WO2025006723A2 - Agonistes de tmem175, compositions et procédés d'utilisation - Google Patents

Agonistes de tmem175, compositions et procédés d'utilisation Download PDF

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WO2025006723A2
WO2025006723A2 PCT/US2024/035781 US2024035781W WO2025006723A2 WO 2025006723 A2 WO2025006723 A2 WO 2025006723A2 US 2024035781 W US2024035781 W US 2024035781W WO 2025006723 A2 WO2025006723 A2 WO 2025006723A2
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WO2025006723A3 (fr
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Rajesh R. Iyengar
Thomas Wai-Ho Lee
Darby R. Schmidt
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Caraway Therapeutics Inc
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Caraway Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—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
    • 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
    • C07D471/04—Ortho-condensed systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • TMEM175 AGONISTS, COMPOSITIONS, AND METHODS OF USE CROSS-REFERENCE TO RELATED APPLICATIONS [0001]
  • This application claims the benefit of priority to U.S. Provisional Application Nos. 63/524,082, filed June 29, 2023, and 63/524,085, filed June 29, 2023, the contents of each of which are hereby incorporated by reference in their entirety.
  • TECHNICAL FIELD [0002] The present disclosure relates to compounds and compositions which activate TMEM175 and are useful for the treatment or prevention of a variety of diseases and disorders, such as neurodegenerative diseases and lysosomal storage diseases.
  • Lysosome dysfunction is a key component in a variety of diseases and disorders such as neurodegenerative diseases and lysosomal storage diseases (e.g., Parkinson’s Disease (PD)) (Robak, L. A. et al., Brain J. Neurol.2017, Vol.140, pp.3191–3203; Nguyen, M. et al., Trends Neurosci.2019, Vol.42, pp.140–149).
  • PD Parkinson’s Disease
  • mutations in the lysosomal TMEM175 gene are prevalent and significant risk factors for PD (Jinn, S. et al., Hum. Mol. Genet.2019, Vol.28, pp.3244-54; Krohn, L.
  • TMEM175 encodes a lysosomal potassium and proton ion channel with unique structure, biophysical properties and pharmacology (see, e.g., Cang, C., et al., Cell 2015, Vol. 162, pp.1101–1112).
  • the 12-transmembrane span architecture and lack of canonical ion selectivity filter in this channel, as well as its higher permeability to cesium ions relative to potassium ions and its ability to permeate protons make TMEM175 distinct from any known ion channel (Brunner, J. D. et al., bioRxiv 2018).
  • the TMEM175 M393T allele is present in 14% of the general population and 25% of PD patients (Paul, K. C., et al., JAMA Neurol.2018, Vol.75, pp.360–366).
  • This mutation significantly alters age-of-onset in PD with a risk factor of 1.2 years per allele and provides the second greatest genetic risk factor for age of onset in the idiopathic population following GBA (Lill, C. M. et al., Mov. Disord. Off. J. Mov. Disord. Soc.2015, Vol.30, pp.847–850; Iwaki, H. et al., Neurol. Genet.2019, Vol.5, e348).
  • M393T allele also showed a significant correlation with reduced glucocerebrosidase (GCase) activity in PD patients.
  • M393T heterozygotes showed a 6.2% decrease in GCase activity compared to wild-type carriers, while homozygotes showed a 12.4% decrease (Krohn, L. et al.2019). These values were corrected for GBA or LRRK2 mutations, emphasizing the deleterious effect of the M393T allele on enzyme activity. Additional studies have identified the M393T mutation as a risk factor for certain diseases and disorders including REM sleep disorder (Krohn, L. et al., Nat.
  • TMEM175 knock-down led to increased phosphorylated alpha-synuclein (p-a-syn) accumulation following exposure to alpha-synuclein pre-formed fibrils (a-syn PFF) (Jinn, S. et al.2017). These results were confirmed in cultured rat primary neurons (Jinn, S. et al. 2019). TMEM175 +/- heterozygous neurons displayed an intermediate phenotype, reinforcing the gene dosing effect observed in human genetic studies.
  • the present disclosure provides compounds of Formula I and pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof, and compositions comprising said compounds or pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof, which activate TMEM175 and are useful for treatment of a variety of diseases and disorders such as diseases and disorders associated with lysosome dysfunction.
  • a compound of Formula I Formula I or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the variables are as defined herein.
  • a compound of Formula II Formula II or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the variables are as defined herein.
  • a compound of Formula II-A Formula II-A or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the variables are as defined herein.
  • a compound of Formula II-B Formula II-B or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the variables are as defined herein.
  • a compound of Formula II-C Formula II-C or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the variables are as defined herein.
  • a compound of Formula III Formula III or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the variables are as defined herein.
  • a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier.
  • the disclosure provides a method of treating a disease or disorder that can be treated by activating TMEM175, the method comprising administering to a patient in need thereof an effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a composition described herein.
  • the present disclosure provides compounds of Formula I and pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof, compositions comprising said compounds or pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof, which activate TMEM175 and are useful for treatment of a variety of diseases and disorders such as diseases and disorders associated with lysosome dysfunction (e.g., neurodegenerative diseases and lysosomal storage diseases).
  • diseases and disorders such as diseases and disorders associated with lysosome dysfunction (e.g., neurodegenerative diseases and lysosomal storage diseases).
