aliphatic and C 5 - C 12 aryl.
  • Embodiment 31 The compound of any one of Embodiments 1-27 or 29, wherein R 2 is halo, -C(O)O-R 2a or optionally substituted C 1 -C 6 aliphatic.
  • Embodiment 32 The compound of any one of Embodiments 1-27, wherein m is 0.
  • Embodiment 30 The compound of any one of Embodiments 1-27 or 29, wherein each R 2 is halo, -C(O)O-R 2a or an optionally substituted group selected from C 1 -C 6 aliphatic and C 5 - C 12 aryl.
  • Embodiment 34 The compound of Embodiment 1, wherein the compound is of formula IIIa: or a pharmaceutically acceptable salt thereof.
  • Embodiment 35 The compound of Embodiment 1, wherein the compound is of formula IIIb: or a pharmaceutically acceptable salt thereof.
  • Embodiment 36 The compound of Embodiment 1, wherein the compound is of formula IIIb: or a pharmaceutically acceptable salt thereof.
  • a compound of formula Ia P 120 f 298 Ia or a pharmaceutically acceptable salt thereof, wherein X is –NR 5 -, -C(R 5 )2-, -C(O)-, or –O-; each of X a , X b , X c , and X d are independently selected from N and CR 6 ; L is an optionally substituted group selected from -C 0 -C 6 alkylenyl–S(O) 2 -, –S(O) 2 -C 0 -C 6 alkylenyl, -S(O)-C 0 -C 6 alkylenyl, -C 0 -C 6 alkylenyl-S(O)-, -C(O)-C 0 -C 6 alkylenyl, - C(O)-C 0 -C 6 alkylenyl, - C(O)-O-C 0 -C 6 al
  • Embodiment 37 A compound of formula Ib Ib or a pharmaceutically acceptable salt thereof, wherein X is –NR 5 -, -C(R 5 ) 2 -, -C(O)-, or –O-; each of X e , X f , and X g is independently selected from S, N, an 7 d CR ; each of Y 1 and Y 2 is independently selected from N and C; L is an optionally substituted group selected from -C 0 -C 6 alkylenyl–S(O) 2 -, –S(O) 2 -C 0 -C 6 alkylenyl, -S(O)-C 0 -C 6 alkylenyl, -C 0 -C 6 alkylenyl-S(O)-, -C(O)-C 0 -C 6 alkylenyl, - P 122 f 298 C(O)-O-C 0 -
  • Embodiment 38 A compound selected from Table 1.
  • Embodiment 39 A compound selected from Table 2.
  • Embodiment 40 A pharmaceutical composition comprising a compound of any one of Embodiments 1-39 and a pharmaceutically acceptable carrier or excipient.
  • Embodiment 41 A method of modulating a TRPML (e.g., TRPML1, TRPML2, TRPML3, or combinations thereof) comprising administering to a subject a compound of any one Embodiments 1-39, or a composition thereof.
  • Embodiment 42 A method of treating a disease, disorder, or condition in a subject comprising administering a compound of any one Embodiments 1-39, or a composition thereof.
  • Embodiment 43 A method of treating a disease, disorder, or condition in a subject comprising administering a compound of any one Embodiments 1-39, or a composition thereof.
  • Embodiment 42 wherein the disease, disorder, or condition is associated with TPRML (e.g., TRPML1, TRPML2, TRPML3, or combinations thereof) modulation.
  • Embodiment 44 The method of Embodiments 42 or 43, wherein the disease, disorder, or condition is a lysosomal storage disorder. P 124 f 298 Embodiment 45.
  • the method of Embodiment 44, wherein the lysosomal storage disorder is selected from Niemann-Pick C disease, Gaucher disease, and Pompe disease.
  • Embodiment 46 The method of Embodiments 42 or 43, wherein the disease, disorder, or condition is age-related common neurodegenerative disease.
  • Embodiment 47 The method of Embodiment 47.
  • Embodiment 46 wherein the disease, disorder, or condition is selected from Alzheimer’s Disease, Parkinson’s Disease, and Huntington’s Disease.
  • Embodiment 48 The method of Embodiment 43, wherein the disease, disorder, or condition is a type IV Mucolipidosis (ML4) neurodegenerative lysosomal storage disease caused by mutations in TRPML (e.g., TRPML1, TRPML2, and/or TRPML3).
  • ML4 Mucolipidosis
  • Embodiment 42 wherein the disease, disorder, or condition is a muscular disease, a liver disease, a metabolic disease, an atherosclerotic disease, an inflammatory bowel disease, an atherosclerotic disease, a neurodegenerative disease, an oncological disease, or an infectious disease.
