Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

• Lysosomal dysfunction due to mutations in the hydrolytic enzyme of lysosomal transport occur in the more than 50 genetically defined Lysosomal Storage Diseases.
• defects in lysosomal processing can have substantial effects on the function of the organelle beyond the actual enzyme that is mutated – in effect, the system can be gummed up – altering lysosomal degradation and membrane transport/trafficking, creating a positive feedback loop.
• understanding the mechanisms underlying the positive feedback loop may provide therapeutic approaches not only for LSDs, but also for common sporadic neurodegenerative diseases.
• TRPML1 A lysosome-localized cation channel, has been recently identified as a key regulator of lysosomal function and membrane trafficking processes in the lysosome.
• Human mutations of TRPML1 cause an inherited lysosomal storage disease, Mucolipidosis IV. This disease is typified by neurodegenerative effects likely driven by the accumulation of lipids and other biomaterials in the cell.
• the related channels TRPML2 and TRPML3 also regulate lysosomal function. [0004] Many reports suggest that TRPML channel activation is involved in multiple, key lysosomal functions. It can drive the translocation of the Transcription factor (TF)EB to the nucleus.
• TF Transcription factor
• TFEB regulates autophagy and lysosome biogenesis.
• Overexpression of TFEB has been reportedly induce cellular clearance in several lysosome storage diseases, including Pompe Disease, Cystinosis, multiple sulfatase deficiency, as well as common neurodegenerative diseases, including Parkinson's disease and Huntington's disease (Settieri, C., et al., Signals from the lysosome: a control centre for cellular clearance and energy metabolism. Nat Rev Mol Cell Biol, 2013.14(5): p .283-96). Therefore, activation of TRPML channels by TRPML agonists may also lead to cellular clearance in all the aforementioned diseases, providing therapeutic targets for these devastating diseases.
• TRPML activators may also be useful in other disorders.
• SUMMARY OF THE DISCLOSURE The present disclosure provides for a compound of Formula (I) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof.
• a compound of Formula (I) or a pharmaceutically acceptable salt thereof wherein W 1 is N or CR 5 ; W 2 is N or CR 6 ; R 1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each R 1 optionally substituted by 1-5 independently selected from R 7 ; R 2 is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -O-cycloalkyl, -O-heterocycloalkyl, C 1-6 alkyl, C 1-6 alkoxy, -(CH 2 ) 1-2 -cycloalkyl, -(CH 2 ) 1-2 -heterocycloalkyl, or NR a R b , each R 2 optionally substituted by 1-5 independently selected from R 8 ; R 3 is each of R 4 , R 5 , and R 6 is independently selected from the group consisting of H, hydroxy, halogen, cyano
• the disclosure provides a method of treating a disease or disorder that can be treated by modulation of TRPML, the method comprising administering to a patient in need thereof a compound described herein or a composition described herein.
• the present disclosure provides compounds (e.g., compounds of Formula (I), and subformulas (Ia), (Iaa), (Iab), (Ib), and (Ic), or compounds of Table 1, or pharmaceutically acceptable salts thereof) that are useful for disorders (e.g., polycystic kidney disease) associated with modulation of TRPML.
• compounds e.g., compounds of Formula (I), and subformulas (Ia), (Iaa), (Iab), (Ib), and (Ic), or compounds of Table 1, or pharmaceutically acceptable salts thereof
• disorders e.g., polycystic kidney disease
• TRPML TRPML
• TRPML ion channel and “TRPML channel” are used interchangeably throughout.
• a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein W 1 is N or CR 5 ; W 2 is N or CR 6 ; R 1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each R 1 optionally substituted by 1-5 independently selected from R 7 ; R 2 is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -O-cycloalkyl, -O-heterocycloalkyl, C 1-6 alkyl, C 1-6 alkoxy, -(CH 2 ) 1-2 -cycloalkyl, -(CH 2 ) 1-2 -heterocycloalkyl, or NR a R b , each R 2 optionally substituted by 1-5 independently selected from R 8 ; R 3 is each of R 4 , R 5 , and R 6 is independently selected from the group consisting of H, hydroxy, halogen
• R 1 and R 2 are not both aryl.
• W 1 is N.
• W 2 is CR 6 .
• W 1 is N and W 2 is CR 6 .
• W 1 is CR 5 and W 2 is N.
• W 1 is N and W 2 is N.
• W 1 is CR 5 and W 2 is CR 6 .
• the compound is of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein R 1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each R 1 optionally substituted by 1-5 independently selected from R 7 ; R 2 is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -O-cycloalkyl, C 1-6 alkyl, C 1-6 alkoxy, or NR a R b , each R 2 optionally substituted by 1-5 independently selected from R 8 ; R 3 is each of R 4 and R 6 is independently selected from the group consisting of H, hydroxy, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, and NR a R b ; each of R 7 and R 8 is independently selected at each occurrence from the group consisting of deuter
• R 1 and R 2 are not both aryl.
• the compound is of formula (Iaa) or a pharmaceutically acceptable salt thereof, wherein R 1 is aryl or heteroaryl, each R 1 is optionally substituted by 1-5 independently selected from R 7 ;
• R 2 is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -O-cycloalkyl, C 1-6 alkyl, C 1-6 alkoxy, or NR a R b , each R 2 optionally substituted by 1-5 independently selected from R 8 ;
• R 3 is each of R 4 and R 6 is H; each of R 7 and R 8 is independently selected at each occurrence from the group consisting of deuterium, hydroxy, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-7 cycloalkyl, and NR a R b , wherein each C 3-7 cycl
• R 1 and R 2 are not both aryl.