  • a compound of Formula I or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Z 1 is C 1-6 alkyl or C 1-4 alkylene-aryl, substituted with one or two halogen, or Ring A is 5-6 membered heteroaryl or 6-membered heterocyclyl attached to X 2 or X 3 ; Ring B is selected from the group consisting of 5-6 membered carbocyclyl, phenyl, 5- 6 membered heteroaryl, and 5-6 membered heterocyclyl, wherein the heteroaryl and heterocyclyl contains one or two heteroatoms selected from S and N; X 1 is absent, CR 5 or N; X 2 , X 3 , X 4 , and X 5 are each independently CR 5 or N; provided that not more than two of X 1 , X 2 , X 3 , X 4 , and X 5 are
  • a compound of Formula II Formula II or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Ring A is 5-6 membered heteroaryl or 6-membered heterocyclyl attached to X 2 or X 3 ; Ring B is selected from the group consisting of 5-6 membered carbocyclyl, phenyl, 5- 6 membered heteroaryl, and 5-6 membered heterocyclyl, wherein the heteroaryl and heterocyclyl contains one or two heteroatoms selected from S and N; X 1 , X 2 , X 3 , X 4 , and X 5 are each independently CR 5 or N; provided that not more than two of X 1 , X 2 , X 3 , X 4 , and X 5 are N; and when X 2 or X 3 to which ring A is attached is CR 5 , R 5 of the CR 5 to which X 2 or
  • a compound of Formula II-A Formula II-A or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Ring A is 5-6 membered heteroaryl containing 1-2 heteroatoms selected from O, S, and N; Ring B is selected from the group consisting of 5-6 membered carbocyclyl, phenyl, 5- 6 membered heteroaryl, and 5-6 membered heterocyclyl, wherein the heteroaryl and heterocyclyl contains one or two heteroatoms selected from S and N; X 1 , X 2 , X 4 , and X 5 are each independently CR 5 or N; provided that not more than two of X 1 , X 2 , X 4 , and X 5 are N; X 6 is absent or is selected from the group consisting of CH, CH 2 , and N, wherein the hydrogen of CH or CH 2 is optionally substituted by R 3 ; X 7 is
  • Ring A is 5-6 membered heteroaryl or 6-membered heterocyclyl attached to X 2 or X 3 ;
  • Ring B is selected from the group consisting of 5-6 membered carbocyclyl, phenyl, 5- 6 membered heteroaryl, and 5-6 membered heterocyclyl, wherein the heteroaryl and heterocyclyl contains one or two heteroatoms selected from S and N;
  • X 1 , X 2 , X 3 , X 4 , and X 5 are each independently CR 5 or N; provided that not more than two of X 1 , X 2 , X 3 , X 4 , and X 5 are N; and when X 2 or X 3 to which ring A is attached is CR 5 , R 5 of the CR 5 to which X 2 or X 3 is attached is absent;
  • X 6 and X 7 are each independently selected
  • a compound of Formula II-C Formula II-C or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Ring A is 5-6 membered heteroaryl containing 1-2 heteroatoms selected from O, S, and N; Ring B is selected from the group consisting of 5-6 membered carbocyclyl, phenyl, 5- 6 membered heteroaryl, and 5-6 membered heterocyclyl, wherein the heteroaryl and heterocyclyl contains one or two heteroatoms selected from S and N; X 1 , X 2 , X 4 , and X 5 are each independently CR 5 or N; provided that not more than two of X 1 , X 2 , X 4 , and X 5 are N; X 6 and X7 are each independently selected from the group consisting of CH, CH 2 , and N, wherein the hydrogen of CH or CH 2 is optionally substituted by R 3 ;
  • the compound is a compound of Formula II-D: Formula II-D or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the variables are as defined herein.
  • the compound is a compound of Formula II-E: Formula II-E or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the variables are as defined herein.
  • the compound is a compound of Formula II-F: Formula II-F or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the variables are as defined herein.
  • the compound is a compound of Formula II-G: Formula II-G or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the variables are as defined herein.
  • X 1 , X 3 , X 4 , and X 5 are CR 5 or N and X 2 is C.
  • X 1 , X 2 , X 4 , and X 5 are CR 5 or N and X 3 is C.
  • X 1 , X 2 , X 4 , and X 5 are CR 5 .
  • X 1 , X 3 , X 4 , and X 5 are CR 5 .
  • one of X 1 , X 2 , X 4 , and X 5 is N.
  • one of X 1 , X 3 , X 4 , and X 5 is N.
  • the compound is a compound of Formula II-H: Formula II-H or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.
  • the compound is a compound of Formula II-J: Formula II-J or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.
  • the bicyclic ring containing X 6 , X 7 , X 8 , and ring B is selected from the group consisting of: wherein the bicyclic ring is substituted with 0-4 R 3 .
  • the bicyclic ring containing X 6 , X 7 , X 8 , and ring B is selected from the group consisting of:
  • the bicyclic ring containing X 6 , X 7 , X 8 , and ring B is selected from the group consisting of: wherein the bicyclic ring is substituted with 0-4 R 3 .
  • q is an integer 0-3. In some embodiments, q is an integer 0-2. In some embodiments, q is 0. In some embodiments, q is an integer 1-3. In some embodiments, q is an integer 1-2. In some embodiments, q is 1. In some embodiments, q is 2. [0039] In some embodiments, R 1 is H or C 1-2 alkyl.
  • R 1 is H or methyl. In some embodiments, R 1 is H. In some embodiments, R 1 is methyl.
  • R 2 is H or C 1-4 alkyl optionally substituted with one or two halogen, hydroxy, or C1-2 alkoxy. In some embodiments, R 2 is C 1-4 alkyl optionally substituted with hydroxy. In some embodiments, R 2 is methyl or ethyl. In some embodiments, R 2 is H. [0041] In other embodiments, R 1 and R 2 , together with the carbon atom to which R 1 and R 2 are attached, form C 3 -4cycloalkylene.
  • R 1 and R 2 together with the carbon atom to which R 1 and R 2 are attached, form cyclopropylene.
  • R 4 is H.
  • ring A is 5-6 membered heteroaryl or 6-membered heterocyclyl attached to X 2 .
  • ring A is 5-6 membered heteroaryl or 6- membered heterocyclyl attached to X 3 .
  • ring A is 5-6 membered heteroaryl.
  • ring A is 5-6 membered heteroaryl containing 1-2 heteroatoms selected from O, S, and N.
  • ring A is 6-membered heterocyclyl.
  • ring A is selected from the group consisting of pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, pyrazolyl, imidazolyl, and oxazolyl. In some embodiments, ring A is pyridyl, pyrazolyl, or imidazolyl. [0044] In some embodiments, R 3 is selected from the group consisting of halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, di-C 1-4 alkylamine, and 5-6 membered heterocyclyl.
  • R 3 is selected from the group consisting of halogen, hydroxy, C1-2 alkyl, C1-2 alkoxy, di-C 1-4 alkylamine, and 5-membered N-containing heterocyclyl. In some embodiments, R 3 is halogen or C1-2 alkyl. In some embodiments, R 3 is halogen. In some embodiments, R 3 is Cl or F. [0045] In some embodiments, R 5 is each independently selected from the group consisting of H, halogen, hydroxy, cyano, and C 1-6 alkyl. In some embodiments, R 5 is selected from the group consisting of H, halogen, and C 1-6 alkyl.
  • R 5 is selected from the group consisting of H, halogen, and C1-2 alkyl. In some embodiments, R 5 is selected from the group consisting of H or F. [0046] In some embodiments, n is an integer 0-4. In some embodiments, n is an integer 0-3. In some embodiments, n is 0. In some embodiments, n is an integer 1-4. In some embodiments, n is an integer 1-3. In some embodiments, n is an integer 1-2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.
  • R 6 is selected from the group consisting of halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, and C 3-6 cycloalkyl. In some embodiments, R 6 is selected from the group consisting of halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, and C 3-6 cycloalkyl. In some embodiments, R 6 is selected from the group consisting of halogen, hydroxy, cyano, C1-3 alkyl, C1-3 alkoxy, and cyclopropyl.
  • R 6 is selected from the group consisting of F, Cl, hydroxy, cyano, methyl, ethyl, methoxy, and cyclopropyl.
