WO2009076454A2 - Compounds that modulate intracellular calcium - Google Patents

Compounds that modulate intracellular calcium Download PDF

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Publication number
WO2009076454A2
WO2009076454A2 PCT/US2008/086254 US2008086254W WO2009076454A2 WO 2009076454 A2 WO2009076454 A2 WO 2009076454A2 US 2008086254 W US2008086254 W US 2008086254W WO 2009076454 A2 WO2009076454 A2 WO 2009076454A2
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WIPO (PCT)
Prior art keywords
compound
optionally substituted
pharmaceutically acceptable
calcium
alkyl
Prior art date
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Ceased
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PCT/US2008/086254
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French (fr)
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WO2009076454A3 (en
Inventor
Gonul Velicelebi
Kenneth A. Stauderman
Frank King
Yazhong Pei
Jeffrey P. Whitten
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Calcimedica Inc
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Calcimedica Inc
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Priority to US12/747,604 priority Critical patent/US8389567B2/en
Publication of WO2009076454A2 publication Critical patent/WO2009076454A2/en
Publication of WO2009076454A3 publication Critical patent/WO2009076454A3/en
Anticipated expiration legal-status Critical
Priority to US13/734,827 priority patent/US20130123265A1/en
Ceased legal-status Critical Current

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    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
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    • 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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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

  • SOC store operated calcium
  • Calcium plays a vital role in cell function and survival
  • Calcium is a key element in the transduction of signals into and within cells
  • Cellular responses to growth factors, neurotransmitters, hormones and a variety of other signal molecules are initiated through calcium-dependent processes
  • Virtually all cell types depend in some manner upon the generation of cytoplasmic Ca 2+ signals to regulate cell function, or to trigger specific responses
  • Cytosolic Ca 2+ signals control a wide array of cellular functions ranging from short-term responses such as contraction and secretion to longer-term regulation of cell growth and proliferation
  • these signals involve some combination of release of Ca 2+ from intracellular stores, such as the endoplasmic reticulum (ER), and influx OfCa 2+ across the plasma membrane
  • cell activation begms with an agonist binding to a surface potential
  • Store-operated calcium (SOC) influx is a process in cellular physiology that controls such diverse functions such as, but not limited to, refilling of intracellular Ca 2+ stores (Putney et al Cell, 75, 199-201 , 1993), activation of enzymatic activity (Fagan et al , J Biol Chem 275 26530-26537, 2000), gene transcription (Lewis, Annu Rev Immunol 19 497-521, 2001), cell proliferation (Nunez el al , J Physiol 571 1, 57-73, 2006), and release of cytokines (Winslow e ⁇ ⁇ / , Cwr Opin Immunol 15 299-307, 2003)
  • CRAC calcium release-activated calcium
  • compounds of Formulas (I), (II), (III), (IV), (V) or (VI) modulate intracellular calcium by inhibition of store operated calcium channel activity
  • compounds of Formulas (I), (II), (III), (IV), (V) and (VI) modulate intracellular calcium by preventing the activity of activated store operated calcium channel complexes
  • compounds of Formulas (I), (II), (III), (IV), (V) and (VI) inhibit activation of store operated channels
  • compounds of Formulas (I), (II), (III), (IV), (V) and (VI) inhibit activation of calcium-release activated calcium channels
  • compounds of Formulas (I), (II), (III), (IV), (V) and (VI) modulate an activity of, modulate an interaction
  • a compound of Formulas (I), (II), (III), (IV), (V) or (VI) is a selective inhibitor of SOC channel activity
  • a compound of Formulas (I), (II), (HI), (TV), (V) or (VI) is a selective inhibitor of CRAC channel activity
  • L is a bond, Ci-C ⁇ alkyl, Ci-C 6 alkenyl, Ci-C 6 heteroalkyl, aryl, or heteroaryl, wherein Ci-C ⁇ attyl.
  • Ci-Cjalkenyl, Ci-Csheteroalkyl, aryl, or heteroaryl is optionally substituted with at least one R s ,
  • V is a bond, O, -(C(R 6 Ja) n -O or NR 1
  • W is a bond, CpCealkyl, Q-Qalkenyl, Ci-Csheteroalkyl, wherein when Y is S and X is CR 3 then V and W are absent, X is N or CR 3 ,
  • Y is O, S or NR 3 , with the proviso that if Y is S, then X is not CH,
  • R is CO 2 R 1 , a carboxyhc acid bioisostere, an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl,
  • R 1 is hydrogen, C 1 -C ⁇ aIlCyI, Cj-Qhaloalkyl, or benzyl,
  • R 2 and R 4 are each independently an aryl, or a heteroaryl, wherein R 2 and R 4 are independently optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO 2 , -OH, -CF 3 , -OCF 3 , -OR 8 , C 1 - C 6 alkyl, C 3 -C 8 cycloalkyl, Ci-Csheteroalkyl, Ci-C 6 haloalkyl, tetrazolyl, CVCgheterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, NHS(O) 2 R 8 , -S(O) 2 N(R 9 J 2 , -N(R 9 JS(O) 2 N(R 9 J 2 , - C(O)CF 3 , C(O)NHS(O) 2 R 8 , -S(O) 2 NHC(O)R 8 , -N(R 9 J
  • substttuents are selected from among from a subset listed herein.
  • R 1 is hydrogen or Ci-C ⁇ alkyl
  • R 1 is H, methyl, ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, lso-butyl, n-pentyl, or hexyL
  • R 1 is H, methyl, or ethyl
  • R 1 is H
  • R 4 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, CN, -NO 2 , CF 3 , -OH, -OR 8 , -OCF 3 , Ci-C 6 alkyl, Ci-Csfluoroalkyl, Ci-Ceheteroalkyl, C 3 Cgcycloalkyl, and C-CJialoalkyl [0011] In another embodiment R 4 is an optionally substituted heterocycle wherein the heterocycle is selected from
  • R 4 is substituted with at least one substituent selected from -NHS(O) 2 R 8 , - S(O) 2 N(R 9 J 2 , -N(R 9 JS(O) 2 N(R 9 J 2 , -N(R 9 J 2 , -N(R 9 JC(O)R 8 , -N(R 9 JC(O)N(R')* -N(R')C(0)OR 8 , -CO 2 R 9 , -
  • R 4 is selected from phenyl, 2-fluoro ⁇ henyl, 3-fluoroplicnyl. 4-fluoro ⁇ henyl,
  • R 2 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO 2 , -CF 3 , -OH, -OR 8 , -OCF 3 , Ci-C 6 alkyl, Ci-C 3 fluoroalkyl, C r C 6 heteioalkyl, C 3 - Qcycloalkyl, and Ci C ⁇ haloalkyl
  • R 2 is an optionally substituted heterocycle wherein the heterocycle is selected from ⁇ , ⁇ O. O O O 0 OO O O 0.0 O O 0000 CO CO
  • R 2 is selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichloropheny
  • X is N and Y is O
  • X is N and Y is CR 3 , wherein R 3 is selected from H or methyl
  • X is CR 3 and Y is NR 3 , wherein each R 3 is independently selected from H or methyl
  • Ctalkenyl, Ci-C ⁇ heteroalkyl, aryl, or heteroaryl is optionally substituted with at least one R 5 , V is a bond, O, -(qR ⁇ -O or NR 1 , W is a bond, ⁇ -Qalkyl, Cj-Qalkenyl, Ci-C 6 heteroalkyl, X is N or CR 3 , Y is N or CR 3 ,
  • R is CO 2 R 1 , a carboxyhc acid bioisostere, an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl,
  • R 1 is hydrogen, Ci-C 6 IiIlCyI, C 1 -C S hSlOaIlCyI, or benzyl,
  • R 2 is an aryl, or a benzolhienyl, wherein the aryl or benzotinenyl is optionally substituted with at least one R 5 ,
  • each R 6 is independently selected from hydrogen, from F, Cl, Br, I, -CN, -NO 2 , -OH, -CF 3 , -OCF 3 , -OR 8 , Ci-C 6 alkyl, C 3 -C 8 cycloalkyl, CrQheteroalkyl, CrQhaloalkyl, tetrazolyl, C ⁇ -Qheterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(O) 2 R 8 , -S(O) 2 N(R 9 ) 2 , - N(R 9 )S(O) 2 N(Rj) 2 , -C(O)CF 3 , -C(O)NHS(O) 2 R 8 , -S(O)
  • R 3 IS hydrogen, CpC ⁇ alkyl, Ci-C ⁇ haloalkyl, Ci-Cjheteroaikyl, substituted or unsubstituted aryl or benzyl [0024]
  • substituems are selected from among from a subset listed herein
  • R 1 is hydrogen or C r Qalkyl
  • R 1 is H, methyl, ethyl, n propyl, iso-propyl, n-butyl, sec-butyl, lso-butyl, n-pentyl, or hexyl
  • R 1 is H, methyl, or ethyl
  • R 1 is H
  • R 4 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO 2 , -CF 3 , -OH, -OR 8 , -OCF 3 , CrQalkyl, CpQfluoroalkyl, Ci-C ⁇ sheteroalkyl, CVQcycloalkyl, and CrQhaloalkyl [0026]
  • R 4 is an optionally substituted heterocycle wherein the heterocycle is selected from
  • R 4 is selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, A- fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichloroph ⁇ nyl, 2,3-dichlorophenyl, 3,4- dichloropheny], 3,5-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3- lodophenyl, 4-iodophenyl, 2-methy]phenyl, 3-methylphenyl, 4-methyl ⁇ henyl, 2,4-dunethylphenyl, 2,3- dimethylphenyl, 3,4-dunethylphenyl, 3,5-dimethylphenyl, 2-tnfluromethylphenyl, 3-t ⁇ fluromethyIphenyl, and 4-t ⁇ fluromethylphen
  • R 2 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO 2 , -CF 3 , -OH, -OR 8 , -OCF 3 , Ci-Qjalkyl, d-Cefluoroalkyi, Ci-Csheteroalkyl, Q-Cgcycloalkyl, and C, CJialoalkyl
  • R 2 is an optionally substituted heterocycle wherein the heterocycle is selected from o.Q o ⁇ . ⁇ > co. ⁇ . ⁇ . ⁇ ⁇ O O ⁇ . ⁇ ⁇ .
  • X is CR 3 and Y is CR 3 , wherein each R 3 is independently selected from H or methyl
  • X is CR 3 and Y is N, wherein R 3 is selected from H or methyl
  • described herein is a compound of Formula (III), or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof
  • Qalkenyl, Ci-C ⁇ heteroalkyl, aryl, or heteroaryl is optionally substituted with at least one R 10 , V is a bond, O, - ⁇ C(R 3 ) 2 ),,-O or NR 1 , W is a bond, Ci-Qalkyl, CrC ⁇ alkenyl, C r C 6 heteroalkyl R is CO 2 R 1 , a carboxyiic acid bioisostere, an optionally substituted heteroaryl, or an optionally substituted h ⁇ terocycloalkyl,
  • R 1 is hydrogen, Ci-Qalkyl, Ci-Cjbaloalkyl, or benzyl,
  • R 2 is an aryl, or a benzothienyl, wherein the aryl or benzothienyl is optionally substituted with at least one substituent selected from F, Cl, Br, I 1 -CN, -NO 2 , -OH, -CF 3 , -OCF 3 , -OR 8 , Q-Qalkyl, C 3 -
  • R 4 is an aryl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO 2 , - CF 3 , -OH, -OR 8 , -OCF 3 , Ci-C 6 -UCyI, C 3 -Cgcycloalkyl, Q-QfluoroaUtyl, Ci-Ceheteroalkyl, Ci- C ⁇ haloalkyl, tetrazolyl, C 2 C 8 heterocycloalkyi, optionally substituted aryl, optionally substituted heteroaryl, -NHS(O) 2 R*, -S(O) 2 N(RV -N(R 9 JS(O) 2 N(RV -C(O)CF 3 , -C(O)NHS(O) 2 R 8 , - S(O) 2 NHC(O)R 8 , -N(RV -N(R 9 JC(O)R 8 ,
  • R 10 is independently selected from from F, Cl, Br, I, -CN, -NO 2 , -OH, -CF 3 , -OCF 3 , -OR 8 , Cj-C ⁇ lkyl, C 3 - Cscycloalkyl, CpCsheteroalkyl, Q-Qhaloalkyl, tetrazolyl, CrCsheterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(O) 2 R 8 , -S(O) 2 N(R 9 J 2 , - N(R 9 )S(OJ 2 N(R 9 J 2 , -C(O)CF 3 , -C(O)NHS(O) 2 R 8 , -S(O) 2 NHC(O)R 8 , -N(R 9 ),, - N(R 9 )C(O)R 8 , -N(R 9 JC(O)N(R
  • R 1 is hydrogen or C r C 6 alkyl
  • R 1 is H, methyl, ethyl, n- propyl, lso-propyl, n-butyl, sec-butyl, lso-butyl, n-pentyl, or hexyl.
  • R 1 is H, methyl, or ethyl In some embodiments, R 1 is H [0039J In one embodiment R 4 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO 2 , -CF 3 , -OH, -OR 8 , -OCF 3 , Ci-Csalkyl, Cgcycloalkyl, and Ci-Qhaloalkyl
  • R 4 is an optionally substituted heterocycle wherein the heterocycle is selected from. ⁇ . ⁇ . ⁇ ⁇ . ⁇ ⁇ . ⁇ O ⁇ .
  • R 4 is substituted with at least one substituent selected from -NHS(O) 2 R 8 , - SirOWQL 9 ) ! , -N(R 9 JS(O) 2 N(R 9 J 2 , -N(R 9 J 2 , -N(R 9 JC(O)R", -N(R ⁇ )C(O)NCR 9 J 2 , -NCR 9 JC(O)OR 8 , -CO 2 R 9 , -
  • R 4 is selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4- fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichIorophenyl, 2,3-dichlorophenyl, 3,4- dichlorophenyl, 3,5-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3- iodophenyl, 4-iodophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dunethylphenyl, 2,3- dimethylphenyl, 3,4-dunethylphenyl, 3,5-drmethylphenyl, 2-t ⁇ fluromethylphenyl, 3-trifhiromethylphenyl, and
  • R 2 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO 2 , -CF 3 , -OH, -OR 8 , -OCF 3 , C r C «alkyl, Ci-Cefluoroalkyl, C-Ctheteroalkyl, C 3 -C 8 cycloalkyl, and Q-Qhaloalkyl
  • R 2 is an optionally substituted heterocycle wherein the heterocycle is selected from
  • R 2 is substituted with one or more of the substitueirts selected from - NHS(O) 2 R 8 , -S(O) 2 N(R 9 ),, -N(R 9 JS(O) 2 N(R'),, -N(R 9 J 2 , -N(R ⁇ )C(O)R 8 , -N(R 9 JC(O)N(R*),, - N(R')C(0)OR 8 , -CO 2 R 9 , -C(O)R 8 , -OC(O)N(R 9 J 2 , CON(R 9 ) 2 , SR 8 , Or -S(O) 2 R 8 [0046] In additional embodiments R 2 is selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4- fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophen
  • L is a bond, C r C 6 alkyl, C 1 -C 6 alkenyl, Q-Qheteroalkyl, aryl, or heteroaryl, wherein Ci-C «alkyl, C r
  • C 6 alkenyl, Ci-Qheteroalkyl, aryl, or heteroaryl is optionally substituted with at least one R 10 , V is a bond, O, -(C(R 7 J 2 X 1 -O or NR 1 ,
  • W is a bond, Q-Qalkyl, Cj-Csalkenyl, Ci-Qheteroalkyl, X is N or CR 3 ,
  • R 2 is an aryl, or a benzothienyl, wherein the aryl or benzothienyl is optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO 2 , -OH, -CF 3 , -OCF 3 , OR 8 , Ci C 6 alkyl, C 3
  • R 4 is an aryl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO 2 , - CF 3 , -OH, -OR 8 , -OCF 3 , Ci-Cjalkyl, Cj-Cgcycloalkyl, C-Cfluoroalkyl, d-Qheteroalkyl, C 1 - Qhaloalkyl, tetrazolyl, C 2 -C 8 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(O) 2 R 8 , -S(O) 2 N(R 9 J 2 , -N(R 9 JS(O) 2 N(R 9 J 2 , -C(O)CF 3 , -C(O)NHS(O) 2 R 8 , - S(O) 2 NHC(O)R 8 , -N(R 9 J 2 , -N(R
  • subsutuents are selected from among from a subset listed herein.
  • R 1 is hydrogen or Ci-Qalkyl
  • R 1 is H, methyl, ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, n-pentyl, or hexyl
  • R' is H, methyl, or ethyl
  • R 1 is H
  • R 4 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO 2 , -CF 3 , -OH, -OR 8 , OCF 3 , Ci-Csalkyl, C 1 -C 6 fluoroalkyl, Ci-Ccheteroalkyl, C 3 Cscycloalkyl, and C-QhaloalkyL
  • R 4 is an optionally substituted heterocycle wherein the heterocycle is selected from
  • R 4 is selected from phenyl, 2-fiuorophenyl, 3 fluorophenyl, 4-fluorophenyl, 2- chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3,4 dichlorophenyl,
  • R 2 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO 2 , CF 3 , -OH, -OR 8 , OCF 3 , C,-Csalkyl, Ci-Csfluoroalkyl, C,-C 6 heteroalkyl,
  • R 2 is an optionally substituted heterocycle wherein the heterocycle is selected ⁇ ⁇ . ⁇ ⁇ ti O ⁇ . ⁇ ⁇
  • R 2 is substituted with one or more of the substituents selected from - NHS(O) 2 R 8 , -S(O) 2 N(R 9 J 2 , -N(R 9 JS(O) 2 N(R')* -N(R 9 J 2 , -N(R 9 JC(O)R 1 , -N(R 9 JC(O)N(R 9 ),, - N(R 9 JC(O)OR 8 , -CO 2 R', -C(O)R 8 , -OC(O)N(R 9 J 2 , -CON(R 9 J 2 , -SR 8 , or -S(O) 2 R 8
  • R 2 is selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2- chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4- lodophenyl, 2-methylphenyl, 3 methylphenyl, 4 methylphenyl, 2,4-dunethylphenyl, 2,3-dunethylphenyl, 3,4- dunethylphenyl, 3,5-dimethylphenyl, 2-t ⁇ fluromethylphenyl, 3-t ⁇ fluromethylphenyl, and 4- t ⁇ fluromethyl
  • X is N and Y is S
  • V is a bond, O, -(C(R 6 J 2 J n -O or NR 1 ,
  • R is CO 2 R 1 , a carboxyhc acid bioisostere, an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl,
  • R 1 is hydrogen, Ci-C ⁇ alkyl, Ci-Cyialoalkyl, or benzyl
  • R 2 is an aryl, or a benzothienyl, wherein the aryl or benzothienyl is optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO 2 , -OH, -CF 3 , OCF 3 , -OR 8 , C 1 -QaIlCyI, C 3 - Cjcycloalkyl, Ci-C ⁇ jheteroalkyl, Ci-Qnaloalkyl, tetrazolyl, CrCgheterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(OJ 2 R 8 , -S(O) 2 N(R 9 J 2 , - N(R 9 JS(O) 2 N(R 9 J 2 , -C(O)CF 3 ,
  • R 4 is selected from H, F, Cl, Br, I, -CN, -NO 2 , -CF 3 , -OH, OR 8 , -OCF 3 , d-C t alkyl, C 3 C 8 cycloalkyl, C,- C 6 fluoroalkyl, Ci-Cyieteroalkyl, Ci-C 6 haloalkyl, tetrazolyl, QrCsheterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(O) 2 R 8 , -S(O) 2 N(R 9 ) ⁇ - N(R 9 JS(OJ 2 N(R 9 J 2 , -C(O)CF 3 , -C(K))NHS(O) 2 R 8 , -S(O) 2 NHC(O)R 8 , -N(R 9 J 2 , - N(R 9 JC(K))R 8 ,
  • substituents are selected from among from a subset listed herein.
  • R 1 is hydrogen or Ci-C 6 alkyl
  • R 1 is H, methyl, ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, n-pentyl, or hexyl
  • R 1 is H, methyl, or ethyl
  • R 1 is H
  • K* is a substituent selected from H, F, Cl, Br, I, -CN, -NO 2 , -CF 3 , -OH, -OR 8 , - OCF 3 , Ci-Qalkyl, Ci-Qfluoroalkyl, CrQjbeteroalkyl, C 3 -C 8 cycloalkyl, or C,-C 6 haloalkyl
  • R 2 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO 2 , -CF 3 , -OH, -OR 8 , -OCF 3 , Ci-C ⁇ alkyl, Ci-C ⁇ fluoroalkyl, C,-C 6 heteroalkyl, C 3 - Qcycloalkyl, and C-Qhaloalkyl
  • R 2 is an optionally substituted heterocycle wherein the heterocycle is selected
  • R 2 is ⁇ substitu.tGed with o.one oro more ocf dieQ substitcuentos selec.tecd fro ⁇ m - NHS(OJ 2 R 8 , S(O) 2 N(R 9 J 2 , -N(R 9 JS(O) 2 N(R 9 J 2 , -N(R 9 J 2 , -N(R 9 JC(O)R 8 , -N(R 9 JC(O)N(R 9 J 2 , - N(R 9 JC(O)OR 8 , -CO 2 R 9 , -C(OJR 8 , -OC(OJN(R 9 J 2 , CON(R 9 J 2 , -SR 8 , or -S(O) 2 R 8 [0065] In other embodiment s R 2 is selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-
  • L is a bond, Ci-C 6 aHcyl, Q-Qalkenyl, Ci-C 6 heteroalkyl, aryl, or heteroaryl, wherein Ci-Qalkyl, C L - C 6 alkenyl, C 1 C ⁇ heteroalkyl, aryl, or heteroaryl is optionally substituted with at least one R 5 ,
  • each R 5 is independently selected from F, Cl, Br, I, -CN, -NO 2 , -OH, CF 3 , -OCF 3 , -OR 8 , C,-Csalkyl,
  • In one embodiment is a compound of Formula (VI) wherein Z is substituted with a substituent selected from F, Cl, Br, I, -CN, -NO 2 , -OH, -CF 3 , -OCF 3 , -OR 8 , Ci Csalkyl, C 3 Cgcycloalkyl, and C 1 -
  • substituents arc selected from among from a subset listed herein.
  • R 1 is hydrogen or Ci-Cgalkyl
  • R 1 is H, methyl, ethyl, n- propyl, lso-propyl, n-butyl, sec-butyl, iso-butyl, n-pentyl, or hexyl
  • R 1 is H, methyl, or ethyl.
  • R 1 is H
  • R 4 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, NO 2 , -CF 3 , OH, -OR 8 , -OCF 3 , Ci-C ⁇ alkyl, Q-Csfluoroalkyl, Ci-Qjheteroalkyl, C 3 - C 8 cycloalkyl, and Ci-Qihaloalkyl.
  • R 4 is an optionally substituted heterocycle wherein the heterocycle is selected ⁇ . ⁇ . ⁇ ⁇ .O. ⁇ ⁇ .O ⁇ .
  • R 4 is substituted with at least one substituent selected from -NHSf-O) 2 R 8 , -
  • R 4 is selected from phenyl, 2-fluorophenyl, 3 fluorophenyl, 4-fluorophcnyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl,
  • R 2 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, NO 2 , CF 3 , -OH, -OR 8 , -OCF 3 , C ⁇ Csalkyl, C,-C 6 fluoroalkyl, Q-Qheteroalkyl, C 3 -
  • R 2 is an optionally substituted heterocycle wherein the heterocycle is selected ox; oo ⁇ > as. 0 0 0 0 O ex) oo oo CO
  • R 2 is selected from phenyl, 2-fluorophe ⁇ yl, 3-fluorophenyl, 4-fluoro ⁇ henyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5 dichlorophenyl, 2-bromophenyl, 3 bromophenyl, 4 bromophenyl, 2-iodophenyl, 3-iodophenyl, 4- lodophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dmiethylphenyl, 2,3-dimethylphenyl, 3,4- dimethylphenyl, 3,5-dimethylphenyl, 2-t ⁇ fluromethylphenyl, 3-t ⁇ fluromethylphenyl, and 4- tnfluromethylphenyl
  • a method of modulating store-operated calcium (SOC) channel activity composing contacting the store-operated calcium (SOC) channel complex, or portion thereof, with a compound of Formula (I), (II), (IH), (IV), (V), or (Vl) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof
  • the contacting occurs m vitro
  • the contacting occurs m vcvo
  • the compound of Formula (I), (II), (III), (TV), (V), or (VI) modulates an activity of, modulates an interaction of, or modulates the level of, or binds to, or interacts with at least one portion of the store operated calcium channel complex selected from stromal interaction molecules (STIM) family of proteins
  • the compound of Formula (I), (II), (III), (IV), (V), or (VI) modulates an activity of, modulates an interaction of, or modulates the level of, or
  • a method of modulating calcium release activated calcium channel (CRAC) activity in a mammal comprising administering a compound of Formula (I), (II), (in), (TV), (V), or (VI), or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof
  • the compound of Formula (I), (II), (EI), (IV), (V), or (VT) modulates an activity of, modulates an interaction of, or modulates the level of, or bmds to, or interacts with at least one component of the calcium release activated (CRAC) channel complex selected from stromal interaction molecules (STM) family of proteins
  • the compound of Formula (I), (II), (III), (IV), (V), or (VI) modulates an activity of, modulates an interaction of, or modulates the level of, or bmds to, or interacts with STIMl or STIM2
  • modulating calcium release activated calcium (CRAC) modulates an activity of, modulates an interaction of, or modulates the
  • modulating calcium release activated calcium (CRAC) channel activity with a compound of Formula (I), (II), (III), (IV), (V), or (VI) inhibits the electrophysiological current (I C RAC) directly associated with activated CRAC channels
  • the compound of Formula (I), (II), (III), (IV), (V), or (VI) inhibits SOCE with an IC 511 below about 10 ⁇ M
  • the compound of Formula (I), ( ⁇ ), (m), (TV), (V), or (VI) inhibits electrophysiological current (I C RA C ) directly associated with activated CRAC channels at a concentration below about 10 ⁇ M
  • Also provided herein is a method of decreasing cytokine expression by inhibiting the store-operated calcium entry activation of NFAT m a mammal comprising administering a compound of Formula (I), (II), (III), S (IV), (V), or (VI), or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof
  • the compound of Formula (I), ( ⁇ ), (HI), (TV), (V), or (VI) modulates an interaction of, or modulates the level of, or bmds to, or interacts with a mammalian STIMl protein or a mammalian STIM2 protein
  • the cytokine is selected from IL-2, IL-3, IL-4, IL-S, IL-6, IL-7, IL-8, IL-9, DL-IO, IL-Il, IL-12, IL- 13, IL-15, IL-16, IL-17, IL-18, IL-Io, IL-
  • a pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient or binder, and a compound of Formulas (I), (II), (III), (IV), (V) or (VI), or pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof
  • a pharmaceutical composition which includes an effective amount of a compound provided herein, and a pharmaceutically acceptable excipient
  • compositions further including a second pharmaceutically active ingredient
  • a pharmaceutical composition containing i) a physiologically acceptable earner, diluent, and/or excipient, and u) one or more compounds described herein
  • a pharmaceutical composition containing i) a physiologically acceptable earner, diluent, and/or excipient, and u) one or more compounds described herein
  • further embodiments that include smgle administrations of the effective amount of the compound of Formulas (I), (II), (IH), (IV), (V) or (VI), including further embodiments in which (i) the compound of Formulas (I), (U), (in), (IV), (V) or (W) is administered once, (li) the compound of Formulas (I), (II), (IQ), (IV), (V) or (VI) is administered to the mammal multiple times over the span of one day, (in)
  • any of the aforementioned aspects are further embodiments that include multiple administrations of me effective amount of the compound of Formulas (I), (II), (III), (TV), (V) or (VI), including further embodiments m which (i) the compound of Formulas (I), (II), (UI), (IV), (V) or (VI) is administered in a smgle dose, (n) the time between multiple administrations is every 6 hours, (in) the compound of Formulas (I), (II), (IH), (IV), (V) or (VI) is administered to the mammal every 8 hours
  • the method comprises a drug holiday, wherein the administration of the compound of Formulas (I), (II), (IH), (IV), (V) or (VT) is temporarily suspended or the dose of the compound of Formulas (I), (H), (TH), (IV), (V) or (VI) being administered is temporarily reduced, at the end of the drug holiday, dosing of the compound of Formulas (I), (II),
  • compounds of Formulas (I), (H), (IH), (IV), (V) and (VI) descnbed herein are administered to a human
  • compounds of Formulas (I), (TI), (III). (IV), (V) and (VI) described herein are orally administered
  • Compounds provided herein are used for modulating intracellular calcium
  • compounds provided herein modulate SOC channel activity
  • compounds provided herein modulate CRAC channel activity
  • compounds provided herein modulate STIM protein activity
  • compounds provided herein modulate Oral protein activity
  • compounds provided herein modulate the functional interactions of STIM proteins with Oral proteins
  • compounds provided herein reduce the number of functional SOC channels
  • compounds provided herein reduce the number of functional CRAC channels
  • compounds descnbed herein are SOC channel blockers
  • compounds descnbed herein are CRAC channel blockers
  • Figure 1 outlines the ICRAC channel pathway
  • Cellular calcium homeostasis is a result of the summation of regulatory systems involved in the control of intracellular calcium levels and movements
  • Cellular calcium homeostasis is achieved, at least m part, by calcium binding and by movement of calcium into and out of the cell across the plasma membrane and within the cell by movement of calcium across membranes of intracellular organelles including, for example, the endoplasmic reticulum, sarcoplasmic reticulum, mitochondria and endocytic organelles including endosomes and lysosomes
  • VOC voltage-operated calcmm
  • SOC store-operated calcium
  • sodium/calcium exchangers operating in reverse mode VOC channels are activated by membrane depolarization and are found in excitable cells like nerve and muscle and are for the most part not found m nonexcitable cells
  • Ca 2+ can enter cells via Na + -Ca 2+ exchangers operating m reverse mode
  • Endocytosis provides another process by which cells take up calcium from the extracellular medium through endosomes In addition, some cells, e g , exocrine cells, can release calcium via exocytosis
  • Cytosohc calcium concentration is tightly regulated with resting levels usually estimated at approximately 0 1 ⁇ M in mammalian cells, whereas the extracellular calcium concentration is typically about 2 mM This tight regulation facilitates transduction of signals into and within cells through transient calcium flux across the plasma membrane and membranes of intracellular organelles
  • intracellular calcium transport and buffer systems in cells that serve to shape intracellular calcium signals and maintain the low resting cytoplasmic calcium concentration.