• R 1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each R 1 optionally substituted by 1-5 independently from R 7 ;
• R 2 is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -O-cycloalkyl, -O-heterocycloalkyl, C 1-6 alkyl, C 1-6 alkoxy, -(CH 2 ) 1-2 -cycloalkyl, -(CH 2 ) 1-2 -heterocycloalkyl, or NR a R b , each R 2 optionally substituted by 1-5 independently selected from R 8 ; each of R 7 and R 8 is independently selected at each occurrence from the group consisting of deuterium, hydroxy, halogen, cyano, C 1-6 alkyl, C 1-6 alk
• R 1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each R 1 optionally substituted by 1-5 independently selected from R 7 ;
• R 2 is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -O-cycloalkyl, -O-heterocycloalkyl, C 1-6 alkyl, C 1-6 alkoxy, -(CH 2 ) 1-2 -cycloalkyl, -(CH 2 ) 1-2 -heterocycloalkyl, or NR a R b , each R 2 optionally substituted by 1-5 independently selected from R 8 ; each of R 7 and R 8 is independently selected at each occurrence from the group consisting of deuterium, hydroxy, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-7 cycloalkyl
• the compound is of formula (Iab) or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl or pyridyl, each R 1 is optionally substituted by 1-5 independently selected from R 7 ; R 2 is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -O-cycloalkyl, C 1-6 alkyl, C 1-6 alkoxy, or NR a R b , each R 2 optionally substituted by 1-5 independently selected from R 8 ; R 3 is each of R 4 and R 6 is H; each of R 7 and R 8 is independently selected at each occurrence from the group consisting of deuterium, hydroxy, halogen, cyano, C 1-6 alkyl, and C 1-6 alkoxy; R 9 is heteroaryl optionally substituted with 1-4 independently selected from R 11 ; each R 10 is selected independently from the group consisting of C 1-6 alkyl, and C 1-6 haloalkyl, each optionally
• R 1 when R 1 is phenyl, R 2 is not aryl.
• R 1 is aryl (e.g., phenyl) optionally substituted by 1-5 independently selected from R 7 .
• R 1 is phenyl optionally substituted with 1-3 independently selected from R 7 .
• each R 7 is independently selected from H, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, or C 1-6 haloalkoxy.
• R 7 is chloro.
• R 7 is fluoro.
• R 1 is , or .
• R 1 is heteroaryl (e.g., of 5-6 ring atoms with 1, 2 or 3 ring atoms selected independently from N, O, and S) optionally substituted by 1-5 independently selected from R 7 .
• R 1 is monocyclic heteroaryl (e.g., of 5-6 ring atoms with 1, 2 or 3 ring atoms selected independently from N, O, and S) optionally substituted by 1-5 independently selected from R 7 .
• R 1 is monocyclic heteroaryl of 5-6 ring atoms with 1, 2 or 3 ring atoms selected independently from N, O, and S, wherein R 1 is optionally substituted by 1-4 independently selected from R 7 .
• R 1 is monocyclic nitrogen-containing heteroaryl of 5-6 ring atoms with 1, 2 or 3 ring heteroatoms selected from N only, wherein R 1 is optionally substituted by 1-4 independently selected from R 7 .
• R 7 is cyano.
• R 1 is , or .
• each R 8 is independently selected from deuterium, hydroxy, halogen, cyano, or C 1-6 alkoxy.
• R 2 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each R 2 optionally substituted by 1-5 independently selected from R 8 .
• R 2 is aryl (e.g., phenyl) optionally substituted by 1-5 independently selected from R 8 .
• R 2 is phenyl optionally substituted with 1-3 independently selected from R 8 .
• each R 8 is independently selected from H, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, or C 1-6 haloalkoxy.
• R 8 is fluoro.
• R 2 is aryl optionally substituted by 1-5 independently selected from R 8 . In some embodiments, R 2 is , or . [0032] In some embodiments, R 2 is heteroaryl, cycloalkyl, or heterocycloalkyl, each R 2 optionally substituted by 1-5 independently selected from R 8 . In some embodiments, R 2 is heteroaryl or heterocycloalkyl, each R 2 optionally substituted by 1-5 independently selected from R 8 . In some embodiments, R 2 is heteroaryl (e.g., of 5-6 ring atoms with 1, 2 or 3 ring atoms selected independently from N, O, and S) optionally substituted by 1-5 independently selected from R 8 .
• R 2 is heteroaryl (e.g., of 5-6 ring atoms with 1, 2 or 3 ring atoms selected independently from N, O, and S) optionally substituted by 1-5 independently selected from R 8 .
• R 2 is monocyclic heteroaryl (e.g., of 5-6 ring atoms with 1, 2 or 3 ring atoms selected independently from N, O, and S) optionally substituted by 1-5 independently selected from R 8 .
• R 2 is monocyclic heteroaryl of 5-6 ring atoms with 1, 2 or 3 ring atoms selected independently from N, O, and S, wherein R 2 is optionally substituted by 1-4 independently selected from R 8 .
• R 2 is , , , or .
• R 2 is cycloalkyl optionally substituted by 1-5 independently selected from R 8 .
• R 2 is C 3-8 cycloalkyl optionally substituted with 1-5 independently selected from R 8 . In some embodiments, R 2 is . [0035] In some embodiments, R 2 is heterocycloalkyl (e.g., of 4-6 ring atoms with 1, 2 or 3 ring atoms selected independently from N, O, and S) optionally substituted by 1-5 independently selected from R 8 . In some embodiments, R 2 is monocyclic heterocycloalkyl (e.g., of 4-6 ring atoms with 1, 2 or 3 ring atoms selected independently from N, O, and S) optionally substituted by 1-5 independently selected from R 8 .
• R 2 is monocyclic heterocycloalkyl of 4-6 ring atoms with 1, 2 or 3 ring atoms selected independently from N, O, and S, wherein R 2 is optionally substituted by 1-4 independently selected from R 8 .
• R 2 is , or .
• R 2 is C 1-6 alkyl optionally substituted by 1-5 independently selected from R 8 .
• R 2 is C 1-6 alkyl optionally substituted by 1-5 independently selected halogens.
• R 2 is Me, Et, CHF2, or CF3.
• R 2 is CH 3 .
• R 2 is CHF 2 .
• R 2 is CF 3 . In some embodiments, R 2 is , or . In some embodiments, R 2 is , , , or . In some embodiments, R 2 is . In some embodiments, R 2 is . [0037] In some embodiments, R 2 is not substituted. [0038] In some embodiments, m is 1 and n is 1. [0039] In some embodiments, p is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, p is 1 or 2. In some embodiments, p is 1. In some embodiments, p is 2. [0040] In some embodiments, each R 10 is independently selected from the group consisting of C 1-6 alkyl and C 1-6 haloalkyl.