  • R 1 is H or C 1-4 alkyl
  • R 2 is C 1-4 alkyl
  • X 1 is absent, CH, or N
  • X 3 is C or N
  • X 2 , X 4 , and X 5 are each independently CH or N; provided that not more than two of X 1 , X 2 , X 3 , X 4 , and X 5 are N
  • X 6 is absent or is selected from the group consisting of CH, CH 2 , and N
  • X 7 is selected from the group consisting of CH, CH 2 , and N
  • R 3 is halogen
  • R 4 is H or C 1-6 alkyl
  • X 1 is absent. In other embodiments, X 1 is CH. In some embodiments, X 1 is N. [0050] In some embodiments, X 2 , X 4 , and X 5 are each CH. In other embodiments, one of X 2 , X 4 , and X 5 is N. [0051] In some embodiments, X 3 is C. In other embodiments, X 3 is N. [0052] In some embodiments, X 1 is absent and one of X 2 , X 3 , X 4 , and X 5 is N. In some embodiments, X 1 is absent and two of X 2 , X 3 , X 4 , and X 5 are N.
  • X 1 is CH and one of X 2 , X 3 , X 4 , and X 5 is N. In some embodiments, X 1 is N, X 3 is C, and X 2 , X 4 , and X 5 are CH.
  • a compound of Formula III-I or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.
  • a compound of Formula III-II or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.
  • the compound is a compound of Formula III-A: Formula III-A or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.
  • the compound is a compound of Formula III-B: Formula III-B or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.
  • the compound is a compound of Formula III-C: Formula III-C or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.
  • the compound is a compound of Formula III-D: or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.
  • the compound is a compound of Formula III-E: Formula III-E or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.
  • X 6 is absent. In other embodiments, X 6 is CH.
  • X7 is CH. In other embodiments, X7 is CH 2 .
  • X 6 is absent and X 7 is CH 2 .
  • X 6 is CH and X7 is CH.
  • R 1 is H or C 1-2 alkyl. In some embodiments, R 1 is H or methyl. In some embodiments, R 1 is H. In some embodiments, R 1 is C 1-4 alkyl. In some embodiments, R 1 is C 1-2 alkyl. In some embodiments, R 1 is methyl. [0065] In some embodiments, R 2 is C1-2 alkyl. In some embodiments, R 2 is methyl or ethyl. [0066] In some embodiments, R 4 is H. [0067] In some embodiments, R 3 is Cl or F. In some embodiments, R 3 is Cl.
  • Z 1 is C 1-6 alkyl. In some embodiments, Z 1 is ethyl. [0069] In some embodiments, Z 1 is C 1-4 alkylene-aryl optionally substituted with halogen. In some embodiments, Z 1 is benzyl optionally substituted with halogen. In some embodiments, Z 1 is benzyl substituted with F. [0070] In some embodiments, the compound is a compound identified in Table 1 below or a pharmaceutically acceptable salt thereof. Table 1.
  • a method of activating TMEM175 in a subject in need thereof comprising administering to the subject a compound described herein (e.g., a compound of Formula I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a composition described herein.
  • a compound described herein e.g., a compound of Formula I
  • a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof e.g., a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a composition described herein.
  • a method of treating a disease or disorder that can be treated by activation of TMEM175 in a subject in need thereof comprising administering to the subject a compound described herein (e.g., a compound of Formula I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a composition described herein.
  • a compound described herein e.g., a compound of Formula I
  • a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof e.g., a compound of Formula I
  • TMEM175 Diseases or disorders that can be treated by activation of TMEM175 include, but are not limited to, Parkinson’s Disease in TMEM175 mutation carriers, Idiopathic Parkinson’s Disease, GBA Parkinson’s Disease, LRRK2 Parkinson’s Disease, REM Sleep Behavior Disorder (RBD), Dementia with Lewy Bodies (DLB), Frontotemporal Dementia (FTD), Pick’s Disease, Amyotrophic Lateral Sclerosis (ALS), Progressive Supranuclear Palsy, FTDP-17, Alzheimer’s Disease, Multi System Atrophy, Corticobasal Degeneration, Huntington’s Disease, 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-
  • a method of treating a neurodegenerative disease in a subject in need thereof comprising administering to the subject a compound described herein (e.g., a compound of Formula I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a composition described herein.
  • a compound described herein e.g., a compound of Formula I
  • a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof e.g., a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a composition described herein.
  • the neurodegenerative disease is selected from the group consisting of Parkinson’s Disease in TMEM175 mutation carriers, Idiopathic Parkinson’s Disease, GBA Parkinson’s Disease, LRRK2 Parkinson’s Disease, REM Sleep Behavior Disorder (RBD), Dementia with Lewy Bodies (DLB), Frontotemporal Dementia (FTD), Pick’s Disease, Amyotrophic Lateral Sclerosis (ALS), Progressive Supranuclear Palsy, FTDP-17, Alzheimer’s Disease, Multi System Atrophy, Corticobasal Degeneration, and Huntington’s Disease.
  • Parkinson’s Disease in TMEM175 mutation carriers Idiopathic Parkinson’s Disease, GBA Parkinson’s Disease, LRRK2 Parkinson’s Disease, REM Sleep Behavior Disorder (RBD), Dementia with Lewy Bodies (DLB), Frontotemporal Dementia (FTD), Pick’s Disease, Amyotrophic Lateral Sclerosis (ALS), Progressive Supranuclear Palsy, FTDP-17, Alzheimer’s Disease,
  • the neurodegenerative disease is selected from the group consisting of Parkinson’s Disease in TMEM175 mutation carriers, Idiopathic Parkinson’s Disease, GBA Parkinson’s Disease, LRRK2 Parkinson’s Disease, REM Sleep Behavior Disorder (RBD), Dementia with Lewy Bodies (DLB), Frontotemporal Dementia (FTD), Pick’s Disease, and Amyotrophic Lateral Sclerosis (ALS).
  • Parkinson’s Disease in TMEM175 mutation carriers Idiopathic Parkinson’s Disease, GBA Parkinson’s Disease, LRRK2 Parkinson’s Disease, REM Sleep Behavior Disorder (RBD), Dementia with Lewy Bodies (DLB), Frontotemporal Dementia (FTD), Pick’s Disease, and Amyotrophic Lateral Sclerosis (ALS).
  • Parkinson’s Disease in TMEM175 mutation carriers Idiopathic Parkinson’s Disease, GBA Parkinson’s Disease, LRRK2 Parkinson’s Disease, REM Sleep Behavior Disorder (RBD), Dementia with Lewy Bodies (DL
  • a method of treating a lysosomal storage disease in a subject in need thereof comprising administering to the subject a compound described herein (e.g., a compound of Formula I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a composition described herein.
  • a compound described herein e.g., a compound of Formula I
  • a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof e.g., a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a composition described herein.