  • NFAT In lymphocytes and mast cells, activation of antigen or Fc receptors causes the release of Ca 2+ from intracellular stores, which in turn leads to Ca 2+ influx through CRAC channels in the plasma membrane The subsequent rise in intracellular Ca 2 * activates calcineu ⁇ n a phosphatase that regulates the transcription factor NFAT
  • NFAT In resting cells, NFAT is phosphorylated and resides m the cytoplasm, but when dephosphorylated by calcineu ⁇ n, NFAT translocates to the nucleus and activates different genetic programmes depending on stimulation conditions and cell type
  • AP-I transcription factor AP-I
  • the endoplasmic reticulum carries out a variety processes
  • the ER has a role as both an agonist-sensitive Ca 2+ store and sink, protein folding/processing takes place within its lumen
  • numerous Ca 2+ -de ⁇ endent chaperone proteins ensure that newly synthesized proteins are folded correctly and sent off to the appropriate destination
  • the ER is also involved m vesicle trafficking, release of stress signals, regulation of cholesterol metabolism, and apoptosis Many of these processes require intraluminal Ca 2+ , and protein misfolding, ER stress responses, and apoptosis can all be induced by depleting the ER of Ca 2+ for prolonged periods of tune
  • ER Ca 2+ content must Ml after stimulauo ⁇
  • it is vital that the Ca 2+ content does not fall too low or is maintained at a low level Replenishment of the ER with Ca 2+ is therefore
  • Store-operated calcium channels can be activated by any procedure that empties the stores, it does not seem to matter how the stores are emptied, the net effect is activation of store-operated Ca 2+ entry Physiologically, store emptying is evoked by an mcrease in the levels OfIP 3 or other Ca 2t -releasing signals followed by Ca 2+ release from the stores But there are several other methods for emptying stores These S methods include the following
  • SERCA sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPaSe
  • TPEN lowers free intraluminal Ca 2+ concentration without changing total store Ca 24 such that the store depletion-dependent signal is generated
  • CCE capacitanve calcium entry
  • Isoc store-operated current
  • ICRAC calcium release-activated current
  • Electrophysiological analysis of store-operated or calcium release-activated currents reveals distinct biophysical properties of these currents
  • the current are activated by depletion of intracellular calcium stores (e g , by nonphysiological activators such as thapsigargin, CPA 1 ionomycin and BAPTA, and physiological activators such as IP 3 ) and can be selective for divalent cations, such as calcium, over monovalent ions in physiological solutions or conditions, can be influenced by changes m cytosolic calcium levels, and can show altered selectivity and conductivity in the presence of low extracellular concentrations of divalent cations
  • the current may also be blocked or enhanced by 2 -APB (depending on concentration) and blocked by SKF96365 and Gd 3+ and generally are described as a calcium current that is not strictly voltage-gated
  • Patch-clamp studies m mast cells and Jurkat leukaemic T cells have established the CRAC entry mechanism as an ion channel with distinctive biophysical characteristics, including a high selectivity
  • Intracellular calcium stores are characterized by sensitivity to agents, which are physiological or pharmacological, which activate release of calcium from the stores or inhibit uptake of calcium into the stores
  • agents which are physiological or pharmacological, which activate release of calcium from the stores or inhibit uptake of calcium into the stores
  • Different cells have been studied m characterization of intracellular calcium stores, and stores have been characterized as sensitive to various agents, including, but not limited to, IP 3 and compounds that effect the IP 3 receptor, thapsigargm, ionomycm and/or cyclic ADP- ⁇ bose (cADPR)
  • cADPR cyclic ADP- ⁇ bose
  • Accumulation of calcium within endoplasmic reticulum and sarcoplasmic reticulum (SR, a specialized version of the endoplasmic reticulum m striated muscle) storage organelles is achieved through sarcoplasmic-endoplasmic reticulum calcium ATPases (SERCAs), commonly referred to as
  • ER free calcium can decrease from a range of about 60-400 uM to about 1-50 ⁇ M when HeLa cells are treated with histamine, an agonist of PLC-linked histamine receptors (Miyawaki et al (1997) Nature 388 882-887)
  • Store operated calcium entry 13 activated as the free calcium concentration of the intracellular stores is reduced.
  • Cytoplasmic Calcium Bufferimg Agonist activation of signaling processes m cells can involve dramatic increases in the calcium permeability of the endoplasmic reticulum, for example, through opening OfIF 3 receptor channels, and the plasma membrane through store-operated calcium entry These increases in calcium permeability are associated with an increase in cytosolic calcium concentration that are separated into two components a "spike" of calcium release from the endoplasmic reticulum during activation of the IF 3 receptor and a plateau phase which is a sustained elevation of calcium levels resulting from entry of calcium into the cytoplasm from the extracellular medium Upon stimulation, the resting intracellular free calcium concentration of about 10011M can rise globally to greater than 1 ⁇ M The cell modulates these calcium signals with endogenous calcium buffers, including physiological buffering by organelles such as mitochondria, endoplasmic reticulum and Golgi Mito
  • diseases, disorders or conditions that are treated or prevented using the compounds, compositions, and methods provided herein include diseases, conditions or disorders involving inflammation and/or that are related to the immune system These diseases include but are not limited to asthma, chrome obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis, neuroinflammatory diseases such as multiple sclerosis, and disorders of the immune system
  • modulation of intracellular calcium, and particularly store- S operated calcium entry is a method for treating immune and immune-related disorders, including, for example, chrome immune diseases/disorders, acute immune diseases/disorders, autoimmune and immunodeficiency diseases/disorders, diseases/disorders involving inflammation, organ transplant graft rejections and graft-versus-host disease and altered (e g , hyperactive) immune responses
  • immune disorders include psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scler
  • the pyrazole derivative BTP-2 a direct ICRAC blocker inhibits SOCE and proliferation m Jurkat cells and in colon cancer cells It has been suggested that sustained SOCE requires mitochonrial Ca 2+ uptake and that prevention of mitochondrial Ca 2+ uptake leads to SOCE inhibition. Stimulation of Jurkat cells induces sustained SOCE and activation of the Ca 2+ - dependent phosphatase calcineu ⁇ n that dephosphorylates NFAT, promoting expression of interleukin-2 and0 proliferation.
  • compounds of Formulas (I), (II), (III), (TV), (V) and (VI) inhibit SOCE and are used in the treatment of cancer or other proliferative diseases or conditions Liver Diseases and Disorders
  • diseases, disorders or conditions that are treated or prevented using the compounds of Formulas (I), (II), (III), (IV), (V) and (VI), compositions thereof, and methods provided herein5 include hepatic or liver diseases and disorders These diseases, conditions or disorders include but are not limited to liver injury, for example, due to transplantation, hepatitis and cirrhosis
  • the CRAC channel has a distinctive biophysical fingerprint, quantifiable store-dependence, and essential function in T cells Studies have shown that CRAC channels are formed from two component proteins, which interact to form CRAC channels
  • the CRAC channel is assembled by two functional components, STIMl and Orail STIMl (stromal interaction molecule 1) was identified as the mammalian ER Ca 2+ sensor
  • Orail/CRACMl was identified as a component of the mammalian CRAC channel
  • STIMl is the sensor OfCa 2+ within ER Ca 2+ stores, moving in response to store depletion into ER puncta close to the plasma membrane
  • Orail is a pore forming CRAC channel subunit in the plasma membrane
  • the two membrane proteins STIMl and Orail have each been shown to be essential for the activation of CRAC channels
  • TIRF Total internal reflection fluorescence
  • confocal microscopy reveal that STIM 1 is distributed throughout the ER when Ca 2+ stores are full, but redistributes into discrete puncta near the plasma membrane on store depletion. Although the redistribution of STIM 1 into junctional ER regions is slow, it does precede the opening of CRAC channels by several and is therefore rapid enough to be an essential step m the activation of CRAC channels
  • Compounds of Formulas (I), (II), (HI), (TV), (V) and (VI) described herein modulate intracellular calcium, such as, inhibition or reduction of SOCE and/or ICRAC
  • the modulation by compounds of Formulas (I), (II), (HI), (IV), (V) and (VI) result from a variety of effects, such as, but not limited to, binding to a protein, interaction with a protein, or modulation of interactions, activities, levels or any physical, structural or other property of a protein involved m modulating intracellular calcium (e g a STIM protein and/or Oral protein)
  • methods for assessing binding or interaction of a test agent with a protein mvolved m modulating intracellular calcium include NMR, mass spectroscopy, fluorescence spectroscopy, scintillation proximity assays, surface plasmon resonance assays and others
  • methods for assessing modulation of interactions, activities, levels or any physical, structural or other property of a protem mvolved in modulating intracellular calcium include, but are not limited to, FRET assays to assess effects on protein interactions, NMR, X-ray crystallography and circular dichroism to assess effects on protein interactions and on physical and structural properties of a protein, and activity assays suitable for assessing a particular activity of a protein Monitoring or Assessing Effects on Intracellular Calcium [00155] In some embodiments, monitoring or assessing the effect of a compound of Formula (I) or Formula (H) on intracellular calcium in any of the screening/identification methods described herein, a direct or indirect evaluation or measurement of cellular (including cytosolic and
  • reagents and conditions are known, and are used, for specifically evaluating store-operated calcium entry, resting cytosolic calcium levels, calcium buffering and calcium levels and uptake by or release from intracellular organelles and calcium stores
  • the effect of a compound of Formulas (I), (II), (IQ), (FV), (V) or (VI) on intracellular calcium is monitored or assessed using, for example, a cell, an intracellular organelle or calcium storage compartment, a membrane (including, e g , a detached membrane patch or a lipid bilayer) or a cell-free assay system (e g , outside-out membrane vesicle)
  • a membrane including, e g , a detached membrane patch or a lipid bilayer
  • a cell-free assay system e g , outside-out membrane vesicle
  • modulation of intracellular calcium is any alteration or adjustment m intracellular calcium including but not limited to alteration of calcium concentration or level m the cytoplasm and/or intracellular calcium storage organelles, e g , endoplasmic reticulum, alteration m the movement of calcium into, out of and within a cell or intracellular calcium store or organelle, alteration in the location of calcium within a cell, and alteration of the kinetics, or other properties of calcium fluxes into, out of and within cells
  • intracellular calcium modulation involves alteration or adjustment, e g reduction or inhibition, of store-operated calcium entry, cytosohc calcium buffering, calcium levels in or movement of calcium mto, out of or within an intracellular calcium store or organelle, and/or basal or resting cytosolic calcium levels
  • modulation of intracellular calcium involves an alteration or adjustment in receptor-mediated ion (e g , calcium) movement, second messenger-operated ion (e
  • compounds described herein modulate intracellular calcium, such as but not limited to, modulation (e g reduction or inhibition) of SOC channel activity, such as inhibition of CRAC channel activity (e g inhibition of ICRAC. inhibition of SOCE), in an immune system cell (e g , a lymphocyte, white blood cell, T cell, B cell), a fibroblast (or a cell de ⁇ ved from a fibroblast), or an epidermal, dermal or skin cell (e g , a keratinocyte)
  • the step of modulating one or more proteins involved m modulating intracellular calcium (e g a STIM protein and/or Oral protein) mvolves, for example, reducing the level, expression of, an activity of, function of and/or molecular interactions of a protein.
  • modulating involves reducing the level of, expression of, an activity or function of, or a molecular interaction of a protein, e g a STIM protein and/or Orai protem Treatment Methods
  • a method of modulating store-operated calcium (SOC) channel activity comprising contacting the store-operated calcium (SOC) channel complex, or portion thereof, with a compound of Formula (I), (II), (m), (IV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof
  • a method of modulating store-operated calcium channel activity comprising contacting the store-operated calcium (SOC) channel complex, or portion thereof, with a compound of Formula (I), (II), (III), (TV), (V) or (VI) wherein the contacting occurs in vitro
  • a method of modulating store-operated calcium channel activity comprising contacting the store-operated calcium (SOC) channel complex, or portion thereof, with a compound of Formula (I), (II), (III), (IV), (V) or (VI) wherein the contacting occurs m vivo
  • a method of modulating store operated calcium channel activity comprising contacting the store-operated calcium (SOC) channel complex, or portion thereof, with a compound of Formula (I), (II), (M), (IV), (V) or (VI) wherein the compound of Formula (I), (II), (IE), (IV), (V) or (VI) modulates an activity of, modulates an interaction of, or modulates the level of, or binds to, or interacts with at least one portion of the store operated calcium channel complex selected from stromal interaction molecules (STIM) family of proteins [00162]
  • a method of modulating store-operated calcium channel activity comprising contacting the store-operated calcium (SOC) channel complex, or portion thereof, with a
  • a method of modulating store-operated calcium channel activity comprising contacting the store-operated calcium (SOC) channel complex, or portion thereof, with a compound of Formula (I), (II), (III), (IV), (V) or (VI) wherein modulating calcium release activated calcium (CRAC) activity with a compound of Formula (I), ( ⁇ ), (IH), (IV), (V) or (Vl) inhibits the electrophysiological current (Ic K ⁇ c) directly associated with activated CRAC channels
  • CRAC calcium release activated calcium channel
  • CRAC calcium release activated calcium channel
  • a mammal comprising administering a compound of Formula (I), (II), (HI), (IV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof wherein (he compound of Formula (I), (II), (III), (IV), (V) or (VI) modulates an activity of, modulates an interaction of, or modulates the level of, or binds to, or interacts with at least one component of the calcium release activated (CRAC) channel complex selected from stromal interaction molecules (STlM) family of proteins [00168] In another embodiment is a method of modulating calcium release activated calcium channel
  • (CRAC) activity in a mammal comprising administering a compound of Formula (I), (II), (JS), (TV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof wherein the compound of Formula (I), (II), (III), (IV), (V) or (VI) modulates an activity of, modulates an interaction of, or modulates the level of, or binds to, or interacts with STIMl or STIM2 [00169] In yet another embodiment is a method of modulating calcium release activated calcium channel
  • CRAC activity in a mammal comprising administering a compound of Formula (I), (II), (111), (IV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof wherein modulating calcium release activated calcium (CRAC) channel activity with a compound of Formula (I), (H), (IH), (IV), (V) or (VI) inhibits store-operated calcium entry (SOCE) [00170]
  • a further embodiment is a method of modulating calcium release activated calcium channel
  • CRAC activity in a mammal comprising administering a compound of Formula (I), (II), (III), (IV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof wherein modulating calcium release activated calcium (CRAC) channel activity with a compound of Formula (I), (II), (ID), (IV), (V) or (VI) inhibits the electrophysiological current (ICRAC) directly associated with activated CRAC channels
  • [00171] in yet a further embodiment is a method of modulating calcium release activated calcium channel (CRAC) activity m a mammal comprising administering a compound of Formula (I), (II), (ITI), (IV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof wherein the compound of Formula (I), (II), (IE), (IV), (V) or (VI) inhibits SOCE with an IC 50 below 10 ⁇ M
  • [00172] in another embodiment is a method of modulating calcium release activated calcium channel (CRAC) activity in a mammal comprising administering a compound of Formula (I), (II), (III), (IV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof wherein the compound of Formula (I), (II), (III), (IV), (V) or (VI) inhibits electrophysiological current (ICR A C) directly associated with activated CRAC channels at a concentration below 10 uM
  • a method of treating a disease, disorder or condition in a mammal mat would benefit from inhibition of store operated calcium channel activity comprising administering to the mammal a compound of Formula (I), (II), (HI), (IV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof
  • a method of treating a disease, disorder or condition in a mammal that would benefit from inhibition of store operated calcium channel activity comprising administering to the mammal a compound of Formula (I), (II), (III), (IV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof wherein the compound of v modulates the activity of, modulates an interaction of, or binds to, or interacts with a mammalian STIMl protein, or a mammalian STIM 2 protein
  • [00175] in another embodiment is a method of treating a disease, disorder or condition in a mammal that would benefit from inhibition of store operated calcium channel activity comprising administering to the mammal a compound of Formula (I), (II), (IH), (TV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof wherein the disease, disorder or condition in a mammal is selected from diseases/disorders involving inflammation, glomerulonephritis, uveitis, hepatic diseases or disorders, renal diseases or disorders, chrome obstructive pulmonary disease, rheumatoid arthritis, psoriasis, inflammatory bowel disease, vasculitis, dermatitis, osteoarthritis, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, organ transplant rejection, allogeneic or xen
  • a further embodiment is a method of treating a disease, disorder or condition in a mammal that would benefit from inhibition of store operated calcium channel activity comprising administering to (he mammal a compound of Formula (I), (II), (IH), (IV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof wherein the disease, disorder or condition is organ transplant rejection [00181]
  • a method of treating a disease, disorder or condition in a mammal that would benefit from inhibition of store operated calcium channel activity comprising administering to the mammal a compound of Formula (I), (II), (III), (IV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof wherein the disease, disorder or condition is multiple sclerosis
  • [00182] in yet a further embodiment is a method of treating a disease, disorder or condition in a mammal that would benefit from inhibition of store operated calcium channel activity comprising administering to the mammal a compound of Formula (I), (II), (III), (IV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof further comprising administering to the mammal a second therapeutic agent
  • a method of treating a disease, disorder or condition in a mammal that would benefit from inhibition of store operated calcium channel activity comprising administering to the mammal a compound of Formula (T), (II), (III), (IV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof, wherein the second therapeutic agent is selected from immunosuppressants, glucocorticoids, non-steroidal anti inflammatory drugs, Cox-2-speciftc inhibitors, leflunomide, gold thioglucose, gold thiomalate, aurofin, sulfasalazine, hydroxychloroqumine, minocycline, anti-TNF- ⁇ agents, abatacept, anakmra, mterferon- ⁇ , interferon- ⁇ , interleukm-2, allergy vaccines, antihistamines, antileukotnenes, beta-agonists, theophylline, and
  • Also described herein is a method of inhibiting store-operated calcium entry (SOCE) activation of nuclear factor of activated T cells (NFAT) m a mammal comprising administering a compound of Formula (I), (II), (IE), (IV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof
  • a method of inhibiting store-operated calcium entry (SOCE) activation of nuclear factor of activated T cells (NFAT) m a mammal comprising administering a compound of Formula (I), (II), (III), (TV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof, wherein the compound of Formula (I), (II), (HI), (IV), (V) or (VI) 5 modulates an interaction of, or modulates the level of, or binds to, or interacts with a mammalian STIMl protein, or
  • a method of decreasing cytokine expression by inhibiting the store-operated calcium entry activation of NFAT in a mammal comprising administering a compound of Formula (J), (II), (III), (IV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically 0 acceptable prodrug thereof
  • [00188] in another embodiment is a method of decreasing cytokine expression by inhibiting the store- operated calcium entry activation of NFAT in a mammal comprising administering a compound of Formula (I), (II), (in), (IV), (V) or (VT) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof wherein the compound of Formula (I), (II), (IH), (IV), (V) or (VI) S modulates an interaction of , or modulates the level of, or binds to, or interacts with a mammalian STIM 1 protein or a mammalian STIM2 protein
  • cytokine is selected from IL-2, IL-3, IL-4, IL-S, IL-6, IL-7, IL-8, IL-9, IL-IO, IL-Il, IL-12, IL-13, IL-15, IL-16, IL-17, IL-18, IL-Io, IL-l ⁇ , IL-I RA, granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), oncostaUn M, erythropoietin, leukemia inhibitory factor (LIF), interferons, gam
  • compounds described herein modulate intracellular calcium and are used m the treatment of diseases, disorders or conditions where modulation of intracellular calcium has a beneficial effect
  • compounds described herein inhibit store operated calcium entry
  • compounds0 of Formulas (I), (II), (in), (JY), (V) and (VI) interrupt the assembly of SOCE units
  • compounds of Formulas Q), (JI), (JJI), (IV), (V) and (VT) alter the functional interactions of proteins that form store operated calcium channel complexes
  • compounds of Formulas (J), (TL), (IH), (IV), (V) and (VI) alter the functional interactions of STTMl with Orail
  • compounds of Formulas (I), (II), (HI), (TV), (V) and (VI) are SOC channel pore blockers
  • compounds of Formulas5 (I), 01), (HI), (JV), (V) and (VT) are CRAC channel pore blockers
  • compounds of Formulas (I), (U), (TII), (TV), (V) and (VI) inhibit the electrophysiological current (Isoc) directly associated with activated SOC channels
  • compounds of Formulas (J), (TI), (TTI), (TV), (V) and (VI) inhibit the electrophysiological current (ICRAC) directly associated with activated CRAC channels
  • the diseases, conditions or disorders that benefit from modulation of intracellular calcium include, but are not limited to, an immune system-related disease (e g , an autoimmune disease), a disease or disorder involving inflammation (e g , asthma, chrome obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis, neuroinflammatory diseases, multiple 5 sclerosis, and disorders of the immune system), cancer or other proliferative disease, kidney disease and liver disease Ih
  • compounds described herein are used as immunosuppresants to prevent transplant graft rejections
  • compounds described herein modulate an activity of, modulate an interaction of, or binds to, or interacts with at least one portion of a protein in the store operated calcium channel complex
  • compounds described herein modulate an activity of, modulate an interaction of, or binds to, or interacts with at least one portion of a protein in the calcium release activated calcium channel complex
  • compounds described herein reduce the level of functional store operated calcium channel complexes
  • compounds described herem reduce the level of activated store operated calcium channel complexes
  • store operated calcium channel complexes are calcium release activated calcium channel complexes
  • Compounds described herem for treatment of a disease or disorder, when administered to a subject0 having a disease or disorder effectively reduces, ameliorates or eliminates a symptom or manifestation of the disease, condition or disorder
  • compounds described herem also are administered to a subject predisposed to a disease, condition or disorder that does not yet manifest a symptom of the disease, condition or disorder, prevent
  • the compounds described herem, pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, or pharmaceutically acceptable solvates thereof modulate intracellular calcium, and are used to treat patients where modulation of intracellular calcium provides benefit
  • desc ⁇ bed herem is a compound of Formula (I), or pharmaceutically acceptable salt,0 pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof
  • L is a bond, Q-Qalkyl, Ci-C ⁇ alkenyl, Ci-C ⁇ heteroalkyl, aryl, or heteroaryl, wherein CpQalkyl, CpCealkenyl,5 Ci C ft heteroalkyl, aryl, or heteroaryl is optionally substituted with at least one R 5 ,
  • V is a bond, O, -(C(R 6 J 2 ), ⁇ or NR 1
  • W is a bond, Ci-C «alkyl, C t -C ⁇ alkenyl, Ci-Qjheteroalkyl, wherein when Y is S and X is CR 3 then V and W are
  • X is N or CR 3 ,
  • Y is O, S or NR 3 , with the proviso that if Y is S, then X is not CH, R is CO 2 R 1 , a carboxylic acid bioisostere, an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl,
  • R 1 is hydrogen, Ci-C ⁇ alkyl, Ct-Cehaloalkyl, or benzyl,
  • R 1 is hydrogen or C,-C 6 alkyl
  • R 1 is H, methyl, ethyl, n-propyi, iso propyl, n-butyl, sec-butyl, iso butyl, n-pentyl, or hexyl
  • R 1 is H, methyl, or ethyl
  • R 1 is H
  • L is a bond.
  • L is phenyl
  • L is -CH 2 CH 2 -
  • L is -CH 2 -
  • V is O or a bond
  • V is NR 1
  • W is C,-C 6 alkyl
  • W is a bond
  • V and W are both bonds
  • W is a compound of Formula (I) wherem W is -(CH 2 J n , and n is an integer from 1-4
  • W is d-Qheteroalkyl
  • W is -(CH ⁇ -O- wherein n is 0-6
  • n is 1-4
  • R is CO 2 R 1
  • R is a carboxylic acid bioisostere
  • R is an optionally substituted heteroaryl
  • R is an optionally substituted heterocycloalkyl
  • R 4 is a phenyl, optionally substituted with at least one subsbtuent selected from F, Cl, Br, I, -CN, -NO 2 , -CF 3 , -OH, -OR 8 , -OCF 3 , C-Qalkyl, d-Qsfluoroalkyl, Ci-Csheteroalkyl, C 3 - Cgcycloalkyl, and Ci-C ⁇ haloalkyl [00205] In another embodiment R 4 is an optionally substituted heterocycle wherein the heterocycle is selected from
  • R 4 is substituted with at least one substituent selected from -NHS(O) 2 R 8 , -
  • R 4 ts selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,
  • R 2 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO 2 -CF 3 , -OH, -OR 8 , -OCF 3 , CrC ⁇ alkyl, Ci-Cefluoroalkyl, C-Qheteroalkyl, C 3 -
  • R 2 is an optionally substituted heterocycle wherein the heterocycle is selected from
  • R 2 is selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluoro ⁇ henyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl,
  • X is N and Y is CR 3 , wherein R 3 is selected from H or methyl
  • X is CR 3 and Y is O, wherein R 3 is selected from H or methyl
  • X is CR 3 and Y is NR 3 , wherein each R 3 is independently selected from H or methyl
  • X is N.
  • Y is S. L. V. and W are each a bond.
  • R is COjR' where R 1 ⁇ hydrogen, R 4 is a phenyl group substituted with bromine at the para position and R 2 is a phenyl group substituted with F at the para position
  • X is N
  • Y is S
  • L is V
  • W arc each a bond
  • R is CO 2 R 1 where R 1 is hydrogen
  • R 4 is a phenyl group substituted with bromine at the para position
  • R 2 is a phenyl group substituted with F at the ortho position
  • X is N, Y is S, L, V, and W are each a bond, R is CO 2 R 1 where R 1 is hydrogen, R 4 is a phenyl group substituted with bromine at the para position and R 2 is a phenyl group substituted with F at the para position and a methyl group at the ortho position
  • X is N, Y is S, L, V, and W are each a bond
  • R is CO 2 R 1 where R 1 is methyl
  • R 4 is a phenyl group substituted with bromine at the para position
  • R 2 is a phenyl group substituted with F at the para position
  • X is N, Y is S, L, V, and W are each a bond, R is CO 2 R 1 where R 1 is methyl, R 4 is a phenyl group substituted with bromine at the para position and R 2 is a phenyl group substituted with F at the ortho position.
  • X is N, Y is S, L, V, and W are each a bond, R is CO 2 R 1 where R 1 is methyl, R 4 is a phenyl group substituted with bromme at the para position and R 2 is a phenyl group substituted with methyl at the para position.
  • X is N
  • Y is S
  • L, V, and W are each a bond
  • R is CO 2 R 1 where R 1 is methyl
  • R 4 is a phenyl group substituted with bromme at the para position
  • R 2 is a phenyl group substituted with F at the meta position
  • X is N
  • Y is S
  • L, V, and W are each a bond
  • R is CO 2 R-' where R 1 is hydrogen
  • R 4 is a phenyl group substituted with bromine at the para position
  • R 2 is a phenyl group substituted with F at the meta position.
  • C 6 alkenyl, Q-Qheteroalkyl, aryl, or heteroaryl is optionally substituted with at least one R 5 , V is a bond, O, -(CCR't ⁇ .-O or NR 1 ,
  • W is a bond, CrQplkyl, Q-Qalkenyl, C,-C ⁇ jheteroalkyl, X is N or CR 3 , Y is N or CR 3 ,
  • R is CO 2 R 1 , a carboxyhc acid bioisostere, an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl,
  • R 1 is hydrogen, CrQalkyl, C r C 6 haloalkyl, or benzyl
  • R 2 is an aryl, or a benzothienyl, wherein the aryl or benzothienyl is optionally substituted with at least one
  • R 4 is an aryl, optionally substituted with at least one R 5 , each R 5 is independently selected fiom F, Cl, Br, I, -CN, -NO 2 , -OH, -CF 3 , -OCF 3 , -OR 8 , Ci-Qplkyl, C 3 -
  • each R 8 is independently selected from Ci-C 1S aIlCyI, Ci-Cjhaloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl
  • each R* IS independently selected from H, Ci-Qjalkyl, Q-Cjhaloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl
  • R 3 is hydrogen, Q-Qalkyl, Ci-C ⁇ haloalkyl, Ci-Qheteroalkyl, substituted or unsubsrxtuted aryl or benzyl 100226]
  • substituents are selected from among a subset described herein
  • R 1 is hydrogen or Ci-C ⁇ alkyl
  • R 1 is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, n-pentyl, or hexyl
  • R 1 is H, methyl, or ethyl
  • R 1 is H S [00227]
  • In one embodiment is a compound of Formula (II) wherein L is a bond
  • L is phenyl
  • L is -CH 2 CH 2 -
  • L is -CH 2
  • n is an integer from 1-2
  • W is Ci-C 6 heteroalkyl
  • W is -(CHz) 11 -O- wherein n is 0-6
  • n is 1 -4
  • R is CO 2 R 1
  • R is a carboxylic acid bioisostere
  • R is an optionally substituted heteroaryl
  • R is an optionally substituted heterocycloalkyl
  • R 4 is a phenyl, optionally substituted with at least one subsutuent selected0 from F, Cl, Br, I, -CN, -NO 2 , -CF 3 , -OH, -OR 8 , -OCF 3 , d-Csalkyl, d-Qfluoroalkyl, Ci-C f iheteroalkyl, C 3 -
  • R 4 is an optionally substituted heterocycle wherein the heterocycle is selected from.
  • R 2 is an optionally substituted heterocycle wherein the heterocycle is selected from
  • X is N and Y is CR 3 , wherem R 3 is selected from H or methyl
  • X is N and Y is N
  • X is CR 3 and Y is CR 3 , wherein each R 3 is independently selected from H or methyl
  • X is CR 3 and Y is N, wherem R 3 is selected from H or methyl
  • X is CR 3 , wherem R 3 is H, Y is N, L is a bond, R is CO 2 R 1 , wherein R 1 is hydrogen, R 4 is a phenyl group substituted at the para position with Br, V is a bond, W is a bond, and R 2 is a phenyl group substituted at the para position with F
  • L is a bond, C,-C «alkyl, d-Csalkenyl, Ci-Qheteroalkyl, aryl, or heteroaryl, wherem CpC ⁇ alkyl, C 1 - Qalkenyl, Ci-CsheteroalkyL, aryl, or heteroaryl is optionally substituted with at least one R 10 , V is a bond, O, -CC(R 3 J 2 J n -O or NR 1 , W is a bond, Ci-C ⁇ lkyl, Ci-C 6 alkenyl, Ci-Qjheteroalkyl
  • R is COjR 1 , a carboxyhc acid bioisostere, an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl,
  • R 1 is hydrogen, Ci-C 6 alkyl, Ct-Qhaloalkyl, or benzyl
  • R 2 is an aryl, or a benzothienyl, wherein the aryl or benzothienyl is optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO 2 , -OH, -CF 3 , -OCF 3 , -OR 8 , d-Cj-lkyl, C 3 - Cscycloalkyl, Ci Qsheteroalkyl, Ci-C 6 haloalkyl, tetrazolyl, C ⁇ -Csheterocyoloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(O) 2 R 8 , -S(O) 2 N(R 9 ) !
  • R 4 is an aryl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO 2 , - CF 3 , -OH, -OR 8 , -OCF 3 , C,-C 6 alkyl, C 3 -C,cycloallcyl, C-Ofluoroalkyl, Ci-Ceheteroalkyl, C,- Cshaloalkyl, tetrazolyl, C 2 -C 8 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(O) 2 R 8 , S(O) 2 N(R 9 J 2 , -N(R 9 JS(O) 2 N(R 9 J 2 , -C(OJCF 3 , -C(O)NHS(O) 2 R 8 , -
  • each R 3 is independently selected from hydrogen, from F, Cl, Br, I, -CN, -NO 2 , -OH, -CF 3 , -OCF 3 , -OR 8 ,
  • R 5 , R 6 and R 7 are independently selected from a hydrogen, -OH, halogen, Ci-Cjalkyl, C r Cyialoalkyl, C 1 - Cjheteroalkyl, substituted or unsubstituted aryl or benzyl
  • R 1 is hydrogen or Ci-Csalkyl
  • R 1 is H, methyl, ethyl, n-propyl, lso-propyl, n-butyl, sec-butyl, iso-butyl, n-pentyl, or hexyl
  • R 1 is H, methyl, or ethyl
  • R 1 is H
  • [00249] In one embodiment is a compound of Formula (in) wherein L is a bond
  • L is phenyl
  • L is -CH 2 CH 2 -
  • L is -CH 2 -
  • [002S1] In one embodiment is a compound of Formula (IH) wherein V is NR 1 [00252] In another embodiment is a compound of Formula (m) wherein W is Ci-Qalkyl In one embodiment, W is a bond In another embodiment, V and W are both bonds
  • n is an integer from 1-2
  • W is Ci-Cyieteroalkyl
  • W is -(CH 2 J n -O- wherein n is 0-6
  • n is 1-4
  • R is CO 2 R 1
  • R is a carboxyhc acid bioisostere
  • R is an optionally substituted heteroaryl.