• each R 10 is methyl.
• R 3 is .
• R 3 is , or .
• R 3 is , , , , , , or .
• R 3 is substituted by one or more substituents selected from R 10 .
• R 3 is not substituted by any additional R 10 .
• R 4 is H.
• R 5 is H.
• R 6 is H.
• R 4 and R 6 are H.
• R 4 , R 5 , and R 6 are H.
• R 9 is monocyclic heteroaryl of 5-6 ring atoms with 1, 2 or 3 ring atoms selected independently from N, O, and S, wherein R 1 is optionally substituted by 1-4 independently selected from R 11 .
• R 9 is monocyclic nitrogen-containing heteroaryl of 5-6 ring atoms with 1, 2 or 3 ring heteroatoms selected from N only, wherein R 1 is optionally substituted by 1-4 independently selected from R 11 .
• R 9 is pyridine, pyrimidine, pyrazine, pyridazine, thiazole, oxazole, pyrrole, imidazole, or pyrazole, optionally substituted by 1-4 independently selected from R 11 .
• R 11 is OCH3 or CH3.
• R 9 is [0049] In some embodiments, R 9 is [0050] In some embodiments, R 9 is . [0051] In another aspect, provided is a compound of formula (Ib) R 1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each R 1 optionally substituted by 1-5 independently selected from R 7 ; R 2 is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -O-cycloalkyl, -O-heterocycloalkyl, C 1-6 alkyl, C 1-6 alkoxy, -(CH 2 ) 1-2 -cycloalkyl, -(CH 2 ) 1-2 -heterocycloalkyl, or NR a R b , each R 2 optionally substituted by 1-5 independently selected from R 8 ; each of R 7 and R 8 is independently selected at each occurrence from
• R 1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each R 1 optionally substituted by 1-5 independently selected from R 7 ;
• R 2 is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -O-cycloalkyl, -O-heterocycloalkyl, C 1-6 alkyl, C 1-6 alkoxy, -(CH 2 ) 1-2 -cycloalkyl, -(CH 2 ) 1-2 -heterocycloalkyl, or NR a R b , each R 2 optionally substituted by 1-5 independently selected from R 8 ; each of R 7 and R 8 is independently selected at each occurrence from the group consisting of deuterium, hydroxy, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-7 cycloalkyl
• the compound achieves at least 50% of the maximal current obtained with 30 ⁇ M ML-SA1 in a patch clamp assay for a TRPML and has an EC50 less than 1 ⁇ M. In some embodiments, the compound achieves at least 50% of the maximal current obtained with 30 ⁇ M ML-SA1 in a patch clamp assay for TRPML1 and has an EC 50 less than 1 ⁇ M.
• the compound achieves a maximal current obtained with 30 ⁇ M ML-SA1 in a patch clamp assay for TRPML1 which is at least 10 fold the maximal current achieved for any other TRPML.
• pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound selected from the compounds disclosed in the specification or claims, or a pharmaceutically acceptable salt thereof.
• the compound is a compound identified in Table 1 below or a pharmaceutically acceptable salt thereof. Table 1.
• Deuterated Compounds are deuterium-enriched.
• Deuterium (D or 2 H) is a stable, non-radioactive isotope of hydrogen and has an atomic weight of 2.0144. Hydrogen naturally occurs as a mixture of the isotopes 1 H (hydrogen or protium), D ( 2 H or deuterium), and T ( 3 H or tritium). The natural abundance of deuterium is 0.015%.
• isotopic enrichment factor means the ratio between the isotopic abundance of D at the specified position in a compound of this invention and the naturally occurring abundance of that isotope.
• a compound herein e.g., a compound of Formula I, Ia, Iaa, Iab, Ib, or Ic
• deuterium-enrichment e.g., a compound of Formula I, Ia, Iaa, Iab, Ib, or Ic
• deuterium-enrichment e.g., a compound of Formula I, Ia, Iab, Ib, or Ic
• the percentage of enrichment refers to the percentage of deuterium present in the compound.
• a compound of this invention has an isotopic enrichment factor for each deuterium present at a site designated at a potential site of deuteration on the compound of at least 3500 (52.5.% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6633.3 (99.5% deuterium incorporation). It is understood that the isotopic enrichment factor of each deuterium present at a site designated as a site of deuteration is independent of other deuterated sites.
• the natural abundance of deuterium is about 0.015%, a small percentage of naturally occurring compounds of herein (e.g., a compound of Formula I, Ia, Iaa, Iab, Ib, or Ic) would be expected to have one naturally occurring compound with one deuterium present.
• the compounds herein comprise an amount of deuterium-enrichment that is more than the amount of deuterium-enrichment present in naturally occurring compounds herein (e.g., a compound of Formula I, Ia, Iaa, Iab, Ib, or Ic)
• All percentages given for the amount of deuterium present are mole percentages. It can be difficult in the laboratory to achieve 100% deuteration at any one site of a lab scale amount of compound (e.g., milligram or greater).
• Deuterium-enriched can be achieved by either exchanging protons with deuterium or by synthesizing the molecule with enriched starting materials.
• a method of modulating TRPML ion channels comprising administering to a patient in need thereof a compound described herein (e.g., a compound of Formula I, Ia, Iaa, Iab, Ib, or Ic) or pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives thereof, or a composition described herein.
• a compound described herein e.g., a compound of Formula I, Ia, Iaa, Iab, Ib, or Ic
• pharmaceutically acceptable salts solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives thereof, or a composition described herein.
• a method of treating a disease or disorder that can be treated by modulation of TRPML ion channels comprising administering to a patient in need thereof a compound described herein (e.g., a compound of Formula I, Ia, Iaa, Iab, Ib, or Ic) or pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives thereof, or a composition described herein.
• a compound described herein e.g., a compound of Formula I, Ia, Iaa, Iab, Ib, or Ic
• pharmaceutically acceptable salts solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives thereof, or a composition described herein.