  • the lysosomal storage disease 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, Pompe disease, lysosomal acid lipase deficiency, Niemann- Pick disease, metachromatic leukodystrophy, Saposin B deficiency, multiple sulfatase deficiency, Hurler syndrome, Scheie syndrome, Hurler-Scheie syndrome, Hunter syndrome, Sanfilippo syndrome, Morquio syndrome, Maroteaux-Lamy syndrome, Sly syndrome, hyaluronidase deficiency, Sialidosis, I-cell disease, pseudo-Hurler
  • provided herein is a method of treating a disease or disorder in a subject in need thereof, the method comprising: (a) detecting a disease or disorder associated with TMEM175; and (b) administering to the subject an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a composition described herein.
  • the disease or disorder is selected from the group consisting of Parkinson’s Disease in TMEM175 mutation carriers, Idiopathic Parkinson’s Disease, GBA Parkinson’s Disease, LRRK2 Parkinson’s Disease, REM Sleep Behavior Disorder (RBD), Dementia with Lewy Bodies (DLB), Frontotemporal Dementia (FTD), Pick’s Disease, Amyotrophic Lateral Sclerosis (ALS), Progressive Supranuclear Palsy, FTDP-17, Alzheimer’s Disease, Multi System Atrophy, Corticobasal Degeneration, Huntington’s Disease, 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,
  • the methods further comprise administering to the subject a second therapeutic agent.
  • the second therapeutic agent is an mTOR inhibitor, a V2 receptor antagonist, a tyrosine kinase inhibitor, a glucosylceramide synthase inhibitor, a microRNA-17 inhibitor, a siRNA against p53, a KEAP1-Nrf2 activator, a xanthine oxidase inhibitor, a PPAR ⁇ agonist, 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)
  • compositions and Routes of Administration also provides pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and at least one pharmaceutically acceptable carrier.
  • the amount and concentration of compounds of Formula I, or pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers thereof, 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
  • 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.
  • another aspect of the present disclosure provides pharmaceutically acceptable compositions comprising a therapeutically effective amount of one or more of the compounds described above, or pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers thereof, formulated together with one or more pharmaceutically acceptable carriers.
  • 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.3,270,960.
  • Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to: (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
  • 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 include, but are not limited to: (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
  • 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.
  • 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, but are not limited to, 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. [0105] 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% (e.g., 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% (e.g., 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.
  • biocompatible polymers including hydrogels
  • biodegradable and non-degradable polymers can be used to form an implant for the sustained release of a compound at a particular target site.
  • Dosages [0110] 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 selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present disclosure employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the amount of compound that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1% to 99% of compound, e.g., from about 5% to about 70%, e.g., from 10% to about 30%.
  • Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50.
  • Compositions that exhibit large therapeutic indices are preferred.
  • the data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the EC 50 (i.e., the concentration of the therapeutic which achieves a half- maximal effect) as determined in cell culture.
  • Levels in plasma may be measured, for example, by high performance liquid chromatography.
  • the effects of any particular dosage can be monitored by a suitable bioassay.
  • the dosage may be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment.
  • the dosing schedule can vary from once a week to daily depending on a number of clinical factors, such as the subject's sensitivity to the drugs.
  • 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.
  • 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. For example, where a structure is described having two R groups that are simultaneously present on the same compound; 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.
  • C 1-4 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 carbon-carbon double bonds and optionally one or more carbon–carbon triple bonds that can occur in any stable point along the chain. In some embodiments, alkenyl does not contain any triple bonds.
  • C 2-6 alkenyl is intended to include C2, C 3 , C 4 , C 5 , and C 6 alkenyl groups and C2-8 alkenyl is intended to include C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , and C 8 alkenyl groups.
  • C 2–6 alkenyl groups include ethenyl (C 2 ), 1–propenyl (C 3 ), 2–propenyl (C 3 ), 1–butenyl (C 4 ), 2–butenyl (C 4 ), butadienyl ( C 4 ), pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like.
  • Additional examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), and the like.
  • alkynyl is intended to include hydrocarbon chains of either straight or branched configuration and one or more carbon-carbon triple bonds and optionally one or more carbon–carbon double bonds that can occur in any stable point along the chain. In some embodiments, alkynyl does not contain any double bonds. The one or more carbon– carbon double bonds can be internal (such as in 2–butenyl) or terminal (such as in 1–butenyl).
  • C 2-6 alkynyl is intended to include C 2 , C 3 , C 4 , C 5 , and C 6 alkynyl groups and C 2- 8 alkynyl is intended to include C2, C 3 , C 4 , C 5 , C 6 , C 7 , and C 8 alkynyl groups.
  • the one or more carbon–carbon triple bonds can be internal (such as in 2–butynyl) or terminal (such as in 1–butynyl).
  • C2–6 alkynyl groups include, without limitation, ethynyl (C2), 1– propynyl (C 3 ), 2–propynyl (C 3 ), 1–butynyl (C 4 ), 2–butynyl (C 4 ), pentynyl (C 5 ), hexynyl (C 6 ), and the like.
  • Additional examples of alkynyl include heptynyl ( C 7 ), octynyl (C 8 ), and the like.
  • alkylene As used herein, “alkylene,” “alkenylene,” and “alkynylene,” refer to a divalent radical of an alkyl, alkenyl, and alkynyl group respectively.
  • a non-limiting example of such an alkylene moiety that is a diradical is -CH 2 CH 2 -, i.e., a C2 alkyl group that is covalently bonded via each terminal carbon atom to the remainder of the molecule.
  • the alkylene, alkenylene, and alkynylene diradicals are also known as "alkylenyl,” “alkenylenyl,” and “alkynylenyl” radicals, respectively.
  • alkylene alkenylene
  • alkynylene alkynylene
  • cycloalkyl is intended to include saturated or unsaturated nonaromatic ring groups, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl and includes cyclic, bicyclic, tricyclic, spiro, fused, or bridged cyclic hydrocarbon groups.
  • 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.
  • cycloalkyl groups are optionally substituted at one or more ring positions with, for example, alkanoyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl or thiocarbonyl.
  • Cycloalkyl groups can be fused to other cycloalkyl, aryl, or heterocyclyl groups. In some embodiments, the cycloalkyl group is unsubstituted.
  • the term "heterocycloalkyl,” “heterocyclyl,” or “heterocyclic” 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, Se, B, Si, or P), unless specified otherwise.
  • a heterocyclyl 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 heterocyclyl is a monocyclic 4-6 membered heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members.
  • the heterocyclyl is a monocyclic or bicyclic 4-10 membered heterocyclyl having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members.
  • heterocyclyl 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-oxa
  • a heterocyclyl group is a 5–10 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5–10 membered heterocyclyl”).
  • a heterocyclyl group is a 5–8 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”).
  • a heterocyclyl group is a 5–6 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”).
  • the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3–membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl.
  • Exemplary 4–membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
  • Exemplary 5–membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl–2,5–dione.
  • Exemplary 5– membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.
  • Exemplary 5–membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6–membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6–membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6– membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7–membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8–membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary 5-membered heterocyclyl groups fused to a C 6 aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
  • Exemplary 6-membered heterocyclyl groups fused to an aryl ring include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
  • 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, an aryl group has six ring carbon atoms (“C 6 aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1– naphthyl and 2–naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C 14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • 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 polycyclic aromatic ring which contains 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).