  • R is an optionally substituted heterocycloalkyl
  • R 4 is a phenyl, optionally substituted with at least one substituent selected from
  • R 4 is an optionally substituted heterocycle wherein the heterocycle is selected from
  • R 4 is selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4- fluorophenyl, 2-chlorophenyI, 3 chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl; 2,3-dichlorophenyl, 3,4- dichlorophenyl, 3,5-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3 iodophenyl, 4-iodophenyl, 2-methylphenyl, 3-methylphenyL, 4-methylphenyl, 2,4-dimethylphenyl, 2,3- dunethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2-t ⁇ fluromethylphenyl, 3-t ⁇ fluromethylphenyl, and 4-t ⁇ fluromethylphenyl
  • R 2 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO 2 , -CF 3 , -OH, -OR 8 , -OCF 3 , d-Qalkyl, Ci-C 6 fluoroalkyl, C-Qjheteroalkyl, C 3 -Cgcycloalkyl, and C r C 6 haloalkyl [00261] In a further embodiment R 2 is an optionally substituted heterocycle wherein the heterocycle is selected from. O Q CO CO CO CO
  • R 2 is selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4- fluorophenyl
  • L is a bond, Ci-Cjalkyl, Ci-C 3 alkenyl, Ci-Ceheteroalkyl, aryl, or heteroaryl, wherein Ci-C «alkyl, Ci-
  • C 6 alkenyl, d-C ⁇ heteroalkyl, aryl, or heteroaryl is optionally substituted with at least one R 10 , V is a bond, 0, -(C(R' ⁇ 0 or NR 1 ,
  • W is a bond, Ci-Csalkyl, Q-C ⁇ alkenyl, CpC ⁇ heteroalkyl,
  • X is N or CR 3 ,
  • Y is O, S, NR 3 or -CR 5 -CR 6 -,
  • R 2 is an aryl, or a benzothienyl, wherein the aryl or benzothienyl is optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO 2 , -OH, -CF 3 , -OCF 3 , -OR 8 , C,-C 6 alkyl, C 3 -
  • R 4 is an aryl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO 2 , - CF 3 , -OH, -OR 8 , -OCF 3 , Ci-C 6 alkyl, C 3 -C B cycloalkyl, C,-C 6 fluoroalkyl, C I -C 6 heteroalkyl, C,- C ft haloalkyl, tetrazolyl, C 2 -Cghetorocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(O) 2 R 8 , S(O) 2 N(R 9 J 2 , -NCR 9 JS(OJ 2 N(R 9 J 2 , -C(O)CF 3 , -C(O)NHS(OJ 2 R 8 , - S(O) 2 NHC(O)R 8 , -N(R 9 J 2
  • R 3 is hydrogen, Ci-Qalkyl, Q-Qhaloalkyl, Ci-Qheteroalkyl, substituted or unsubstituted aryl or benzyl, and
  • R s and R 6 are independently selected from a hydrogen, -OH, halogen,
  • R 1 is hydrogen or Ci-C ⁇ alkyl
  • R 1 is H, methyl, ethyl, n-propyl, lso-propyl, n-butyl, sec-butyl, iso-butyl, n-pentyl, or hexyl
  • R 1 is H, methyl, or ethyl
  • R 1 is H
  • L is a bond
  • L is phenyl.
  • L is -CH 2 CH 2 -
  • L is -CH 2 -
  • V is O or a bond
  • V is NR 1
  • W is Ci-C 6 alkyl
  • W is a bond.
  • V and W are both bonds
  • n is a compound of Formula (TV) wherein W is -(CH 2 J n , and n is an integer [00271] In yet another embodiment is a compound of Formula (TV) wherein n is an integer from 1-2 In a further embodiment, W is Ci-Cyieteroalkyl In yet a further embodiment, W is -(CH 2 J n -O- wherein n is 0-6 In another embodiment, n is 1-4
  • R 4 is a phenyl, optionally substituted with at least one substrtuent selected from F, Cl, Br, I, -CN, -NO 2 , -CF 3 , -OH, -OR 8 , -OCF 3 , d-Csalkyl, Ci-Csfluoroalkyl, Ci-Qheteroalkyl, C 3 - Cjjcycloalkyl, and CrCehaloalkyl [00273] In other embodiments R 4 is an optionally substituted heterocycle wherein the heterocycle is selected from. ⁇ ⁇ O ⁇ O ⁇ ⁇ ⁇
  • R 4 is selected from phenyl, 2 fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2 chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4 dichlorophenyl, 2,3 dichlorophenyl, 3,4 dichlorophenyl,
  • R 2 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO 2 , -CF 3 , -OH, -OR 8 , -OCF 3 , Q-C ⁇ alkyl, d-Qjfluoroalkyl, C,-C 6 heteroalkyl, C 3 -
  • R 2 is an optionally substituted heterocycle wherein the heterocycle is selected from ⁇ ⁇ .O " ⁇ ⁇ O ⁇ ⁇
  • R 2 iso substitut ⁇ ed with ocne oor more oof theo subs ⁇ touentos selectecd froom -
  • R 2 is selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2- chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 23-dichlorophenyl, 3,4-dichlorophenyl,
  • each R 6 is independently selected from hydrogen, from F, Cl, Br, I, -CN, -NO 2 , -OH, -CF 3 , -OCF 3 , -OR 8
  • each R 8 is independently selected from C 1 -C 6 alkyl, C r C «haloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl, and each R 9 is independently selected from H, C r C 6 alkyl, Ci-C d haloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl
  • R 1 is hydrogen or Ci-C 6 alkyl
  • R 1 is H, methyl, ethyl, ⁇ -propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, n-pentyl, or hexyl
  • R 1 is H, methyl, or ethyl
  • R 1 is H
  • V is MR 1
  • W is Cj-C 6 alkyl
  • W is a bond. In another embodiment, V and W are both bonds
  • n is a compound of Formula (V) wherein n is an integer from 1 -2
  • W is Ci-Cyieteroalkyl
  • W is -(CH 2 ) o -O- wherein n is 0-6
  • n is 1-4
  • R is CO 2 R 1
  • R is a carboxylic acid bioisostere
  • R is an optionally substituted heteroaryl
  • R is an optionally substituted heterocycloalkyl
  • R 4 is a substituent selected from H, F, Cl, Br, I, -CN, -NO 2 , -CF 3 , -OH, -OR S , -
  • R 2 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO 2 , -CF 3 , -OH, -OR 8 , OCF 3 , CrCjalkyl, CpCsfluoroalkyl, Ci-C 6 heteroalkyl, C 3 -
  • R 2 is an optionally substituted heterocycle wherein the heterocycle is selected
  • R 2 is O substitut Oed with o Cne oOr more o cf thoe substit CuentOs selecte cd fro ⁇ m - NHS(O) 2 R 8 , -S(O) 2 N(RV -N(R 9 JS(O) 2 N(RV -N(R 9 J 2 , -N(R 9 JC(O)R 8 , -N(RVXO)N(RV, - N(R*)C(0)OR 8 , -CO 2 R 9 , -C(O)R 8 , -OC(O)N(R 9 J 2 , -CON(RV -SR 8 , or -S(O) 2 R 8
  • R 2 is selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2- chlorophenyl, 3-chlorophenyl, 4-chloro ⁇ henyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromo ⁇ henyl, 2-iodophenyl, 3-iodophenyl, 4- lodophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 2,3-dimethylphenyl, 3,4- dimethylphenyl, 3,5-dimetiiylphenyl, 2-t ⁇ fluromethylphenyl, 3-t ⁇ fluromethylphenyl, and 4- t ⁇ fluromethylphenyl
  • Z is Ci-C ⁇ alkyl, Ci-Qjhaloalkyl.
  • each R 8 is independently selected from Ci-C ⁇ alkyl, C,-C 6 haloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl, and each R 9 is independently selected from H, Ci-Qalkyl, Ci-C 6 haloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl.
  • a compound of Formula (VI) wherem Z is CpQalkyl [00298] In another embodiment is a compound of Formula (VI) wherein Z is CH 3 [00299] In yet another embodiment is a compound of Formula (VIJ wherem Z is CH 2 CH 3 [00300] In one embodiment is a compound of Formula (VI) wherem Z is substituted with a substituent selected from F, Cl, Br, I, -CN, -NO 2 , -OH, -CF 3 , -OCF 3 , -OR 8 , Ci-C «alkyl, C 3 -C 8 cycloalkyl, and C,- Qjheteroalkyl.
  • R 1 is hydrogen or CrC ⁇ alkyl
  • R 1 is H, methyl, ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, lso-butyl, n-pentyl, or hexyl
  • R 1 is H, methyl, or ethyl
  • R 1 is H
  • R 4 is a phenyl, optionally substituted with at least one substit ⁇ ent selected from F, Cl, Br, I, -CN, -NO 2 , -CF 3 , -OH, -OR 8 , -OCF 3 , d-Cjalkyl, Ci-Qfluoroalkyl, C-Qheteroalkyl, C 3 -
  • R 4 is an optionally substituted heterocycle wherein the heterocycle is selected from
  • R 4 is selected from phenyl, 2-fluorophenyI, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl,
  • R 2 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO 2 , -CF 3 , -OH, -OR 8 , -OCF 3 , C-C ⁇ alkyl, CrCyiuoroalkyl, Ci-Cshetero
  • R 2 is an optionally substituted heterocycle wherein the heterocycle is selected from
  • R 2 O is substit outedo with on Ce or Q more o of the ⁇ substitu centso selected from - NHS(O) 2 R 8 , S(OJ 2 N(R 9 J 2 , -N(R 9 JS(OJ 2 NCR 9 J 2 , -NCR 9 J 2 , -NCR 9 JC(O)R 8 , -NCR 9 JC(O)N(R 9 J 2 , - NCR 9 JC(O)OR 8 , -CO 2 R 9 , -C(O)R 8 , -OC(O)N(R 9 J 2 , -CONCR 9 J 2 , -SR 8 , or -S(OJ 2 R 8
  • R 2 is selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-bromophenyl, 3-bromophenyl; 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4- lodophenyl, 2-methylphenyl; 3-methylphenyl, 4-methylphenyl; 2,4-dimethylphenyl; 2,3-dimethylphenyl; 3,4- dimethylphenyl, 3,5-dimethylphenyl; 2-t ⁇ fluromethylphenyl; 3-tnfluromethylphenyl; and 4- tnfluromethylphenyl
  • the compounds described herein exist as diastereomers, enantiomers, or other stereoisomerism forms
  • the compounds presented herein include all diastercomenc, enantiomeric, and epimenc forms as well as the appropriate mixtures (hereof Separation of stereoisomers are performed by chromatography or by the forming diastereomenc and separation by recrystalhzation, or chromatography, or any combination thereof (Jean Jacques, Andre Collet, Samuel H Wilen, "Enantiomers, Racemates and Resolutions", John Wiley
  • stereoisomers are obtained by stereoselective synthesis
  • prodrugs refers to an agent that is converted into the parent drug in vivo Prodrugs are often useful because, m some situations, they are easier to administer than the parent drug
  • the prodrug is bioavailable by oral administration whereas the parent is not
  • the prodrug also has improved solubility in pharmaceutical compositions over the parent drug
  • An example, without limitation, of a prodrug would be a compound described herein, which is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabohcally hydrolyzed to the carboxyhc acid, the active entity, once mside the cell where water-sotubihty is beneficial
  • the prodrug is a short peptide (poiyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety
  • prodrug is a short peptide (poiyaminoacid) bonded to an acid group where the
  • a pharmaceutically active compound is modified such that the active compound will be regenerated upon in vtvo administration
  • the prodrug is designed to alter the metabolic stability or (he transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug
  • Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound of Formulas (I), (II), (III), (TV), (V) or (VI) as set forth herein are included within the scope of the claims hi some cases, some of the herein-described compounds are a prodrug for another derivative or active compound
  • prodrugs that are designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues
  • the design of a prodrug increases the effective water solubility
  • sites on the aromatic ⁇ ng portion of compounds described herein are susceptible to various metabolic reactions, therefore incorporation of appropriate substituents on the aromatic ⁇ ng structures, such as, by way of example only, halogens can reduce, minimize or eliminate this metabolic pathway
  • the compounds described herein are labeled isotopically (e g with a radioisotope) or by other means, including, but not limited to, the use of chromophores or fluorescent moieties, biolummescent labels, photoacuvatable or chemiluminescent labels [00322]
  • Compounds described herem include isotopically labeled compounds, which are identical to those recited m the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature
  • isotopes that are incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorme, such as.
  • compositions described herem are formed as, and/or used as, pharmaceutically acceptable salts
  • pharmaceutically acceptable salts include, but are not limited to (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphonc acid, and the like, or with an organic acid, such as, for example, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycohc acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumanc acid, tnfluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesuUbnic acid,
  • a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs
  • Solvates contain either stoichiometric or non-stoichiomet ⁇ c amounts of a solvent, and in some embodiments are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol
  • solvates of compounds described herem are conveniently prepared or formed during the processes described herem.
  • the compounds provided herein exist in unsolvated as well as solvated forms In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • compounds described herein such as compounds of Formulas (I), (JI), (HI), (IV), (V) and (VI), are in various forms, including but not limited to, amorphous forms, milled forms and nano- particulate forms
  • compounds described herein include crystalline forms, also known as polymorphs
  • Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound.
  • Polymorphs usually have different X-ray diffraction patterns, melting points, density, hardness, crystal shape, optical properties, stability, and solubility Various factors such as the recrystalhzation solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate [00327]
  • the screening and characterization of the pharmaceutically acceptable salts, polymorphs and/or solvates are accomplished using a variety of techniques including, but not limited to, thermal analysis, x-ray diffraction, spectroscopy, vapor sorption, and microscopy
  • Thermal analysis methods address thermo chemical degradation or thermo physical processes including, but not limited to, polymorphic transitions, and such methods are used to analyze the relationships between polymorphic forms, determine weight loss, to find the glass transition temperature, or for excrpient compatibility studies
  • Such methods include, but are not limited to, Differential scanning calo ⁇ metry (DSC), Modulated Differential Scanning Calo ⁇ metry (MDCS), The ⁇ nogravimet ⁇ c analysis (TGA
  • the compounds described herein are modified using various electrophiles and/or nucleophiles to form new functional groups or subs ⁇ tuents Table 2 entitled "Examples of Covalent Linkages and Precursors Thereof lists selected non-hnuting examples of covalent linkages and precursor functional groups which yield the covalent linkages Table 2 is used as guidance toward the variety of electrophiles and nucleophiles combinations available that provide covalent linkages Precursor functional groups are shown as electrophihc groups and nucleophihc groups Table 2: Examples of Covalent Linkages and Precursors Thereof
  • Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed
  • each protective group is removable by a different means
  • Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal [00333)
  • protective groups are removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and/or oxidative conditions
  • groups such as tntyl, dimethoxyt ⁇ tyl, acetal and t-butyldimethylsilyl are acid labile and are used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable
  • C 1 -C includes C r C 2 , Ci-C 3 C 1 -C x Cj-C 1 refers to the number of carbon atoms mat make up the moiety to which it designates (excluding optional substmients)
  • An "alkyl” group refers to an aliphatic hydrocarbon group In some embodiments, the alkyl groups include or do not include units of unsaturation In some embodiments, the alkyl moiety is a "saturated alkyl” group, which means that it does not contain any units of unsaturation (i e a carbon-carbon double bond or a carbon-carbon triple bond) In further embodiments, the alkyl group also is an "unsaturated alkyl" moiety, which means that it contains at least one unit of unsaturation In some embodiments, the alkyl moiety, whether saturated or unsaturated, is branched, straight chain, or eye he [00356] In other embodiments, the "alkyl"
  • alkoxy refers to a "-O-alkyl” group, where alkyl is as defined herein.
  • the alkenyl moiety are branched, straight chain, or cyclic (in which case, it would also be known as a "cycloalkenyl" group)
  • Alkenyl groups may have 2 to 6 carbons
  • Alkenyl groups are substituted or unsubsr ⁇ tuted
  • an alkenyl group is a monoradical or a diradical (i e , an alkenylene group)
  • alkynyl refers to a type of alkyl group m which the first two atoms of the alkyl group form a triple bond That is, an alkynyl group begins with the atoms -C ⁇ C-R, wherein R refers to the remaining portions of the alkynyl group
  • R refers to the remaining portions of the alkynyl group
  • the "R" portion of the alkynyl moiety is branched, straight chain, or cyclic
  • An alkynyl group can have 2 to 6 carbons Alkynyl groups are substituted or unsubstituted
  • an alkynyl group is a monoradical or a diradical (i e , an alkynylene group)
  • “Ammo" refers to a
  • aromatic refers to a planar ring having a delocalized ⁇ -electron system containing 4n+2 ⁇ electrons, where n is an integer In other embodiments, aromatic rings are formed from five, six, seven, eight, nine, or more than nine atoms In some other embodiments, aromatics are optionally substituted.
  • aromatic includes both aryl groups (e g , phenyl, napthalenyl) and heteroarji groups (e g , pyndinyl, qumohnyl)
  • aryl refers to an aromatic nog wherein each of the atoms forming the nng is a carbon atom
  • aryl rings are formed by five, six, seven, eight, nine, or more than nine carbon atoms
  • aryl groups are optionally substituted Examples of aryl groups include, but are not limited to phenyl, and naphthalenyl In other embodiments, depending on the structure, an aryl group is a monoradical or a diradical (l e , an arylene group)
  • Carboxy refers to -CO 2 H
  • oarboxy moieties may be replaced with a "carboxyhc acid bioisostere", which refers to a functional group or moiety that exhibits similar physical and/or chemical properties as a carboxyhc acid moiety
  • carboxyhc acid bioisostere has similar biological properties to that of a carboxyhc acid group
  • a compound with a carboxyhc acid moiety can have the carboxyhc acid moiety exchanged with a carboxyhc acid bioisostere and have similar physical and/or biological properties when compared to the carboxyhc acid-containing compound
  • a carboxyhc acid bioisostere would ionize at physiological pH to roughly the same extent as a carboxyhc acid group
  • bioisoteres of a carboxyhc acid include, but are not limited to,
  • cycloalkyl refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the nng (i e skeletal atoms) is a carbon atom
  • cycloalkyls are saturated, or partially unsaturated
  • cycloalkyls are fused with an aromatic rmg (m which case the cycloalkyl is bonded through a non-aromatic nng carbon atom)
  • Cycloalkyl groups include groups having from 3 to 10 nng atoms
  • Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties
  • heteroaryl or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more nng heteroatoms selected from nitrogen, oxygen and sulfur
  • An ⁇ T-containing “heteroaromatic” or “heteroaryl' * moiety refers to an aromatic group in which at least one of the skeletal atoms of the nng is a nitrogen atom.
  • polycychc heteroaryl groups are fused or non-fused.
  • Illustrative examples of heteroaryl groups include the following moieties
  • a ' heterocycloalkyl group or “heteroalicyclic” group refers to a cycloalkyl group, wherein at least one skeletal nng atom is a heteroatom selected from nitrogen, oxygen and sulfur
  • the radicals are fused with an aryl or heteroaryl
  • heterocycloalkyl groups also referred to as non-aromatic heterocycles, include
  • heteroalicyclic also includes all ⁇ ng forms of the carbohydrates, including but not limited to the monosaccharides, the disacchandes and the oligosaccharides Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons m the ⁇ ng It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i e skeletal atoms of the heterocycloalkyl ⁇ ng)
  • halo or, alternatively, “halogen” means fluoro, chloro, bromo and iodo
  • haloalkyl refers to an alkyl group that is substituted with one or more halogens In some embodiments, the halogens are the same or they are different Non-limiting examples of haloalkyls include - CH 2 Cl, -CF 3 , -CHF 2 , -CH 2 CF 3 , -CF 2 CF 3 , -CF(CH 3 ) 3 , and the like
  • fluoroalkyl and “fluoroalkoxy” mclude alkyl and alkoxy groups, respectively, that are substituted with one or more fluorine atoms
  • fluoroalkyls include -CF 3 , -CHF 2 , - CH 2 F, -CH 2 CF 3 , -CF 2 CF 3 , -CF 2 CF 2 CF 3 , -CF(CKi) 3 , and the like
  • Non-hmiting examples of fluoroalkoxy groups include OCF 3 , -OCHF 2 , -OCH 2 F, -OCH 2 CF 3 , -OCF 2 CF 3 , -OCF 2 CF 2 CF 3 , -OCF(CH 3 ) 2 , and the like
  • heteroalkyl refers to an alkyl radical where one or more skeletal chain atoms is selected from an atom other than
  • the substituent "R” appealing by itself and without a number designabon refers to a substituent selected from among from alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloalkyl
  • the term "optionally substituted” or “substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkyisulfone, arylsulfone, -CN, halo, acyl, acyloxy, -CO 2 H, -C ⁇ 2 -alkyl, nitro, halo
  • the methods and formulations described herein include the use of crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds having the structure of Formulas (I), (II), (DI), (IV), (V) and (VI), as well as active metabolites of these compounds having the same type of activity
  • compounds exist as tautomers All tautomers are included within the scope of the compounds presented herein
  • the compounds described herein exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ⁇ thanol, and the like
  • the solvated forms of the compounds presented herein are also considered to be disclosed herein [00377]
  • the terms “kit' and "article of manufacture” are used as synonyms
  • the term "subject” or "patient” encompasses mammals and non-mammals Examples of mammals include, but are not limited to, any member of the Mammalian class humans, non-human primates such as chimpanzees, and other apes
  • treat include alleviating, abating or ameliorating a disease, disorder or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying causes of symptoms, inhibiting the disease, disorder or condition, e g , arresting the development of the disease, disorder or condition, relieving the disease, disorder or condition, causing regression of the disease, disorder or condition, relieving a condition caused by the disease, disorder or condition, or stopping the symptoms of the disease, disorder or condition either prophylactically and/or therapeutically
  • target protem refers to a protein or a portion of a protein capable of being bound by, or interacting with a compound described herein, such as a compound of Formulas (I), (II), (III), (IV), (V) or (VI)
  • a target protein is a STIM protein
  • a target protem is an Oral protem
  • STIM protem includes but is not limited to, mammalian STIM-I, such as human and rodent (e g , mouse) STIM-I, Drosophila melanogaster D-STIM, C elegans C-STIM, Anopheles gambiae STIM and mammalian ST1M-2, such as human and rodent (e g , mouse) STIM-2
  • mammalian STIM-I such as human and rodent (e g , mouse) STIM-I
  • Drosophila melanogaster D-STIM such as human and rodent (e g , mouse) STIM-2
  • ST1M-2 such as human and rodent (e g , mouse) STIM-2
  • such proteins have been identified as being involved in, participating m and/or providing for store-operated calcium entry or modulation thereof, cytoplasmic calcium buffering and/or modulation of calcium levels m or movement of calcium into, within or out of intracellular calcium stores (e g , endoplasmic
  • fragment or “derivative” when referring to a protein (e g STIM, Oral) means proteins or polypeptides which retain essentially the same biological function or activity in at least one assay as the native protein(s) For example, the fragments or derivatives of the referenced protein maintains at least about 50% of the activity of the native proteins, at least 75%, at least about 95% of the activity of the native proteins, as determined e g by a calcium influx assay
  • amelioration of the symptoms of a particular disease, disorder or condition by administration of a particular compound or pharmaceutical composition refers to any lessening of seventy, delay m onset, slowing of progression, or shortening of duration, whether permanent or temporary, lasting or transient that are attributed to or associated with administration of the compound or composition
  • modulate means to interact with a target protein either directly or indirectly so as to alter the activity of the target protein, including, by way of example only, to inhibit the activity of the target, or to limit or reduce the activity of the target [00386]
  • the term “modulator” refers to a compound that alters an activity of a target
  • a modulator causes an increase or decrease in the magnitude of a certain activity of a target compared to the magnitude of the activity m the absence of the modulator
  • a modulator is an inhibitor, which decreases the magnitude of one or more activities of a target
  • an inhibitor completely prevents one or more activities of a target
  • modulation with reference to intracellular calcium refers to any alteration or adjustment in intracellular calcium including but not limited to alteration of calcium concentration in the cytoplasm and/or intracellular calcium storage organelles, e g , endoplasmic reti
  • pharmaceutically acceptable refers a material, such as a earner or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i e , the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained
  • pharmaceutical combination as used herem, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the 5 active ingredients
  • fixed combination means that one active ingredient, e g a compound of Formulas (I), (II), (III), (TV), (V) or (VI), and a co-agent, are both administered to a patient simultaneously in the form
  • composition refers to a mixture of a compound of Formulas (I), (II), (III), (TV), (V) or (VI) described herem with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients
  • pharmaceutical composition S facilitates administration of the compound to an organism
  • Multiple techniques of administering a compound exist in the art including, but not limited to intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and topical administration
  • an "effective amount” or “therapeutically effective amount,” as used herem, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more0 of the symptoms of the disease or condition bemg treated. The result is reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an "effective amount” for therapeutic uses is the amount of the composition that includes a compound of Formulas (I), (II), (in), (IV), (V) or (VI) described herem required to provide a clinically significant decrease m disease symptoms
  • an appropriate "effective" amount in any individual case is determined using5 techniques, such as a dose escalation study
  • enhancing means to increase or prolong either in potency or duration a desired effect
  • enhancing refers to the ability to increase or prolong, either m potency or duration, the effect of other therapeutic agents on a system
  • co-administration or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are mtended to include treatment regimens m which the agents are administered by the same or different route of administration or at the same or different time
  • agent refers to relatively nontoxic chemical compounds or agents that5 facilitate the incorporation of a compound into cells or tissues
  • diluent refers to chemical compounds that are used to dilute the compound of interest prior to delivery
  • diluents are used to stabilize compounds because they provide a more stable environment
  • Salts dissolved in buffered solutions (which also provide pH control or maintenance) are utilized as diluents, including, but not limited to a phosphate buffered saline solution
  • a "metabolite" of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized.
  • active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized
  • metabolism refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism
  • enzymes produce specific structural alterations to a compound
  • cytochrome P450 catalyzes a variety of oxidative and reductive reactions while undine diphosphate glucuronyltransrerases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups
  • Metabolites of the compounds disclosed herein are identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds
  • Bioavailability refers to (he percentage of the weight of the compound disclosed herein (e g compound of Formulas (I), (II), (ET), (TV), (V) or (VT)), mat is delivered into the general circulation of the animal or human being studied The total exposure (AUC(O- ⁇ )) of a drug when administered intravenously is usually defined as 100% bioavailable (F%) "Oral bioavailability” refers to the extent to which a compound disclosed herein, is absorbed into the general circulation when the pharmaceutical composition is taken orally as compared to intravenous injection [00400] "Blood plasma concentration” refers to the concentration of a compound of Formulas Q), (U), (III), (IV), (V) or (VT) disclosed herein, in the plasma component of blood of a sub j ect It is understood that the plasma concentration of compounds described herein may vary significantly between subjects, due to variability with respect to metabolism and/or possible interactions with other therapeutic agents In accordance with one embodiment disclosed herein, the blood plasma
  • calcium homeostasis refers to the maintenance of an overall balance in intracellular calcium levels and movements, including calcium signaling, within a cell
  • intracellular calcium refers to calcium located m a cell without specification of a particular cellular location
  • cytosolic or “cytoplasmic” with reference to calcium refers to calcium located m the cell cytoplasm.
  • an effect on intracellular calcium is any alteration of any aspect of intracellular calcium, including but not limited to, an alteration Ui intracellular calcium levels and location and movement of calcium into, out of or within a cell or intracellular calcium store or organelle
  • an effect on intracellular calcium is an alteration of the properties, such as, for example, the kinetics, sensitivities, rate, amplitude, and electrophysiological characteristics, of calcium flux or movement that occurs m a cell or portion thereof
  • an effect on intracellular calcium is an alteration in any intracellular calcium-modulating process, including, store-operated calcium entry, cytosolic calcium buffenng, and calcium levels in or movement of calcium into, out of or within an intracellular calcium store Any of these aspects are assessed in a variety of ways including, but not limited to, evaluation of calcium or other ion (particularly cation) levels, movement of calcium or other ion (particularly cation), fluctuations in calcium or other ion (particularly cation
  • Such an alteration or reduction in expression or activity can occur by virtue of an alteration of expression of a gene encoding the protein or by altering the levels of the protein
  • a protein involved in an aspect of intracellular calcium such as, for example, store-operated calcium entry, thus, are one that provides for or participates in an aspect of intracellular calcium or intracellular calcium regulation
  • a protein that provides for store-operated S calcium entry are a STIM protein and/or an Oral protein
  • a protein that is a component of a calcium channel is a protein that participates in multi-protein complex that forms the channel
  • cation entry or “calcium entry” into a cell refers to entry of cations, such as calcium, into an intracellular location, such as the cytoplasm of a cell or into the lumen of an intracellular0 organelle or storage site
  • cation entry is, for example, the movement of cations into the cell cytoplasm from the extracellular medium or from an intracellular organelle or storage site, or the movement of cations into an intracellular organelle or storage site from the cytoplasm or extracellular medium Movement of calcium into the cytoplasm from an intracellular organelle or storage site is also referred to as "calcium release" from the organelle or storage site 5
  • protein that modulates intracellular calcium refers to any cellular protein that is mvolved in regulating, controlling and/or altering intracellular calcium For example, in some embodiments, such a protein is involved in altering or adjusting intracellular calcium m a number of ways, including, but not
  • cell response refers to any cellular response that results from ion movement into or out of a cell or within a cell
  • the cell response is associated with any cellular activity that is dependent, at least in part, on ions such as, for example, calcium.
  • ions such as, for example, calcium.
  • activities may include, for example,0 cellular activation, gene expression, endocytosis.
  • immunosis include cells of the immune system and cells that perform a function or activity in an immune response, such as, but not limited to, T-cells, B-cells, lymphocytes, macrophages, dendritic cells, neutrophils, eosinophils, basophils, mast cells, plasma cells, white blood cells, antigen presenting cells and natural killer cells [00411]
  • 'cytokine refers to small soluble protems secreted by cells that in some embodiments, alter the behavior or properties of the secreting cell or another cell Cytokines bmd to cytokine receptors and trigger a behavior or property within the cell, for example, cell proliferation, death or differentiation
  • cytokines include, but are not limited to, interleukins (e g , lL-2, lL-3, IL-4, 1L-5, IL- 6, IL-7,
  • Selective inhibitor of SOC channel activity means that the inhibitor is selective for SOC channels and does not substantially affect the activity of other types of ion channels
  • Selective inhibitor of CRAC channel activity means that the inhibitor is selective for CRAC channels and does not substantially affect the activity of other types of ion channels and/or other SOC channels.
  • compositions are formulated m a conventional manner using one or more physiologically acceptable earners including excipients and auxiliaries which facilitate processing of the active compounds into preparations which are used pharmaceutically Proper formulation is dependent upon the route of administration chosen.
  • any of the well-known techniques, carriers, and excipients are used as suitable.
  • a summary of pharmaceutical compositions described herein are found, for example, in Remington The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa Mack Publishing Company, 1995), Hoover, John E , Remington's Pharmaceutical Sciences, Mack Publishing Co , Easton, Pennsylvania 1975, Liberman, H A.
  • a pharmaceutical composition refers to a mixture of a compound of Formulas (I), (II), (IE), (TV), (V) or (VI) described herein, with other chemical components, such as earners, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients
  • the pharmaceutical composition facilitates administration of the compound to an organism
  • therapeutically effective amounts of compounds described herein are administered in a pharmaceutical composition to a mammal having a disease, disorder, or condition to be treated
  • the mammal is a human
  • a therapeutically effective amount vanes widely depending on the seventy of the disease, the age and relative health of the subject, the potency of the compound used and other factors
  • the compounds of Formulas (I), (II), (III), (TV), (V) and (VI) are used singly or in combination with one or more therapeutic agents as components of mixtures
  • the pharmaceutical formulations described herein are administered to a sub j ect by multiple administration routes, including but not limited to, oral, parenteral (e g , intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes
  • the pharmaceutical compositions described herein which include a compound of Formulas (I), (II), (III), (IV), (V) or (VI) described herein, are formulated into any suitable dosage form, including but not limited to, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, aerosols, controlled release formulations, fast melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled
  • the compounds and/or compositions are administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ or tissue, often m a depot preparation or sustained release formulation
  • such long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection
  • the drug is administered in a targeted drug delivery system, for example, in a liposome coated with organ-specific antibody The liposomes will be targeted to and taken up selectively by the organ.
  • the drug is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
  • compositions including a compound described herein is manufactured m a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes [00420]
  • the pharmaceutical compositions will include at least one compound of Formulas (I), (II), (III), (TV), (V) or (VI) described herein, as an active ingredient in free-acid or free-base form, or in a pharmaceutically acceptable salt form.