  • Embodiment 50 The method of Embodiment 49, wherein the disease, disorder, or condition is a muscular disease.
  • Embodiment 51 The method of Embodiment 50, wherein the muscular disease is a muscular dystrophy.
  • Embodiment 52 The method of Embodiment 51, wherein the muscular dystrophy is Duchenne muscular dystrophy.
  • Embodiment 53 The method of Embodiment 53.
  • Embodiment 49 wherein the disease, disorder, or condition is an infectious disease.
  • EXEMPLIFICATION [0209]
  • the present teachings include descriptions provided in the Examples that are not intended to limit the scope of any claim. Unless specifically presented in the past tense, inclusion in the Examples is not intended to imply that the experiments were actually performed. The following non-limiting examples are provided to further illustrate the present teachings.
  • Step-2 Procedure for synthesis of spiro[cyclopentane-1,3'-indoline 4: [0215] To a solution of spiro[cyclopentane-1,3'-indolin]-2'-one 3 (1.3, 16 g, 85.5 mmol) in THF (200 mL) cooled at 0°C was added LiAlH4 (1.0 M in THF, 111 mL, 111.2 mmol) dropwise. The reaction mixture was stirred at room temperature for 4 h and refluxed at 80 °C for 2 hours, following which it was cooled to room temperature and quenched with saturated aq. Na 2 SO 4 solution.
  • Step-1 Procedure for synthesis of tert-butyl 1-((4- (methylsulfonyl)phenyl)sulfonyl)spiro[indoline-3,4'-piperidine]-1'-carboxylate 3.3: [0222] To a stirred solution of tert-butyl spiro[indoline-3,4'-piperidine]-1'-carboxylate 3.1 (1 g, 3.46 mmol, 1 eq.) and 4-(methylsulfonyl)benzenesulfonyl chloride 3.2 (971 mg, 3.
  • Step-2 Procedure for synthesis of 1-((4-(methylsulfonyl)phenyl)sulfonyl)spiro[indoline- 3,4'-piperidine] 3.4: P 146 f 298
  • Step-3 Procedure for synthesis of l'-(4-chioro-2-fluorophenyl)-l-((4- (methylsulfonyl)phenyl)sulfonyl)spiro[indoline-3,4'-piperidine]
  • a microwave tube was charged with a solution of I-((4- (methylsulfonyl)phenyl)sulfonyl)spiro[indoline-3, 4 ’-piperidine] 3.4 (300 mg, 0.74 mmol, 1 eq), 1- bromo-4-chloro-2-fluorobenzene 3.5 (230 mg, 1.1 mmol, 1.5 eq) and sodium tert-butoxide ( 141 mg, 1.47 mmol, 2 eq) in 1,4-dioxane (10 mL). The tube was sealed with a septum and the reaction mixture was purged with argon for 10 min.
  • Tris(dibenzylideneacetone)dipaliadium(0) 47 mg, 0.052 mmol, 0.07 eq
  • Brettphos 59 mg, 0.11 mmol, 0.15 eq
  • the tube was then sealed with an aluminium cap and the reaction mixture was irradiated in a microwave reactor at 140 °C for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through a pad of Celite and the Celite pad was washed with ethyl acetate.
  • Step-1 Procedure for synthesis of spiro[cyclopentane-1,3'-indolin]-2'-one 1.3: [0229] To a solution of indolin-2-one 1.1 (20 g, 150 mmol) in THF (200 mL) cooled to -78°C, was added LiHMDS (1.0 M in THF, 300 mL, 300 mmol) dropwise.
  • Step-2 Procedure for synthesis of spiro[cyclopentane-1,3'-indoline 1.4: [0231] To a solution of spiro[cyclopentane-1,3'-indolin]-2'-one 1.3 (16 g, 85.5 mmol) in THF (200 mL) cooled at 0 °C was added LiAlH4 (1.0 M in THF, 111 mL, 111.2 mmol) dropwise.
  • Step-3 Procedure for synthesis of 1'-((1,1-dimethyl-1,3-dihydroisobenzofuran-5- yl)sulfonyl)spiro[cyclopentane-1,3'-indoline]: P 148 f 298 [0233] To a stirred solution of spiro[cyclopentane-1,3'-indoline 1.4 (100 mg, 0.57 mmol, 1 eq) in acetonitrile (10 mL) was added pyridine (0.09 mL, 1.1 mmol, 2 eq) at room temperature and stirred for 5 min, 1,1-dimethyl-1,3-dihydroisobenzofuran-5-sulfonyl chloride 4.1 (142 mg, 0.57 mmol, 1 eq) was added and the reaction mixture was stirred at room temperature for 2 h.