  • the total number of S and O atoms in the aromatic heterocycle is not more than 1.
  • the total number of S and O atoms in the aromatic heterocycle is not more than 2. In other embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 3.
  • 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
  • a heteroaryl group is a 5–10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heteroaryl”).
  • a heteroaryl group is a 5–8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heteroaryl”).
  • a heteroaryl group is a 5–6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heteroaryl”).
  • the 5–6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 5–membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
  • Exemplary 5–membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5–membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5–membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6–membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl.
  • Exemplary 6–membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6–membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7–membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6–bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • Exemplary 6,6– bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Examples of representative heteroaryls include the following: wherein each Z is selected from carbonyl, N, NR * , O, and S; and R* is independently hydrogen, C 1 -C 8 alkyl, C 3 -C 10 carbocyclyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl, and 5- 10 membered heteroaryl.
  • amine or “amino” refers to unsubstituted -NH 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.
  • alkoxyl or “alkoxy” 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 C1, 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.
  • haloalkoxy refers to an alkoxy group, as defined herein, which is substituted one or more halogen.
  • haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.
  • 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.
  • nitro refers to -NO 2 .
  • 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.
  • a ring atom such as X 1 , or X 6 is absent, the remaining ring atoms form a ring. For example, if X 6 is absent from Formula II, then X7 forms a bond with the nitrogen adjacent to X 6 in Formula II.
  • the phrase "pharmaceutically acceptable” refers to those compounds or salts, solvates, hydrates, tautomers, and stereoisomers 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.
  • 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.
  • 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 s
  • 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, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction, and formulation into an efficacious therapeutic agent.
  • a “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle–aged adult or senior adult)) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • the terms “human,” “patient,” and “subject” are used interchangeably herein.
  • Disease, disorder, and condition are used interchangeably herein.
  • the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (also “therapeutic treatment”).
  • the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response.
  • the effective amount of a compound of the disclosure may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject.
  • a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, e.g., by activating TMEM175, or to delay or minimize one or more symptoms associated with the disease, disorder or condition.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition.
  • terapéuticaally effective amount can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.
  • the present disclosure contemplates administration of the compounds of the present disclosure or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or pharmaceutically acceptable composition thereof, as a prophylactic before a subject begins to suffer from the specified disease, disorder or condition.
  • prophylactic treatment contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition.
  • a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder or condition.
  • the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • 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.
  • 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).
  • tautomer refers to constitutional isomers of the disclosed compounds that readily convert by tautomerization or tautomerism. The interconversion commonly results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond.
  • Exemplary tautomeric pairs include, but are not limited to, ketone and enol, enamine and imine, nitroso and oxime, amide and imidic acid, lactam and lactim (an amide and imidic tautomerism in heterocyclic rings), and open-chain and cyclic forms of an acetal or hemiacetal.
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
  • a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess).
  • an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form.
  • enantiomerically pure or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer.
  • the weights are based upon total weight of all enantiomers or stereoisomers of the compound.
  • an enantiomerically pure compound can be present with other active or inactive ingredients.
  • a pharmaceutical composition comprising enantiomerically pure R–compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R–compound.
  • the enantiomerically pure R–compound in such compositions can, for example, comprise, at least about 95% by weight R–compound and at most about 5% by weight S–compound, by total weight of the compound.
  • a pharmaceutical composition comprising enantiomerically pure S–compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S–compound.
  • the enantiomerically pure S– compound in such compositions can, for example, comprise, at least about 95% by weight S– compound and at most about 5% by weight R–compound, by total weight of the compound.
  • the active ingredient can be formulated with little or no excipient or carrier.
  • Compound described herein may also comprise one or more isotopic substitutions.
  • H may be in any isotopic form, including 1 H, 2 H (D or deuterium), and 3 H (T or tritium); C may be in any isotopic form, including 12 C, 13 C, and 14 C; O may be in any isotopic form, including 16 O and 18 O; F may be in any isotopic form, including 18 F and 19 F; and the like.
  • the singular forms also include the plural, unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the case of conflict, the present specification will control. [0171] All percentages and ratios used herein, unless otherwise indicated, are by weight.
  • 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.
  • EXAMPLES [0174] Examples are provided below to facilitate a more complete understanding of the disclosure. The following examples illustrate exemplary modes of making and practicing the disclosure.
  • LCMS example conditions [0176] Column: Shim-pack Scepter C18-120, 33*3.0mm, 3um or YMC Triart C18, 50x4.6mm, 3um; Mobile Phase: A: H2O(0.1%FA) B: CH 3 CN: Temperature: 35°C; Flow rate: 1.2mL/min; Run time: 0.1min@20%B,1.7min gradient (20-95% B), then 0.7min@95% B, then 0.4min@20% B; Injection volume: 5 uL; Detector: UV 220/254nm; Mass range: 100-1000; Scan: Postive/Negative.
  • Step 1.4-Fluoro-1-methyl-1H-pyrazole To a solution of 4-fluoro-1H-pyrazole (5.0 g, 58 mmol) in THF (100 mL) was added NaH (4.7 g, 60% in mineral oil, 120 mmol) at 0°C. The mixture was stirred at 0°C for 30 min. Then CH 3 I (9.9 g, 70 mmol) was added. The mixture was stirred at rt overnight and carefully poured into water.
  • Step 2.4-Fluoro-5-iodo-1-methyl-1H-pyrazole To a solution of 4-fluoro-1-methyl-1H-pyrazole (4.0 g, 40 mmol) in THF (40 mL) was added 1.6 M n-BuLi (33 mL, 52 mmol) at -78°C dropwise. The mixture was stirred at -78°C for 1 h. Then a solution of I2 (13.5 g, 52.0 mmol) in THF (20 mL) was added dropwise at - 78°C. The reaction was allowed to warm up to room temperature and stirred for 2 h and was quenched with saturated Na 2 S 2 O 3 (10 mL).
  • Step 3.4-(4-Fluoro-1-methyl-1H-pyrazol-5-yl)aniline [0182] To a solution of 4-fluoro-5-iodo-1-methyl-1H-pyrazole (3.27 g, 14.5 mmol) in dioxane (50 mL) and water (5 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)aniline (3.5 g, 16 mmol), Na 2 CO 3 (4.6 g, 43 mmol) and Pd(dppf)Cl 2 (530 mg, 0.72 mmol). The mixture was stirred at 100°C under N 2 for 18 h.
  • Step 2.4-(4-Fluoro-1-methyl-1H-pyrazol-3-yl)aniline To a solution of crude 3-bromo-4-fluoro-1-methyl-1H-pyrazole (1.2 g, 6.7 mmol) in dioxane (20 mL) and water (4 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)aniline (1.5 g, 6.7 mmol), K 2 CO 3 (2.3 g, 17 mmol) and Pd(dppf)Cl 2 (490 mg, 0.67 mmol).