  • compositions provided herem also mclude one or more preservatives to inhibit microbial activity Suitable preservatives mclude quaternary ammonium compounds such as benzalkomum chloride, cetylt ⁇ methylammonium bromide and cetylpy ⁇ dimum chloride [00422]
  • pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein (e g compounds of Formulas (I), (II), (III), (IV), (V) and (VI)), optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets, pills, or capsules
  • Suitable excipients m include, for example, fillers such as sugars, including lactos
  • Dragee cores are provided with suitable coatings
  • suitable coatings for this purpose, in some embodiments, concentrated sugar solutions are used, which optionally contain gum arable, talc, polyvinylpyrrolidone, carbopol 5 gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures
  • dyestuffs or pigments are added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses
  • pharmaceutical preparations that are used orally include push fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol Ih0
  • he push-fit capsules contain the active ingredients m admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers
  • stabilizers are added S
  • the solid dosage forms disclosed herein are in the form of a tablet, (including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid-disintegration tablet, an effervescent tablet, or a caplet
  • the pharmaceutical formulation is in the form of a powder
  • the pharmaceutical formulation is in the form of a tablet, including but not limited to, a fast- melt tablet
  • pharmaceutical formulations of the compounds described herein are administered as a single capsule or m multiple capsule dosage form
  • the pharmaceutical formulation is5 administered m two, or three, or four, capsules or tablets
  • solid dosage forms e g , tablets, effervescent tablets, and capsules, are prepared by mixing particles of a compound of Formulas (I), (II), (III), (IV), (V) or (VI) described herein, with one or more pharmaceutical excipients to form a bulk blend composition
  • a bulk blend composition it is meant that the particles of the compound of Formulas (I), (IT), (1C), (IV),0 (V) or (VI) described herein, are dispersed evenly throughout the composition so that the composition are readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules
  • the individual unit dosages also mclude film coatings, which disintegrate upon oral ingestion or upon contact with diluent
  • these formulations are manufactured by conventional pharmacological techniques 5
  • the pharmaceutical solid dosage forms described herein include a compound of Formulas (I), (U), (
  • Suitable carriers for use in the solid dosage forms described herein include, but are not limited to, acacia gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodext ⁇ n, glycerine, magnesium silicate, sodium casemate, soy lecithin, sodium chloride, r ⁇ calcram phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyce ⁇ de, diglycende, pregelaunized starch, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol and the like
  • Suitable filling agents for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatmized starch, hydroxypropylmethycellulose (HPMC), hy ⁇ roxypropylmemycellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lacntol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like
  • disintegrants are often used in the formulation, especially when the dosage forms are compressed with binder Disintegrants help rupturing the dosage form matrix by swelling or capillary action when moisture is absorbed into the dosage form
  • Suitable disintegrants for use in the solid dosage forms described herein include, but are not limited to, natural starch such as com starch or potato starch, a pregelatmized starch such as National 1551 or Amijel ⁇ , or sodium starch glycolate such as Promogel ® or Explotab ® , a cellulose such as a wood product, methylcrystalline cellulose, e g , Avicel", Avicel* PHlOl, Avicel ® PH102, Avicel” PH105, Elcema ® PlOO, Emcocel ® Vivacef, Ming Tia ⁇ , and Solka-Floc
  • binder levels of about 20to about 70% are used in powder-filled gelatin capsule formulations
  • binder usage level in tablet formulations vanes whether direct compression, wet granulation, roller compaction, or usage of other excipients such as fillers which itself act as moderate binder
  • are tablet formulations comprising binder usage levels of up to about 70%
  • Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, com starch, sodium stearyl ftimcratc, alkali-metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zmc, stea ⁇ c acid, sodium stearates, magnesium stearate, zinc stearate, waxes, Stearowet ® , bone acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol or a methoxypolyethylene glycol such as CaIbOWaX 111 , PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate, and the like [
  • Suitable wetting agents for use m the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, tnethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e g , Polyquat 10 s ), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, t ⁇ acetin, vitamin E TPGS and the like
  • Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e g , Phironic ® (BASF), and the like
  • Suitable suspending agents for use m the solid dosage forms described here include, but are not limited to, polyvinylpyrrolidone, e g , polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol, e g , in some embodiments, the polyethylene glycol has a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about
  • a plastcizer is generally a high boiling point solid or liquid
  • suitable plasncizers are added from about 0 01% to about 50% by weight (w/w) of the coating composition.
  • Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycendes, t ⁇ acetin, polypropylene glycol, polyethylene glycol, tnethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil
  • Compressed tablets are solid dosage forms prepared by compacting the bulk blend of the formulations described above
  • compressed tablets which are designed to dissolve in the mouth will include one or more flavoring agents
  • the compressed tablets will include a film surrounding the final compressed tablet
  • the film coating provides a delayed release of the compounds of Formulas (I), (S), (Ul), (TV), (V) or (VI) described herein from the formulation
  • the film coating aids in patient compliance (e g , Opadry" coatings or sugar coating)
  • Film coatings including Opadry ® typically range from about 1% to about 3% of the tablet weight
  • the compressed tablets include one or more excipients
  • a capsule is prepared, for example, by placing the bulk blend of the formulation of the compound described above, inside of a capsule
  • the formulations non-aqueous suspensions and solutions
  • the formulations are placed in a soft gelatin capsule
  • the formulations are placed in standard gelatin capsules or non-gelatin capsules such as capsules comprising HPMC
  • the formulation is placed in a sprinkle capsule, wherein the capsule is swallowed whole or the capsule is opened and the contents sprinkled on food prior to eating
  • the therapeutic dose is split into multiple (e g , two, three, or four) capsules
  • the entire dose of the formulation is delivered in a capsule form
  • the particles of the compound of Formulas (I), (II), (TII), (IV), (V) or (VI) described herein and one or more excipients are dry blended and compressed into a mass, such as a tablet, having a hardness sufficient to
  • Microencapsulated compounds of Formulas (I), (H), (IH), (IV), (V) and (VI) described herein are formulated by methods which in some embodiments, include, e g , spray drying processes, spinning disk-solvent processes, hot melt processes, spray chilling methods, fluidized bed, electrostatic deposition, centrifugal extrusion, rotational suspension separation, polymerization at hquid-gas or solid-gas interface, pressure extrusion, or spraymg solvent extraction bath.
  • several chemical techniques e g , complex coacervaUon, solvent evaporation, polymer-polymer incompatibility, interfacial polymerization in liquid media, in situ polymerization, m-liquid drying, and desolvation in liquid media are used
  • other methods such as roller compaction, extrosion/spheromzation, coacervation, or nanoparucle coating also are used [00449]
  • other methods such as roller compaction, extrosion/spheromzation
  • Effervescent salts are granules or coarse powders containing a medicinal agent in a dry mixture, usually composed of sodium bicarbonate, citnc acid and/or tartaric acid When such salts are added to water, the acids and the base react to liberate carbon dioxide gas, thereby causing "effervescence "
  • effervescent salts include, e g , the following ingredients sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, citnc acid and/or tartaric acid Any acid-base combination that results in the liberation of carbon dioxide are used in place of the combination of sodium bicarbonate and citnc and tartaric acids, as long as the ingredients were suitable for pharmaceutical use and result in a pH of about 6 0 or higher
  • the formulations described herein which include a compound described S herein, are solid dispersions
  • the formulations described herein are solid solutions Solid solutions incorporate a substance together with the active agent and other excrpients such that heating the
  • the solid dosage forms described herein are formulated as enteric coated delayed release oral dosage forms, i e , as an oral dosage form of a pharmaceutical composition as described herem which utilizes an ente ⁇ c coating to affect release m the small intestine of the gastrointestinal tract
  • the enteric coated dosage form is a compressed or molded or extruded tablet/mold (coated5 or uncoated) containing granules, powder, pellets, beads or particles of the active ingredient and/or other composition components, which are themselves coated or uncoated
  • the enteric coated oral dosage form is also a capsule (coated or uncoated) containing pellets, beads or granules of the solid carrier or the composition, which are themselves coated or uncoated
  • delayed release refers to the delivery so that the release is accomplished at0 some generally predictable location in the intestinal tract more distal to that which would have been accomplished if there had been no delayed release
  • Suitable cellulose derivatives are ethyl cellulose, reaction mixtures of partial acetate esters of cellulose with phthalic anhydride
  • the performance varies based on the degree and type of substitution
  • Cellulose acetate phfhalate (CAP) dissolves m pH > about 6
  • Aquatenc (FMC) is an aqueous based system and is a spray dried CAP pseudolatex with particles ⁇ 1 ⁇ m
  • other components m Aquatenc include pluronics, Tweens, and acetylated monoglycendes
  • Other suitable cellulose derivatives include cellulose acetate tnmellitate (Eastman), methylcellulose (Pha ⁇ nacoat, Methocel), hydroxypropylmethyl cellulose phthalate (HPMCP), hydroxypropylmethyl celhilose succinate (HPMCS), and hydroxypropyknethylcellulose acetate succinate (e g , AQ
  • HPMCP such as, HP-50, HP-55, HP-55S, HP-55F grades are suitable
  • the performance vanes based on the degree and type of substitution include, but are not limited to, AS LG (LF), which dissolves at pH about 5, AS-MG (MF), which dissolves at pH about S S, and AS-HG (HF), which dissolves at higher pH
  • AS LG LF
  • AS-MG MF
  • AS-HG HF
  • PVAP Poly Vinyl Acetate Phthalate
  • the coating contains a plasticizcr and possibly other coating excipients such as colorants, talc, and/or magnesium stearate
  • Suitable plasticizers include tnethyl citrate (Citroflex 2), t ⁇ acetin (glyceryl triacetate), acetyl tnethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycendes, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate
  • anionic carboxyhc acrylic polymers contain about 10 to about 25% by weight of a plasucizer, especially dibutyl phthalate,
  • colorants e g , carnuba wax or PEG are added to the coatings besides plasticizers to solubihze or disperse the coating material, and to improve coating performance and the coated product
  • the formulations descnbed herein which include a compound of Formulas (I), (C), (in), (IV), (V) or (VI) descnbed herein, are delivered using a pulsatile dosage form.
  • a pulsatile dosage form is capable of providing one or more immediate release pulses at predetermined time points after a controlled lag tune or at specific sites.
  • pulsatile dosage forms are administered usmg a variety of pulsatile formulations
  • Examples of such delivery systems include, e g , polymer-based systems, such as polylactic and polyglycolic acid, polyanhydndes and polycaprolactone, porous matrices, nonpolymer-based systems that are lipids, including sterols, such as cholesterol, cholesterol esters and tatty acids, or neutral fats, such as mono-, di- and t ⁇ glycendes, hydrogel release systems, silastic systems, peptide-based systems, wax coatings, bioerodible dosage forms, compressed tablets using conventional binders and the like [00461]
  • pharmaceutical formulations are provided that include particles of the compounds described herein, e g compounds of Formulas (I), (H), (HI), (IV), (V) and (VI), and at least one dispersing agent or suspending agent for oral administration to a subject
  • the formulations are a powder and/or granules for suspension, and upon admixture with water, a substantially 5
  • liquid formulation dosage forms for oral administration are aqueous suspensions selected from the group including, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups [00463] In other embodiments, the aqueous suspensions and dispersions described herein remain m a
  • an aqueous suspension is re-suspended into a homogenous suspension by physical agitation lasting less than about 1 minute In another embodiment, an aqueous suspension is re-suspended into a homogenous suspension by physical agitation lasting less than about
  • an aqueous suspension is re-suspended into a homogenous suspension by physical agitation lasting less than about 30 seconds In still another embodiment, no agitation is necessary to maintain a homogeneous aqueous dispersion.
  • the pharmaceutical formulations described herein are self-emulsifying drug
  • Emulsions are dispersions of one immiscible phase in another, usually in the form of droplets Generally, emulsions are created by vigorous mechanical dispersion. SEDDS, as opposed to emulsions or microemulsions, spontaneously form emulsions when added to an excess of water without any external mechanical dispersion or agitation An advantage of SEDDS is that only gentle mixing is required to distribute fhe droplets throughout the solution. Additionally, in other embodiments, water or the aqueous phase
  • the SEDDS provides an effective delivery system for oral and parenteral delivery of hydrophobic active ingredients
  • SEDDS provides improvements in the bioavailability of hydrophobic active ingredients
  • compositions and formulations prepared with suitable nontoxic pharmaceutically acceptable ingredients are found m REMINGTON THE SCIENCE AND PRACTICE OF PHARMACY, 21st edition, 2005 The choice of suitable earners is highly dependent upon the exact nature of
  • the nasal dosage form desired e g , solutions, suspensions, ointments, or gels
  • Nasal dosage forms generally contain large amounts of water in addition to the active ingredient Minor amounts of other ingredients such as pH adjusters, emulsiflers or dispersing agents, preservatives, surfactants, gelling agents, or buffering and other stabilizing and solubilrzing agents may also be present
  • the nasal dosage form is isotonic with nasal secretions [00468]
  • the compounds described herein are in a form as an aerosol, a mist or a powder
  • Pharmaceutical compositions described herein are conveniently delivered m the form of an aerosol spray presentation from pressurized packs or a nebuhser, with the use of a suitable propellent, e g , dichlorodifluoromethane, tnchlorofhioromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas
  • a suitable propellent e g , dichloro
  • buccal formulations that include compounds described herein are administered using a variety of formulations
  • the buccal dosage forms described herein further include a bioerodible (hydrolysable) polymeric earner that also serves to adhere the dosage form to the buccal mucosa
  • the buccal dosage form is fabricated so as to erode gradually over a predetermined time period, wherem the delivery of the compound is provided essentially throughout Buccal drug delivery, avoids the disadvantages encountered with oral drug administration, e g , slow absorption, degradation of the active agent by fluids present in the gastrointestinal tract and/or first-pass lnactivation in the liver
  • the bioerodible (hydrolysable) polymeric carrier it will be appreciated that virtually any such earner is used, so long as the desired drug release profile is not compromised, and the carrier is compatible with the compound of Formulas (I), (II), (III), (IV), (V) or (VI) described herein, and any other components that are present m the
  • transdermal formulations described herein administered using a variety of devices
  • the transdermal dosage forms described herein incorporate certain pharmaceutically acceptable excipients
  • the transdermal formulations described herein include at least three components (1) a formulation of a compound of Formulas (I), (II), (HI), (IV), (V) or (VI), (2) a penetration enhancer, and (3) an aqueous adjuvant
  • transdermal formulations mclude additional components such as, but not limited to, gelling agents, creams and ointment bases, and the like
  • the transdermal formulation further includes a woven or non-woven backing material to enhance absorption and prevent the removal of the transdermal formulation from the skin
  • the transdermal formulations described herein maintains a saturated or supersaturated state to promote diffusion into the skin
  • formulations suitable for transdermal administration of compounds described herein employ transdermal delivery devices and transdermal delivery patches and are lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive
  • Such patches are constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents
  • transdermal delivery of the compounds described herein are accomplished by means of iontophorebc patches and the like
  • transdermal patches provide controlled delivery of the compound of Formulas (I), (K), (HI), (IV), (V) or (VI) described herein.
  • the rate of absorption is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel
  • absorption enhancers are used to increase absorption
  • An absorption enhancer or earner includes absorbable pharmaceutically acceptable solvents to assist passage through the skin.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with earners, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged penod of tune, and means to secure the device to the skin
  • formulations suitable for intramuscular, subcutaneous, or intravenous injection include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution mto sterile injectable solutions or dispersions
  • suitable aqueous and non-aqueous earners, diluents, solvents, or vehicles including water, ethanol, polyols
  • formulations suitable for subcutaneous injection also contain additives such as preserving, wetting, emulsifying, and dispensing agents Prevention of the growth of microorganisms is ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like Prolonged absorption of the injectable pharmaceutical form are brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin.
  • compositions described herein are in a form suitable for parenteral injection as a sterile suspensions, solutions or emulsions m oily or aqueous vehicles, and contain formulatory agents such as suspending, stabilization, and delivery of physiologically compatible buffers.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer
  • penetrants appropriate to the barrier to be permeated are used m the formulation
  • appropriate formulations may include aqueous or nonaqueous solutions, in other embodiments, with physiologically compatible buffers or excipients
  • parenteral injections mvolve bolus injection or continuous infusion
  • formulations for injection are presented m unit dosage form, e g , in ampoules or in multi-dose containers, with an added preservative
  • the pharmaceutical compositions described herein are in a form suitable for parenteral injection as a sterile suspensions, solutions or emulsions m oily or aqueous vehicles, and contain formula
  • suspensions of the active compounds are prepared as appropriate oily in j ection suspensions
  • suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes
  • aqueous in j ection suspensions contain substances which increase the viscosity of die suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran
  • the suspension also contains suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions
  • the active ingredient is in powder form for constitution with a suitable vehicle, e g , sterile pyrogen-free water, before use [00476]
  • delivery systems for pharmaceutical compounds are employed, such as, for example, liposomes and emulsions
  • compositions provided herein can also include an mucoadhesive poly(vinyl)
  • the compounds described herem are also formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycendes, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like
  • a low- melting wax such as, but not limited to, a mixture of fatty acid glycendes, optionally m combination with cocoa butter is first melted
  • an agent such as a compound of Formulas (I), (II), (IH), (TV), (V) or (VI), is administered man amount effective for amelioration of, or prevention of the development of symptoms of, the disease, condition or disorder (i e , a therapeutically effective amount)
  • a compound of Formulas (I), (II), (IH), (TV), (V) or (VI) is administered man amount effective for
  • determination of effective amounts also involves in vitro assays in which varying doses of agent are administered to cells in culture and the concentration of agent effective for ameliorating some or all symptoms is determined m order to calculate the concentration required m vtvo Effective amounts are also based on in vivo animal studies [00481]
  • an agent is administered prior to, concurrently with and subsequent to the appearance of symptoms of a disease, condition or disorder
  • an agent is administered to a subject with a family history of the disease, condition or disorder, or who has a phenotype that indicates a predisposition to a disease, condition or disorder, or who has a genotype which predisposes the subject to the disease, condition or disorder
  • the particular delivery system used depends on a number of factors, including, for example, the intended target and the route of administration, e g , local or systemic Targets for delivery are specific cells which are causing or contributing to a disease, condition or disorder, including
  • the compounds described herein are used in the preparation of medicaments for the modulation of intracellular calcium, or for the treatment of diseases, disorders or conditions that would benefit, at least in part, from modulation of intracellular calcium.
  • a method for treating any of the diseases, disorders or conditions described herein in a subject in need of such treatment involves administration of pharmaceutical compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject
  • the compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments
  • the compositions are administered to a patient already suffering from a disease, disorder or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease, disorder or condition Amounts effective for this use will depend on the seventy and course of the disease, disorder or condition, previous therapy, the patient's health status, weight, and response to the drugs
  • the dose of drug bemg administered is temporarily reduced or temporarily suspended for a certain length of tune (i e , a "drug holiday")
  • the length of the drug holiday vanes between about 2 days and about 1 year, including by way of example only, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 10 days,
  • the dose reduction during a drug holiday is from about 10% to about 100%, including, by way of example only, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about
  • a maintenance dose is administered if necessary.
  • the dosage or the frequency of administration, or both is reduced, as a function of the symptoms, to a level at which the unproved disease, disorder or condition is retained.
  • patients however, require intermittent treatment on a long-term basis upon any
  • the amount of a given agent vanes depending upon factors such as the particular compound, disease, disorder or condition and its seventy, the identity (e g , weight) of the subject or host in need of treatment, but is nevertheless determined in a manner according to the particular circumstances surrounding the case, including, e g , the specific agent bemg administered, the route of administration, the
  • doses employed for adult human treatment are typically m the range of about 0 02 to about 5000 mg per day, m other embodiments, about 1 to about 1500 mg per day
  • the desired dose is convemently presented in a smgle dose or as divided doses administered simultaneously (or over a short period of tune) or at appropriate intervals, for example as two, three, four or more sub-doses per day
  • the pharmaceutical composition described herein is m unit dosage forms suitable for smgle administration of precise dosages
  • the formulation is divided into unit doses containing appropnatc quantities of one or more compound.
  • the unit dosage is in the form of a package containing discrete quantities of the formulation
  • Non-limiting examples are packaged tablets or capsules, and powders m vials or ampoules
  • aqueous suspension compositions are packaged tablets or capsules, and powders m vials or ampoules.
  • compositions for parenteral injection are presented in unit dosage form, which include, but are not limited to ampoules, or m multi-dose containers, with an added preservative [00491]
  • the daily dosages appropriate for the compounds described herein described herein are from about
  • the daily dosages are from about 0 1 mg/kg to about 10 mg/kg
  • An indicated daily dosage in the larger mammal, including, but not limited to, humans, is m the range from about 0 5 mg to about 1000 mg, conveniently administered in a single dose or in divided doses, including, but not limited to, up to four times a day or in extended release form
  • Suitable unit dosage forms for oral administration include from about 1 to about 500 mg active ingredient
  • the unit dosage is about 1 mg, about 5 mg, about, 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 250 mg, about 400 mg, or about 500 mg
  • the foregoing ranges are merely suggestive, as the number of variables in regard to an individual treatment regime is large, and considerable excursions from these recommended values are not uncommon In some embodiments, such dosages are altered depending on a number of variables, not limited to the activity of the compound used, the disease, disorder or condition to be treated, the mode of administration, the requirements of the
  • toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population)
  • the dose ratio between the toxic and therapeutic effects is the therapeutic mdex and it are expressed as the ratio between LD 50 and ED 50
  • the data obtained from cell culture assays and animal studies are used in formulating a range of dosage for use in human
  • the dosage of such compounds lies withm a range of circulating concentrations that include the ED 90 with minimal toxicity
  • the dosage varies within this range depending upon the dosage form employed and the route of administration utilized.
  • the compounds of Formulas (I), (II), (III), (TV), (V) and (VI), and compositions thereof are also used in combmation with other therapeutic agents that are selected for their therapeutic value for the condition to be treated.
  • compositions described herein and, m embodiments where combinational therapy is employed other agents do not have to be administered m the same pharmaceutical composition, and in some embodiments, because of different physical and chemical characteristics, have to be administered by different routes [00494]
  • another therapeutic agent such as a compound of Formulas (I), (II), (III), (IV), (V) or (VI)
  • the therapeutic effectiveness of one of the compounds described herem is enhanced by administration of an adjuvant (i e , by itself the adjuvant has minimal therapeutic benefit, but in combmation with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced)
  • an adjuvant i e , by itself the adjuvant has minimal therapeutic benefit, but in combmation with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced
  • an adjuvant i e , by itself the adjuvant
  • therapeutically-effective dosages vary when die drugs are used in treatment combinations
  • Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient
  • combination therapies described herein dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease, disorder or condition being treated and so forth
  • the compound provided herein is administered either simultaneously with the biologically active agent(s), or sequentially
  • the attending physician decides on the appropriate sequence of administering protein in combination with the biologically active agent(s)
  • the multiple therapeutic agents are administered in any order or even simultaneously
  • the multiple therapeutic agents are provided in a single, unified form, or m multiple forms (by way of example only, either as a single pill or as two separate pills)
  • one of the therapeutic agents are given in multiple doses, or both are given as multiple doses
  • the tuning between the multiple doses vary from more than zero weeks to less than about four weeks
  • the combination methods, compositions and formulations are not to be limited to the use of only two agents, the use of multiple therapeutic combinations are also envisioned (00499] It is understood that the dosage regimen to treat, prevent, or ameliorate the conditions) for which relief is sought, is modified in accordance with a variety of factors These factors include the disorder, disease or condition from which the subject suffers, as well as the age, weight, sex, diet
  • the two-step administration regimen calls for sequential administration of the active agents or spaced-apart administration of the separate active agents
  • the time period between the multiple administration steps range from, a few minutes to several hours, depending upon the properties of each pharmaceutical agent, such as potency, solubility, bioavailability, plasma half-life and kinetic profile of the pharmaceutical agent
  • circadian variation of the target molecule concentration also determines the optimal dose interval
  • the compounds described herein also are used m combination with procedures that m some embodiments, provide additional or synergistic benefit to the patient By way of example only, patients are expected to find therapeutic and/or prophylactic benefit in the methods descnbed herein, wherein pharmaceutical composition of a compound disclosed herein and /or combinations with other therapeutics are combined with genetic testing to determine whether that individual is a earner of a mutant gene that is known to be correlated with certain diseases or conditions [00502]
  • the compounds described herein and combination therapies are administered before, during or
  • compounds of Formulas (I), (H), (III), (TV), (V) and (VI) are administered or used m conjunction with other inhibitors of SOCE
  • the inhibitors of SOCE are non-selective inhibitors
  • the inhibitors of SOCE are selective inhibitors
  • Inhibitors of SOCE include a) Cations, which include lanthanide cations, such as for example, Gd 3+ , La 3+ , b) P-450 inhibitors, which include econazole, miconazole, clotrimazole, ketoconazole, c) Cyclooxygenase inhibitors, which include niflumic acid, flufenamic acid, tenidap, d) Lipoxygenase inhibitors, which mclude nordihydroguaiaretic acid, eicosatetraynoic acid, e) Compounds that are channel blockers, which include SK&F 96365, SC38249, LU52396, L-651,582, tetrandnne, 2-APB, f) Compounds that inhibit SOCE not by an action on the SOC channels themselves, which include U73122 (phospholipase C inhibitor), wortmann
  • Immunosuppressive therapy is clinically used to prevent the rejection of transplanted organs and tissues (e g bone marrow, heart, kidney, liver), treatment of autoimmune diseases or diseases that are most likely of autoimmune origin (e g rheumatoid arthritis, myasthenia gravis, systemic lupus erythematosus, Crohn's disease, and ulcerative colitis), and treatment of some other non-autoimmune inflammatory diseases (e g long term allergic asthma control)
  • transplanted organs and tissues e g bone marrow, heart, kidney, liver
  • autoimmune diseases or diseases that are most likely of autoimmune origin e g rheumatoid arthritis, myasthenia gravis, systemic lupus erythematosus, Crohn's disease, and ulcerative colitis
  • some other non-autoimmune inflammatory diseases e g long term allergic asthma control
  • a compound of Formulas (I), (H), (HT), (IV), (V) or (VI) is administered with other immunosuppresants selected from among Calcineurm inhibitors (such as, but not limited to, cyclosporin, tacrolimus).
  • niTOR inhibitors such as, but not limited to, sirolimus, everohmus
  • antiproliferatives such as, but not limited to, azathioprine, mycophenohc acid
  • corticosteroids such as, but not hunted to, prednisone, cortisone acetate, prednisolone, methylpredmsolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone, hydrocortisone
  • antibodies such as, but not limited to, monoclonal anti-IL-2R ⁇ receptor antibodies (basiliximab, daclizumab), polyclonal anti-T-cell antibodies (anti-fhymocyte globulin (ATG), anti-lymphocyte globulin (ALG)))
  • immunosuppresants include, but are not limited to glucocorticoids (alclometasone, aldosterone, amcinomde, beclometasone, betamethasone, budesonide, ciclesonide, clobetasol, clobetasone, clocortolone, cloprednol, cortisone, cortivazol, deflazacort, deoxycorticosterone, desomde, desoximetasone, desoxycortone, dexamethasone, diflorasone, diflucortolone, difluprednate.
  • glucocorticoids alclometasone, aldosterone, amcinomde, beclometasone, betamethasone, budesonide, ciclesonide, clobetasol, clobetasone, clocortolone, cloprednol, cortisone, cortivazol, deflazacor
  • fluclorolone Fludrocortisone, fludroxycortide, flumetasone, flunisohde, fluocmolone acetonide, fluocinomde, fluocortin, fluocortolone, fluorometholone, fluperolone, flupredmdene, fluticasone, formocortal, halcinomde, halometasone, hydrocortisone/Cortisol, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone butyrate, loteprednol, medrysone, mepredmsone, methylpredmsolone, methylpredmsolone aceponate, mometasone f ⁇ roate, paramethasone, prednicarbate, prednisone, prednisolone, prednylidene, nmexolone, tixocortol, triamcinolone,
  • a compound of Formulas (I), (II), (III), (TV), (V) or (VI) is administered in any combination with one or more of the following therapeutic agents immunosuppressants (e g , tacrolimus, cyclosporin, rapamicin, methotrexate , cyclophosphamide, azathiopnne, mercaptopunne, mycophenolate, or FTY720), glucocorticoids (e g , prednisone, cortisone acetate, prednisolone, methylpredmsolone, dexamethasone, betamethasone triamcinolone, beclometasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone), non-steroidal antiinflammatory drugs
  • immunosuppressants e g , tacrolimus, cyclosporin, rapamicin, methotrexate , cyclophosp
  • NSAIDs include, but are not limited to aspi ⁇ n, salicylic acid, gentisic acid, choline magnesium salicylate, choline salicylate, choline magnesium salicylate, choline salicylate, magnesium salicylate, sodium salicylate, diflunisal, carprofen, fenoprofen, fenoprofen calcium, flurobrprofen, lbuprofen, ketoprofen, nabutone, ketolorac, ketorolac tromethamine, naproxen, oxaprozin, diclofenac, etodolac, lndomethacin, sulindac, tolmeun, S meclofenamate, mcclofcnamate sodium, mefenamic acid, prroxicam, meloxicam, COX-2 specific inhibitors (such as, but not limited to, celecoxib, rofccoxib, valdecoxib, parecoxi
  • anb-inflammatones include, but are not limited to Arthrotec* (diclofenac and misoprostol), Asacol ⁇ (S-aminosahcyclic acid), Salofelk ® (S-aminosalicychc acid), Auralgan ® (antipy ⁇ ne and benzocaine), Azulf ⁇ dine ® (sulfasalazine), Daypro ® (oxaprozin), Lodme ⁇ (etodolac), Ponstan ® (mefenamic acid), Solumedrol ® (methylprednisolone), Bayer ⁇ (aspi ⁇ n), Buffe ⁇ n ® (aspirin), Indocin ® 5 (lndomethacin), Vioxx ® (rofe
  • kits and articles of manufacture are also described herein.
  • such kits include a carrier, package, or container mat is
  • Suitable containers include, for example, bottles, vials, syringes, and test tubes
  • the containers are formed from a variety of materials such as glass or plasbc [00520]
  • the articles of manufacture provided herein contain packaging materials Examples of
  • compositions include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment
  • a wide array of formulations of the compounds and compositions provided herein are contemplated as are a variety of treatments for any disease, disorder, or condition that would benefit by inhibition of CRAC channel activity
  • the containers includes one or more compounds described herein, optionally in a composition or in combination with another agent as disclosed herein.
  • the contamer(s) optionally have a sterile access port (for example the container is an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle)
  • kits optionally comprising a compound with an identifying description or label or instructions relating to its use ui the methods described herein
  • a kit includes one or more additional containers, each with one or more of various materials (such as reagents, optionally m concentrated form, and/or devices) desirable from a commercial and user standpoint for use of a compound described herein.
  • materials include, but not limited to, buffers, diluents, filters, needles, syringes, earner, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use
  • reagents such as reagents, optionally m concentrated form, and/or devices
  • a set of instructions is also included
  • the label is a label on or associated with the container
  • the label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself, a label is associated with a container when it is present within a receptacle or earner that also holds the container, e g , as a package insert.
  • a label is used to indicate that the contents are to be used for a specific therapeutic application
  • the label also indicates directions for use of the contents, such as in the methods described herein
  • die pharmaceutical compositions are presented m a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein
  • the pack contains metal or plastic foil, such as a blister pack.
  • the pack or dispenser device is accompanied by instructions for administration
  • the pack or dispenser also accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration
  • a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration
  • Such notice for example, is the labeling approved by the U S Food and Drug Administration for prescription drugs, or the approved product insert.