  • Step 1 Synthesis of 1',2'-dihydrospiro[cyclohexane-1,3'-indol]-4-ol
  • a solution of 1',2'-dihydrospiro[cyclohexane-1,3'-indole]-2',4-dione (1 g, 4.64 mmol) in anhydrous THF (10 mL) was added to a solution of LiAIH4 (0.44 g, 11.57 mmol) in anhydrous THF (15 mL) at 0 °C dropwise for 1 hour.
  • Step 2 The organic layer was dried over Na2SO4, filtered and the filtrate was evaporated under reduced pressure to afford 1- ⁇ 1,2-dihydrospiro[indole-3,3'-pyrrolidin]-1'-yl ⁇ -2,2-dimethylpropan- 1-one (0.6 g, 2.32 mmol, 79.55% purity, 91.5% yield) that was used in next step without further purification. [0257] Step 2.
  • Example 12 Synthesis of 1'- ⁇ [1-(3-methylphenyl)-1H-pyrazol-4-yl]sulfonyl ⁇ -1',2'- dihydrospiro[cyclopentane-1,3'-indole] (I-75) P 156 f 298 [0260] 1-(3-methylphenyl)-1H-pyrazole-4-sulfonyl chloride (0.5 g, 1.94 mmol) was added to the mixture of 1',2'-dihydrospiro[cyclopentane-1,3'-indole] (0.34 g, 1.96 mmol) and pyridine (0.23 g, 2.9 mmol) in dry THF (20 mL).
  • Step 4 The residue was treated with water/ethyl acetate mixture (20 mL/20 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure to afford crude 1,2-dihydrospiro[indole-3,3'-oxolane] (0.3 g, 1.71 mmol, 46.6% purity, 37.6% yield) that was used in the next step without further purification. [0267] Step 4.
  • Example 14 Synthesis of 4-( ⁇ 1,2-dihydrospiro[indole-3,2'-oxolan]-1-yl ⁇ sulfonyl)-N,N- dimethylbenzene-1-sulfonamide (I-77) [0269]
  • Step 1 Synthesis of 2-(2-bromophenyl)-1,3-dioxane
  • Propane-1,3-diol (2.26 g, 29.7 mmol) and p-TsOH (0.464 g, 2.7 mmol) were added to a solution of 2-bromobenzaldehyde (5g, 27mmol) in toluene (50 mL).
  • Zinc iodide (1.96 g, 6.15 mmol) was added to an ice-cold solution of 2-(2-bromophenyl)- 1,3-dioxane (3 g, 12.3 mmol) in DCM (30 mL) followed by addition of trimethylsilyl cyanide (1.82 g, 18.4 mmol) over a period of 10 minutes keeping the temperature at 0 0 C. After cooling was removed and the reaction was stirred for 40 hours at room temperature until the completion (TLC control).
  • Example 19 Synthesis of 1'-methyl-1-phenylmethanesulfonyl-1,2-dihydrospiro[indole-3,4'- piperidine] (I-82) [0307] Step 1. Synthesis of tert-butyl 1'-methyl-1,2-dihydrospiro[indole-3,4'-piperidine]-1- carboxylate [0308] A mixture of tert-butyl 1,2-dihydrospiro[indole-3,4'-piperidine]-1-carboxylate (5 g, 17.3 mmol) and formaldehyde 37% aq.
  • tert-butyl 1'-methyl-1,2-dihydrospiro[indole-3,4'-piperidine]-1-carboxylate (4 g, 13.2 mmol) was dissolved in 1M HCl solution in methanol (100 mL). The reaction mixture was stirred for 1 h at room temperature, evaporated to dryness. Obtained residue was treated with ether (100 mL), formed solid was filtered-off, washed with ether (100 mL) and dried on air to give 1'-methyl- 1,2-dihydrospiro[indole-3,4'-piperidine] dihydrochloride as yellow solid (3.5 g, 12.7 mmol, 95% purity, 91.4% yield).
  • Step 3 Synthesis of 1'-methyl-1-phenylmethanesulfonyl-1,2-dihydrospiro[indole-3,4'- piperidine]
  • Phenylmethanesulfonyl chloride 0.434 g, 2.28 mmol was added to a solution of 1'- methyl-1,2-dihydrospiro[indole-3,4'-piperidine] dihydrochloride (0.6 g, 2.18 mmol) and pyridine (0.517 g, 6.54 mmol) in dichloromethane (10 mL), the reaction mixture was stirred for 16 h at room temperature and diluted with water (10 mL).