• a method of treating a disease or disorder that can be treated by activation of TRPML ion channels comprising administering to a patient in need thereof a compound described herein (e.g., a compound of Formula I, Ia, Iaa, Iab, Ib, or Ic) or pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives thereof, or a composition described herein.
• a compound described herein e.g., a compound of Formula I, Ia, Iaa, Iab, Ib, or Ic
• pharmaceutically acceptable salts solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives thereof, or a composition described herein.
• a method of treating a disease or disorder that can be treated by activation of TRPML1 comprising administering to a patient in need thereof a compound described herein (e.g., a compound of Formula I, Ia, Iaa, Iab, Ib, or Ic) or pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives thereof, or a composition described herein.
• a compound described herein e.g., a compound of Formula I, Ia, Iaa, Iab, Ib, or Ic
• pharmaceutically acceptable salts solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives thereof, or a composition described herein.
• the TRPML ion channel is TRPML1. In some embodiments, the TRPML ion channel is TRPML2. In some embodiments, the TRPML ion channel is TRPML3. [0072] In some embodiments, the compound is a modulator of TRPML1. In some embodiments, the compound is a modulator of TRPML2. In some embodiments, the compound is a modulator of TRPML3.
• modulation of the TRPML ion channel comprises activation of the ion channel.
• the disease or disorder is a ciliopathy (e.g., polycystic kidney disease).
• ciliopathies include, but not limited to, polycystic kidney disease, pancreatic cysts in polycystic kidney disease, Bardet-Biedl syndrome, nephronophthisis, Joubert Syndrome, Mecke-Gruber Syndrome, oral-facial-digital syndrome, Senior Loken Syndrome, Birt-Hogg-Dube syndrome, Leber’s congenital amaurosis, Alstrom syndrome, Jeune asphyxiating thoracic dystrophy, Ellis van Creveld syndrome, Sensenbrenner syndrome, and primary ciliary dyskinesia.
• a method of treating a disorder which can be treated by modulation of lysosomes comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition of the disclosure or a compound of the disclosure.
• a muscular disease e.g., muscular dystrophy
• a disease related to aging e.g., photo aging of the skin
• macular degeneration e.g., Stargardt’s or age-
• the disorder is a ciliopathy.
• the ciliopathy is selected from the group consisting of polycystic kidney disease, pancreatic cysts in polycystic kidney disease, Bardet-Biedl syndrome, nephronophthisis, Joubert Syndrome, Mecke-Gruber Syndrome, oral-facial-digital syndrome, Senior Loken Syndrome, Birt-Hogg-Dube syndrome, Leber’s congenital amaurosis, Alstrom syndrome, Jeune asphyxiating thoracic dystrophy, Ellis van Creveld syndrome, Sensenbrenner syndrome, and primary ciliary dyskinesia.
• the disorder is polycystic kidney disease. In some embodiments, the disorder is autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, or pancreatic cysts associated with autosomal dominant polycystic kidney disease. In some embodiments, the disorder is autosomal dominant polycystic kidney disease. In some embodiments, the disorder is a neurodegenerative disorder.
• the neurodegenerative disorder is selected from the group consisting of Parkinson’s disease, GBA-Parkinson’s disease, LRRK2 Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, progressive supranuclear palsy, frontotemporal dementia, FTDP-17, corticobasal degeneration, Lewy body dementia, Pick’s disease, and multi system atrophy.
• the disorder is a lysosomal storage disorder.
• the lysosomal storage disorder is selected from the group consisting of Niemann-Pick disease, Gaucher’s disease, neuronopathic Gaucher’s disease, sphingolipidoses, Farber disease, Krabbe disease, Galactosialidosis, gangliosidoses, Gaucher Disease, Lysosomal acid lipase deficiency, sulfatidoses, mucopolysaccharidoses, mucolipidoses, lipidoses, and oligosaccharidoses.
• the lysosomal storage disorder is selected from the group consisting of sphingolipidoses, Farber disease, Krabbe disease, Galactosialidosis, Fabry disease, Schindler disease, beta-galactosidase disorder, GM1 gangliosidosis, GM2 gangliosidosis AB variant, GM2 gangliosidosis activator deficiency, Sandhoff disease, Tay-Sachs disease, Gaucher disease, lysosomal acid lipase deficiency, Niemann-Pick disease, metachromatic leukodystrophy, Saposin B deficiency, multiple sulfatase deficiency, Hurler syndrome, Scheie sundrome, Hurler- Scheie syndrome, Hunter syndrome, Sanfilippo syndrome, Morquio syndrome, Maroteaux-Lamy syndrome, Sly syndrome, hyaluronidase deficiency, sialidosis, I-cell disease, pseudo-H
• the lysosomal storage disorder is selected from the group consisting of Niemann-Pick disease, Gaucher’s disease, and neuronopathic Gaucher’s disease.
• the disorder is a lysosomal transport disease selected from the group consisting of cystinosis, pycnodysostosis, Salla disease, sialic acid storage disease, and infantile free sialic acid storage disease.
• the disorder is a glycogen storage disease selected from the group consisting of Pompe disease and Danon disease.
• a method of treating a ciliopathy disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound capable of modulating TRPML, or a therapeutically effective amount of a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient.
• the compound is selected from the compounds disclosed in the specification.
• the ciliopathy is selected from the group consisting of polycystic kidney disease, pancreatic cysts in polycystic kidney disease, Bardet-Biedl syndrome, nephronophthisis, Joubert Syndrome, Meckel-Gruber Syndrome, oral-facial-digital syndrome, Senior Loken Syndrome, Birt-Hogg-Dube syndrome, Leber’s congenital amaurosis, Alstrom syndrome, Jeune asphyxiating thoracic dystrophy, Ellis van Creveld syndrome, Sensenbrenner syndrome, and primary ciliary dyskinesia.
• the disorder is polycystic kidney disease [0090] In some embodiments, the disorder is autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, or pancreatic cysts associated with autosomal dominant polycystic kidney disease. [0091] In some embodiments, the disorder is autosomal dominant polycystic kidney disease. [0092] In some embodiments, the method further comprises the use of a second therapeutic agent. [0093] In some embodiments, the method is to treat a ciliopathy.