  • compositions containing a compound provided herein formulated m a compatible pharmaceutical carrier are also prepared, placed m an appropriate container, and labeled for treatment of an indicated condition Assays [00525]
  • techniques include, but are not limited to, patch clamp eleclrophysiology (measurement of calcium ions or other ions across cell membranes, such as plasma membranes), capacitance measurements (allows exocytosis to be followed at the level of single cells), calcium imaging using fluorescent dyes allows patterns of calcium movement within the cytoplasm to be tracked, fluorescence resonance energy transfer (FRET) enables protein-protein interactions to be evaluated, and molecular biology methods allow for the manipulation of the levels of expression of proteins of interest
  • FRET fluorescence resonance energy transfer
  • assays include in vitro cell based assays as well as in vivo animal models
  • assays that detect, monitor or measure an effect on intracellular calcium, including calcium entry-mediated events
  • assays include, but are not limited to, assays monitoring, measuring and/or detecting intracellular calcium levels, modulation of calcium levels, and movement of calcium into, out of or within cells and intracellular organelles
  • assays winch also include monitoring, measuring and/or detecting calcium entry-mediated events and molecules involved in calcium entry-mediated events such as, but not limited to, signal transduction molecules, transcription factors, secreted molecules and other molecules that are affected by changes m calcium homeostasis Assays mclude, but are not limited to, those described herein and those described m US patent publication no 2007/003
  • the cell is one in which store-operated calcium entry occurs or that is manipulated such that store-operated calcium entry occurs in the cell
  • the cell contains one or more proteins involved in modulating intracellular calcium (and, m particular, is involved m, participates m and/or provides for store-operated calcium entry, movement of calcium into, out of or within an intracellular organelle or calcium store, modulation of calcium levels in an intracellular organelle or calcium store (e g , endoplasmic reticulum) and/or calcium buffering), such as those provided herein
  • the protein(s) m clude a STIM proteins (including STIMI, ST ⁇ M2, DSTIM and CSTIM protein) and/or Oral proteins (Orail, O ⁇ u2, O ⁇ u3)
  • the cell may
  • cells for use in the methods are of any species
  • the cells are eukaryotic cells
  • the cells are yeast, insect (e g , Drosophila or Anopheles), or mammalian cells
  • Mammalian cells mclude, but are not limited to, rodent (e g , mouse, rat and hamster), primate, monkey, dog, bovine, rabbit and human cells
  • rodent e g , mouse, rat and hamster
  • primate monkey
  • dog bovine
  • a variety of cell types are used in the methods, including, for example, neuronal, nervous system, brain, immune system cells, e g , T lymphocytes and B cells, primary cells, blood and hematopoietic cells, stromal cells, myeloid cells, lymphoid cells, and a variety of tumor and cancer cells
  • Particular cells mclude Drosophila Schneider 2 or S2 cells, human embryonic kidney (HEK293) cells, rat basophilic leukemia (
  • cells from a known cell line are used, such as neuroblastoma SH SYSY cells, pheochromocytoma PC12 cells, neuroblastoma SK-N-BE(2)C or SK-N-SH cells, human SK-N-MC neuroepithelioma cells, SMS-KCNR cells, human LAN-5 neuroblastoma cells, human GI-CA-N neuroblastoma cells, human GOTO neuroblastoma cells, mouse Neuro 2a (N2A) neuroblastoma cells and/or human IMR 32 neuroblastoma cells, chronic myeloid leukemia cells (e g , human KS62 cells), promyelocyte leukemia cells (e g , HL60 cells) and histiocytic lymphoma cells (e g , U937 cells), Burkitt's lymphoma cells (e g , CA46 cells), B-cells (e g , NALM6), acute lympho
  • reagents and conditions are known, and are used, for specifically evaluating store-operated calcium entry, resting cytosolic calcium levels, calcium buffering, and calcium levels of and calcium uptake by or release from intracellular organelles in further embodiments, resting cytosolic calcium levels, intracellular organelle calcium levels and cation movement are assessed using any of the methods described herein
  • Such methods of assessing modulation m intracellular calcium include, but are not limited to, calcium-sensihve indicator-based measurements, such as fluo-3, mag-fiira 2 and ER-targeted aequo ⁇ n, labeled calcium (such as 45 Ca 2+ )-based measurements, and electrophysiological measurements
  • Particular aspects of ion flux that are assessed include, but are not limited to, a reduction (including elimination) in the amount of ion flux, altered biophysical properties of the ion current, and altered sensitivities of the flux to activators or inhibitors of calcium flux processes, such as, for example, store-operated calcium entry Rea
  • compounds of Formulas (I), (II), (III), (IV), (Y) and (VI) are added to cells under conditions that permit store-operated calcium entry to occur m order to assess the effects of compounds of Formulas (I), (II), (HI), (TV), (V) and (VI) on store-operated calcium entry
  • m one method cells are treated to reduce the calcium levels of intracellular calcium stores and then analyzed for evidence of ion (e g , calcium) influx m response thereto in the presence of a compound of Formulas (I), (IT), (IE), (IV), (V) or (VI) Techniques for reducing calcium levels of intracellular stores and for analyzing cells for evidence of ion (e g , calcium) influx are described herein.
  • evaluation of molecules involved in calcium-entry mediated events are used to monitor intracellular calcium, and are used, for example m screening assays described herein to monitor the effects of compounds of Formulas (I), (II), (HI), (IV), (V) and (VI)
  • assays include but are not limited to assays which detect, or determine the presence, levels, alteration of levels, production, modification (such as phosphorylation and dephosphorylation), translocation, degradation and activity of molecules involved in calcium-entry mediated events (see for example, Trevillyan et al (200I) J BIoI Chem 276 48118-26)
  • the assays described herein are used with cells that have been treated with or contacted with a compound of Formulas (I), (II), (III), (IV), (V) or (VT), or that express an altered amount of a test molecule (such as a protein involved in calcium regulation, including a STIM protein, Oral protein), or with control cells
  • the assays include but are not limited
  • ⁇ -hexosaminidase In mast cells, Ca 2+ influx results m degranulation and release of inflammatory mediators such as heparin, histamine and enzymes such as ⁇ -hexosaminidase
  • detecting and/or measuring release of such molecules is used to monitor intracellular calcium.
  • media from mast cells are collected
  • suitable substrate for ⁇ -hexosamimdase e g p-
  • CaN phosphatase calcineunn
  • radiolabeled peptide 15 for example a radiolabeled peptide corresponding to a sequence m the Ru subunit of c AMP dependent kinase, either with or without a compound of Formulas (I), (II), (III), (IV), (V) or (VT) (see, Trevillyan et al (2001) J BmI Chem 27648118-26)
  • the level of radiolabeled peptide and/or the amount of free inorganic phosphate released is measured to assess CaN dephosphorylation activity NFAT Transcriptional Activity
  • NFAT nuclear factor of activated T cells
  • NFAT proteins regulate the transcription of cytokine genes mvolved m the immune response
  • promoters from NFAT-reguIated genes, and/or regulatory regions and elements from these genes are used to monitor NFAT regulated expression and thereby monitor intracellular calcium
  • reporter gene fusions are constructed with NFAT
  • NFAT-regulated elements operably linked to a reporter gene such as hiciferase, ⁇ - galactosidase, green fluorescent protein (GFP) or any other known reporter (see for example, Published U S Application no 2002-0034728)
  • a reporter gene such as hiciferase, ⁇ - galactosidase, green fluorescent protein (GFP) or any other known reporter (see for example, Published U S Application no 2002-0034728)
  • the amount of reporter protein or activity is a measure of NFAT activity
  • NFAT activation is regulated primarily through its phosphorylation, which in turn regulates its
  • NFAT is a hyperphosphorylated cytosolic protein
  • Activated calcineunn dephosphorylates multiple serine residues within the regulatory region of the NFAT molecule
  • NFAT is rephosphorylated m response to decreases in Ca 2+ levels or CaN inhibition
  • the phosphorylation state of NFAT is monitored for example, by expressing a detectably tagged NFAT protein m cells, such as a His6 tagged-NFAT Tagged NFAT is purified from cells using Ni 2+ chromatography and subjected to gel electrophoresis and staining or western blotting More highly phosphorylated forms of NFAT are distinguished by their slower migration
  • the state of phosphorylated NFAT is used as a measure of NFAT activation (see, Trevillyan et al (2001) / BwI Chem
  • NFAT localization between the cytoplasm and nucleus is regulated by the phosphorylation state of NFAT Phosphorylation of NFAT prevents nuclear localization by masking the nuclear localization sequence NFAT nuclear localization are monitored, for example, by expressing fluorescently tagged NFAT, for example, 5 GFP-NFAT, in cells
  • confocal microscopy is used to monitor nuclear localization of the tagged NFAT (see, Trevillyan e/ ⁇ / (2001)7 BwI Chem 27648118-26)
  • cytokine secretion such as IL-2 secretion
  • protein detection assays For example, supernatant is collected from immune cells
  • an ELISA0 assay or other suitable format with IL-2 antibodies is used to detect and/or measure the amount of IL-2 secreted as compared to control cells Secretion of other cytokines, for example, TNF- ⁇ , is also detected in similar assays
  • Cytokine Expression is assessed either directly or indirectly in S cells
  • cytokines such as, but not limited to IL-2
  • an IL-2 promoter are operably linked to a reporter gene such as luciferase or ⁇ -galactosidase, and the reporter construct introduced into cells
  • reporter gene expression is monitored and compared to gene expression in control cells (see, Trevillyan et al (2001) J BwI Chem 27648118-26)
  • expression of endogenous or recombinant IL-2 mRNA or protein is assessed 0 T Cell Proliferation
  • Cytokines such as IL-2 are necessary for T-cell proliferation in response to mitogen or alloantigen stimulation, and thus T-cell proliferation is altered by changes in cytokine expression or secretion.
  • T cells are induced, such as with c ⁇ ncanavalin A or alloreacbve lymphocytes and T cell proliferation measured, for example, by subjecting cells to a pulse of 3 H- thymidine and measuring 3 H-thymidine5 incorporation (see, Trevillyan et al (2001) J Biol Chem 27648118-26)
  • the modulation (e g inhibition or reduction) of SOCE by compounds of Formulas (I), (II), (HI), (IV), (V) and (VI) is determined by evaluation of any of the following criteria a. there is direct inhibition of increased [Ca 2+ ]I as measured by a calcium indicator, b there is a direct inhibition OfI 80C or I C RA C as measured by patch clamp, 0 c there is inhibition of downstream signaling functions such as calcmeurm activity, NFAT subcellular localization, NFAT phosphorylation, and/or cytokine, e g , IL-2, production, or d. there are modifications m activation-induced cell proliferation, differentiation and/or apopto ⁇ c signaling
  • Animal models that are used in embodiments of the methods further include animals, such as, but not limited to non-human animals, which have, m at least some of their cells, an alteration or defect in, or aberrant functioning of, a cellular process which relies on or is regulated by intracellular calcium
  • Cellular processes that rely on or are regulated by intracellular calcium include, for example, cellular activation, gene expression, cellular trafficking, and apoptosis
  • are diseases/disorders that involve defects that are at0 least partially compensated for by modulation of intracellular calcium include, but are not limited to autoimmune disorders, including rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome (cytokines associated with lymphocyte invasion of salivary epithelial cells can reduce calcium mobilization in parotid cells, also, T-cell activation, including activation of transcription factors, cytokine gene expression and cell proliferation, depends on sustained elevation of intracellular calcium level provided by store-operated calcium
  • Animal models include transgenic and non-transgenic animals
  • AHR airway hyperresponsiveness
  • This model are generated, for example, by sensitization through immunization with ovalbumin followed by exposure to aerosolized ovalbumin and challenge by cholinergic stimulation (e g , via administration of methacholine or acetylcholine) (see, e g , Xu et al (2002) J Appl Physiol 93 1833-1840, Humbles etal (2002) Proc Nad Acad Sa 99 1479-1484)
  • Airway hyperresponsiveness (which in some embodiments are evaluated using methods such as, for e g , using barometric plethysmography to record respiratory pressure curves and through measurement of pulmonary parameters such as pulmonary conductance and pulmonary compliance) are assessed and compared in animals treated and not treated with a compound of Formulas (I), (II), (I
  • Step 1 Claisen condensation ⁇ Organic Syntheses 1943, Coll VoI 2, 111) between ester 3-1 and acid chloride 3-2 will give ketoester 3-3.
  • Step 2- Condensation of ketoester 3-3 with hydrazine will be performed by heating ketoester 3-3 in ethanol with excess hydrazine hydrate
  • Step 3 Reaction of aminoprazole 3-4 with an acid chlo ⁇ de will provide pyrazole 3-5
  • Step 4 Hydrolysis of the ester in compound 3-5 will give acid 3-6 Examples 3B-3M
  • Step 1 Following the procedure of Burness (Organic Syntheses 1960, 40, 29) the methyl ester of 3- iuran carboxylic acid is oxidized with bromine in methanol to give the 2,5-dihydro-2,5-dimethoxyfuran 4-2 Step 2 Reduction of 4-2 by hydrogenation with palladium-on-carbon will afford tetrahydrofiiran 4-3 Step 3 Condensation of aniline with 4-3 according to the procedure of Josey (Organic Syntheses 1967, 47, 81) will yield substituted pyrrole 4-4 Step 4 Hydrolysis of the methyl ester followed by Curtius rearrangement with diphenylphosphorylazidate (Organic Syntheses 1984, 62, 187) gives the 3-aminopyrrole 4-5 Step 5 Acylation of pyrrole 4-5 with tnchloroacetyl chlo ⁇ de according to the procedure of Bailey et al (Organic Syntheses 1971, 5/, 100) produces
  • Step / Following the procedure of Penning (J. Med. Chem. 1997, 40, 1347) nitro ketone 5-1 is condensed with dimethylformamide to provide the enamide 5-2.
  • Step 2 Reaction of phenyl hydrazine hydrochloride with enamide 5-2 in methanol gives pyrazole 5-3.
  • Step 3 Reduction of nitro compound 5-3 according to (he procedure of Penning (J. Med. Chem. 1997, 40, 1347) will yield the aminopyrazole which is acetylated with benzoyl chloride to give compound 5-4.
  • Step 4 Hydrolysis of the me ⁇ iyl ester gives the compound 5-5. Examples 5B-5M
  • Step I BromoanthraiuUc acid derivative 6-1 is subjected to a palladium-catalyzed cross-coupling reaction (Organic Syntheses 1998 75, 53) with phenyl boronic acid to give amino ester 6-2
  • Step 2 Reaction of 6-2 with benzoyl chloride will give amide 6-3
  • Step 3 Hydrolysis of the methyl ester gives the compound 6-3
  • Step 1 Bromothiophene derivative 7-1 is subjected to a palladium-catalysed cross-coupling reaction (Organic Syntheses 1998, 75, 53) with phenyl boronic acid to give acid 7-2
  • Step 2 Treatment of 7-2 with butyl lithium will result in metalation of the thiophene nng at the 2 -position with the carboxylate group serving to direct metalation as shown in intermediate 7-2a (See Organic Syntheses 1970, 50, 104, Organic Syntheses 1995, 72, 163)
  • Addition of the Weinreb's amide derived from oxalic acid (Sibi et alJ Org Chem , 1995, 60, 5016, Nahm, S , Weinreb, S M Tetrahedron Lett 1981, 22, 3815-3818) to this lithium species will afford ketone 7-3
  • Step 3 Treatment of amide 7-3 with phenyl magnesium bromide yields ketone 7-4 Activation of the acid in 7-4 and condensation with
  • Step 1 Tetralone 8-1 is subjected to thiophene annulation according to the procedure of Amr et al (Bioorg Med Chem 2006, 14, 5481) wherein methyl cyanoacetate is added to the ketone in the presence of elemental sulphur and diethyl amine to give the tricyclic thiophene 8-3
  • Step 2 Treatment of 8-3 with benzoyl chloride affords amide 8-4
  • Step 3 Hydrolysis of the ester in 8-4 will be performed with aqueous sodium hydroxide to give acid 8-5
  • Fluorescence-based assays are used for screening the compounds described herein, such as compounds of Formulas (I), (II), (HI), (TV), (V) and (VI) 1 which modulate intracellular calcium
  • RBL-2H3 cells plated m 384-well plates are loaded for 45 mm with FLUO-4-AM (2 ⁇ M final concentration) m a Hanks-buffered salt solution Cells are washed and placed m a nominally Ca 2+ - and Mg 2+ - free Hanks solution.
  • Tg thapsigargin
  • 1 ⁇ M thapsigargin (Tg) is added to inhibit the ER Ca 2+ pump and discharge intracellular Ca 2+ stores Fifteen minutes after addition of Tg, store-operated calcium entry is initiated by adding external Ca 2+ to a final concentration of 1 8 mM and the cells monitored for a further 10-15 minutes Calcium levels are monitored throughout the assay using a FLIPR 384 (Molecular Devices fluorimetnc imaging plate reader for high throughput screening) [00578]
  • 1 ⁇ M Tg is added to the SH-SY5Y cells Fifteen minutes after addition of Tg, test compound or vehicle is added, followed by another 15 minute incubation in Ca 2+ -free buffer
  • Store-operated calcium entry is then initiated by adding external Ca 2+ to a final concentration of 1 S mM and the response monitored for a further 10-15 minutes
  • the screening assay alternatively uses external Ba 2+ (final concentration of 10 mM) in place of external Ca 2+
  • external Ba 2+ final concentration of 10 mM
  • thapsigargin- induced store-operated Ba 2+ entry serves as a surrogate for store-operated Ca 2+ entry
  • Up IQ the rate constant derived from first-order association of RFUs from 2 seconds to peak response
  • Time to peak the tune at which the peak RFU is achieved. Peak/Basal the difference between peak and mean basal RFU
  • Decay slope linear regression of the decrease in RFU from the peak to the end of the measurement period
  • Decay rate constant (Decay K) the rate constant derived from first-order decay of RFUs from the peak to the end of the measurement pe ⁇ od
  • AUC Area under the curve
  • Example 10 In Vitro Effects of Agents that Modulate Intracellular Calcium on Degranulation
  • RBL-2H3 cells are plated and stimulated with 20 nM thapsigargm/20 nM TPA for 20 hr in the presence or absence of compound of Formulas (I), (II), (HI), (IV), (V) or (VI) Media is collected and assayed for the release of the inflammatory mediator ⁇ -hexosammidase or for the release of the cytokine TNF- ⁇
  • the ⁇ -hexosaminidase enzymatic assay is performed by adding 200 ⁇ L 1 mM p- mtrophenyl-acetyl-glucosamide substrate (Sigma #N9376) in 0 OSM sodium citrate (pH 4 5) to 50 ⁇ L of conditioned medium, incubating for 60 mm at 37 0 C, then adding 500 ⁇ L 005M sodium carbonate, 0 05M sodium bicarbonate pH 10 5, mixing thoroughly, and reading the absorbance at 405
  • Example 11 Modulation of Intracellular Calcium by a SOCl Inhibitor in STIMl-Overexpressing Cells
  • Store-operated calcium entry is sensitive to the inhibitor 2-aminoethoxydiphenyl borate (2-APB)
  • 2-aminoethoxydiphenyl borate (2-APB) To test whether the Ca 2+ entry pathway consutuuvely activated by STIM 1 overexpression is pharmacologically similar to endogenous SOCE, HEK[STIMl] cells are pre-incubated with increasing doses of 2-APB and STIMl-induced Ca 2+ entry is measured.
  • Example 13 Dose-Response Effects of Test Compound, CSA or Rapamycin in Mouse Footpad DTH
  • Purpose Determine dose-response effects of Test Compound on mBSA induced DTH response in foot pads when dosmg is done during the sensitization as well as induction phase
  • Materials Methylated BSA (Sigma) Freund's complete adjuvant (Difco) phis supplemental M tuberculosis H37 RA (Difco) [00591] General Study Design.
  • mice are anesthetized with Isoflurane and given intradermal antigen injections of 0 1 ml at the base of the tail (DO, D07)
  • Antigen is prepared by making a 4 mg/ml solution in sterile water Equal volumes of antigen and Freund's complete adjuvant to which 4 mg/ml MTB are added (sonicate for 5 minutes after adding MTB to oil), are emulsified by hand mixing until a bead of this materia!
  • Test Compound sodium salt
  • PEG400 as liquid
  • Type II collagen Type II collagen
  • Freund's incomplete adjuvant acetic acid
  • Test Compound is prepared at a concentration of up to 100 mg/ml in 70% PEG400 / 30% water
  • Collagen is prepared by making a 4 mg/ml solution m 00 IN Acetic acid
  • Equal volumes of collagen and Freund's incomplete adjuvant, are emulsified by hand mixing until a bead of this material holds its form when placed in water
  • Example 15 Effect of compounds of Formulas (I), (II), (HI), (TV), (V) and (Vl) on DNBS-Induced Colitis in Rats
  • the subject must have a diagnosis of RA according to (he revised 1987 criteria of the American College of Rheumatology (ACR), • The subject must have a DAS28 disease activity score of greater than 42 at screening and pie-dose,
  • the subject must have a CRP serum level of >/05mg/dl or an ESR level 28mm/hour at screening and pre-dose,
  • the subject has NOT received any biological therapy in the past, including biologicals for the treatment of rheumatoid arthritis, •
  • the subject must have liver function tests including alanine transaminase (ALT) and aspartate transaminase (AST) within 1 5 times the upper limit of normal (ULN) and alkaline phosphatase (ALP) within 3 times ULN at screening
  • ALT alanine transaminase
  • AST aspartate transaminase
  • UPN upper limit of normal
  • ALP alkaline phosphatase
  • the patient must also have total bilirubin Within the ULN at screening, •
  • the subject must have received at least 3 months of methotrexate and must be on a stable dose of methotrexate (up to 25 mg/week) for at least 8 weeks prior to screening and be willing to remain on this dose throughout the study,
  • NSAIDs Non Steroidal Anti Inflammatory Drugs
  • COX-2 inhibitors oral glucocorticoids e g prednisolone ( ⁇ 10mg/day) must be on stable dosing regimens for at least 4 weeks p ⁇ or to screening and be willing to remain on this regime throughout the study
  • the subject must be on a stable dose of folate supplements (5 mg/week) for at least 4 weeks p ⁇ or
  • the subject has a positive Hepatitis B surface antigen or Hepatitis C antibody result at screening, • The subject has a history of elevated liver function tests on more than one occasion (ALT, AST and
  • the subject has a history of repeated, chrome or opportunistic infections that, in the opinion of the investigator and/or GSK medical monitor, places the subject at an unacceptable risk as a participant in this trial,
  • the subject has a history of malignancy, except for surgically cured basal cell carcinoma or females with cured cervical carcinoma (> 2 yrs p ⁇ or),
  • the subject has a history of human immunodeficiency virus (HIV) or other immunodeficiency disease, * The subject whose calculated creatinine clearance is less than 50ml/min,
  • the subject has significant cardiac, pulmonary, metabolic, renal, hepatic or gastrointestinal conditions that, ui the opinion of the investigator and/or GSK medical monitor, places the subject at an unacceptable risk as a participant m this trial,
  • Subjects with a history of haematological disease or acquired platelet disorders including drug-induced thrombocytopaenia, acute idiopathic thrombocytopaenia or von Willebrand's disease, • Subjects with a known risk of lntra-crarual haemorrhage including Central Nervous System (CNS) surgery within the last 12 months, arterial vascular malformations, aneurysms, significant closed head trauma within 6 months or any other incident the investigator and/or medical monitor considers to be relevant,
  • CNS Central Nervous System
  • the subject has Hb ⁇ 10 g/decihter (dL) and platelet count ⁇ 150 x 109/Liter (L), • Donation ofblood m excess of 500 ml within a 56 day penod prior to dosing,
  • An unwillingness of male subjects to abstain from sexual intercourse with pregnant or lactatmg women, or an unwillingness of the male subject to use a condom with spermicide in addition to having their female partner use another form of contraception such as an mterute ⁇ ne device (IUD), diaphragm with spermicide, oral contraceptives, injectable progesterone, subdermal implants of levonorgestrel or a tubal ligation if the woman could become pregnant for at least 12 weeks after dosing,
  • IUD mterute ⁇ ne device
  • diaphragm with spermicide diaphragm with spermicide
  • oral contraceptives injectable progesterone
  • subdermal implants of levonorgestrel or a tubal ligation if the woman could become pregnant for at least 12 weeks after dosing
  • the subject has a history of use of drugs of abuse within 12 months p ⁇ or to screening, • History of regular alcohol consumption exceeding average weekly intake of greater than 21 units or an average daily intake of greater than 3 units (males) or an average weekly intake of greater than 14 units or an average daily intake of greater than 2 units (females) Subjects who regularly consume more than 12 units of alcohol in a 24h period will also be excluded 1 unit is equivalent to a half-pint (220ml) of beer/lager or 1 (25ml) measure of spirits or 1 glass (125ml) of wine, • Positive pregnancy test or lactatuig at screening,
  • Study Design This is a randomized, double-blinded, placebo-controlled adaptive, dose finding study to investigate the safety, tolerabihty, PK, PD and efficacy of single and repeat intravenous infusions of a compound of Formula (I), (II), (in), (IV), (V) or (VI) in patients with active rheumatoid arthritis
  • the study is divided into 2 parts Part A is an adaptive, dose finding phase which will provide safety, tolerabihty, PK and PD on single intravenous infusions
  • Part B is a repeat dose phase which will provide safety, tolerabihty, PK, PD and efficacy following repeat intravenous infusions of a selected dose level • Safety and Tolerabihty following single ascending doses of a compound of Formula (I), (II), (HI), (FV),
  • the patient has severe, recalcitrant, plaque-type psoriasis and has failed at least 1 systemic therapy (for the purposes of this study psoralen with ultraviolet light A is considered to be a systemic therapy),
  • the patient has psoriatic involvement of at least 10% of BSA
  • the patient has a PSGA score of 4 or greater;
  • Exclusion Criteria The patient has received treatment with systemic psoriasis treatments (specifically, retinoids, methotrexate, cyclospo ⁇ ne A, etanercept, efalizumab, other biological agents or other lmmunomodulators) within 4 weeks, or UV based therapy within 2 weeks, or alefacept within 6 weeks of the planned 1st day of study treatment,
  • systemic psoriasis treatments specifically, retinoids, methotrexate, cyclospo ⁇ ne A, etanercept, efalizumab, other biological agents or other lmmunomodulators
  • potent CYP3A4 inhibitors including cyclosporme, clotrimazole, fluconazole, itraconazole, ketoconazole, vo ⁇ conazole, erythromycin, clarithromycin, and troleandomycin, human immunodeficiency virus (HIV) protease inhibitors, or nefazodone within 1 week (7 days) of the planned 1st day of study treatment,
  • the patient has hypersensitivity to a compound of Formula (I), (E), (III), (IV), (V) or (Vl) or any component of a compound of Formula (I), (H), (IH), (IV), (V) or (VT),
  • the patient has one or more of the following serum chemistry values as determined at the screening visit (visit 1)
  • Study Design This is an exploratory, open-label, nonrandomized, dose-escalation study of the efficacy, safety, and tolerability of a compound of Formula (I), (II), (HI), (IV), (V) or (VI) m patients with severe, recalcitrant, plaque-type psoriasis Phase ⁇ Clinical Trial of the Safety and Efficacy of Compounds of Formula (I), TO, (m), (IV), (V) or (VT) for Prophylaxis of Acute Rejection after Renal Transplantation
  • the standard immunosuppressive treatment after renal transplantation is a combination of tacrolimus, mycophenolate mofetil, and prednisolone With this regimen the incidence of acute rejection within the first six months after transplantation can drop to about 20% The main challenge at present remains to improve long-term outcome by
  • Study Design This is a randomized, double blind, placebo controlled intervention study on the efficacy and safety of the prophylactic use of a compound of Formula (I), (II), (III), (TV), (V) or (VI)
  • One group will receive a single dose of a compound of Formula (I), (U), (III), (IV), (V) or (VI) intravenously at the time of transplantation, and the other group receives a placebo infusion
  • Subjects on the following medications may be enrolled into the study if the medications were according to the following schedules prior to study drug administration and if no changes are anticipated during the study, o prednisolone ⁇ 20 mg daily (or equivalent) (dose must be stable for at least 2 weeks prior to study drug administration), o 5-ASA (dose must be stable for at least 4 weeks p ⁇ or to study drug administration), o AZA or 6-MP (dose must be stable for at least 3 months p ⁇ or to study drug administration), o Rectal steroids or 5-ASA (must have been stable for at least 4 weeks p ⁇ or to study drug),
  • Study Design This is a phase II, double-blind, placebo-controlled, randomized, multi-dose study of a compound of Formula (I), (II), (HI), (TV), (V) or (VI) m subjects with active UC experiencing flare All subjects will have active disease while on a 5-ASA containing medication and are either on stable doses of corticosteroids and/or azathiop ⁇ ne or 6-mercaptopunne, or who have previously been on these medications but could not tolerate them.
  • Flare is defined as a Mayo score of 6 to 10 with moderate to severe disease activity on endoscopy (Mayo endoscopic subscore of at least 2) within 2 weeks of receiving study drug administration
  • Doses of permitted concomitant medications corticosteroids, azathiop ⁇ ne (AZA), 6-mercaptopu ⁇ ne (6-MP), and 5-aminosalicylates (5-ASA) containing compounds
  • should remain constant during the course of the study Subjects will be randomized to receive placebo or a compound of Formula (I), (II), (ID), (IV), (V) or (VI) intravenously on Days 1, 15, 29, and 43 All subjects will be seen in the clinic at regular intervals up to Day 85 for safety, efficacy, pharmacokinetic, and/or pharmacodynamic assessments AU subjects will be contacted 70 days after the last dose of study drug Assessment of safety will be determined by vital sign measurements, cluneal laboratory tests, physical examinations, immunogenicity assessments, chest x-ray, electrocardiograms, and the incidence and sevent
  • Study Design This is a phase II, double-bhnd, placebo-controlled, randomized, dose-ranging study of multiple subcutaneous injections of a compound of Formula Q), (II), (HI), (IV), (V) or (VI) m patients with relapsing-remitting multiple sclerosis Patients will receive subcutaneous injections of a compound of Formula Q), (II), (HI), (IV), (V) or (VI) m patients with relapsing-remitting multiple sclerosis Patients will receive subcutaneous injections of a compound of Formula Q), (II), (HI), (IV), (V) or (VI) m patients with relapsing-remitting multiple sclerosis Patients will receive subcutaneous injections of a compound of Formula Q), (II), (HI), (IV), (V) or (VI) m patients with relapsing-remitting multiple sclerosis Patients will receive subcutaneous injections of a compound of Formula Q), (II), (HI), (IV), (V) or (VI)
  • the following ingredients are mixed to form a solution/suspension for oral administration.
  • a pharmaceutical composition for buccal delivery such as a hard lozenge
  • a pharmaceutical composition for buccal delivery such as a hard lozenge
  • the mixture is gently blended and poured into a mold to form a lozenge suitable for buccal administration
  • a pharmaceutical composition for inhalation delivery 20 mg of a compound of Formulas (I), (H), (HI), (TV), (V) or (VI) is mixed with 50 mg of anhydrous citnc acid and 100 mL of 09% sodium chloride solution The mixture is incorporated into an inhalation delivery unit, such as a nebulizer, which is suitable for inhalation administration
  • a pharmaceutical composition for rectal delivery 100 mg of a compound of Formulas (I), (II), (III), (TV), (V) or (VI) is mixed with 2 5 g of methyicelluose (1500 mPa), 100 mg of methylparapen, 5 g of glycerin and 100 mL of purified water
  • the resulting gel mixture is chen incorporated into rectal delivery units, such as syringes, which are suitable for rectal administration
  • a suppository of total weight 2 5 g is prepared by mixing a compound of Formulas (I), (II), (III), (IV), (V) or (VI) with WitepsolTM H- 15 (triglycerides of saturated vegetable fatty acid, Riches-Nelson, Inc , New York), and has the following composition
  • a pharmaceutical topical gel composition 100 mg of a compound of Formulas (I), (II), (III), (TV), (V) or (VI) is mixed with 1 75 g of hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of isopropyl mynstate and 100 mL of purified alcohol USP The resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topical administration
  • a pharmaceutical opthaknic solution composition 100 mg of a compound of Formulas (I), (II), ( ⁇ i), (TV), (V) or (VI) is mixed with 0 9 g of NaCl in 100 mL of purified water and filtered using a 0 2 micron filter The resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration.
  • ophthalmic delivery units such as eye drop containers

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Abstract

Described herein are compounds and pharmaceutical compositions containing such compounds, which modulate the activity of store-operated calcium (SOC) channels. Also described herein are methods of using such SOC channel modulators, alone and in combination with other compounds, for treating diseases, disorders or conditions that would benefit from inhibition of SOC channel activity.