  • Example 20 [0313] The following compounds were prepared using standard chemical manipulations and procedures similar to those used for the preparation in Example 19. P 169 f 298
  • Step 2 Synthesi s of 1 -[4-(difluoromethyl)benzenesulfonyl]- 1 '-(2,2,2-trifluoroethyl)" 1 ,2- dihydrospiro-[indole-3,3'-pyrrolidine]
  • Step-1 Procedure for synthesis of 1-bromo-2-((2-methylallyl)oxy)benzene 28.2: [0336] To a stirred solution of 2-bromophenole 28.1 (5.0 g, 28.90 mmol, 1.0 eq.) in acetonitrile (50 mL) was added 3-bromo-2-methylprop (4.27 g, 31.70 mmol, 1.1 eq.) and potassium carbonate (9.97 g, 72.20 mmol, 2.5 eq.) at room temperature. The reaction mixture was heated to 85 °C and stirred for 16 h. The
  • Step-2 Procedure for synthesis of 3,3-dimethyl-2,3-dihydrobenzofuran 28.3
  • 1-bromo-2-((2-methylallyl)oxy)benzene 28.2 (3.0 g, 13.20 mmol, 1.0 eq) in N,N-Dimethylformamide (60 mL) was added Sodium Formate (1.07 g, 15.80 mmol, 1.2 eq.), sodium acetate (2.7 g, 33.0 mmol, 2.5 eq), Tetraethyl ammonium chloride (2.61 g, 15.80 mmol, 1.2 eq.) and palladium acetate (296 mg, 1.32 mmol, 0.1 eq.) at room temperature under N 2 .
  • Step-3 Procedure for synthesis of spiro[cyclopentane-1,3'-indoline 28.4: [0340] To the mixture of 3,3-dimethyl-2,3-dihydro-1-benzofuran 28.3 (188 mg, 1.26 mmol, 1.0 eq.) in DCM (8 mL) was added sulfurochloridic acid (220 mg, 1.89 mmol, 1.5 eq.) drop-wise at 0 °C. The resulting mixture was stirred for 20 min at this temperature. When TLC show the reaction was completely. The resulting mixture was poured into ice-water (100 mL) and extracted with DCM (100 mL x 3).
  • Step-4 Procedure for synthesis of 1'-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5- yl)sulfonyl]-1',2'-dihydrospiro[cyclohexane-1,3'-indole]: [0343] To the mixture of 1',2'-dihydrospiro[cyclohexane-1,3'-indole] (30 mg, 160 ⁇ mol, 1.0 eq), TEA (32.3 mg, 320 ⁇ mol, 2.0 eq.) in DCM (5 mL ) was added 3,3-dimethyl-2,3-dihydro-1- benzofuran-5-sulfonyl chloride (39.4 mg, 160 ⁇ mol, 1.0 eq.) portion-wise at 20 °C.
  • Step-1 Procedure for synthesis of 4'-fluorospiro[cyclopentane-1,3'-indole] 29.2: [0346] To a solution of 4-fluoro-1H-indole 29.1 (500 mg, 3.69 mmol, 1.0 eq.) in THF (10 mL) was added t-BuOK (910 mg, 8.11 mmol, 2.2 eq.), the reaction mixture was stirred at room temperature for 30 min under N 2 .
  • Step-2 Procedure for synthesis of 4'-fluorospiro[cyclopentane-1,3'-indoline] 29.3: [0348] To a solution of 4'-fluorospiro[cyclopentane-1,3'-indole] 29.2 (300 mg, 1.59 mmol, 1.0 eq.) in THF (5 mL) was slowly added LiAlH 4 (120.8 mg, 3.18 mmol, 2.0 eq.) at 0°C. The reaction mixture was stirred 0 °C for 3 h. The mixture was quenched with NH 4 Cl (5 mL), extracted with EA (15 mL ⁇ 3). The organic layer was combined, dried over anhydrous Na 2 SO 4 , filtered and P 179 f 298
  • Step-3 Procedure for synthesis of 4-((4'-fluorospiro[cyclopentane-1,3'-indolin]-1'- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide: [0350] To a solution of 4'-fluoro-1',2'-dihydrospiro[cyclopentane-1,3'-indole] (100 mg, 522 ⁇ mol, 1.0 eq.) in DCM (2 mL ) were added 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (148 mg, 522 ⁇ mol, 1.0 eq.) and TEA (157 mg, 1.56 mmol, 3.0 eq.).