• the second therapeutic agent is selected from the group consisting of an mTOR inhibitor, V2 receptor antagonist, tyrosine kinase inhibitor, somatostatin analog, glucosylceramide synthase inhibitor, microRNA-17 inhibitor, siRNA against p53, KEAP1-Nrf2 activator, xanthine oxidase inhibitor, PPAR ⁇ agonist, metformin, and beta hydroxybutyrate.
• the second therapeutic agent is selected from the group consisting of tolvaptan, lixivaptan, mozavaptan, satavaptan, sirolimus, tacrolimus, everolimus, bosutinib, tesavatinib, imatinib, gefitinib, erlotinib, dasatinib, octreotide, pasireotide, venglustat, eliglustat, miglustat, microRNA-17 inhibitor, bardoxolone methyl, allopurinol, oxypurinol, pioglitazone, rosiglitazone, lobeglitazone, metformin, and beta hydroxybutyrate.
• the second therapeutic agent is selected from the group consisting of an immunomodulator, a calcineurin inhibitor, a renin angiotensin aldosterone system inhibitor, an antiproliferative agent, an alkylating agent, a corticosteroid, an angiotensin converting enzyme inhibitor, an adrenocorticotropic hormone stimulant, an angiotensin receptor blocker, a sodium- glucose transport protein 2 inhibitor, a dual sodium-glucose transport protein 1/2 inhibitor, a nuclear Factor- 1 (erythroid-derived 2)-like 2 agonist, a chemokine receptor 2 inhibitor, a chemokine receptor 5 inhibitor, an endothelin 1 receptor antagonist, a beta blocker, a mineralocorticoid receptor antagonist, a loop or thiazide diuretic, a calcium channel blocker, a statin, a short- intermediate or long-acting insulin, a dipeptidyl peptidase 4 inhibitor,
• L-DOPA dopamine agonists
• dopamine agonists e.g. bromocriptine, cabergoline, pergolide, pramipexole and apomorphine
• MAO-B inhibitors e.g. rasagiline and selegiline
• anticholinergics e.g. orphenadrine, procyclidine and trihexyphenidyl
• enhancers of b-glucocerebrosidase activity e.g. ambroxol and afegostat
• amantadine and agents capable of treating Alzheimer’s (e.g., acetylcholinesterase inhibitors such as tacrine, rivastigmine, galantamine, donepezil, and NMDA receptor antagonists such as memantine).
• the present disclosure further provides pharmaceutical compositions comprising a compound provided herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
• the present disclosure further provides methods of modulating TRPML in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof.
• the present disclosure further provides a method of treating a disease or disorder in a subject, the method comprising: (a) detecting a disease or disorder associated with TRPML; and (b) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof.
• exemplary compounds of Formula (I) or (II) include the compounds described in Table 1 and in the Examples, as well as pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof.
• the present disclosure provides compounds useful for treating ciliopathies and related diseases.
• Compounds that modulate TRPML channels may be useful in the prophylaxis and treatment of any of the foregoing injuries, diseases, disorders, or conditions. In addition to in vitro assays of the activity of these compounds, their efficacy can be readily tested in one or more animal models.
• This disclosure is not limited in its application to the details of the methods and compositions described herein.
• compositions comprising a compound provided herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. Also provided herein are methods of modulating TRPML channels in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof.
• compositions containing compounds described herein such as a compound of Formula I, Ia, Iaa, Iab, Ib, or Ic, or pharmaceutically acceptable salt thereof can be used to treat or ameliorate a disorder described herein, for example, a ciliopathy.
• the amount and concentration of compounds of Formula I, Ia, Iaa, Iab, Ib, or Ic in the pharmaceutical compositions, as well as the quantity of the pharmaceutical composition administered to a subject, can be selected based on clinically relevant factors, such as medically relevant characteristics of the subject (e.g., age, weight, gender, other medical conditions, and the like), the solubility of compounds in the pharmaceutical compositions, the potency and activity of the compounds, and the manner of administration of the pharmaceutical compositions.
• medically relevant characteristics of the subject e.g., age, weight, gender, other medical conditions, and the like
• solubility of compounds in the pharmaceutical compositions e.g., the solubility of compounds in the pharmaceutical compositions
• the potency and activity of the compounds e.g., the solubility of compounds in the pharmaceutical compositions
• the potency and activity of the compounds e.g., the solubility of compounds in the pharmaceutical compositions
• the manner of administration of the pharmaceutical compositions e.g., administration of the pharmaceutical compositions
• a compound disclosed herein While it is possible for a compound disclosed herein to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation, where the compound is combined with one or more pharmaceutically acceptable diluents, excipients or carriers.
• the compounds according to the disclosure may be formulated for administration in any convenient way for use in human or veterinary medicine.
• the compound included in the pharmaceutical preparation may be active itself, or may be a prodrug, e.g., capable of being converted to an active compound in a physiological setting.
• the compounds of the present disclosure which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present disclosure, are formulated into pharmaceutically acceptable dosage forms such as described below or by other conventional methods known to those of skill in the art.
• pharmaceutically acceptable compositions comprising a therapeutically effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
• compositions of the present disclosure may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), lozenges, dragees, capsules, pills, tablets (e.g., those targeted for buccal, sublingual, and systemic absorption), boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; (8) transmucosally; (9) nasally
• oral administration for example,
• compounds can be implanted into a patient or injected using a drug delivery system. See, for example, Urquhart, et al., (1994) Ann Rev Pharmacol Toxicol 24:199-236; Lewis, ed. “Controlled Release of Pesticides and Pharmaceuticals” (Plenum Press, New York, 1981); U.S. Patent No.3,773,919; and U.S. Patent No.353,270,960.
• terapéuticaally effective amount means that amount of a compound, material, or composition comprising a compound of the present disclosure, which is effective for producing some desired therapeutic effect, e.g., by modulating EHMT1 or EHMT2, in at least a sub-population of cells in an animal and thereby blocking the biological consequences of that function in the treated cells, at a reasonable benefit/risk ratio applicable to any medical treatment.
• systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
• pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms 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, solvent or encapsulating material, involved in carrying or transporting the subject antagonists from one organ, or portion of the body, to another organ, or portion of the body.
• a pharmaceutically acceptable material, composition or vehicle such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject antagonists from one organ, or portion of the body, to another organ, or portion of the body.
• 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: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
• pharmaceutically acceptable salt is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
• base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
• pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
• acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
• Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
• inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like,
• salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge et al, Journal of Pharmaceutical Science 66: 1-19 (1977)).
• Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
• These salts may be prepared by methods known to those skilled in the art.
• Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for the present disclosure.
• wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
• antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
• water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
• oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
• Formulations of the present disclosure include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
• the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
• the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
• the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.
• Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present disclosure with the carrier and, optionally, one or more accessory ingredients.
• the formulations are prepared by uniformly and intimately bringing into association a compound of the present disclosure with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
• Formulations of the disclosure suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present disclosure as an active ingredient.
• lozenges using a flavored basis, usually sucrose and acacia or tragacanth
• a compound of the present disclosure may also be administered as a bolus, electuary or paste.
• the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerator
• the pharmaceutical compositions may also comprise buffering agents.
• Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
• a tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
• Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
• the tablets, and other solid dosage forms of the pharmaceutical compositions of the present disclosure may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
• compositions may be sterilized by, for example, filtration through a bacteria- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
• These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
• embedding compositions that can be used include polymeric substances and waxes.
• the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
• Liquid dosage forms for oral administration of the compounds of the disclosure include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.
• the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
• inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents
• the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
• adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
• Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
• Formulations of the pharmaceutical compositions of the disclosure for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the disclosure with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
• suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
• compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device.
• compositions can be formulated for delivery via a dialysis port.
• Ophthalmic formulations, eye ointments, powders, solutions and the like are also contemplated as being within the scope of this disclosure.
• Exemplary modes of administration include, but are not limited to, injection, infusion, instillation, inhalation, or ingestion.
• “Injection” includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intraventricular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, sub capsular, subarachnoid, intraspinal, intracerebro spinal, and intrasternal injection and infusion.
• the compositions are administered by intravenous infusion or injection.
• parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
• compositions of this disclosure suitable for parenteral administration comprise one or more compounds of the disclosure in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
• aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
• polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
• vegetable oils such as olive oil
• injectable organic esters such as ethyl oleate.
• Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
• These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents.
• microorganisms Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin. [0132] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility.
• Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides).
• Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.
• the compounds of the present disclosure When the compounds of the present disclosure are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
• a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
• the addition of the active compound of the disclosure to animal feed is preferably accomplished by preparing an appropriate feed premix containing the active compound in an effective amount and incorporating the premix into the complete ration. Alternatively, an intermediate concentrate or feed supplement containing the active ingredient can be blended into the feed.
• a subject can be one who has been previously diagnosed with or identified as suffering from or having a neurodegenerative disease or disorder, a disease or disorder associated with cancer, a disease or disorder associated with viral infection, or one or more complications related to such diseases or disorders but need not have already undergone treatment.
• Dosages [0139] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this disclosure may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
• the desired dose can be administered at one time or divided into subdoses, e.g., 2-4 subdoses and administered over a period of time, e.g., at appropriate intervals through the day or other appropriate schedule.
• Such sub-doses can be administered as unit dosage forms.
• administration is chronic, e.g., one or more doses daily over a period of weeks or months.
• dosing schedules are administration daily, twice daily, three times daily or four or more times daily over a period of 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months or more.
• the present disclosure contemplates formulation of the subject compounds in any of the aforementioned pharmaceutical compositions and preparations.
• the present disclosure contemplates administration via any of the foregoing routes of administration.
• One of skill in the art can select the appropriate formulation and route of administration based on the condition being treated and the overall health, age, and size of the patient being treated.
• Selected Chemical Definitions [0150]
• substituents of compounds of the disclosure are disclosed in groups or in ranges. It is specifically intended that the disclosure include each and every individual subcombination of the members of such groups and ranges.
• C 1-6 alkyl is specifically intended to individually disclose methyl, ethyl, propyl, butyl, pentyl, and hexyl
• each variable can be a different moiety selected from the Markush group defining the variable.
• the two R groups can represent different moieties selected from the Markush group defined for R.
• substituted means that any one or more hydrogens on the designated atom, usually a carbon, oxygen, or nitrogen atom, is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
• 2 hydrogens on the atom are replaced.
• alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
• C1-4 alkyl is intended to include C 1 , C 2 , C 3 , and C 4 .
• C 1-6 alkyl is intended to include C 1 C 2 , C 3 , C 4 , C 5 , and C 6 alkyl groups and
• C 1-8 alkyl is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , and C 8 .
• alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, s- butyl, t-butyl, n-pentyl, s-pentyl, n- hexyl, n-heptyl, and n-octyl.
• alkenyl is intended to include hydrocarbon chains of either straight or branched configuration and one or more unsaturated carbon-carbon bond that can occur in any stable point along the chain, such as ethenyl and propenyl.
• alkylene is intended to include moieties which are diradicals, i.e. , having two points of attachment.
• a non-limiting example of such an alkylene moiety that is a diradical is -CH 2 CH 2 -, i.e., a C 2 alkyl group that is covalently bonded via each terminal carbon atom to the remainder of the molecule.
• alkylene diradicals are also known as "alkylenyl" radicals.
• alkylene groups include 1 to 9 carbon atoms (for example, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms).
• alkylene groups include, but are not limited to, methylene, ethylene, n- propylene, iso-propylene, n-butylene, iso-butylene, sec-butylene, tert-butylene, n- pentylene, iso- pentylene, sec-pentylene and neo-pentylene.
• cycloalkyl is intended to include saturated or unsaturated nonaromatic ring groups, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
• C 3 - 8 cycloalkyl is intended to include C 3 , C 4 , C 5 , C 6 , C 7 , and C 8 cycloalkyl groups.
• Cycloalkyls may include multiple spiro- or fused or bridged rings.
• cycloalkyl can include, but is not limited to, spiro butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl groups, bicyclo butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl groups, adamantyl groups, and norbornyl groups.