Description

COMPOUNDS THAT MODUIATE INTRACELLULAR CALCIUM
CROSS-REFERENCE
[0001] This application claims the benefit of U S provisional application Serial No 61/013,227, entitled
"Compounds That Modulate Intracellular Calcium" filed December 12, 2007, which is incorporated by reference in its entirety
FIELD OF THE INVENTION
[0002] Described herein are compounds, pharmaceutical compositions and medicaments that include such compounds, and methods of using such compounds to modulate store operated calcium (SOC) channel activity BACKGROUND OF THE INVENTION [0003] Calcium plays a vital role in cell function and survival For example, calcium is a key element in the transduction of signals into and within cells Cellular responses to growth factors, neurotransmitters, hormones and a variety of other signal molecules are initiated through calcium-dependent processes [0004] Virtually all cell types depend in some manner upon the generation of cytoplasmic Ca2+ signals to regulate cell function, or to trigger specific responses Cytosolic Ca2+ signals control a wide array of cellular functions ranging from short-term responses such as contraction and secretion to longer-term regulation of cell growth and proliferation Usually, these signals involve some combination of release of Ca2+ from intracellular stores, such as the endoplasmic reticulum (ER), and influx OfCa2+ across the plasma membrane In one example, cell activation begms with an agonist binding to a surface membrane receptor, coupled to phosphohpase C (PLC) through a G-protein mechanism PLC activation leads to the production of inositol 1,4,5-tπphosphate (IP3), which in turn activates the IP3 receptor causing release OfCa2+ from the ER The fall in ER Ca2+ then signals to plasma membrane store-operated calcium (SOC) channels
[0005] Store-operated calcium (SOC) influx is a process in cellular physiology that controls such diverse functions such as, but not limited to, refilling of intracellular Ca2+ stores (Putney et al Cell, 75, 199-201 , 1993), activation of enzymatic activity (Fagan et al , J Biol Chem 275 26530-26537, 2000), gene transcription (Lewis, Annu Rev Immunol 19 497-521, 2001), cell proliferation (Nunez el al , J Physiol 571 1, 57-73, 2006), and release of cytokines (Winslow e< α/ , Cwr Opin Immunol 15 299-307, 2003) In some nonexcitable cells, e g , blood cells, immune cells, hematopoietic cells, T lymphocytes and mast cells, SOC influx occurs through calcium release-activated calcium (CRAC) channels, a type of SOC channel [0006] The calcium influx mechanism has been referred to as store-operated calcium entry (SOCE) Stromal interaction molecule (STIM) proteins are an essential component of SOC channel function, serving as the sensors for detecting the depletion of calcium from internal stores and for activating SOC channels
SUMMARY OF THE INVENTION
[0007] Described herein are compounds of Formulas Q), (S), QS), (IV), (V), and (VI), compositions that include such compounds, and methods of use thereof, for modulating intracellular calcium In another aspect, compounds of Formulas (I), (II), (III), (IV), (V) or (VI) modulate intracellular calcium by inhibition of store operated calcium channel activity In a further aspect, compounds of Formulas (I), (II), (III), (IV), (V) and (VI) modulate intracellular calcium by preventing the activity of activated store operated calcium channel complexes In one aspect, compounds of Formulas (I), (II), (III), (IV), (V) and (VI) inhibit activation of store operated channels In another aspect, compounds of Formulas (I), (II), (III), (IV), (V) and (VI) inhibit activation of calcium-release activated calcium channels In yet another aspect, compounds of Formulas (I), (II), (III), (IV), (V) and (VI) modulate an activity of, modulate an interaction of, or modulate the level of, or bind to, or interact with at least one protein of the SOC channel complex In one aspect, compounds of Formulas (I), (II), (EI), (FV), (V) and (VI) modulate an activity of, modulate an interaction of, or modulate the level of, or bind to, or interact with at least one protein of the CRAC channel complex. In another aspect, a compound of Formulas (I), (II), (III), (IV), (V) or (VI) is a selective inhibitor of SOC channel activity In one aspect, a compound of Formulas (I), (II), (HI), (TV), (V) or (VI) is a selective inhibitor of CRAC channel activity
[0008] In one aspect, described herein is a compound of Formula (I), or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof
Figure imgf000004_0001
Formula (I), wherein
L is a bond, Ci-Cβalkyl, Ci-C6alkenyl, Ci-C6heteroalkyl, aryl, or heteroaryl, wherein Ci-Cβattyl. Ci-Cjalkenyl, Ci-Csheteroalkyl, aryl, or heteroaryl is optionally substituted with at least one Rs,
V is a bond, O, -(C(R6Ja)n-O or NR1, W is a bond, CpCealkyl, Q-Qalkenyl, Ci-Csheteroalkyl, wherein when Y is S and X is CR3 then V and W are absent, X is N or CR3,
Y is O, S or NR3, with the proviso that if Y is S, then X is not CH,
R is CO2R1, a carboxyhc acid bioisostere, an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl,
R1 is hydrogen, C1-C^aIlCyI, Cj-Qhaloalkyl, or benzyl,
R2 and R4 are each independently an aryl, or a heteroaryl, wherein R2 and R4 are independently optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8, C1- C6alkyl, C3-C8cycloalkyl, Ci-Csheteroalkyl, Ci-C6haloalkyl, tetrazolyl, CVCgheterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, NHS(O)2R8, -S(O)2N(R9J2, -N(R9JS(O)2N(R9J2, - C(O)CF3, C(O)NHS(O)2R8, -S(O)2NHC(O)R8, -N(R9J2, -N(R9JC(O)R8, -N(R9JC(O)N(R9J2, - N(R9JC(O)OR*, -CO2R9, -C(O)R8, -OC(O)R8, -OC(O)N(R9J2, -CON(R9J2, -SR8, S(O)R8, and -S(O)2R8, n is an integer from 1-6, R5 is selected from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8, CpQalkyl, C3-C8cycloalkyl, C,- Qheteroalkyl, CrCehaloalkyl, tetrazolyl, C2-C8heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(O)2R8, -S(OJ2N(R9J2, -N(R9JS(O)2N(R9J2, -C(O)CF3, -C(O)NHS(O)2R8, - S(O)2NHC(OJR8, -N(R9J2, -N(R9JC(O)R8, -N(R9JC(O)N(R9J2, -N(R9JC(O)OR8, -CO2R9, -C(OJR8, - OC(O)R8, -OC(O)N(R9J2, CON(R9J2, -SR8, -S(O)R8, and -S(O)2R8, each R6 is independently hydrogen, F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8, Ci-Csalkyl, C3- C8cycloalkyl, Ci-Cjheteroalkyl, Ci-Cδhaloalkyl, tetrazolyl,
Figure imgf000004_0002
optionally substituted heteroaryl, -NHS(OJ2R8, -S(O)2N(R9J2, -N(R9JS(O)2N(R9J2, -C(O)CF3, - C(O)NHS(O)2R8, -S(O)2NHC(O)R8, -N(R*)2, -N(R^)C(O)R8, -N(R9JC(O)N(R9J2, -N(R9JC(O)OR8, - CO2R', -C(O)R8, -OC(O)R8, -OC(O)N(R9J2, -CON(R")2, -SR8, -S(O)R8, and -S(O)2R8, each R8 is independently selected from Ci-Q-lkyl, Ci-Cjhaloalkyl, C3-C8cycloalkyl, phenyl, and benzyl, each R9 is independently selected from H, Ci-C6OUCyI, Ci-Qhaloalkyl, C3-C8cycloalkyl, phenyl, and benzyl, and R3 is hydrogen, Ci-C6alkyl, CpCshaloalkyl, Ci-Cβheteroalkyl, C3-Cgcycloalkyl, substituted or unsubstituted aryl or benzyl
[0009] In some embodiments, substttuents are selected from among from a subset listed herein. For example, in some embodiments, R1 is hydrogen or Ci-Cβalkyl In other embodiments, R1 is H, methyl, ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, lso-butyl, n-pentyl, or hexyL In yet other embodiments, R1 is H, methyl, or ethyl In some embodiments, R1 is H
[0010] In some embodiments R4 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, CN, -NO2, CF3, -OH, -OR8, -OCF3, Ci-C6alkyl, Ci-Csfluoroalkyl, Ci-Ceheteroalkyl, C3 Cgcycloalkyl, and C-CJialoalkyl [0011] In another embodiment R4 is an optionally substituted heterocycle wherein the heterocycle is selected from
O O- ύ 0.0 ύ 0.0 όό O
O O O O O OO OO CO cύ
[0012] In a further embodiment R4 is substituted with at least one substituent selected from -NHS(O)2R8, - S(O)2N(R9J2, -N(R9JS(O)2N(R9J2, -N(R9J2, -N(R9JC(O)R8, -N(R9JC(O)N(R')* -N(R')C(0)OR8, -CO2R9, -
C(O)R8, -OCX=O)N(R9J2, -CON(R9J2, -SR8, or -S(O)2R8
[0013] In another embodiment R4 is selected from phenyl, 2-fluoroρhenyl, 3-fluoroplicnyl. 4-fluoroρhenyl,
2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl.
3,5-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3 iodophenyl, 4- iodophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 2,3-dnnethylphenyl, 3,4 dimefhylphenyl, 3,5-dimetliylphenyl, 2-tnfluromethylphenyl, 3-1πfluromethylphenyl, and4- tπfluromethylphenyl
[0014] In yet another embodiment R2 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3, Ci-C6alkyl, Ci-C3fluoroalkyl, CrC6heteioalkyl, C3- Qcycloalkyl, and Ci C^haloalkyl
[0015] m another embodiment R2 is an optionally substituted heterocycle wherein the heterocycle is selected from π, ύ O. O O O 0 OO O O 0.0 O O 0000 CO CO
[0016] In some embodiments R2 is substituted with one or more of the substituents selected from - NHSt=O)2R8, -S(O)2N(R9J2, -N(R9JS(O)2N(R')* -N(R9J2, -N(R^)C(O)R8, -NtR^CXOJNφ9)^ - N(R')C(=O)OR8, -CO2R9, -C(=O)R8, -OQ-OJNCR'JJ, -CONφ'k, -SR8, or -S(O)2R8 [0017J In another embodiment R2 is selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dicblorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromoρhenyl, 2-iodophenyl, 3-iodophenyl, 4- lodophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 2,3-dimethylphenyl, 3,4- dimethylphenyl, 3,5-dimethylphenyl, 2-tn£luromethylphenyl, 3-tnfluromethylphenyl, and 4- tnfluromethylphenyl
[0018] In one embodiment X is N and Y is O
[0019] In yet another embodiment X is N and Y is CR3, wherein R3 is selected from H or methyl
[0020] Ih a further embodiment X is CR3 and Y is O, wherein R3 is selected from H or methyl
[0021] hi some embodiments X is CR3 and Y is NR3, wherein each R3 is independently selected from H or methyl
[0022] Any combination of the groups described above for the various variables is contemplated herein In some embodiments, it is understood that substituents and substitution patterns on the compounds provided herein are selected to provide compounds that are chemically stable and that are synthesized by standard techniques, as well as those set forth herein [0023] In one aspect, described herein is a compound of Formula (II), or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof
Figure imgf000006_0001
Formula (II) wherein L is a bond, Ci-Cjalkyl, Ci-C6alkenyl, Ci-Csheteroalkyl, aryl, or heteroaryl, wherein Ci-Qalkyl, Ci-
Ctalkenyl, Ci-Cδheteroalkyl, aryl, or heteroaryl is optionally substituted with at least one R5, V is a bond, O, -(qR^-O or NR1, W is a bond, ^-Qalkyl, Cj-Qalkenyl, Ci-C6heteroalkyl, X is N or CR3, Y is N or CR3,
R is CO2R1, a carboxyhc acid bioisostere, an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl,
R1 is hydrogen, Ci-C6IiIlCyI, C1-CShSlOaIlCyI, or benzyl,
R2 is an aryl, or a benzolhienyl, wherein the aryl or benzotinenyl is optionally substituted with at least one R5,
R4 is an aryl, optionally substituted with at least one R5, each R5 is independently selected from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8, CpC^alkyl, C3- C8cycloalkyl, CπQjheteroalkyl, CrC<jhaloalkyl, tetrazolyl, C2-Csheterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHSC=O)2R8, -S(=O)2N(R9)2, - NOWSH^NCR,),, -CC=O)CF3, -CC=O)NHSC=O)2R8, -SC=O)2NHCC=O)R8, -NCR,)2, - N(R9)CC=O)R8, -N(R9)C(=O)N(R9)2, -N(R9)CC=O)OR8, -CO2R9, -CC=O)R8, -OCC=O)R8, -
OCC=O)NCR9^, -CON(Rs)2, -SR8, -S(O)R8, and -S(O)2R8, each R6 is independently selected from hydrogen, from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8, Ci-C6alkyl, C3-C8cycloalkyl, CrQheteroalkyl, CrQhaloalkyl, tetrazolyl, C^-Qheterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(O)2R8, -S(O)2N(R9)2, - N(R9)S(O)2N(Rj)2, -C(O)CF3, -C(O)NHS(O)2R8, -S(O)2NHC(O)R8, -N(RJ)2, -
N(R9)C(O)R8, -N(R9)C(O)N(Rj)2, -N(R9)C(O)OR8, -CO2R9, -C(O)R8, -OC(O)R8, - OC(O)N(R9),, -CON(Rj)2, -SR8, S(O)R8, and -S(O)2R8, n is an integer from 1-ύ, each R8 is independently selected from CrQalkyl, Q-Qjhaloalkyl, Cj-Qcycloalkyl, phenyl, and benzyl, each R' is independently selected from H, Ci-Qalkyl, Ci-Qhaloalkyl, C3-C8cycloalkyl, phenyl, and benzyl, and
R3 IS hydrogen, CpC^alkyl, Ci-C^haloalkyl, Ci-Cjheteroaikyl, substituted or unsubstituted aryl or benzyl [0024] In some embodiments, substituems are selected from among from a subset listed herein For example, m some embodiments, R1 is hydrogen or CrQalkyl In other embodiments, R1 is H, methyl, ethyl, n propyl, iso-propyl, n-butyl, sec-butyl, lso-butyl, n-pentyl, or hexyl In yet other embodiments, R1 is H, methyl, or ethyl In some embodiments, R1 is H
[0025] In some aspects R4 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3, CrQalkyl, CpQfluoroalkyl, Ci-C<sheteroalkyl, CVQcycloalkyl, and CrQhaloalkyl [0026] In another embodiment R4 is an optionally substituted heterocycle wherein the heterocycle is selected from
O.Q . Qύ.CO .CO ύ .ύ O ό.O.ό όύ. ύ .
[0027] I 0n a furt.h0er embo.d0iment R40 is subs.ti0tuted wit .h0 at le0ast one C subsQtituent C selecQted fro.m C -NOHS(O)2R8, - S(O)2NCR^)2, NCR^SCO)2N(R9J2, N(R9),, N(R^)C(O)R8, NCR9^(O)NCR9J2, -N(R9)C(O)0R8, -CO2R9, - C(O)R8, -OCCOJNCR9^, -CONCR9)* -SR8, or -S(O)2R8
[0028] In yet another embodiment R4 is selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, A- fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophβnyl, 2,3-dichlorophenyl, 3,4- dichloropheny], 3,5-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3- lodophenyl, 4-iodophenyl, 2-methy]phenyl, 3-methylphenyl, 4-methylρhenyl, 2,4-dunethylphenyl, 2,3- dimethylphenyl, 3,4-dunethylphenyl, 3,5-dimethylphenyl, 2-tnfluromethylphenyl, 3-tπfluromethyIphenyl, and 4-tπfluromethylphenyl
[0029] In a further aspect R2 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3, Ci-Qjalkyl, d-Cefluoroalkyi, Ci-Csheteroalkyl, Q-Cgcycloalkyl, and C, CJialoalkyl
[0030] In another embodiment R2 is an optionally substituted heterocycle wherein the heterocycle is selected from o.Q oα. α> co. ύ .ύ.ύ ό O O ό.ύ ύ .
[0031] I 0n one e.m0bodime.n0t R2 is su Obstituted O with one C or mOore of t che soubstitue Cnts sOelected fr ComO - NHS(=O)2R8, -S(=O)2N(R')2, -N^SC-O^NCR'^ -N(R9)2, -N(R9)C(=O)R8, -N(R»)C(=O)N(R')2, - N(R9JC(O)OR8, -CO2R9, -C(=O)R8, -OC(=O)N(R9)2, -CON(R9J2, -SR8, or -SC=O)2R8 [0032] In yet another embodiment R2 is selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4- fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3,4- dichlorophenyl, 3,5-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3- lodophenyl, 4-iodophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 2,3- dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2-tπfluromethylphenyl, 3-tπfluromethylphenyl, and 4-tnfhirometliylphenyl [0033] In an additional embodiment X is N and Y is CR3, wherein R3 is selected from H or methyl [0034] In a further embodiment X is N and Y is N
[0035] In yet another embodiment X is CR3 and Y is CR3, wherein each R3 is independently selected from H or methyl [0036] In one embodiment X is CR3 and Y is N, wherein R3 is selected from H or methyl [0037] In another aspect, described herein is a compound of Formula (III), or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof
Figure imgf000008_0001
Formula (III) wherein L is a bond, Q-Qalkyl, Ci-C«alkeayl, Ci-C6heteroalkyl, aryl, or heteroaryl, wherein CrC6aIkyl, C,-
Qalkenyl, Ci-Cβheteroalkyl, aryl, or heteroaryl is optionally substituted with at least one R10, V is a bond, O, -<C(R3)2),,-O or NR1, W is a bond, Ci-Qalkyl, CrC^alkenyl, CrC6heteroalkyl R is CO2R1, a carboxyiic acid bioisostere, an optionally substituted heteroaryl, or an optionally substituted hβterocycloalkyl,
R1 is hydrogen, Ci-Qalkyl, Ci-Cjbaloalkyl, or benzyl,
R2 is an aryl, or a benzothienyl, wherein the aryl or benzothienyl is optionally substituted with at least one substituent selected from F, Cl, Br, I1 -CN, -NO2, -OH, -CF3, -OCF3, -OR8, Q-Qalkyl, C3-
Cgcycloalkyl, Ci-Qsheteroalkyl, d-Cβhaloalkyl, tetrazolyl, QrCyieterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -
Figure imgf000009_0001
NHSC=O)2R8, - N(R9JS(O)2N(RV -C(=O)CF3, -C(O)NHSC=O)2R8, -S(O)2NHC(O)R8, -N(RV - N(R')C(O)R8, -N(R9JC(O)N(RV -N(R')C(0)OR8, -CO2R', -C(O)R8, -OC(O)R', - OC(O)N(RV -CON(RV -SR8, -S(O)R8, and -S(O)2R8,
R4 is an aryl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, - CF3, -OH, -OR8, -OCF3, Ci-C6-UCyI, C3-Cgcycloalkyl, Q-QfluoroaUtyl, Ci-Ceheteroalkyl, Ci- Cβhaloalkyl, tetrazolyl, C2 C8heterocycloalkyi, optionally substituted aryl, optionally substituted heteroaryl, -NHS(O)2R*, -S(O)2N(RV -N(R9JS(O)2N(RV -C(O)CF3, -C(O)NHS(O)2R8, - S(O)2NHC(O)R8, -N(RV -N(R9JC(O)R8, -N(R9)C(O)N(RV -N(R9JC(O)OR8, -CO2R9, -
C(O)R8, -OC(O)R8, -OC(O)N(RV -CON(RV -SR8, -S(O)R8, and -S(O)2R8, each R3 is independently selected from hydrogen, from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8, Ci-C6alltyl, C3-C8cycloalkyl, CpCβheteroalkyl, C
Figure imgf000009_0002
rC^haloalkyl, tetrazolyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(OJ2R8, -SC=O)2N(R9J2, - N(R9JS(O)2NCR9J2, -C(O)CF3, -C(O)NHS(O)2R8, -S(O)2NHC(O)R8, -NCR9J2, -
N(R9)C(O)R8, -NCR9)C(O)NCR9)J, -N(R9)C(O)OR8, -CO2R9, -C(O)R8, -OC(O)R8, - OC(O)N(R9J2, -CON(R9J2, -SR8, -S(O)R8, and -S(O)2R8, n is an integer from 1 to 6,
R10 is independently selected from from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8, Cj-Cββlkyl, C3- Cscycloalkyl, CpCsheteroalkyl, Q-Qhaloalkyl, tetrazolyl, CrCsheterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(O)2R8, -S(O)2N(R9J2, - N(R9)S(OJ2N(R9J2, -C(O)CF3, -C(O)NHS(O)2R8, -S(O)2NHC(O)R8, -N(R9),, - N(R9)C(O)R8, -N(R9JC(O)N(R9J2, -NCR9)C(O)OR8, -CO2R9, -C(O)R8, -OC(O)R8, - OC(O)N(R9J2, -CON(R9J2, -SR8, -S(O)R8, and S(O)2R8, each R8 is independently selected from Ci-Qalkyl, CpCohaloalkyl, C3-C3cycloalkyl, phenyl, and benzyl, each R9 is independently selected from H, Ci-Qalkyl, Ci-Qhaloalkyl, C3-C8cycloalkyl, phenyl, and benzyl, and R5, R6 and R7 are independently selected from a hydrogen, -OH, halogen, C^Csalkyl, CpCβhaloalkyl, Ci-
Ctiheteroalkyl, substituted or unsubstituted aryl or benzyl [0038] In some embodiments, substituents are selected from among from a subset listed herein. For example, in some embodiments, R1 is hydrogen or CrC6alkyl In other embodiments, R1 is H, methyl, ethyl, n- propyl, lso-propyl, n-butyl, sec-butyl, lso-butyl, n-pentyl, or hexyl. In yet other embodiments, R1 is H, methyl, or ethyl In some embodiments, R1 is H [0039J In one embodiment R4 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3, Ci-Csalkyl,
Figure imgf000010_0001
Cgcycloalkyl, and Ci-Qhaloalkyl
[0040] In some embodiments R4 is an optionally substituted heterocycle wherein the heterocycle is selected from.
Figure imgf000010_0002
ύ .ύ.ύ ύ.ύ ύ .ύO ύ .
O O 0 O O Oc) CQ OO CO
[0041] In another embodiment R4 is substituted with at least one substituent selected from -NHS(O)2R8, - SirOWQL9)!, -N(R9JS(O)2N(R9J2, -N(R9J2, -N(R9JC(O)R", -N(R^)C(O)NCR9J2, -NCR9JC(O)OR8, -CO2R9, -
C(O)R8, OC(O)N(R9J2, CON(R*)2, -SR8, or -S(O)2R8
[0042] In an additional embodiment R4 is selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4- fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichIorophenyl, 2,3-dichlorophenyl, 3,4- dichlorophenyl, 3,5-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3- iodophenyl, 4-iodophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dunethylphenyl, 2,3- dimethylphenyl, 3,4-dunethylphenyl, 3,5-drmethylphenyl, 2-tπfluromethylphenyl, 3-trifhiromethylphenyl, and
4-tπfluromethylphenyl
[0043} In some other embodiments R2 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3, CrC«alkyl, Ci-Cefluoroalkyl, C-Ctheteroalkyl, C3-C8cycloalkyl, and Q-Qhaloalkyl
[0044] In a further embodiment R2 is an optionally substituted heterocycle wherein the heterocycle is selected from
O Q Cύ.CO O) ό .ό O ό O O ύό ό 0.0.0 0 0 OC) CO CO CCi
[0045] In yet another embodiment R2 is substituted with one or more of the substitueirts selected from - NHS(O)2R8, -S(O)2N(R9),, -N(R9JS(O)2N(R'),, -N(R9J2, -N(R^)C(O)R8, -N(R9JC(O)N(R*),, - N(R')C(0)OR8, -CO2R9, -C(O)R8, -OC(O)N(R9J2, CON(R9)2, SR8, Or -S(O)2R8 [0046] In additional embodiments R2 is selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4- fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3,4- dichlorophenyl, 3,5-dichtorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3- lodophenyl, 4-iodophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 2,3- dimethylphenyl, 3,4-dimeihylphenyl, 3,5-dimethylphenyl, 2-tnfluromethylphenyl, 3-tπfluromeUiylphenyl, and
4-tπfluromethylphenyl
[0047] In one aspect, described herein is a compound of Formula (IV), or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof
Figure imgf000011_0001
wherein
L is a bond, CrC6alkyl, C1-C6alkenyl, Q-Qheteroalkyl, aryl, or heteroaryl, wherein Ci-C«alkyl, Cr
C6alkenyl, Ci-Qheteroalkyl, aryl, or heteroaryl is optionally substituted with at least one R10, V is a bond, O, -(C(R7J2X1-O or NR1,
W is a bond, Q-Qalkyl, Cj-Csalkenyl, Ci-Qheteroalkyl, X is N or CR3,
Y is O, S, NR3 or-CR5=CR'-,
R2 is an aryl, or a benzothienyl, wherein the aryl or benzothienyl is optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, OR8, Ci C6alkyl, C3
Qcycloalkyl, CrCjhβteroalkyl, Ci-Qhaloalkyl, tetrazolyl, C2-C8heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(O)2R8, -S(O)2N(R9J2, N(R9JS(O)2N(R9J2, -C(O)CF3, -C(O)NHS(O)2R8, -S(O)2NHC(O)R8, -N(R9^, - N(R9JqO)R8, -N(R9JC(O)N(R9J2, -N(R')C(=O)OR8, -CO2R9, -C(O)R8, -OC(O)R8, - OC(O)N(R9J2, -CON(R9J2, -SR8, -S(O)R8, and -S(O)2R8,
R4 is an aryl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, - CF3, -OH, -OR8, -OCF3, Ci-Cjalkyl, Cj-Cgcycloalkyl, C-Cfluoroalkyl, d-Qheteroalkyl, C1- Qhaloalkyl, tetrazolyl, C2-C8heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(O)2R8, -S(O)2N(R9J2, -N(R9JS(O)2N(R9J2, -C(O)CF3, -C(O)NHS(O)2R8, - S(O)2NHC(O)R8, -N(R9J2, -N(R9JC(O)R8, -N(R9JC(O)N(R9J2, -N(R9JC(O)OR8, -CO2R9, -
C(O)R8, -OC(O)R8, -OQOJNtR9^, -CON(R9J2, -SR8, -S(O)R8, and -S(OJ2R8, each R7 is independently selected from hydrogen, from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8, Ci-C6alkyl, C3-C8cycloalkyl, Ci-Cjheteroalkyl, C,-C6haloalkyl, tetrazolyl, Q-Cβheterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(O)2R8, -S(O)2N(R9)2, - N(R9)Sf=O)2N(R9J2, -C(OJCF3, -C(OJNHS(OJ2R8, -S(O)2NHC(O)R8, -N(R9J2, -
N(R9)C(O)R8, -N(R9)C(OJN(Rs)2, -N(R9)C(OJOR8, -CO2R9, -C(O)R8, -OC(O)R8, OC(O)N(R9J2, -CON(R9J2, -SR8, -S(OJR8, and -S(O)2R8, n is an integer from 1-6, each R8 is independently selected from Q-Cjalkyl, Cj-Cehaloalkyl, C3-C8CyClOaBCyI, phenyl, and benzyl, each R9 is independently selected from H, CrC^alkyl, CrCehaloalkyl, C3-C8cycloalkyl, phenyl, and benzyl,
R10 is selected from F, Cl, Br, I, -CN, NO2, -CF3, -OH, OR8, -OCF3, d-C^alkyl, C3-C8cycloalkyl, C,- Cβfluoroalkyl, Ci-Cβheteroalkyl, Ci-Cδhaloalkyl, tetrazolyl, QrCβheterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(O)2R8, -S(O)2N(R9J2, - N(R9JS(O)2N(R9J2, -C(=O)CF3 -C(O)NHS(OJ2R8, -S(O)2NHC(O)R8, -N(R9J2, - N(R9JCX=O)R8, -N(R9JC(O)N(R9J2, -N(R9JC(O)OR8, -CO2R9, -C(=0)R8, -OC(=O)R8, - OC(O)N(R9J2, -CON(R9J2, -BR8, -S(=O)RS, and -S(O)2R8, R3 is hydrogen, C,-C,,alkyl. CpCyialoalkyl, Ci-Qheteroalkyl, substituted or unsubstituted aiyl or benzyl, and R5 and R6 are independently selected from a hydrogen, -OH, halogen, Ci-Qalkyl, Ci-Cβhaloalkyl, Q-
Cfjheteroalkyl, substituted or unsubstituted aryi or benzyl
[0048] In some embodiments, subsutuents are selected from among from a subset listed herein. For example, in some embodiments, R1 is hydrogen or Ci-Qalkyl In other embodiments, R1 is H, methyl, ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, n-pentyl, or hexyl In yet other embodiments, R' is H, methyl, or ethyl In some embodiments, R1 is H
[0049] Li some embodiments R4 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, OCF3, Ci-Csalkyl, C1-C6fluoroalkyl, Ci-Ccheteroalkyl, C3 Cscycloalkyl, and C-QhaloalkyL
[0050] In other embodiments R4 is an optionally substituted heterocycle wherein the heterocycle is selected from
Figure imgf000012_0001
0 0 0 0 O CO CO CO CO
[0051] In some embodiments R4 is substituted with at least one substituent selected from -NHSt=O)2R8, -
S(O)2N(R9J2, -N(R9JS(O)2N(R9),, -N(R')2, -N(R9JC(O)R8, -N(R9JC(O)N(R')* -N(R9)C(=O)OR8, -CO2R9, -
C(OJR8, -OC(OJN(R9J2, -CON(R9J2, -SR8, or -S(O)2R8
[0052] In other embodiments R4 is selected from phenyl, 2-fiuorophenyl, 3 fluorophenyl, 4-fluorophenyl, 2- chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3,4 dichlorophenyl,
3,5-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4- lodophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 2,3-dnnethylphenyl, 3,4 dimethyhihβnyl, 3,5-dimethylphenyl, 2-trifluromethylphenyl, 3-tπfluromethylphenyl, and 4- tnfluromethylphenyl [0053] In some embodiments R2 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, CF3, -OH, -OR8, OCF3, C,-Csalkyl, Ci-Csfluoroalkyl, C,-C6heteroalkyl, C3-
Cscycloalkyl, and Ci-Cohaloalkyl
[0054] In other embodiments R2 is an optionally substituted heterocycle wherein the heterocycle is selected
Figure imgf000012_0002
ύ ύ.ύ ύ ti O ό.ό ύ
0 0.0 0 0 OC) CO OO OO
[0055] In some embodiments R2 is substituted with one or more of the substituents selected from - NHS(O)2R8, -S(O)2N(R9J2, -N(R9JS(O)2N(R')* -N(R9J2, -N(R9JC(O)R1, -N(R9JC(O)N(R9),, - N(R9JC(O)OR8, -CO2R', -C(O)R8, -OC(O)N(R9J2, -CON(R9J2, -SR8, or -S(O)2R8
[0056] In other embodiments R2 is selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2- chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4- lodophenyl, 2-methylphenyl, 3 methylphenyl, 4 methylphenyl, 2,4-dunethylphenyl, 2,3-dunethylphenyl, 3,4- dunethylphenyl, 3,5-dimethylphenyl, 2-tπfluromethylphenyl, 3-tπfluromethylphenyl, and 4- tπfluromethylphenyl
[0057] In another embodiment X is N and Y is S
[0058] In a further aspect, described herein is a compound of Formula (V), or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof
Figure imgf000013_0001
wherein
V is a bond, O, -(C(R6J2Jn-O or NR1,
W is a bond, C,-C6alkyl, d-Cβalkenyl, Ci-Cjheteroalkyl, n= l or2, m is an integer from 1-6,
R is CO2R1, a carboxyhc acid bioisostere, an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl,
R1 is hydrogen, Ci-C^alkyl, Ci-Cyialoalkyl, or benzyl, R2 is an aryl, or a benzothienyl, wherein the aryl or benzothienyl is optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, OCF3, -OR8, C1-QaIlCyI, C3- Cjcycloalkyl, Ci-C<jheteroalkyl, Ci-Qnaloalkyl, tetrazolyl, CrCgheterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(OJ2R8, -S(O)2N(R9J2, - N(R9JS(O)2N(R9J2, -C(O)CF3, -C(O)NHS(OJ2R8, -S(O)2NHC(O)R8, -N(R9J2, - N(R*)C(O)R8, -N(R9JC(O)N(R9J2, -N(R9JC(OJOR8, -CO2R9, -C(O)R8, -OC(O)R8, -
OC(O)N(R9J2, -CON(R9J2, -SR8, -S(OJR8, and -S(O)2R8,
R4 is selected from H, F, Cl, Br, I, -CN, -NO2, -CF3, -OH, OR8, -OCF3, d-Ctalkyl, C3 C8cycloalkyl, C,- C6fluoroalkyl, Ci-Cyieteroalkyl, Ci-C6haloalkyl, tetrazolyl, QrCsheterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(O)2R8, -S(O)2N(R9)^ - N(R9JS(OJ2N(R9J2, -C(O)CF3, -C(K))NHS(O)2R8, -S(O)2NHC(O)R8, -N(R9J2, - N(R9JC(K))R8, -N(R9)C(=O)N(R9)2, -N(R9)C(=O)OR8, -CO2R9, -C(O)R8, -OC(O)R8, - OC(O)N(R9J2, -CON(R9J2, -SR8, -S(O)R8, and -S(O)2R8, each R6 is independently selected from hydrogen, from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8, CrQalkyl, C3-C8CyOlOaIlSyI, CrQheteroalkyl, Q-Qhaloalkyl, tetrazolyl, QrQheterocycloaJkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHSC=O)2R8, -S(O)2N(R9J2, - N(R9)S(O)2N(R9J2, -C(O)CF3, -C(OJNHS(OJ2R8, -S(O)2NHC(OJR,, N(R9J2, N(R9)C(O)R8, -N(Re)C(O)N(R9J2, -N(R9JC(OJOR8, -CO2R9, -C(O)R8, -OC(O)R8, - OC(=O)N(R9)2, -CON(R9J2, -SR8, -S(O)R8, and -S(O)2R8, each R8 is independently selected from d-Coalkyl, Ci-Cyialoalkyl, QrCscycloalkyl, phenyl, and benzyl, and each R9 is independently selected from H, CrC6aUcyl. CrC6haloalkyl, C3-C8cycloalkyl, phenyl, and benzyl
[0059] In some embodiments, substituents are selected from among from a subset listed herein. For example, m some embodiments, R1 is hydrogen or Ci-C6alkyl In other embodiments, R1 is H, methyl, ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, n-pentyl, or hexyl In yet other embodiments, R1 is H, methyl, or ethyl In some embodiments, R1 is H
[0060] In some embodiments K* is a substituent selected from H, F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, - OCF3, Ci-Qalkyl, Ci-Qfluoroalkyl, CrQjbeteroalkyl, C3-C8cycloalkyl, or C,-C6haloalkyl [0061] In other embodiments R4 is one or more substituents selected from -NHS(O)2R8, -S(O)2N(R9J2, - N(R9JS(OJ2N(R9J2, -N(R9J2, -N(R9JC(OJR8, -N(R9JC(O)N(RV -N(R9JCK=O)OR8, -CO2R9, -C(O)R8, - OC(K))N(R9J2, -CON(R9J2, -SR8, or -S(O)2R8
[0062] Ih some embodiments R2 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3, Ci-Cβalkyl, Ci-Cδfluoroalkyl, C,-C6heteroalkyl, C3- Qcycloalkyl, and C-Qhaloalkyl
[0063] In other embodiments R2 is an optionally substituted heterocycle wherein the heterocycle is selected