  • reaction mixture was stirred at r.t for 4 h. Then the mixture was diluted with H 2 O (10 mL), extracted with DCM (15 mL ⁇ 3). The organic layer was combined, dried over anhydrous Na 2 SO 4 , filtered and concentrated.
  • Step-1 Procedure for synthesis of 1'-(tetrahydro-2H-pyran-4-carbonyl)spiro[indoline-3,3'- pyrrolidin]-2-one 30.2: [0353] A 50 mL round-bottomed flask was charged with spiro[indoline-3,3'-pyrrolidin]-2-one 30.1 (100 mg, 531 ⁇ mol, 1 eq.), oxane-4-carbonyl chloride (86.7 mg, 584 ⁇ mol, 1.1 eq.), triethylamine (53.7 mg, 531 ⁇ mol, 1 eq.) and DCM (20 mL ) at 0 °C under N 2 .
  • Step-2 Procedure for synthesis of 1'-((tetrahydro-2H-pyran-4-yl)methyl)spiro[indoline- 3,3'-pyrrolidine] 30.3: [0355] A 50 mL round-bottomed flask was charged with 1'-(tetrahydro-2H-pyran-4- carbonyl)spiro[indoline-3,3'-pyrrolidin]-2-one 30.2 200 mg, 665 ⁇ mol, 1 eq.) and 1 M trifluoro(oxolan-1-ium-1-yl)boranuide (20 mL, 20.0 mmol, 30 eq.) under N 2 .
  • the reaction mixture was stirred at 70°C for 8 h. LCMS indicated the SM was consumed.
  • the reaction was quenched with MeOH (1 mL).
  • the reaction mixture was poured into water (20 mL).
  • the pH was adjusted to 8-9 with solid NaHCO 3 .
  • the aqueous layer was extracted with EA (20 mL) 3 times.
  • the combined organic layer was washed with brine and dried over Na 2 SO 4 .
  • the solvent was removed under vacuum.
  • Step-3 Procedure for synthesis of N,N-dimethyl-4-((1'-((tetrahydro-2H-pyran-4- yl)methyl)spiro[indoline-3,3'-pyrrolidin]-1-yl)sulfonyl)benzenesulfonamide: [0357] A 50 mL round-bottomed flask was charged with 1'-((tetrahydro-2H-pyran-4- yl)methyl)spiro[indoline-3,3'-pyrrolidine] 30.3 (80 mg, 293 ⁇ mol, 1 eq.), 4- (dimethylsulfamoyl)benzene-1-sulfonyl chloride (83.1 mg, 293 ⁇ mol, 1 eq.), triethylamine (59.2 mg, 586 ⁇ mol, 2 eq.) and DCM (10 mL) at room temperature.
  • the reaction mixture was stirred for 2 h when LCMS revealed the starting material completely consumed.
  • the reaction mixture was poured into H 2 O (20 mL).
  • the aqueous layer was extracted with DCM (25 mL) 3 times.
  • Step-1 Procedure for synthesis of tert-butyl 1'-(2-oxopropyl)spiro[indoline-3,4'- piperidine]-1-carboxylate 31.2: P 182 f 298 [0360] To the mixture of tert-butyl l,2-dihydrospiro[indole-3,4’-piperidine]-l-carboxylate 31.1 (HC1 salt, 650 mg, 1.85 mmol, 1.0 eq.) , TEA (935 mg, 9.25 mmol, 5.0 eq.) in DCM (10 mL ) was added
  • Step-2 Procedure for synthesis of l-(spiro[indoline-3,4'-piperidin]-T-yl)propan-2-one 31.3:
  • Step-3 Procedure for synthesis of N,N-dimethyl-4-((r ⁇ (2-oxopropyl)spiro[indoline-3,4'- piperidin]- 1 -yl )sulfonyl)benzenesulfonamide 31.4:
  • Step-4 Procedure for synthesis of 4-((r-(2,2-difluoropropyl)spiro[indoline-3,4'- piperidi n] - 1 -yl)sulfonyl)-N,N-dimethylbenzenesulfonamide :
  • Step-1 Procedure for synthesis of tert-butyl 1'-((tetrahydro-2H-pyran-4- yl)methyl)spiro[indoline-3,4'-piperidine]-1-carboxylate 32.2: [0369] To a solution of tert-butyl 1,2-dihydrospiro[indole-3,4'-piperidine]-1-carboxylate 32.1 (200 mg, 693 ⁇ mol, 1 eq.) and oxane-4-carbaldehyde (157 mg, 1.38 mmol, 2 eq.) in ethyl alcohol (10
  • Step-2 Procedure for synthesis of 1'-((tetrahydro-2H-pyran-4-yl)methyl)spiro[indoline- 3,4'-piperidine] 32.3: [0371] A 50 mL round-bottomed flask was charged with tert-butyl 1'-[(oxan-4-yl)methyl]-1,2- dihydrospiro[indole-3,4'-piperidine]-1-carboxylate 32.2 (268 mg, 693 ⁇ mol, 1 eq.), trifluoroacetic acid (790 mg, 6.93 mmol, 10 eq.) and methylene chloride (15 mL). The reaction mixture was stirred at room temperature for 1 h.