  • (R)-2-(6-chloro-1-oxoisoquinolin-2(1H)-yl)propanoic acid 100 mg, 0.40 mmol
  • 4-(1,4-dimethyl-1H-pyrazol-5-yl)aniline 120 mg, 0.60 mmol
  • HATU 290 mg, 0.70 mmol
  • DIPEA 0.20 mL, 1.8 mmol
  • Step 2.6,7-Difluorophthalazin-1(2H)-one and 5,6-difluorophthalazin-1(2H)-one [0204] To a solution of crude mixture of 4,5-difluoro-2-formylbenzoic acid and 3,4-difluoro- 2-formylbenzoic acid (400 mg, 2.1 mmol) in ethanol (15 mL) were added N 2 H 4 -H 2 O (540 mg, 8.6 mmol) and 3 M HCl (0.1 mL). The resulting mixture was stirred at 80°C for 2 h. After being cooled down to room temperature, the reaction mixture was quenched with water and extracted with DCM twice. The organic layers were dried over Na 2 SO 4 and concentrated.
  • Step 2.4-(4-Methyloxazol-2-yl)aniline To a solution of 2-bromo-4-methyloxazole (190 mg, 1.1 mmol) in dioxane/H 2 O (5 mL/1 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (270 mg, 1.2 mmol), Pd(dppf)Cl 2 (80 mg, 0.1 mmol) and K 2 CO 3 (460 mg, 3.3 mmol). The mixture was sealed and stirred at 90°C under N 2 overnight. The volatile solvents were evaporated. The residue was extracted with EtOAc twice.
  • Step 1 (R)-2-(7-Chloro-4-oxoquinazolin-3(4H)-yl)propanoic acid [0219] At 0°C, to a solution of Mg(Ot-Bu)2 (9.4 g, 55 mmol) in THF (50 mL) was added (S)- 2-chloropropanoic acid (3.6 g, 33 mmol) dropwise. The resulting mixture was stirred at 0°C for 10 min. Then t-BuOK (31 mL, 1.0 M in THF) was added to the reaction.
  • step 2 The following examples were prepared using the aniline intermediate (step 2) prepared by a procedure similar to that described for Intermediate A using the corresponding aryl halide and aryl-Bpin.
  • step 2 the aniline intermediate used in step 2 was prepared by a procedure similar to that described for Intermediate B using the corresponding aryl halide and aminophenyl-Bpin.
  • the aniline intermediate used in step 2 was prepared by a procedure similar to that described for intermediate C.
  • the aniline intermediate used in step 2 was prepared by the procedure described for Intermediate D.
  • Example 48 Synthesis of (R)-N-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)-2-(1-oxo-6- (pyrrolidin-1-yl)isoquinolin-2(1H)-yl)propanamide (48)
  • a solution of 6-fluoroisoquinolin-1(2H)-one (100 mg, 0.6 mmol) in tetrahydropyrrole (6 mL) was stirred at 100°C overnight.
  • Step 2.2-(6-Chloro-1-oxoisoquinolin-2(1H)-yl)acetic acid To a suspension of ethyl 2-(6-chloro-1-oxoisoquinolin-2(1H)-yl)acetate (100 mg, 0.38 mmol) in ethanol (3 mL) was added LiOH (aq) (0.8 mL, 1 M). The mixture was stirred at rt for 3 h and concentrated.6 N HCl was added to adjust the pH to ⁇ 2.
  • 2-(6-chloro-1-oxoisoquinolin-2(1H)-yl)acetic acid 90 mg, 0.38 mmol
  • 4-(3-fluoropyridin-2-yl)aniline 86 mg, 0.45 mmol
  • NMI 65 mg, 0.8 mmol
  • TCFH 117 mg, 0.42 mmol
  • Step 1 Methyl 4,5-difluoro-2-vinylbenzoate [0232] To a solution of methyl 2-bromo-4,5-difluorobenzoate (1.0 g, 4.0 mmol) in THF (17 mL) and water (3 mL) were added potassium trifluoro(vinyl)borate (590 mg, 4.4 mmol), Cs 2 CO 3 (3.9 g, 12 mmol) and Pd(PPh 3 ) 2 Cl 2 (280 mg, 0.40 mmol). The mixture was stirred at 80°C under N 2 for 18 h and concentrated.
  • Methyl 4,5-difluoro-2-formylbenzoate [0233] To a solution of methyl 4,5-difluoro-2-vinylbenzoate (590 mg, 3.0 mmol) in THF (5 mL) and water (5 mL) were added K 2 O s O 4 (100 mg, 0.3 mmol) and NaIO 4 (1.9 g, 9.0 mmol). The reaction was stirred at rt for 2 h. Then it was diluted with EtOAc and water. The organic layer was separated, washed with brine, and concentrated in vacuo.
  • Step 3.6,7-Difluorophthalazin-1(2H)-one To a solution of methyl 4,5-difluoro-2-formylbenzoate (450 mg, 2.3 mmol) in EtOH (5 mL) was added N 2 H4-H 2 O (280 mg, 5.6 mmol). The mixture was stirred at 80°C for 1 h. The solid was filtered off. The filtrate was diluted with EtOAc and water.
  • step 2 The aniline intermediate used in step 2 was prepared by a procedure similar to that described for Intermediate B. Step 1.
  • (R)-2-(6-Fluoro-1-oxoisoquinolin-2(1H)-yl)propanoic acid [0238] At 0°C, to a suspension of Mg(Ot-Bu) 2 (1.5 g, 8.6 mmol) in THF (20 mL) under N 2 was added (S)-2-chloropropanoic acid (610 mg, 5.6 mmol) dropwise. The resulting mixture was stirred at 0°C for 10 min. Then t-BuOK (5.2 mL, 1.0 M in THF) was added.
  • the aniline intermediate used in step 2 was prepared by a procedure similar to that described for Intermediate B using the corresponding aryl halide and aminophenyl-Bpin.
  • the aniline intermediate used in step 2 was prepared by the procedure described for intermediate C.
  • Step 1.6-Bromo-2-((2-(trimethylsilyl)ethoxy)methyl)isoquinolin-1(2H)-one [0243] To a solution of 6-bromoisoquinolin-1(2H)-one (1.0 g, 4.5 mmol) in THF (15 mL) were added t-BuOK (13 mL, 1.0 M in THF) and SEM-Cl (1.1 g, 6.7 mmol) at 0°C. Then the mixture was stirred at rt under N 2 overnight and quenched with H 2 O. The mixture was extracted with EtOAc twice.