• heterocycloalkyl refers to a saturated or unsaturated nonaromatic 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, or Se), unless specified otherwise.
• a heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring- forming atom of the fused aromatic ring.
• the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 4-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members.
• heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3, 6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa- 5- azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-ox
• amine or “amino” refers to unsubstituted - H 2 unless otherwise specified.
• halo or “halogen” refers to fluoro, chloro, bromo, and iodo substituents.
• haloalkyl examples include, but are not limited to, trifluoromethyl, trichlorom ethyl, pentafluoroethyl, and pentachloroethyl.
• haloalkoxy refers to an alkoxy group, as defined herein, which is substituted one or more halogen.
• haloalkoxy groups include, but are not limited to, tnfluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.
• alkoxyl refers to an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge.
• C 1-6 alkoxy is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , and C 6 alkoxy groups.
• C 1-8 alkoxy is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , and C 8 alkoxy groups.
• alkoxy examples include, but are not limited to, methoxy, ethoxy, n-propoxy, i- propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, s-pentoxy, n- heptoxy, and n- octoxy.
• aryl includes groups with aromaticity, including “conjugated,” or multicyclic systems with at least one aromatic ring and do not contain any heteroatom in the ring structure.
• Aryl may be monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings).
• C n-m aryl refers to an aryl group having from n to m ring carbon atoms. In some embodiments, aryl groups have from 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl.
• aromatic heterocycle As used herein, the terms "aromatic heterocycle,” “aromatic heterocyclic” or “heteroaryl” ring are intended to mean a stable 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic or bicyclic aromatic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, independently selected from nitrogen, oxygen, and sulfur.
• the second ring can also be fused or bridged as defined above for heterocycles.
• the nitrogen atom can be substituted or unsubstituted (i.e., N or R wherein R is H or another substituent, as defined).
• aromatic heterocycles, aromatic heterocyclics or heteroaryls include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, benzooxadiazoly, carbazolyl, 4aH- carbazolyl, carbolinyl, cinnolinyl, furazanyl, imidazolyl, imidazolonyl, lH-indazolyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindo
• hydroxyalkyl means an alkyl group as defined above, where the alkyl group is substituted with one or more OH groups. Examples of hydroxyalkyl groups include HO-CH 2 -, HO-CH 2 -CH 2 - and CH 3 -CH(OH)-.
• cyano as used herein means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, i.e., C ⁇ N.
• the phrase "pharmaceutically acceptable” refers to those compounds or tautomers thereof, or salts thereof, materials, compositions, and/or dosage forms 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 salts refer to derivatives of the disclosed compounds or tautomers thereof, wherein the parent compound or a tautomer thereof, is modified by making of the acid or base salts thereof of the parent compound or a tautomer thereof.
• Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
• the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound, or a tautomer thereof, formed, for example, from non- toxic inorganic or organic acids.
• such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxy ethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic,
• the pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound or a tautomer thereof that contains a basic or acidic moiety by conventional chemical methods.
• such pharmaceutically acceptable salts can be prepared by reacting the free acid or base forms of these compounds or tautomers thereof with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
• stable compound and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
• treating refers to administering a compound or pharmaceutical composition as provided herein for therapeutic purposes.
• terapéutica treatment refers to administering treatment to a patient already suffering from a disease thus causing a therapeutically beneficial effect, such as ameliorating existing symptoms, ameliorating the underlying metabolic causes of symptoms, postponing, or preventing the further development of a disorder, and/or reducing the severity of symptoms that will or are expected to develop.
• unsaturated refers to compounds having at least one degree of unsaturation (e.g., at least one multiple bond) and includes partially and fully unsaturated compounds.
• an effective amount refers to an amount of a compound or a pharmaceutically acceptable salt of the compound or tautomer (including combinations of compounds and/or tautomers thereof, and/or pharmaceutically acceptable salts of said compound or tautomer) of the present disclosure that is effective when administered alone or in combination as an antimicrobial agent.
• an effective amount refers to an amount of the compound or tautomer thereof, or a pharmaceutically acceptable salt said compound or tautomer that is present in a composition, a formulation given to a recipient patient or subject sufficient to elicit biological activity.
• compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present disclosure also consist essentially of, or consist of, the recited components, and that the processes of the present disclosure also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions are immaterial so long as the disclosure remains operable. Moreover, two or more steps or actions can be conducted simultaneously.
• Contemplated equivalents of the compounds described above include compounds which otherwise correspond thereto, and which have the same general properties thereof (e.g., the ability to modulate TRPML), wherein one or more simple variations of substituents are made which do not adversely affect the efficacy of the compound.
• the compounds of the present disclosure may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are in themselves known, but are not mentioned here.
• the articles “a” and “an” refer to one or to more than one (e.g., to at least one) of the grammatical object of the article.
• “About” and “approximately” shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given value or range of values.
• treat refers to the application or administration of a compound, alone or in combination with, an additional agent to a subject, e.g., a subject who has a disorder (e.g., a disorder as described herein), a symptom of a disorder, or a predisposition toward a disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disorder.
• a subject is intended to include human and non-human animals. Exemplary human subjects include a human subject having a disorder, e.g., a disorder described herein.
• non-human animals of the disclosure includes all vertebrates, e.g., non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domesticated and/or agriculturally useful animals, e.g., sheep, dog, cat, cow, pig, etc.
• antagonist and “inhibitor” are used interchangeably to refer to an agent that decreases or suppresses a biological activity.
• activator and “agonist” are used interchangeably to refer to an agent that increases or initiates a biological activity.
• hydrate refers to a compound formed by the union of water with the parent compound.
• preventing when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition.
• a condition such as a local recurrence (e.g., pain)
• a disease such as cancer
• a syndrome complex such as heart failure or any other medical condition
• prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and/or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and/or clinically significant amount.
• Prevention of an infection includes, for example, reducing the number of diagnoses of the infection in a treated population versus an untreated control population, and/or delaying the onset of symptoms of the infection in a treated population versus an untreated control population.