  • Step-3 Procedure for synthesis of N,N-dimethyl-4-((1'-((tetrahydro-2H-pyran-4- yl)methyl)spiro[indoline-3,4'-piperidin]-1-yl)sulfonyl)benzenesulfonamide: [0373] A 50 mL round-bottomed flask was charged with 1'-[(oxan-4-yl)methyl]-1,2- dihydrospiro[indole-3,4'-piperidine] (181.9 mg, 631 ⁇ mol), 4-(dimethylsulfamoyl)benzene-1- sulfonyl chloride 32.3 (196 mg, 694 ⁇ mol, 1 eq.), triethylamine (127 mg, 1.26 mmol, 1.8 eq.) and methylene chloride (15 mL) at RT.
  • Example 33 [0375] The following compounds were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 32. P 186 f 298
  • Step 5 Synthesis of 4-( ⁇ r,2'-dihydrospiro[cyclohexane-1,3'-pyrazolo[1,5-a]imidazol]-r- yl ⁇ sulfonyl)-N,N-dimethylbenzene- 1 -sulfonamide
  • Step 3 Synthesis of N,N-dimethyl-4-((l-(2,2,2-trifluoroethyl)-2',3'-dihydro-rH- spiro[piperidine-4,4 ! -quinolin]-r ⁇ yl)sulfonyl)benzenesulfonamide
  • Step 3 Synthesis of 2-(3-bromopyridin-4-yl)acetonitrile
  • Potassium cyanide (5.67 g, 87.1 mmol) was added to a solution of 3-bromo-4- (chloromethyl)pyridine (12 g, 58.1 mmol) in DMSO (50 mL), the mixture was stirred overnight and diluted with water (100 mL).
  • Step 7 Synthesis of 4-( ⁇ r,2'-dihydrospiro[cyclopentane-l,3’-pyrrolo[2,3-c]pyridin]-T- yl ⁇ sulfonyl)-N,N-dimethylbenzene-l-sulfonamide
  • Step 4 Synthesis of 4-( ⁇ 2',3'-dihydro-rH-spiro[cyclohexane-l,4'-quinolin]-r- yl ⁇ sulfonyl)-N,N-dimethylbenzene-l-sulfonamide
  • Step 1 Synthesis of 4-[(tert-butyldimethylsilyl)dimethyl-S-aminosulfonimidoyl]benzene- 1-sulfonyl chloride
  • 2.5M n-butyllithium (0.382 g, 5.97 mmol) in hexane (2.38 mL) was added to a solution of 4-bromo-N'-(tert-butyldimethylsilyl)-N,N-dimethylbenzenesulfonimidamide (1.88 g, 4.98 mmol) in anhydrous tetrahydrofuran (20 mL) at -78 °C under argon atmosphere and the mixture was stirred for 1 h at -78 °C.