  • Step 2.6-(Dimethylamino)-2-((2-(trimethylsilyl)ethoxy)methyl)isoquinolin-1(2H)-one A mixture of 6-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)isoquinolin-1(2H)-one (870 mg, 2.5 mmol), dimethylamine (1.4 mL, 2.0 M, 2.7 mmol), Pd2(dba)3 (230 mg, 0.2 mmol), BINAP (310 mg, 0.5 mmol) and t-BuONa (710 mg, 7.4 mmol) in toluene (8 mL) was stirred at 110°C under N 2 overnight. The solvents were evaporated.
  • Step 3.6-(Dimethylamino)isoquinolin-1(2H)-one To a solution of 6-(dimethylamino)-2-((2-(trimethylsilyl)ethoxy)methyl)isoquinolin- 1(2H)-one (750 mg, 2.3 mmol) in THF (3 mL) was added TBAF (7.0 mL, 1.0 M in THF, 7.0 mmol). Then the mixture was stirred at 60°C overnight, cooled to rt and quenched with H 2 O. The mixture was extracted with EtOAc twice.
  • step 3 The acid intermediate used in step 3 was prepared by the procedure described for intermediate E.
  • Step 1.1-Ethyl-5-iodo-1H-pyrazole [0249] At -78°C, to a solution of 1-ethyl-1H-pyrazole (1.0 g, 10 mmol) in THF (20 mL) were slowed added n-BuLi (12 mL, 1.6 M in hexanes) followed by a solution of I2 (3.96 g, 15.6 mmol) in THF (10 mL). After being stirred at -78°C for 1 h, the reaction quenched with NH4Cl (aq) and Na2S2O3 (aq). The mixture was extracted with EtOAc twice.
  • Step 2.4-(1-Ethyl-1H-pyrazol-5-yl)aniline To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (400 mg, 1.8 mmol) and 1-ethyl-5-iodo-1H-pyrazole (810 mg, 3.7 mmol) in dioxane (10 mL) and H 2 O (2 mL) were added Pd(dppf)CI 3 (130 mg, 0.18 mmol) and Na 2 CO 3 (580 mg, 5.5 mmol). The resulting mixture was heated to 100 o C under N 2 overnight and concentrated by rotary evaporation.
  • Step 2.4-(1-Ethyl-1H-pyrazol-3-yl)aniline To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (630 mg, 2.87 mmol) and 500 mg mixture of 3-bromo-1-ethyl-1H-pyrazole and 5-bromo-1-ethyl-1H- pyrazole in dioxane (20 mL) and H 2 O (6 mL) were added Pd(dppf)Cl 2 (210 mg, 0.29 mmol) and K 2 CO 3 (1.19 g, 8.63 mmol). The resulting mixture was heated to 100°C under N 2 overnight.
  • Example 99 Synthesis of (R)-N-(4-(4-chloro-1-methyl-1H-pyrazol-5-yl)phenyl)-2-(7- f [0259]
  • the acid intermediate used in step 3 was prepared by a procedure similar to that described for intermediate E.
  • Step 1.4-Chloro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole To a solution of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole (1.0 g, 4.8 mmol) in DMF (10 mL) was added NCS (705 mg, 5.28 mmol). The resulting mixture was heated at 70°C for 3 h. After being cooled down to room temperature, the mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc twice.
  • Step 2.4-(4-Chloro-1-methyl-1H-pyrazol-5-yl)aniline To a solution of 4-chloro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole (500 mg, 2.1 mmol) and 4-bromoaniline (390 mg, 2.3 mmol) in dioxane/H 2 O (15 mL/3 mL) were added K 2 CO 3 (860 mg, 6.3 mmol) and Pd(dppf)Cl 2 (75 mg, 0.1 mmol). The mixture was stirred at 90°C under N 2 overnight. The solvents were removed by rotary evaporation.
  • Step 1.5-(2-Fluoro-4-nitrophenyl)-4-methyloxazole To a solution of 2-fluoro-4-nitrobenzaldehyde (100 mg, 0.6 mmol) in MeOH (5 mL) were added K 2 CO 3 (250 mg, 1.8 mmol) and 1-((1-isocyanoethyl)sulfonyl)-4-methylbenzene (120 mg, 0.6 mmol). The mixture was stirred at 75°C for 1.5 h, cooled to rt and quenched with H 2 O. The mixture was extracted with EtOAc twice.
  • reaction mixture was stirred for 12 h at room temperature. After the completion of the reaction, water was added and the reaction mixture was extracted into ethyl acetate (2 X 10 mL), combined organic layer washed with saturated sodium bicarbonate solution (5 mL) and with brine (5 mL), dried over sodium sulfate, filtered, concentrated, and subjected to flash chromatography (60% EtOAc/hexane) to obtain the (R)-2-(5-fluoro-1-oxoisoindolin-2-yl)-N- (4-(1-methyl-1H-pyrazol-5-yl)phenyl)propenamide (95 mg, 75%) as a white solid.
  • reaction mixture was stirred for 12 h at room temperature. After the completion of the reaction, water (100 mL) was added and the reaction mixture was extracted into ethyl acetate (3 X 100 mL), washed with sat. bicarbonate solution (2 X 100 mL), and brine (2 X 100 mL), dried over Na 2 SO 4 , filtered, concentrated, and purified by flash chromatography (75% EtOAc/hexane) to obtain a white solid. The solid was diluted with methanol (60 vol). The resulting mixture was heated at 70 °C for 45 min.
  • Example 26-1 Synthesis of (R)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(1-methyl- 1H-pyrazol-5-yl)phenyl)propanamide (26-1) Step 1.4-(1-Methyl-1H-pyrazol-5-yl)aniline [0283] To a mixture of 5-bromo-1-methyl-1H-pyrazole (20.0 g, 124 mmol) in dioxane (200 mL) and water (20 mL) was added (4-aminophenyl) boronic acid hydrochloride (28.0 g, 161 mmol) and potassium carbonate (42.9 g, 311 mmol) at room temperature.
  • the reaction mixture was treated with DIPEA (0.46 mL, 2.7 mmol) and stirred overnight at room temperature under nitrogen atmosphere. After the completion of the reaction, water (10 mL) was added and the mixture was extracted into ethyl acetate (5 X 10 mL).
  • Example 203 Synthesis of 1-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(4-fluoro-1- methyl-1H-pyrazol-5-yl)phenyl)cyclopropane-1-carboxamide (203) Step 1.
  • 1-amino-N-(4-(4-fluoro-1-methyl-1H-pyrazol-5- yl)phenyl)cyclopropane-1-carboxamide 150 mg, 0.55 mmol
  • methyl (E)-4-chloro-2- (((dimethylamino)methylene)amino)benzoate 260 mg, 1.1 mmol
  • TEA 278 mg, 2.75 mmol
  • Step 1 tert-Butyl (4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)phenyl)carbamate [0306] A mixture of 4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)aniline (100 mg, 0.52 mmol) and Boc 2 O (170 mg, 0.78 mmol) in dioxane (5 mL) was stirred at 100°C for 5 h. The solvent was evaporated. The residue was purified by flash column chromatography to afford tert-butyl (4- (4-fluoro-1-methyl-1H-pyrazol-5-yl)phenyl)carbamate (100 mg, 68%). Step 2.