• Prevention of pain includes, for example, reducing the magnitude of, or alternatively delaying, pain sensations experienced by subjects in a treated population versus an untreated control population.
• solvate refers to a compound formed by solvation (e.g., a compound formed by the combination of solvent molecules with molecules or ions of the solute).
• a pharmaceutical preparation suitable for use in a human patient, or for veterinary use comprising an effective amount of a compound of the formulae of the disclosure (or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt), and one or more pharmaceutically acceptable excipients.
• the disclosure further contemplates the use of compounds of the formulae of the disclosure in the manufacture of a medicament or pharmaceutical preparation to treat or reduce the symptoms of any of the diseases or conditions provided in the specification.
• the compounds of the formulae of the disclosurefor use in treating a particular disease or condition can be formulated for administration via a route appropriate for the particular disease or condition.
• Compounds of the formulae of the disclosure can be administered alone or in combination with another therapeutic agent.
• the compounds of the formulae of the disclosure can be administered conjointly with one or more of an agent for treating polycystic kidney disease, etc.
• Compounds of the formulae of the disclosure can be administered topically, orally, transdermally, rectally, vaginally, parentally, intranasally, intrapulmonary, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intraorbitally, intracardiacly, intradermally, intraperitoneally, transtracheally, subcutaneously, subcuticularly, intraarticularly, subcapsularly, subarachnoidly, intraspinally, intrasternally, sublingually, or by inhalation.
• compounds of Formula I, Ia, Iaa, Iab, Ib, or Ic can be administered topically.
• compounds of Formula I, Ia, Iaa, Iab, Ib, or Ic can be administered orally.
• compounds of Formula I, Ia, Iaa, Iab, Ib, or Ic can be administered parentally.
• Compounds of Formula I, Ia, Iaa, Iab, Ib, or Ic include molecules having an aqueous solubility suitable for oral or parenteral (e.g., intravenous) administration leading to or resulting in the treatment of a disorder described herein, for example the treatment of pain.
• the compound is formulated into a composition suitable for oral administration.
• a compound of Formula I, Ia, Iaa, Iab, Ib, or Ic can be administered as part of an oral or parenteral (e.g., intravenous) pharmaceutical composition to treat a disorder described herein in a therapeutically effective manner.
• an oral or parenteral (e.g., intravenous) pharmaceutical composition to treat a disorder described herein in a therapeutically effective manner.
• Certain compounds disclosed herein may exist in particular geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis- and trans- isomers, R- and S-enantiomers, diastereomers, (d)-isomers, (l)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the disclosure.
• the disclosure includes racemic mixtures, enantiomerically enriched mixtures, and substantially enantiomerically or diastereomerically pure compounds.
• the composition can contain, e.g., more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, more than 95%, or more than 99% of a single enantiomer or diastereomer. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this disclosure.
• the “enantiomeric excess” or “% enantiomeric excess” of a composition can be calculated using the equation shown below.
• a composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an enantiomeric excess of 80%.
• the “diastereomeric excess” or “% diastereomeric excess” of a composition can be calculated using the equation shown below.
• a composition containing 90% of one diastereomer and 10% of the other diastereomer is said to have a diastereomeric excess of 80%.
• Certain compounds disclosed herein can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds disclosed herein may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.
• LCMS Liquid Chromatography/Mass Spectrometry
• tert-Butyl (2R,5S)-4-(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate [0222] To a solution of tert-butyl (2R,5S)-4-(5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-2,5-dimethylpiperazine-1-carboxylate (20 g, 37 mmol) in THF (200 mL) was added TBAF (180 mL, 1.0 M in THF). After 3 h, the reaction was diluted with water and extracted twice with EtOAc.
• tert-Butyl (2R,5S)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (1.1 g, 2.1 mmol) in THF (20 mL) was added TBAF (11 mL, 1.0 M in THF).
• tert-Butyl (2R,5S)-4-(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate [0230] To a solution of tert-butyl (2R,5S)-4-(5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-2,5-dimethylpiperazine-1-carboxylate (20 g, 37 mmol) in THF (200 mL) was added TBAF (180 mL, 1.0 M in THF). After stirring at room temperature for 3 h, the reaction was diluted with water and extracted twice with EtOAc.
• the resulting mixture was heated at 50°C for 2 h. After cooling to room temperature, the reaction was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated.
• TRPML1 Assay Cell Culture [0256] HEK-293 Trex cells were stably transfected with a construct consisting of the human coding sequence for TRPML1 cloned into the tet-inducible plasmid pCDNA5 T/O. Mutations were introduced into the TRPML1 sequence to facilitate expression on the cell surface (Silvia Vergarajauregui, Rosa Puertollano Traffic.2006 Mar; 7(3): 337–353). Briefly, the cells are cultured in 150 mm round tissue culture dishes containing 20 mL of media.
• Dye Loading [0257] The day of the experiment cells are lifted from the plates as above and collected by centrifugation. The cells are then suspended in dye loading buffer consisting of Ringer’s solution supplemented with 0.1% Pluronic Acid and 1 micromolar Fluo4-AM dye. Cells are loaded for ⁇ 60 minutes in the dark with occasional mixing.
• the cells are collected by centrifugation, the loading media aspirated, and the cells resuspended in 25 mL Ringer’s solution and incubated ⁇ 60 minutes in the dark. The cells are again collected by centrifugation, rinsed in Ringer’s Solution and resuspended to 0.2 x10 ⁇ 6 cells / mL in modified Ringer’s solution containing 10 mM calcium.
• Compound Assay Plates [0258] Compounds are dissolved to a concentration of 10 millimolar with DMSO. Compound plates are created by dispensing compounds into 384 well black wall clear bottom plates (Greiner 781091). Positive and negative controls are included on each plate.
• TRPML2 and TRPML3 Assays [0261] Assays for TRPML2 and TRPML3 were performed as above for TRPML1, by substituting the appropriate TRPML2 or TRPML3 subtype for the TRPML1. [0262] EC50 values were calculated using a non-linear regression of Prism. The EC50 determined for each compound using the assay is summarized in Table 3 below. The compound numbers correspond to those shown in Table 1.

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