O. Q CO CO . CO ύ .ύ .ύ ύ.ύ.ύ ύ.Cf ύ .
[0064] I on some. eQmbodim.eonts R2 isα substitu.tGed with o.one oro more ocf dieQ substitcuentos selec.tecd froαm - NHS(OJ2R8, S(O)2N(R9J2, -N(R9JS(O)2N(R9J2, -N(R9J2, -N(R9JC(O)R8, -N(R9JC(O)N(R9J2, - N(R9JC(O)OR8, -CO2R9, -C(OJR8, -OC(OJN(R9J2, CON(R9J2, -SR8, or -S(O)2R8 [0065] In other embodiment s R2 is selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, A- iodophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 2,3-dimethylphenyl, 3,4- dimethylphenyl, 3,5-dunethylphenyl, 2-tnfluromethylphenyl, 3-triflurometb.ylphenyl, and 4- tπfluromethylphenyl [0066] In a further embodiment n = 2
[0067] In one aspect is a compound having the structure of Formula (VI)
Figure imgf000015_0001
Formula (VI) wherem
L is a bond, Ci-C6aHcyl, Q-Qalkenyl, Ci-C6heteroalkyl, aryl, or heteroaryl, wherein Ci-Qalkyl, CL- C6alkenyl, C1 C^heteroalkyl, aryl, or heteroaryl is optionally substituted with at least one R5,
Z is CrC(,alky], C,-CJialoalkyl, C-CJieteroalkyl, wherem C,-Qalkyl and Ci-Cβheteroalkyl are independently optionally substituted with at least one substituent selected from F, Cl, Br, I, CN, NO2, -OH, -CF3, -OCF3, -OR8, Ci Qalkyl, C3 Qcycloalkyl, Cj Qheteroalkyl, Ci-Cδhaloalkyl, tetrazolyl, CrC8heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, - NHSC=O)2R8, -SO-O)2N(R.9)* -N(R9JS(O)2N(R9J2, -C(=O)CF3, -C(=O)NHS(=O)2R8, -
S(=O)2NHC(=O)R8, -NCR9J2, -N(R9)C(=O)R8, -N(R9)C(=O)N(R9)2, -N(R9JCC-O)OR8, -CO2R9, -
Figure imgf000015_0002
-SR8, -S(=O)R8, and -S(^O)2R8 R is CO2R1, a carboxylic acid bioisostere, an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl, R1 is hydrogen, C1-QaIlCyI, C,-C6haloalkyl, or benzyl,
R2 and R4 are independently an aryl, or a heteroaryl, wherein R2 and R4 are independently optionally substituted with at least one subshtuent selected rrorα F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, - OR8, C,-C6alkyl, C3-C8cycloalkyl, CrQheteroalkyl, Ci-Qhaloalkyl, tetrazolyl, C2- Cgheterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHStND^R8, - SC=O)2N(R9),, -NCR^O^NCR^, <:(=O)CF3, -C(=O)NHS(=O)2R8, -SC=O)2NHCC-O)R8, -N(R9J2,
-NCR9JCC=O)R8, N(R9JCC=O)N(R9J2, NCR9JCC=OJOR8, -CO2R9, -CC=O)R8, -OC(=O)R8, OCC=O)N(R9J2, -CON(R9)2, -SR8, -S(=O)R8, and S(=O)2R8, each R5 is independently selected from F, Cl, Br, I, -CN, -NO2, -OH, CF3, -OCF3, -OR8, C,-Csalkyl,
C3-Cgcycloalkyl, Ci-Cβheteroalkyl, Ci-Qhaloalkyl, tetrazolyl, CrCgheterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHSC=OJ2R8, SC=OJ2N(R9J2, -
N(R9)SC=OJ2NCR9J2, -CC=O)CF3, -CC=O)NHSC=O)2R8, -SC=O)2NHCC=O)R8, -NCR9J2, - N(R9)CC=O)R8, -NCR^C^ONCR,)* -N(R9)C(O)OR8, -CO2R9, -CC=O)R8, -OCC=O)R8, - OCC-OJNCR,^, -CON(R9J2, -SR8, -SC=O)R8, and -SC=O)2R8, each R8 is independently selected from Ci-Csalkyl, d-Qshaloalkyl, C3-C8cycloalkyl, phenyl, and benzyl, and each R9 is independently selected from H, Ci-Qalkyl, Ci-Qjhaloalkyl, C3-C8cycloalkyl, phenyl, and benzyl. [0068] In one embodiment is a compound of Formula (VI) wherein Z is Ci-C^alkyl
[0069] In another embodiment is a compound of Formula (VI) wherein Z is CH3
[0070] In yet another embodiment is a compound of Formula (VI) wherein Z is CH2CH3
[0071] In one embodiment is a compound of Formula (VI) wherein Z is substituted with a substituent selected from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8, Ci Csalkyl, C3 Cgcycloalkyl, and C1-
Cjheteroalkyl
[0072] In yet another embodiment is a compound of Formula (VI) wherein the substituent is selected from
F, Cl, Br, and I
[0073] In some embodiments, substituents arc selected from among from a subset listed herein. For example, in some embodiments, R1 is hydrogen or Ci-Cgalkyl In other embodiments, R1 is H, methyl, ethyl, n- propyl, lso-propyl, n-butyl, sec-butyl, iso-butyl, n-pentyl, or hexyl In yet other embodiments, R1 is H, methyl, or ethyl. In some embodiments, R1 is H
[0074] In some embodiments R4 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, NO2, -CF3, OH, -OR8, -OCF3, Ci-Cδalkyl, Q-Csfluoroalkyl, Ci-Qjheteroalkyl, C3- C8cycloalkyl, and Ci-Qihaloalkyl.
[0075] In another embodiment R4 is an optionally substituted heterocycle wherein the heterocycle is selected
Figure imgf000016_0001
ύ .ό.ύ ύ.O.ύ ό.O ύ .
Figure imgf000016_0002
[0076] In a further embodiment R4 is substituted with at least one substituent selected from -NHSf-O)2R8, -
S(MD)2N(R9)!,
Figure imgf000016_0003
-N(R9Jq=O)N(R'^ -NCR'jC^OJOR8, -CO2R9, -
C(=O)R8, -OC(=O)N(R')2, -CONtR9),, -SR8, or -S(O)2R8
[0077] In another embodiment R4 is selected from phenyl, 2-fluorophenyl, 3 fluorophenyl, 4-fluorophcnyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl,
3,5-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2 lodophenyl, 3-iodophenyl, 4- lodophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dunethylphenyl, 2,3-dimethylphenyl, 3,4- dimethylphenyl, 3, S-dimethy (phenyl, 2-tπfluromethylphenyl, 3-trifluromethylphenyl, and 4- tafluromethylphenyl [0078] In yet another embodiment R2 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, NO2, CF3, -OH, -OR8, -OCF3, C^Csalkyl, C,-C6fluoroalkyl, Q-Qheteroalkyl, C3-
Cgcycloalkyl. and Ci-Cehaloalkyl
[0079] In another embodiment R2 is an optionally substituted heterocycle wherein the heterocycle is selected ox; oo α> as. 0 0 0 0 O ex) oo oo CO
[0080] In some embodiments R2 is substituted with one or more of the substituents selected from -
Figure imgf000017_0001
-N(R9XX=O)R8, - N(R')C(=O)OR8, -CO2R9, -C(=O)R8,
Figure imgf000017_0002
or -S(O)2R8
[0081] In another embodiment R2 is selected from phenyl, 2-fluoropheαyl, 3-fluorophenyl, 4-fluoroρhenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5 dichlorophenyl, 2-bromophenyl, 3 bromophenyl, 4 bromophenyl, 2-iodophenyl, 3-iodophenyl, 4- lodophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dmiethylphenyl, 2,3-dimethylphenyl, 3,4- dimethylphenyl, 3,5-dimethylphenyl, 2-tπfluromethylphenyl, 3-tπfluromethylphenyl, and 4- tnfluromethylphenyl
[0082] Any combination of the groups described above for the various variables is contemplated herein. It is understood that substituents and substitution patterns on the compounds provided herein are selected to provide compounds that are chemically stable and that are synthesized by known techniques, as well as those set forth herein
[0083] In one aspect, described herein is a method of modulating store-operated calcium (SOC) channel activity composing contacting the store-operated calcium (SOC) channel complex, or portion thereof, with a compound of Formula (I), (II), (IH), (IV), (V), or (Vl) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof In one embodiment, the contacting occurs m vitro In another embodiment, the contacting occurs m vcvo In one embodiment, the compound of Formula (I), (II), (III), (TV), (V), or (VI) modulates an activity of, modulates an interaction of, or modulates the level of, or binds to, or interacts with at least one portion of the store operated calcium channel complex selected from stromal interaction molecules (STIM) family of proteins In one embodiment, the compound of Formula (I), (II), (III), (IV), (V), or (VI) modulates an activity of, modulates an interaction of, or modulates the level of, or binds to, or interacts with at least one portion of STIMl or STIM2 In one embodiment, modulating store operated calcium channel activity with a compound of Formula (I), (II), (III), (IV), (V), or (VI) inhibits store-operated calcium entry (SOCE) In another embodiment, the store operated calcium channel complex is calcium-release activated calcium (CRAC) channel complex In one embodiment, modulating calcium release activated calcium (CRAC) activity with a compound of Formula (I), (II), (III), (IV), (V), or (VI) inhibits the electrophysiological current (ICXAC) directly associated with activated CRAC channels
[0084] In another aspect, described herein is a method of modulating calcium release activated calcium channel (CRAC) activity in a mammal comprising administering a compound of Formula (I), (II), (in), (TV), (V), or (VI), or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof In one embodiment, the compound of Formula (I), (II), (EI), (IV), (V), or (VT) modulates an activity of, modulates an interaction of, or modulates the level of, or bmds to, or interacts with at least one component of the calcium release activated (CRAC) channel complex selected from stromal interaction molecules (STM) family of proteins In one embodiment, the compound of Formula (I), (II), (III), (IV), (V), or (VI) modulates an activity of, modulates an interaction of, or modulates the level of, or bmds to, or interacts with STIMl or STIM2 In one embodiment, modulating calcium release activated calcium (CRAC) channel activity with a compound of Formula (I), (II), QlI), (IV), (V). or (VI) inhibits store-operated calcium entry (SOCE) In one embodiment, modulating calcium release activated calcium (CRAC) channel activity with a compound of Formula (I), (II), (III), (IV), (V), or (VI) inhibits the electrophysiological current (ICRAC) directly associated with activated CRAC channels In one embodiment, the compound of Formula (I), (II), (III), (IV), (V), or (VI) inhibits SOCE with an IC511 below about 10 μM In yet another embodiment, the compound of Formula (I), (π), (m), (TV), (V), or (VI) inhibits electrophysiological current (ICRAC) directly associated with activated CRAC channels at a concentration below about 10 μM [0085] Also described herein is a method of treating a disease, disorder or condition in a mamma) that would benefit from inhibition of store operated calcium channel activity comprising administering to the mammal a compound of Formula (I), (II), (III), (IV), (V), or (VI), or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof In one aspect, the compound of Formula (I), (II), (III), (IV), (V), or (VT) modulates the activity of, modulates an interaction of, or bmds to, or interacts with a mammalian STIMl protein, or a mammalian STB12 protein In one embodiment, the disease, disorder or condition m a mammal is selected from diseases/disorders involving inflammation, glomerulonephritis, uveitis, hepatic diseases or disorders, renal diseases or disorders, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, vasculitis, dermatitis, osteoarthritis, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, organ transplant rejection, allogeneic or xenogeneic transplantation, graft rejection, graft-versus-host disease, lupus erythematosus, type I diabetes, pulmonary fibrosis, dermatomyositis, thyroiditis, myasthenia gravis, autoimmune hemolytic anemia, cystic fibrosis, chrome relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis, hepatitis and atopic dermatitis, asthma, psoriasis, multiple sclerosis, Sjogren's syndrome, cancer and other proliferative diseases, and autoimmune diseases or disorders In one embodiment, the disease, disorder or condition is rheumatoid arthritis In one embodiment, the disease, disorder or condition is psoriasis In one embodiment, the disease, disorder or condition is organ transplant rejection In one embodiment, the disease, disorder or condition is multiple sclerosis In one embodiment, the disease, disorder or condition is inflammatory bowel disease In another embodiment, the inflammatory bowel disease is ulcerative colitis In yet another embodiment, the inflammatory bowel disease is Crohn's disease In yet another embodiment, the method further comprises administering to the mammal a second therapeutic agent In one embodiment, the second therapeutic agent is selected from immunosuppressants, glucocorticoids, non-steroidal anti-inflammatory drugs, Cox-2-specific inhibitors, leflunomide, gold thioglucose, gold thiomalate, aurofin, sulfasalazine, hydroxychloroquinine, minocycline, anb-TNF-α agents, abatacept, anakmra, interferon-β, interferon γ, interleukm-2, allergy vacemes, antihistamines, antileukotnenes, beta-agonists, theophylline, and anticholinergics In another embodiment, the second therapeutic agent is selected from tacrolimus, cyclosporin, rapamicin, methotrexate , cyclophosphamide, azathiopπne, mercaptopurtne, mycophenolate, or FTY720, prednisone, cortisone acetate, prednisolone, methylpredmsolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone, aspirin, salicylic acid, genbsic acid, cholme magnesium salicylate, choline salicylate, choline magnesium salicylate, choline salicylate, magnesium salicylate, sodium salicylate, diflunisal, carprofen, fenoprofen, fenoprofen calcium, flurobiprofen, lbuprofen, ketoprofen, nabutonc, ketolorac, ketorolac tromethamine, naproxen, oxaprozin, diclofenac, etodolac, lndomethacin, suhndac, tolmetin, meclofenamate, meclofenamate sodium, mβfenamic acid, piroxicam, meloxicam, celecoxib, rofecoxib, valdecoxib, parecoxib, etoncoxib, lumiracoxib, CS-502, JTE-522, L-745,337 and NS398, leflunomide, gold thioglucose, gold thiomalate, aurofin, sulfasalazine, hydroxychloroquinine, 5 minocycline, infliximab, etanercept, adalumimab, abatacept, anakinra, lnterferon-β, mterferon-γ, interleukin-2, allergy vaccines, antihistamines, antiieukotπenes, beta-agonists, theophylline, and anticholinergics [0086] Also described herein is a method of inhibiting store-operated calcium entry (SOCE) activation of nuclear factor of activated T cells (NFAT) in a mammal comprising administering a compound of Formula (I), (IT), (πi), (IV), (V), or (VI), or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or0 pharmaceutically acceptable prodrug thereof In one embodiment, the compound of Formula (I), (II), (IH), (IV), (V), or (VI) modulates an interaction of, or modulates the level of, or binds to, or interacts with a mammalian STIMl protein, or a mammalian STIM2 protein
[0087] Also provided herein is a method of decreasing cytokine expression by inhibiting the store-operated calcium entry activation of NFAT m a mammal comprising administering a compound of Formula (I), (II), (III), S (IV), (V), or (VI), or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof In one embodiment, the compound of Formula (I), (π), (HI), (TV), (V), or (VI) modulates an interaction of, or modulates the level of, or bmds to, or interacts with a mammalian STIMl protein or a mammalian STIM2 protein In one embodiment, the cytokine is selected from IL-2, IL-3, IL-4, IL-S, IL-6, IL-7, IL-8, IL-9, DL-IO, IL-Il, IL-12, IL- 13, IL-15, IL-16, IL-17, IL-18, IL-Io, IL-lβ, IL-I RA, granulocyte0 colony stimulating fector (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), oncostatm M, erythropoietin, leukemia inhibitory fector (LIF), interferons, gamma-interferon (γ-IFN), B7 1 (CD80), B72 (B70, CD86), TNF-α, TNF-β, LT-β, CD40 ligand, Fas ligand, CD27 ligand, CD30 ligand, 4-1BBL, Trail, and migration inhibitory factor (MIF) [0088] In one aspect, described herein is the use of a compound of Formulas (I), (II), (IH), (IV), (V) or (VE),5 or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof, for the formulation of a medicament for the modulation of store operated calcium (SOC) channel activity m a subject or for the treatment of a disease, disorder or condition in a subject that would benefit from the modulation of store operated calcium (SOC) channel activity In one embodiment, the compound of Formulas (I), (II), (III), (TV), (V) or (VI) inhibits store operated calcium entry (SOCE) In another0 embodiment, the store operated calcium channel activity is calcium release activated calcium channel activity [0089] Also described is an article of manufacture, comprising packaging material, a compound of Formulas (I), (H), (HI), (IV), (V) or (VT), or composition, or pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, which is effective for inhibiting calcium release- activated calcium (CRAC) channel activity, or for the treatment, prevention or amelioration of one or more5 symptoms of a disease, disorder or condition that would benefit from the inhibition of calcium release-activated calcium (CRAC) channel activity, within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used for the inhibition of calcium release activated calcium (CRAC) channel activity, or for the treatment, prevention or amelioration of one or more symptoms of a disease, disorder or0 condition that would benefit from the inhibition of calcium release-activated calcium (CRAC) channel activity In one embodiment, the compound of Formulas (I), (SI), (IK), (IV), (V) or (VT) inhibits store operated calcium entry (SOCE)
[0090] In one aspect, described herein is a pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient or binder, and a compound of Formulas (I), (II), (III), (IV), (V) or (VI), or pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof
[0091] In one embodiment, provided herein is a pharmaceutical composition, which includes an effective amount of a compound provided herein, and a pharmaceutically acceptable excipient In a further embodiment, provided are compositions further including a second pharmaceutically active ingredient [0092] In certain embodiments, provided herein is a pharmaceutical composition containing i) a physiologically acceptable earner, diluent, and/or excipient, and u) one or more compounds described herein [0093] In any of the aforementioned aspects are further embodiments that include smgle administrations of the effective amount of the compound of Formulas (I), (II), (IH), (IV), (V) or (VI), including further embodiments in which (i) the compound of Formulas (I), (U), (in), (IV), (V) or (W) is administered once, (li) the compound of Formulas (I), (II), (IQ), (IV), (V) or (VI) is administered to the mammal multiple times over the span of one day, (in) continually, or (iv) continuously
[0094] In any of the aforementioned aspects are further embodiments that include multiple administrations of me effective amount of the compound of Formulas (I), (II), (III), (TV), (V) or (VI), including further embodiments m which (i) the compound of Formulas (I), (II), (UI), (IV), (V) or (VI) is administered in a smgle dose, (n) the time between multiple administrations is every 6 hours, (in) the compound of Formulas (I), (II), (IH), (IV), (V) or (VI) is administered to the mammal every 8 hours In further embodiments, the method comprises a drug holiday, wherein the administration of the compound of Formulas (I), (II), (IH), (IV), (V) or (VT) is temporarily suspended or the dose of the compound of Formulas (I), (H), (TH), (IV), (V) or (VI) being administered is temporarily reduced, at the end of the drug holiday, dosing of the compound of Formulas (I), (II), (IE), (IV), (V) or (VI) is resumed. In some embodiments, the length of the drug holiday vanes from 2 days to 1 year
[0095] In one embodiment, compounds of Formulas (I), (H), (IH), (IV), (V) and (VI) descnbed herein are administered to a human In some embodiments, compounds of Formulas (I), (TI), (III). (IV), (V) and (VI) described herein are orally administered [0096] Compounds provided herein are used for modulating intracellular calcium In one embodiment, compounds provided herein modulate SOC channel activity In one embodiment, compounds provided herein modulate CRAC channel activity In another embodiment, compounds provided herein modulate STIM protein activity In another embodiment, compounds provided herein modulate Oral protein activity In another embodiment, compounds provided herein modulate the functional interactions of STIM proteins with Oral proteins In another embodiment, compounds provided herein reduce the number of functional SOC channels In another embodiment, compounds provided herein reduce the number of functional CRAC channels In one embodiment, compounds descnbed herein are SOC channel blockers In one embodiment, compounds descnbed herein are CRAC channel blockers [0097] In one embodiment, compounds of Formulas (I), (H), (IH), (IV), (V) and (VI) are selective inhibitors of SOCE In one embodiment, compounds of Formulas (I), (H), (III), (IV), (V) and (VI) are selective inhibitors of CRAC channel activity
[0098] Other objects, features and advantages of the compounds, compositions, methods, and uses described herein will become apparent from the following detailed description It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only All references cited herein, including patents, patent applications, and publications, are hereby incorporated by reference
BRIEF DESCRIPTION OF THE FIGURES [0099] Figure 1 outlines the ICRAC channel pathway
INCORPORATION BY REFERENCE
[00100] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference DETAILED DESCRIPTION
[00101] Cellular calcium homeostasis is a result of the summation of regulatory systems involved in the control of intracellular calcium levels and movements Cellular calcium homeostasis is achieved, at least m part, by calcium binding and by movement of calcium into and out of the cell across the plasma membrane and within the cell by movement of calcium across membranes of intracellular organelles including, for example, the endoplasmic reticulum, sarcoplasmic reticulum, mitochondria and endocytic organelles including endosomes and lysosomes
[00102] Movement of calcium across cellular membranes is earned out by specialized proteins For example, calcium from the extracellular space can enter the cell through various calcium channels and a sodium/calcium exchanger and is actively extruded from the cell by calcium pumps and sodium/calcium exchangers Calcium can also be released from internal stores through inositol triphosphate or ryanodine receptors and can be taken up by these organelles by means of calcium pumps
[00103] Calcium can enter cells by any of several general classes of channels, including but not limited to, voltage-operated calcmm (VOC) channels, store-operated calcium (SOC) channels, and sodium/calcium exchangers operating in reverse mode VOC channels are activated by membrane depolarization and are found in excitable cells like nerve and muscle and are for the most part not found m nonexcitable cells Under some conditions, Ca2+ can enter cells via Na+-Ca2+ exchangers operating m reverse mode
[00104] Endocytosis provides another process by which cells take up calcium from the extracellular medium through endosomes In addition, some cells, e g , exocrine cells, can release calcium via exocytosis [00105] Cytosohc calcium concentration is tightly regulated with resting levels usually estimated at approximately 0 1 μM in mammalian cells, whereas the extracellular calcium concentration is typically about 2 mM This tight regulation facilitates transduction of signals into and within cells through transient calcium flux across the plasma membrane and membranes of intracellular organelles There is a multiplicity of intracellular calcium transport and buffer systems in cells that serve to shape intracellular calcium signals and maintain the low resting cytoplasmic calcium concentration. In cells at rest, the principal components involved in maintaining basal calcium levels are calcium pumps and leaks in the endoplasmic reticulum and plasma membrane Disturbance of resting cytosolic calcium levels can effect transmission of such signals and give rise to defects in a number of cellular processes For example, cell proliferation involves a prolonged calcium signaling sequence Other cellular processes include, but are not limited to, secretion, signaling, and fertilization, involve calcium signaling [00106] Cell-surface receptors that activate phospholipase C (PLC) create cytosolic Ca2+ signals from lntra- and extra-cellular sources An initial transient rise of [Ca2+I1 (intracellular calcium concentration) results from the release of Ca2+ from the endoplasmic reticulum (ER), which is triggered by the PLC product, inositol- 1 ,4,5- tπsphosphate (IP3), opening IP3 receptors in the ER (Streb et al Nature, 306, 67-69, 1983) A subsequent phase of sustained Ca2+ entry across the plasma membrane then ensues, through specialized store operated calcium (SOC) channels (m the case of immune cells the SOC channels are calcium release-activated calcium (CRAC) channels) in the plasma membrane Store-operated Ca2+ entry (SOCE) is the process m which the emptying of Ca2+ stores itself activates Ca2+ channels in the plasma membrane to help refill the stores (Putney, Cell Calcium, 7, 1-12, 1986, Paiάsh etal , Physiol Rev 757-810, 2005) SOCE does more than simply provide Ca2+ for refilling stores, but can itself generate sustained Ca2+ signals that control such essential functions as gene expression, cell metabolism and exocytosis (Parekh and Putney, Physiol Rev 85, 757-810 (2005)
[00107] In lymphocytes and mast cells, activation of antigen or Fc receptors causes the release of Ca2+ from intracellular stores, which in turn leads to Ca2+ influx through CRAC channels in the plasma membrane The subsequent rise in intracellular Ca2* activates calcineuπn a phosphatase that regulates the transcription factor NFAT In resting cells, NFAT is phosphorylated and resides m the cytoplasm, but when dephosphorylated by calcineuπn, NFAT translocates to the nucleus and activates different genetic programmes depending on stimulation conditions and cell type In response to infections and during transplant rejection, NFAT partners with the transcription factor AP-I (Fos-Jun) in the nucleus of "effector" T cells, thereby transactivatmg cytokine genes, genes that regulate T cell proliferation and other genes that orchestrate an active immune response (Rao etal , Anna Rev Immunol , 1997,15 707 47) In contrast, in T cells recognizing self antigens, NFAT is activated in the absence of AP- 1 , and activates a transcriptional programme known as "anergy" that suppresses autoimmune responses (Macian et al , Transcriptional mechanisms underlying lymphocyte tolerance Cell 2002 Jun 14,109(6) 719-31) In a subclass of T cells known as regulatory T cells which suppress autoimmunity mediated by self-reacπve effector T cells, NFAT partners with the transcription factor FOXP3 to activate genes responsible for suppressor function (Wu et al , Cell, 2006 JuI 28,126(2) 375 87, Rudensky AY, Gavin M, Zheng Y Cell 2006 JuI 28,126(2) 253-256)
[00108] The endoplasmic reticulum (ER) carries out a variety processes The ER has a role as both an agonist-sensitive Ca2+ store and sink, protein folding/processing takes place within its lumen Here, numerous Ca2+-deρendent chaperone proteins ensure that newly synthesized proteins are folded correctly and sent off to the appropriate destination The ER is also involved m vesicle trafficking, release of stress signals, regulation of cholesterol metabolism, and apoptosis Many of these processes require intraluminal Ca2+, and protein misfolding, ER stress responses, and apoptosis can all be induced by depleting the ER of Ca2+ for prolonged periods of tune Because of its role as a source OfCa2+, it is clear that ER Ca2+ content must Ml after stimulauoα However, to preserve the functional integrity of the ER, it is vital that the Ca2+ content does not fall too low or is maintained at a low level Replenishment of the ER with Ca2+ is therefore a central process to all eukaryolic cells Because a fall in ER Ca2+ content activates store-operated Ca2+ channels in the plasma membrane, a major function of this Ca2+ entry pathway is believed to be maintenance of ER Ca2+ levels that are necessary for proper protein synthesis and folding However, store-operated Ca2+ channels have other important roles
[00109] The understanding of store operated calcium entry was provided by electrophysiological studies S which established that the process of emptying the stores activated a Ca2+ current in mast cells called Ca2+ release-activated Ca2+ current or ICRAC ICRAC IS non-voltage activated, inwardly rectifying, and remarkably selective for Ca2+ It is found m several cell types mainly of hemapoietic origin ICRAC IS not the only store- operated current, and it is now apparent that store-operated influx encompasses a family of Ca2t-permeable channels, with different properties m different cell types ICRAC was the first store-operated Ca2+current to be 0 described and remains a popular model for studying store-operated influx
[00110] Store-operated calcium channels can be activated by any procedure that empties the stores, it does not seem to matter how the stores are emptied, the net effect is activation of store-operated Ca2+ entry Physiologically, store emptying is evoked by an mcrease in the levels OfIP3 or other Ca2t-releasing signals followed by Ca2+ release from the stores But there are several other methods for emptying stores These S methods include the following
1) elevation of IP3 m the cytosol (following receptor stimulation or, dialyzmg the cytosol with IP3 itself or related congeners like the nonmetabohzable analog Ins(2,4,5)P3),
2) application of the Ca2+ ionophore ionomycin to peπneabilize the ER membrane,
3) dialyzing the cytoplasm with high concentrations of the Ca2+ chelators EGTA or BAPTA, which chelate Ca2+0 that leaks from the stores and hence prevent store refilling,
4) exposure to the sarcoplasmic/endoplasmic reticulum Ca2+-ATPaSe (SERCA) inhibitors hke thapsigargm, cyclopiazomc acid, and di-tert-butylhydroquinone which prevent the P type ATPases from refilling the stores,
5) sensitizing the IP3 receptors to resting levels of InsP3 with agents hke thimerosal, and
6) loading membrane-permeable metal Ca2+ chelators like N,N,^N'-tetratas(2-pyπdylmethyl)ethylene diamine5 (TPEN) directly into the stores
[00111] Through mass action, TPEN lowers free intraluminal Ca2+ concentration without changing total store Ca24 such that the store depletion-dependent signal is generated
[00112] These methods of emptying stores are not devoid of potential problems The key feature of store- operated Ca2+ entry is that it is the fall in Ca2+ content within the stores and not the subsequent rise in0 cytoplasmic Ca2+ concentration that activates the channels However, ionomycin and SERCA pump blockers generally cause a πse in cytoplasmic Ca2+ concentration as a consequence of store depletion, and such a πse in Ca2* could open Ca2+-acttvated cation channels permeable to Ca2+ One way to avoid such problems is to use agents under conditions where cytoplasmic Ca2+ has been strongly buffered with high concentrations of Ca2+ chelator such as EGTA or BAPTA 5 Store-Operated Calcium Entry
[00113] Reduced calcium concentration in intracellular calcium stores such as the endoplasmic reticulum resulting from release of calcium there from provides a signal for influx of calcium from the extracellular medium into the cell This influx of calcium, which produces a sustained "plateau" elevation of cytosolic calcium concentration, generally does not rely on voltage-gated plasma membrane channels and does not0 involve activation of calcium channels by calcium. This calcium influx mechanism is referred to as capacitanve calcium entry (CCE), calcium release-activated, store-operated or depletion-operated calcium entry Store- operated calcium entry can be recorded as an ionic current with distinctive properties This current is referred to as Isoc (store-operated current) or ICRAC (calcium release-activated current)
[00114] Electrophysiological analysis of store-operated or calcium release-activated currents reveals distinct biophysical properties of these currents For example, the current are activated by depletion of intracellular calcium stores (e g , by nonphysiological activators such as thapsigargin, CPA1 ionomycin and BAPTA, and physiological activators such as IP3) and can be selective for divalent cations, such as calcium, over monovalent ions in physiological solutions or conditions, can be influenced by changes m cytosolic calcium levels, and can show altered selectivity and conductivity in the presence of low extracellular concentrations of divalent cations The current may also be blocked or enhanced by 2 -APB (depending on concentration) and blocked by SKF96365 and Gd3+ and generally are described as a calcium current that is not strictly voltage-gated [00115] Patch-clamp studies m mast cells and Jurkat leukaemic T cells have established the CRAC entry mechanism as an ion channel with distinctive biophysical characteristics, including a high selectivity for Ca2+ paired with an exceedingly low conductance Furthermore, the CRAC channel was shown to fulfill the rigorous criteria for being store-operated, which is the activation solely by the reduction OfCa2+ m the ER rather than by cytosolic Ca2+ or other messengers generated by PLC
Regulation of Store-Operated Calcium Entry bv Intracellular Calcium Stores [00116] Store-operated calcium entry is regulated by the level of calcium within an intracellular calcium store Intracellular calcium stores are characterized by sensitivity to agents, which are physiological or pharmacological, which activate release of calcium from the stores or inhibit uptake of calcium into the stores Different cells have been studied m characterization of intracellular calcium stores, and stores have been characterized as sensitive to various agents, including, but not limited to, IP3 and compounds that effect the IP3 receptor, thapsigargm, ionomycm and/or cyclic ADP-πbose (cADPR) [00117] Accumulation of calcium within endoplasmic reticulum and sarcoplasmic reticulum (SR, a specialized version of the endoplasmic reticulum m striated muscle) storage organelles is achieved through sarcoplasmic-endoplasmic reticulum calcium ATPases (SERCAs), commonly referred to as calcium pumps During signaling (i e , when endoplasmic reticulum channels are activated to provide for calcium release from the endoplasmic reticulum into the cytoplasm), endoplasmic reticulum calcium is replenished by the SERCA pump with cytoplasmic calcium that has entered the cell from the extracellular medium [00118] Calcium release channels associated with IF3 and ryanodine receptors provide for controlled release of calcium from endoplasmic and sarcoplasmic reticulum into the cytoplasm resulting in transient increases in cytoplasmic calcium concentration IP3 receptor-mediated calcium release is triggered by IP3 formed in the break down of plasma membrane phosphornositides through the action of phosphohpase C activated by binding of an agonist to a plasma membrane G protein-coupled receptor Ryanodine receptor-mediated calcium release is triggered by an increase m cytoplasmic calcium and is referred to as calcium-induced calcium release (CICR) The activity of ryanodine receptors (which have affinity for ryanodine and caffeine) may also be regulated by cyclic ADP-ribose