  • Step 3 Synthesis of N'-(tert-butyldimethylsilyl)-N,N-dimethyl-4-(spiro[cyclohexane-l,3'- indolin]- 1 '-y 1 sulfonyl)benzenesulfonimi damide
  • Step 4 Synthesis of N,N-dimethyl-4-(spiro[cyclohexane-l,3'-indolin]-r- y ! sulfonyl )benzenesulfonimi damide
  • reaction mixture was stirred for 1 h, tert-butyl N,N-bis(2- chloroethyl)carbamate (25.9 g, 107 mmol) was added over 15 min, and the reaction mixture was stirred at room temperature for 18 h. Then, it was poured into water (1000 mL) and extracted with ethyl acetate (250 mL x 3). The organic layer was washed with water (300 mL) and brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Step-2 Synthesis of 4-(2,6-difluorophenyl)piperidine-4-carbonitrile hydrochloride: [0432] tert-butyl 4-cyano-4-(2,6-difluorophenyl)piperidine-1-carboxylate (5.3 g, 14.6 mmol) was added to a stirred solution of sat. hydrogen chloride solution in dry dioxane (250 mL). The reaction P 201 f 298
  • Step-2 Synthesis of benzyl 1-[4-(difluoromethyl)benzenesulfonyl]-1,2- dihydrospiro[indole-3,4'-piperidine]-1'-carboxylate: [0468] Pyridine (2.57 g, 32.5 mmol) and 4-(difluoromethyl)benzene-1-sulfonyl chloride (5.89 g, 26.0 mmol) were added to a solution of benzyl 1,2-dihydrospiro[indole-3,4'-piperidine]-1'- P 211 f 298
  • Step-1 Synthesis of methyl 4-(hydroxymethyl)cyclohexane-1-carboxylate: [0474] 1-(1H-imidazole-1-carbonyl)-1H-imidazole(5.20 g, 32.1 mmol) was added at 0 o C to a stirred solution of 4-(methoxycarbonyl)cyclohexane-1-carboxylic acid (5 g, 26.8 mmol) in tetrahydrofuran (50 mL). The reaction mixture was stirred for 1 h at 0 o C, and then sodium borohydride(1.51 g, 40.1 mmol) was added. The reaction mixture was stirred at room temperature for 1 h.
  • Step-4 Synthesis of methyl 4-(1,3-dioxolan-2-yl)-1-methylcyclohexane-1-carboxylate: P 214 f 298
  • Step-7 Synthesis of 4-(ethoxymethyl)-4-methylcyclohexane-1-carbaldehyde: P 215 f 298
  • reaction mixture was allowed to warm to room temperature and stir until completion (overnight, NMR control). Afterwards, the reaction mixture was diluted with water (10 mL), and the organic layer was separated, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was subjected to HPLC purification (deionized water/HPLC-grade methanol) to give 1'-[4- (difluoromethyl)benzenesulfonyl]-4,4-difluoro-1',2'-dihydrospiro[cyclohexane-1,3'-indole] (I- 138).
  • Step-1 Synthesis of 1-benzyl 4-methyl piperidine-1,4-dicarboxylate: [0510] Triethylamine (15.7 g, 156 mmol) and benzyl carbonochloridate (23.0 g, 135 mmol) were added to a solution of methyl piperidine-4-carboxylate (15 g, 104 mmol) in dichloromethane (500 mL) at 0 °C. The mixture was stirred at room temperature for 18 h until completion (TLC control). Afterwards, the reaction mixture was washed with water (500 mL) and brine (500 mL), dried over anhydrous sodium sulfate, and filtered through silica.
  • Step-4 Synthesis of (2Z)-3-amino-3-cyclopropylprop-2-enenitrile: [0516] (tert-Butoxy)potassium (25 g, 223 mmol) was added to a stirred solution of cyclopropanecarbonitrile (10 g, 149 mmol) and acetonitrile (9.15 g, 223 mmol) in dry toluene (300 mL). The mixture was stirred at room temperature for 18 h. Afterward, the reaction mixture was poured into water (500 mL) and extracted with ethyl acetate (250 mL x 3).
  • the reaction mixture was stirred at 90 °C for 18 h, cooled to room temperature, and concentrated under reduced pressure.
  • the residue was poured into a 10% aq. solution of potassium carbonate (200 mL) and extracted with ethyl acetate (100 mL x 3).
  • the organic layer was washed with water (300 mL) and brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • reaction mixture was stirred at 80 o C for 16 h. After completion (TLC control), the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the crude product was purified by HPLC (deionized water/HPLC-grade acetonitrile, ammonia) to provide 4-(1- ⁇ 1',2'-dihydrospiro[cyclohexane-1,3'-indol]-1'-yl ⁇ ethyl)-N,N-dimethylbenzene-1-sulfonamide (I- 150).
  • HPLC deionized water/HPLC-grade acetonitrile, ammonia
  • the mixture was stirred for 5 minutes, treated with rhodium(ll) acetate dimer (0.0039 g, 0.0089 mmol), and stirred at room temperature for 12 hours.
  • The, the suspension was diluted with methanol (25 mL), treated with saturated solution of potassium carbonate (30 mL), and stirred at room temperature for 4 hours. Afterwards, the mixture was treated with water (50 mL), and the organic phase was separated and filtered through Celite. The aqueous phase was extracted with dichloromethane (30 mL x 3).