  • tert-Butyl (4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)phenyl)(methyl)carbamate [0307] To a solution of tert-butyl (4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)phenyl)carbamate (100 mg, 0.35 mmol) in THF (2 mL) was added NaH (42 mg, 60% in mineral oil, 1.1 mmol) at 0°C. The mixture was stirred at 0°C for 20 min. CH 3 I (100 mg, 0.7 mmol) in THF (2 mL) was added and the mixture was then stirred at rt for 2 h.
  • Step 2.4-Fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole To a solution of 4-fluoro-1-methyl-1H-pyrazole (300 mg, 3.0 mmol) in THF (10 mL) was added 1.6 M n-BuLi (2.1 mL, 3.3 mmol) at -78°C and stirred for 30 min.2-Isopropoxy- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (670 mg, 3.6 mmol) was then added. The reaction was gradually warmed to rt and stirred for 2 h.
  • Step 3.6-(4-Fluoro-1-methyl-1H-pyrazol-5-yl)pyridin-3-amine [0313] To a solution of 4-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole (400 mg, 1.8 mmol) in THF (10 mL) and water (1 mL) were added 6- bromopyridin-3-amine (310 mg, 1.8 mmol), K 2 CO 3 (610 mg, 4.4 mmol) and Pd(dppf)Cl 2 (130 mg, 0.18 mmol).
  • Example 208 Synthesis of (R)-2-(6-chloro-1-oxoisoquinolin-2(1H)-yl)-N-(4-(1- (difluoromethyl)-1H-pyrazol-5-yl)phenyl)propanamide (208) Step 1.1-(Difluoromethyl)-5-iodo-1H-pyrazole and 1-(difluoromethyl)-3-iodo-1H-pyrazole [0316] To a solution of 3-iodo-1H-pyrazole (1.9 g, 9.8 mmol) in ACN (30 mL) were added diethyl (bromodifluoromethyl)phosphonate (5.23 g, 19.6 mmol) and potassium fluoride (2.28 g, 39.2 mmol).
  • Step 2.4-(1-(Difluoromethyl)-1H-pyrazol-5-yl)aniline To a solution of crude 1-(difluoromethyl)-5-iodo-1H-pyrazole and 1- (difluoromethyl)-3-iodo-1H-pyrazole (2.0 g, 8.2 mmol) in dioxane (50 mL) and H 2 O (10 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.8 g, 8.2 mmol), K 2 CO 3 (3.4 g, 25 mmol) and Pd(dppf)Cl 2 (600 mg, 0.8 mmol).
  • 6-chloroisoquinolin-1(2H)-one (5.0 g, 28 mmol) was added and additional THF (5 mL) was added to rinse the side of the flask. Then the mixture was stirred at rt for 2 h and then at 55°C (internal temperature) overnight.23 mL of 6 M HCl was added. The mixture was partitioned between EtOAc and H 2 O.
  • the method can be used to prepare a variety of related chiral carboxylic acids by using quinazolin-4(3H)-one, phthalazin-1(2H)-one, isoquinolin-1(2H)-one, 5,6,7,8- tetrahydroquinazolin-4(3H)-one, 5,6,7,8-tetrahydroisoquinolin-1(2H)-one and isoindolin-1- one derivatives as the starting materials.
  • quinazolin-4(3H)-one phthalazin-1(2H)-one
  • isoquinolin-1(2H)-one 5,6,7,8- tetrahydroquinazolin-4(3H)-one
  • 5,6,7,8-tetrahydroisoquinolin-1(2H)-one and isoindolin-1- one derivatives as the starting materials.
  • Example 222 General amide coupling procedure using HATU Intermediate CC Compound DD
  • isoindolin-1-one derivative (Intermediate CC, prepared by following a similar procedure used for the synthesis of Intermediate AA) (0.33 mmol), aryl amine (0.33 mmol) and HATU (190 mg, 0.49 mmol) in DMF (1.0 mL) was treated with DIPEA (0.12 mL, 0.66 mmol) at 0 °C.
  • the reaction mixture was stirred for 12 h at room temperature. After the completion of the reaction, water was added and the reaction mixture was extracted into ethyl acetate (2 X 10 mL).
  • Example 225 Synthesis of (R)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(3-fluoro-4-(5- methyloxazol-4-yl)phenyl)propanamide Step 1.2-Bromo-1-(4-bromo-2-fluorophenyl)propan-1-one [0325] To a solution of 1-(4-bromo-2-fluorophenyl)propan-1-one (1.1 g, 4.8 mmol) in DCM (20 mL) at 0°C was added Br2 (910 mg, 5.7 mmol). The reaction was stirred at room temperature for 2h.
  • Step 2.4-(4-Bromo-2-fluorophenyl)-5-methyloxazole A solution of 2-bromo-1-(4-bromo-2-fluorophenyl)propan-1-one (1.3 g, crude material from last step) in formamide (20 mL) was stirred at 110°C under N 2 atmosphere overnight. The resultant mixture was poured into water and extracted with EtOAc. The organic layer was dried over Na 2 SO 4 , filtered and concentrated.
  • Step 3.3-Fluoro-4-(5-methyloxazol-4-yl)aniline To a solution of 4-(4-bromo-2-fluorophenyl)-5-methyloxazole (890 mg, 3.5 mmol) in toluene (15 mL) was added diphenylmethanimine (1.3 g, 7.0 mmol), Pd 2 (dba) 3 (640 mg, 0.69 mmol), BINAP (870 mg, 1.4 mmol) and Cs 2 CO 3 (3.4 g, 10 mmol). The resulting mixture was stirred at 110°C under N 2 overnight. The reaction was quenched with H 2 O and extracted twice with EtOAc.
  • HEK-293 Trex cells were stably transfected with a construct consisting of the human coding sequence for TMEM175 cloned into the tet-inducible plasmid pCDNA5 T/O and serially passaged. Cells are treated with doxycycline to induce expression of TMEM175 18-24 hours prior to testing.
  • CHO-SFM- II media is used to terminate digestion and cells are collected and pelletized by centrifugation before resuspension in Ringer’s solution (supplemented with doxycycline) at a density >800,000 cells per mL of solution.
  • SyncroPatch Experiment Compounds are dissolved to a concentration of 10 mM in DMSO, further dilution to 1000-fold the final tested concentration is done using DMSO. The compounds are mixed 1:313 – 1:1000 with the cell suspension and allowed to incubate approximately 30 minutes.

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Abstract

La présente divulgation concerne des composés de formule I ou un sel pharmaceutiquement acceptable de ceux-ci, les variables étant telles que définies dans la description. L'invention concerne également des compositions comprenant lesdits composés et des méthodes d'utilisation pour traiter certaines maladies ou certains troubles, y compris, par exemple, des maladies neurodégénératives et des maladies lysosomales.
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