  • Example 62 – Biological Activity Example 62a For the TFEB nuclear translocation assay, HeLa wt or HeLa TRPML1 KO cells were plated at 2700 cells/well into black-walled, 384-well Cell carrier Ultra tissue culture treated plates in P 275 f 298 complete media and incubated overnight. The next day, cell s are treated for 2 hrs with compounds and incubated at 37 °C. Cells were then fixed for 30 minutes at room temperature in 4% final PF A and washed five times with 90 pL PBS.
  • PBS is aspirated from the wells and the cells are blocked with 7.5 pL blocking buffer (1:1 PBS/Odyssey block buffer containing 0.1% triton x-100 and 1% goat serum). After 30-60 minutes of block, 7.5 pL of primary anti-TFEB (rabbit) antibody is added for a final dilution of 1 :200 antibody in 15 pL blocking buffer. Plates are incubated overnight at 4 °C.
  • 7.5 pL blocking buffer (1:1 PBS/Odyssey block buffer containing 0.1% triton x-100 and 1% goat serum).
  • 7.5 pL of primary anti-TFEB (rabbit) antibody is added for a final dilution of 1 :200 antibody in 15 pL blocking buffer. Plates are incubated overnight at 4 °C.
  • Table 3 shows the activity of selected compounds of this invention in TFEB assays.
  • Compounds having an activity designated as “++++” provided an ECso of ⁇ 2.00 pM; compounds having an activity designated as “+++” provided an ECso of 2.01-8.00 pM; compounds having an activity designated as “++” provided an ECso of 8.01-9.99 pM; and compounds having an activity designated as provided an ECso of > 10.00 pM.
  • Example 62b For the Lamp1 lysosomal exocytosis assay, a human monocytic suspension cell line (THP- 1) was used. Cells in culture should be used between a density of 800e5/mL and 1.2e6/mL on the day of the assay. For each 96-well assay plate to be used, pellet 11e6 THP-1 cells at 330xg for 5 min in a 50 mL conical tube, aspirate media and resuspend in 22mLs of RPMI 1640/10% FBS media for a final cell concentration of 5e5/mL.
  • THP-1 human monocytic suspension cell line
  • the media was separated from the cell pellets in the plate.
  • the pellets were washed using 200 ⁇ L ice cold buffer (PBS Ca ++ / Mg ++ containing 2% final BSA and 80 ⁇ M final Dynasore).
  • Cells were pelleted again at 400xg-5min in a 4 °C tabletop centrifuge. Buffer was separated from cells.
  • Each well was suspended in 75uL Lamp1-PE antibody buffer (PBS Ca ++ / Mg ++ containing 2% final BSA with 80uM final Dynasore and 1:800 final dilution of Lamp1- PE labeled antibody).
  • sytox green was added (1 drop/mL buffer), and each well was mixed and incubated for an additional 15min on ice. After the 15 min sytox green incubation, 100 ⁇ L of ice-cold buffer (PBS Ca ++ / Mg ++ containing 2% final BSA and 80uM final Dynasore) was added and cells were pelleted for 5min at 400xg. The buffer was removed and each sample was resuspended in 100uL of ice-cold buffer (PBS Ca ++ / Mg ++ containing 2% final BSA and 80 ⁇ M final Dynasore).
  • FACs gating strategy FACS analyze for sytox green (A488) and Lamp1-PE (DsRed). First gate against FSC-A/ SSC-A to find non- fragmented or ‘live’ THP-1 cells. Next gate against FITC-A/FSC-A to omit sytox green positive cells. Then gate for FSC-A/FSC-H to remove any doublet cells. The last gate was a histogram P 279 f 298
  • Table 4 shows the activity of selected compounds of this invention in exocytosis assays. Compounds having an activity designated as “++++” provided an exocytosis readout of ⁇ .50 ⁇ M; compounds having an activity designated as “+++” provided an exocytosis readout of 0.51- 1.00 ⁇ M; compounds having an activity designated as “++” provided an exocytosis readout of 1.01-5.00 ⁇ M; and compounds having an activity designated as "+” provided an exocytosis readout RI ⁇ 5.01 ⁇ M Table 4 P 280 f 298

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US12667572B2 (en) 2021-01-26 2026-06-30 Schrödinger, Inc. Tricyclic compounds useful in the treatment of cancer, autoimmune and inflammatory disorders
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US12698266B2 (en) 2019-12-19 2026-08-04 Casma Therapeutics, Inc. TRPML modulators
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WO2025151402A1 (en) * 2024-01-08 2025-07-17 Libra Therapeutics, Inc. Thiazole trpml1 agonists and uses thereof

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