[00119] Thus, the calcium levels in the stores, and in the cytoplasm, fluctuate For example, ER free calcium can decrease from a range of about 60-400 uM to about 1-50 μM when HeLa cells are treated with histamine, an agonist of PLC-linked histamine receptors (Miyawaki et al (1997) Nature 388 882-887) Store operated calcium entry 13 activated as the free calcium concentration of the intracellular stores is reduced. Depletion of store calcium, as well as a concomitant increase m cytosolic calcium concentration, can thus regulate store- operated calcium entry into cells Cytoplasmic Calcium Bufferimg [00120] Agonist activation of signaling processes m cells can involve dramatic increases in the calcium permeability of the endoplasmic reticulum, for example, through opening OfIF3 receptor channels, and the plasma membrane through store-operated calcium entry These increases in calcium permeability are associated with an increase in cytosolic calcium concentration that are separated into two components a "spike" of calcium release from the endoplasmic reticulum during activation of the IF3 receptor and a plateau phase which is a sustained elevation of calcium levels resulting from entry of calcium into the cytoplasm from the extracellular medium Upon stimulation, the resting intracellular free calcium concentration of about 10011M can rise globally to greater than 1 μM The cell modulates these calcium signals with endogenous calcium buffers, including physiological buffering by organelles such as mitochondria, endoplasmic reticulum and Golgi Mitochondrial uptake of calcium through a uniporter m the inner membrane is driven by the large negative mitochondrial membrane potential, and the accumulated calcium is released slowly through sodium-dependent and -independent exchangers, and, under some circumstances, the permeability transition pore (PTP) Thus, mitochondria can act as calcium buffers by taking up calcium during periods of activation and slowly releasing it later Uptake of calcium into the endoplasmic reticulum is regulated by the sarcoplasmic and endoplasmic reticulum calcium ATPase (SERCA) Uptake of calcium into the Golgi is mediated by a P-type calcium transport ATPase (PMR1/ATP2C1) Additionally, there is evidence that a significant amount of the calcium released upon IP3 receptor activation is extruded from the cell through the action of the plasma membrane calcium ATPase For example, plasma membrane calcium ATPases provide the dominant mechanism for calcium clearance m human T cells and Jurkat cells, although sodium/calcium exchange also contributes to calcium clearance m human T cells Within calcium-stoπng organelles, calcium ions are bound to specialized calcium-buffering proteins, such as, for example, calsequestrtns, calreticulins and calnexins Additionally, there are calcium-buffering proteins in the cytosol that modulate calcium spikes and assist m redistribution of calcium ions Thus, proteins and other molecules that participate in any of these and other mechanisms through which cytosolic calcium levels are reduced are proteins that are involved in, participate m and/or provide for cytoplasmic calcium buffering Thus, cytoplasmic calcium buffering allows for sustained calcium influx through SOC channels Large increases in cytoplasmic Ca2+ or store refilling deactivate SOCE Downstream Calcium Entry-Mediated Events
[00121) In addition to intracellular changes m calcium stores, store-operated calcium entry affects a multitude of events that are consequent to or in addition to the store-operated changes. For example Ca2+ influx results m the activation of a large number of calmodulin-dependent enzymes including the serine phosphatase calcineunn Activation of calcineunn by an increase m intracellular calcium results in acute secretory processes such as mast cell degranulation Activated mast cells release preformed granules containing histamine, heparin, TNFα and enzymes such as β-hexosarninidase Some cellular events, such as B and T cell proliferation, require sustained calcineunn signaling, which requires a sustained increase in intracellular calcium A number of transcription factors are regulated by calcineunn, including NFAT (nuclear fector of activated T cells), MEF2 and NFKB NFAT transcription factors play important roles in many cell types, including immune cells In immune cells NFAT mediates transcription of a large number of molecules, including cytokines, chemokines and cell surface receptors Transcriptional elements for NFAT have been found within the promoters of cytokines such as IL-2, IL-3, IL-4, IL-5, IL-8, IL-13, as well as tumor necrosis factor alpha (TNFα), granulocyte colony-sumulating factor (G-CSF), and gamma-intβrferon (γ-IFN) [00122] The activity of NFAT proteins is regulated by their phosphorylation level, which in turn is regulated by both calcineuπn and NFAT kinases Activation of calcineuπn by an increase in intracellular calcium levels results in dephosphorylation of NFAT and entry into the nucleus Rephosphorylation of NFAT masks the nuclear localization sequence of NFAT and prevents its entry into the nucleus Because of its strong dependence on calcineunn-mediated dephosphorylation for localization and activity, NFAT is a sensitive indicator of intracellular calcium levels
Diseases. Disorders or Conditions
[00123] Clinical studies demonstrate that the CRAC channel is absolutely required for the activation of genes underlying the T cell response to antigen Sustained calcium entry is needed for lymphocyte activation and adaptive immune response Calcium entry into lymphocytes occurs primarily through the CRAC channels Increased calcium leads to NFAT activation and expression of cytokines required for immune response Inhibiting the store operated calcium entry is an efficient way to prevent T cell activation [00124] Inhibition of CRAC channel activity with the compounds described herein, such as compounds of Formulas (I), (D), (HI), (IV), (V) and (VI), provide a means for providing lmmunosuppresive therapy as demonstrated by the elimination of store-operated calcium entry noted in patients with severe-combined immunodeficiency (SCID) T cells, fibroblasts, and m some cases B cells, from patients with T cell immunodeficiency or SCID having a principal defect m T cell activation show a strong defect in store-operated calcium entry SCID patients lack adaptive immune response, but without any impairment or toxicity in major organs The SCID patient phenotype indicates that inhibition of CRAC channels is an effective strategy for immunosuppression. Diseases/Disorders Involving Inflammation and Diseases/Disorders Related to the Immune System [00125] In some embodiments, diseases, disorders or conditions that are treated or prevented using the compounds, compositions, and methods provided herein include diseases, conditions or disorders involving inflammation and/or that are related to the immune system These diseases include but are not limited to asthma, chrome obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis, neuroinflammatory diseases such as multiple sclerosis, and disorders of the immune system
[00126] The activation of neutrophils (PMN) by inflammatory mediators is partly achieved by increasing cytosohc calcium concentration Store-operated calcium influx in particular is thought to play an important role in PMN activation It has been shown that trauma increases PMN store-operated calcium influx and that prolonged elevations of cytosohc calcium concentration due to enhanced store-operated calcium influx may alter stimulus-response coupling to chemotaxins and contribute to PMN dysfunction after injury Modulation of PMN cytosohc calcium concentration through store-operated calcium channels might therefore be useful in regulating PMN-mediated inflammation and spare cardiovascular function after injury, shock or sepsis [00127] Calcium plays a cπhcal role in lymphocyte activation Activation of lymphocytes, e g , by antigen stimulation, results in rapid increases in intracellular free calcium concentrations and activation of transcription factors, including nuclear factor of activated T cells (NFAT), NF-κB, JNKl MEF2 and CREB NFAT is a key transcriptional regulator of the IL-2 (and other cytokine) genes A sustained elevation of intracellular calcium level is required to keep NFAT in a transcriptionally active state, and is dependent on store-operated calcium entry Reduction or blocking of store-operated calcium entry in lymphocytes blocks calcium-dependent lymphocyte activation. Thus, in some embodiments, modulation of intracellular calcium, and particularly store- S operated calcium entry (e g , reduction in, elimination of store-operated calcium entry), in lymphocytes is a method for treating immune and immune-related disorders, including, for example, chrome immune diseases/disorders, acute immune diseases/disorders, autoimmune and immunodeficiency diseases/disorders, diseases/disorders involving inflammation, organ transplant graft rejections and graft-versus-host disease and altered (e g , hyperactive) immune responses For example, m some embodiments treatment of an automimmune0 disease/disorder mvolves reducing, blocking or eliminating store-operated calcium entry in lymphocytes [00128] Examples of immune disorders include psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic or xenogeneic transplantation (organ, bone marrow, stem cells and other cells and tissues) graft rejection, graft versus-host disease, lupus erythematosus, S inflammatory disease, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e g , Hashimoto's and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chrome relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis and atopic dermatitis Cancer and Other Proliferative Diseases 0 [00129] In other embodiments, compounds of Formulas (I), (II), (III), (IV), (V) and (VI), compositions thereof, and methods provided herein are used m connection with treatment of malignancies, including, but not limited to, malignancies of lymphoreϋcular origin, bladder cancer, breast cancer, colon cancer, endometrial cancer, head and neck cancer, lung cancer, melanoma, ovarian cancer, prostate cancer and rectal cancer Store- operated calcium entry is thought to play an important role in cell proliferation m cancer cells 5 [00130] Inhibition of SOCE is sufficient to prevent tumor cell proliferation. The pyrazole derivative BTP-2, a direct ICRAC blocker inhibits SOCE and proliferation m Jurkat cells and in colon cancer cells It has been suggested that sustained SOCE requires mitochonrial Ca2+ uptake and that prevention of mitochondrial Ca2+ uptake leads to SOCE inhibition. Stimulation of Jurkat cells induces sustained SOCE and activation of the Ca2+- dependent phosphatase calcineuπn that dephosphorylates NFAT, promoting expression of interleukin-2 and0 proliferation. In other embodiments, compounds of Formulas (I), (II), (III), (TV), (V) and (VI) inhibit SOCE and are used in the treatment of cancer or other proliferative diseases or conditions Liver Diseases and Disorders
[00131] In some embodiments, diseases, disorders or conditions that are treated or prevented using the compounds of Formulas (I), (II), (III), (IV), (V) and (VI), compositions thereof, and methods provided herein5 include hepatic or liver diseases and disorders These diseases, conditions or disorders include but are not limited to liver injury, for example, due to transplantation, hepatitis and cirrhosis
[00132] Store-operated calcium entry has been implicated in chrome liver disease as well as transplantation injury after cold preservation-warm reoxygenation Kidney Diseases and Disorders [00133] In some embodiments, diseases, conditions or disorders that are treated or prevented using the methods provided herein mcludβ kidney or renal diseases and disorders Mesangial cell hyperplasia is often a key feature of such diseases and disorders In other embodiments, such diseases and disorders are caused by immunological or other mechanisms of injury, including IgAN, membranoproliferative glomerulonephritis or lupus nephritis Imbalances in the control of mesangial cell replication also appear to play a key role in the pathogenesis of progressive renal failure
[00134] The turnover of mesangial cells in normal adult kidney is very low with a renewal rate of less than 1% A prominent feature of glomerular/kidney diseases is mesangial hyperplasia due to elevated proliferation rate or reduced cell loss of mesangial cells When mesangial cell proliferation is mduced without cell loss, for example due to autogenic stimulation, mesangioproliferative glomerulonephritis can result Data have indicated that regulators of mesangial cell growth, particularly growth factors, are thought to act by regulating store- operated calcium channels In yet other embodiments, modulators of store-operated calcium influx aids in the treatment of glomerular diseases by inhibiting mesangial cell proliferation Store Operated Calcium Channels [00135] Clinical studies demonstrate that the CRAC channel, a type of SOC channel, is required for the activation of genes underlying the T cell response to antigen (Partiseti et al , JBwI Chem , 269, 32327-32335, 1994, Feske et al , Curr BwI 15, 1235-1241, 2005) In some embodiments, SOCE contributes directly to the elevation of cytosolic Ca2+ levels ([Ca2+],), as in T lymphocytes where CRAC channels generate the sustained Ca2+ signals needed to drive gene expression underlying T cell activation by antigen. Sustained calcium entry is needed for lymphocyte activation and adaptive immune response Calcium entry into lymphocytes occurs primarily through the CRAC channels Increased calcium levels lead to NFAT activation and expression of cytokines required for immune response
[00136] The CRAC channel has a distinctive biophysical fingerprint, quantifiable store-dependence, and essential function in T cells Studies have shown that CRAC channels are formed from two component proteins, which interact to form CRAC channels The CRAC channel is assembled by two functional components, STIMl and Orail STIMl (stromal interaction molecule 1) was identified as the mammalian ER Ca2+ sensor Orail/CRACMl was identified as a component of the mammalian CRAC channel
[00137] STIMl is the sensor OfCa2+ within ER Ca2+ stores, moving in response to store depletion into ER puncta close to the plasma membrane Orail is a pore forming CRAC channel subunit in the plasma membrane The two membrane proteins STIMl and Orail have each been shown to be essential for the activation of CRAC channels
[00138] Expression of both STLMl and Orail m human embryonic kidney 293 cells (HEK293 cells) reconstitute functional CRAC channels Expression of Orail alone strongly reduces store-operated Ca2+ entry in HEK293 cells and the Ca2+ release-activated Ca2+ current (ICRAC) m rat basophilic leukemia cells However, expressed along with the store-sensing STIMl protein, Orail causes a massive increase in SOCE, enhancing the rate OfCa2+ entry by up to 103-fold This entry is entirely store dependent since the same coexpression causes no measurable store-mdependent Ca2+ entry The entry is completely blocked by the store operated channel blocker, 2-aminoethoxydiphenyIborate STIM proteins are known to mediate Ca2+ store-sensing and endoplasmic reUculum-plasma membrane coupling with no intrinsic channel properties Orail contributes the plasma membrane channel component responsible for Ca2+ entry The suppression of CRAC channel function by Orail overexpression reflects a required stoichiometry between STIMl and Orail Stromal Interacting Molecule (STIM) Proteins
[00139] In RNAi screen in Drosophila S2 cells using thapsigargin-activated Ca2+ entry as a marker for store- operated channels, one gene gave a substantially reduced Ca2+ entry, coding for the protein stromal interaction molecule (Stun) There are two homologues of Stun in mammalian cells, STIMl and STTM2, both of which appear to be distributed ubiquitously STIMl is the ER Ca2+ sensor for store-operated Ca2+ entry STIMl is a 77 kDa type I membrane protein with multiple predicted protein interaction or signaling domains and is located predominantly in the ER, but also to a limited extent in the plasma membrane [00140] Knockdown of STIMl by RNAi substantially reduced ICRAC ω Jurkat T cells, and store-operated Ca2+ entry m HEK293 epithelial cells and SH-SY5Y neuroblastoma cells However, knockdown of the closely related STTM2 had no effect These results indicate an essential role of STIM (Drosophila) and STIMl (mammals) in the mechanism of activation of store-operated channels It is unlikely that STIMl is the store- operated channel itself It has no channel-like sequence, and overexpression of the protein only modestly enhances Ca2+ entry STIMl is located both on the plasma and intracellular membranes, such as the ER The protein sequence suggests that it spans the membrane once, with its NH2 terminus oriented toward the lumen of the ER or the extracellular space The NH2 terminus contains an EF-hand domain, and functions as the Ca2+ sensor in the ER The protein also contains protein-protein interaction domains, notably coiled-coiled domains m the cytoplasm and a sterile motif (SAM) in the ER (or extracellular space), both near the predicted transmembrane domain. STIMl can oligomenze and thus the protein in the ER and plasma membrane could interact bridging the two
[00141] Total internal reflection fluorescence (TIRF) and confocal microscopy reveal that STIM 1 is distributed throughout the ER when Ca2+ stores are full, but redistributes into discrete puncta near the plasma membrane on store depletion. Although the redistribution of STIM 1 into junctional ER regions is slow, it does precede the opening of CRAC channels by several and is therefore rapid enough to be an essential step m the activation of CRAC channels
[00142] It has been suggested that store depletion causes the insertion of STIMl into the plasma membrane where it may control store operated calcium entry through the CRAC channels [00143] Evidence for STIMl as the Ca2+ sensor for SOCE is that mutation of predicted Ca2*-binding residues of the EF hand structural motif, expected to reduce its affinity for Ca2+ and hence mimic the store-depleted state, causes STTMl to redistribute spontaneously into puncta and trigger constitutive Ca2+ influx through SOCs even when stores are full Or.i Proteins [00144] Orail (also known as CRACMl) is a widely expressed, 33 kDa plasma membrane protein widi 4 transmembrane domains and a lack of significant sequence homology to other ion channels
[00145] Studies of T cells from human patients with a severe combined immunodeficiency (SCO) syndrome, m which T cell receptor engagement or store depletion failed to activate Ca2+ entry, was shown to be due to a smgle pomt mutation in Orail [00146] Other mammalian Oral homologues exist, e g Orai2 and Orai3, however then- function is not clearly defined Orai2 and Orai3 can exhibit SOC channel activity when overexpressed with STIMl m HEK cells [00147] Evidence that Orail contributes to the CRAC channel pore was obtained by Orail mutagenesis studies Selectivity of the CRAC channel for Ca2+ ions was shown by mutations at either GIu 106 or GIu 190, which weaken the ability of Ca2+ binding in order block permeation of monovalent cations (similar to mechanisms described for voltage-gated Ca2+ channels) [00148] Neutral-zing the charge on a pair of aspartates in the I-II loop (Asp llO and Asp 112) reduces block by Gd3+ and block of outward current by extracellular Ca2+, indicating that these negatively charged sites may promote accumulation of polyvalent cations near the mouth of the pore
[00149] Currents observed through overexpression of Orail closely resemble ICRAC, and the fact that Orail can form multimers, it is likely that the native CRAC channel is either a multimer of Orail alone or in combination with the closely related subumts Orai2 and/or Orai3 Functional Store Operated Calcium Channels
[00150] The characterization of SOC channels has been largely obtained by one type of SOC channel, the CRAC channel CRAC channel activity is triggered by the loss of Ca2+ from the ER lumen, which is coupled to the opening of CRAC channels in the plasma membrane through the actions of STIMl and Orail Depletion of Ca2+ is sensed by STIMl, causing it to accumulate in junctional ER adjacent to the plasma membrane In a TIRF-based Ca2+-imaging study to map the locations of open CRAC channels, [Ca2+], elevations were seen to co-localize with STIMl puncta, showing directly that CRAC channels open only m extreme proximity to these sites [00151] In cells co-expressing bom STIMl and Orail, store depletion causes Orail itself to move from a dispersed distribution to accumulate m the plasma membrane directly opposite STIMl, enabling STIMl to activate the channel Thus, CRAC channels are formed by apposed clusters of STIMl m the ER and Orail in the plasma membrane, separated by a narrow gap of cytosol The junctional gap (about 10-25 nm) may be small enough to permit protein-protein interactions This is supported by the fact that overexpressed STIMl and Orail can be co-immunoprecipitated [00152] Thus, STIMl and Orail interact either directly or as members of a multiprotern complex. Support for this was observed when the expression of the cytosolic portion of STTM 1 by itself was sufficient to activate CRAC channels m one study, and the effects of deleting the ERM/coiled-coil and other C-teπninal domains suggest roles in STIM 1 clustering and SOC channel activation On the luminal side of STEM 1 , the isolated EF- SAM region forms duners and higher-order multimers on removal OfCa2+ in vitro, indicating that STIMl oligomeπzation may be an early step in store operated calcium activation.
[00153] Compounds of Formulas (I), (II), (HI), (TV), (V) and (VI) described herein modulate intracellular calcium, such as, inhibition or reduction of SOCE and/or ICRAC In some embodiments, the modulation by compounds of Formulas (I), (II), (HI), (IV), (V) and (VI) result from a variety of effects, such as, but not limited to, binding to a protein, interaction with a protein, or modulation of interactions, activities, levels or any physical, structural or other property of a protein involved m modulating intracellular calcium (e g a STIM protein and/or Oral protein)
[00154] For example, methods for assessing binding or interaction of a test agent with a protein mvolved m modulating intracellular calcium include NMR, mass spectroscopy, fluorescence spectroscopy, scintillation proximity assays, surface plasmon resonance assays and others Examples of methods for assessing modulation of interactions, activities, levels or any physical, structural or other property of a protem mvolved in modulating intracellular calcium include, but are not limited to, FRET assays to assess effects on protein interactions, NMR, X-ray crystallography and circular dichroism to assess effects on protein interactions and on physical and structural properties of a protein, and activity assays suitable for assessing a particular activity of a protein Monitoring or Assessing Effects on Intracellular Calcium [00155] In some embodiments, monitoring or assessing the effect of a compound of Formula (I) or Formula (H) on intracellular calcium in any of the screening/identification methods described herein, a direct or indirect evaluation or measurement of cellular (including cytosolic and intracellular organelle or compartment) calcium and/or movement of ions into, within or out of a cell, organelle, calcium store or portions thereof (e g , a membrane) are conducted. A variety of methods are described herein for evaluating calcium levels and ion movements or flux The particular method used and the conditions employed depend on whether a particular aspect of intracellular calcium is being monitored or assessed. For example, in some embodiments described herein, reagents and conditions are known, and are used, for specifically evaluating store-operated calcium entry, resting cytosolic calcium levels, calcium buffering and calcium levels and uptake by or release from intracellular organelles and calcium stores In other embodiments, the effect of a compound of Formulas (I), (II), (IQ), (FV), (V) or (VI) on intracellular calcium is monitored or assessed using, for example, a cell, an intracellular organelle or calcium storage compartment, a membrane (including, e g , a detached membrane patch or a lipid bilayer) or a cell-free assay system (e g , outside-out membrane vesicle) Generally, some aspect of intracellular calcium is monitored or assessed in the presence of test agent and compared to a control, e g , intracellular calcium m the absence of test agent Methods of Modulating Intracellular Calcium
[00156] In some embodiments, modulation of intracellular calcium is any alteration or adjustment m intracellular calcium including but not limited to alteration of calcium concentration or level m the cytoplasm and/or intracellular calcium storage organelles, e g , endoplasmic reticulum, alteration m the movement of calcium into, out of and within a cell or intracellular calcium store or organelle, alteration in the location of calcium within a cell, and alteration of the kinetics, or other properties of calcium fluxes into, out of and within cells In some embodiments, intracellular calcium modulation involves alteration or adjustment, e g reduction or inhibition, of store-operated calcium entry, cytosohc calcium buffering, calcium levels in or movement of calcium mto, out of or within an intracellular calcium store or organelle, and/or basal or resting cytosolic calcium levels In some embodiments, modulation of intracellular calcium involves an alteration or adjustment in receptor-mediated ion (e g , calcium) movement, second messenger-operated ion (e g , calcium) movement, calcium influx into or efflux out of a cell, and/or ion (e g , calcium) uptake into or release from intracellular compartments, including, for example, endosomes and lysosomes
[00157] In one aspect, compounds described herein modulate intracellular calcium, such as but not limited to, modulation (e g reduction or inhibition) of SOC channel activity, such as inhibition of CRAC channel activity (e g inhibition of ICRAC. inhibition of SOCE), in an immune system cell (e g , a lymphocyte, white blood cell, T cell, B cell), a fibroblast (or a cell deπved from a fibroblast), or an epidermal, dermal or skin cell (e g , a keratinocyte) In some embodiments, the step of modulating one or more proteins involved m modulating intracellular calcium (e g a STIM protein and/or Oral protein) mvolves, for example, reducing the level, expression of, an activity of, function of and/or molecular interactions of a protein. For instance, if a cell exhibits an increase m calcium levels or lack of regulation of an aspect of intracellular calcium modulation, e g , store-operated calcium entry, then in other embodiments, modulating involves reducing the level of, expression of, an activity or function of, or a molecular interaction of a protein, e g a STIM protein and/or Orai protem Treatment Methods
[00158] Presented herein is a method of modulating store-operated calcium (SOC) channel activity comprising contacting the store-operated calcium (SOC) channel complex, or portion thereof, with a compound of Formula (I), (II), (m), (IV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof
[00159] In one embodiment is a method of modulating store-operated calcium channel activity comprising contacting the store-operated calcium (SOC) channel complex, or portion thereof, with a compound of Formula (I), (II), (III), (TV), (V) or (VI) wherein the contacting occurs in vitro
[00160] In another embodiment is a method of modulating store-operated calcium channel activity comprising contacting the store-operated calcium (SOC) channel complex, or portion thereof, with a compound of Formula (I), (II), (III), (IV), (V) or (VI) wherein the contacting occurs m vivo [00161] In yet another embodiment is a method of modulating store operated calcium channel activity comprising contacting the store-operated calcium (SOC) channel complex, or portion thereof, with a compound of Formula (I), (II), (M), (IV), (V) or (VI) wherein the compound of Formula (I), (II), (IE), (IV), (V) or (VI) modulates an activity of, modulates an interaction of, or modulates the level of, or binds to, or interacts with at least one portion of the store operated calcium channel complex selected from stromal interaction molecules (STIM) family of proteins [00162] In a further embodiment is a method of modulating store-operated calcium channel activity comprising contacting the store-operated calcium (SOC) channel complex, or portion thereof, with a compound of Formula (I), (II), (HI), (IV), (V) or (VI) wherein the compound of Formula (I), (II), (IE), (IV), (V) or (VI) modulates an activity of, modulates an interaction of, or modulates the level of, or binds to, or interacts with at least one portion of STIMl or STIM2 [00163] In another embodiment is a method of modulating store-operated calcium channel activity comprising contacting the store-operated calcium (SOC) channel complex, or portion thereof, with a compound of Formula (I), (II), (HI), (IV), (V) or (VI) wherein modulating store operated calcium channel activity with a compound of Formula (I), (II), (III), (IV), (V) or (VI) inhibits store-operated calcium entry (SOCE) [00164] In yet another embodiment is a method of modulating store-operated calcium channel activity comprising contacting the store-operated calcium (SOC) channel complex, or portion thereof, with a compound of Formula (I), (II), (HI), (IV), (V) or (VI) wherein the store operated calcium channel complex is calcium- release activated calcium (CRAC) channel complex
[00165] In a further embodiment is a method of modulating store-operated calcium channel activity comprising contacting the store-operated calcium (SOC) channel complex, or portion thereof, with a compound of Formula (I), (II), (III), (IV), (V) or (VI) wherein modulating calcium release activated calcium (CRAC) activity with a compound of Formula (I), (π), (IH), (IV), (V) or (Vl) inhibits the electrophysiological current (IcKΛc) directly associated with activated CRAC channels
[00166] Also presented herein is a method of modulating calcium release activated calcium channel (CRAC) activity in a mammal comprising administering a compound of Formula (I), (II), (III), (IV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof
[00167] In one embodiment is a method of modulating calcium release activated calcium channel (CRAC) activity in a mammal comprising administering a compound of Formula (I), (II), (HI), (IV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof wherein (he compound of Formula (I), (II), (III), (IV), (V) or (VI) modulates an activity of, modulates an interaction of, or modulates the level of, or binds to, or interacts with at least one component of the calcium release activated (CRAC) channel complex selected from stromal interaction molecules (STlM) family of proteins [00168] In another embodiment is a method of modulating calcium release activated calcium channel
(CRAC) activity in a mammal comprising administering a compound of Formula (I), (II), (JS), (TV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof wherein the compound of Formula (I), (II), (III), (IV), (V) or (VI) modulates an activity of, modulates an interaction of, or modulates the level of, or binds to, or interacts with STIMl or STIM2 [00169] In yet another embodiment is a method of modulating calcium release activated calcium channel
(CRAC) activity in a mammal comprising administering a compound of Formula (I), (II), (111), (IV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof wherein modulating calcium release activated calcium (CRAC) channel activity with a compound of Formula (I), (H), (IH), (IV), (V) or (VI) inhibits store-operated calcium entry (SOCE) [00170] In a further embodiment is a method of modulating calcium release activated calcium channel
(CRAC) activity in a mammal comprising administering a compound of Formula (I), (II), (III), (IV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof wherein modulating calcium release activated calcium (CRAC) channel activity with a compound of Formula (I), (II), (ID), (IV), (V) or (VI) inhibits the electrophysiological current (ICRAC) directly associated with activated CRAC channels
[00171] In yet a further embodiment is a method of modulating calcium release activated calcium channel (CRAC) activity m a mammal comprising administering a compound of Formula (I), (II), (ITI), (IV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof wherein the compound of Formula (I), (II), (IE), (IV), (V) or (VI) inhibits SOCE with an IC50 below 10 μM
[00172] In another embodiment is a method of modulating calcium release activated calcium channel (CRAC) activity in a mammal comprising administering a compound of Formula (I), (II), (III), (IV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof wherein the compound of Formula (I), (II), (III), (IV), (V) or (VI) inhibits electrophysiological current (ICRAC) directly associated with activated CRAC channels at a concentration below 10 uM
[00173] In one aspect is a method of treating a disease, disorder or condition in a mammal mat would benefit from inhibition of store operated calcium channel activity comprising administering to the mammal a compound of Formula (I), (II), (HI), (IV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof [00174] In one embodiment is a method of treating a disease, disorder or condition in a mammal that would benefit from inhibition of store operated calcium channel activity comprising administering to the mammal a compound of Formula (I), (II), (III), (IV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof wherein the compound of v modulates the activity of, modulates an interaction of, or binds to, or interacts with a mammalian STIMl protein, or a mammalian STIM 2 protein
[00175] In another embodiment is a method of treating a disease, disorder or condition in a mammal that would benefit from inhibition of store operated calcium channel activity comprising administering to the mammal a compound of Formula (I), (II), (IH), (TV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof wherein the disease, disorder or condition in a mammal is selected from diseases/disorders involving inflammation, glomerulonephritis, uveitis, hepatic diseases or disorders, renal diseases or disorders, chrome obstructive pulmonary disease, rheumatoid arthritis, psoriasis, inflammatory bowel disease, vasculitis, dermatitis, osteoarthritis, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, organ transplant rejection, allogeneic or xenogeneic transplantation, graft rejection, graft- versus-host disease, lupus erythematosus, type I diabetes, pulmonary fibrosis, deπnatomyosins, thyroiditis, myasthenia gravis, autoimmune hemolytic anemia, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis, hepatitis and atopic dermatitis, asthma, multiple sclerosis, Sjogren s syndrome, and autoimmune diseases or disorders [00176] In yet another embodiment is a method of treating a disease, disorder or condition in a mammal that would benefit from inhibition of store operated calcium channel activity comprising administering to the mammal a compound of Formula (I), (II), (HT), (IV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof wherein the disease, disorder or condition is rheumatoid arthritis [00177] In a further embodiment is a method of treating a disease, disorder or condition in a mammal that would benefit from inhibition of store operated calcium channel activity comprising administering to the mammal a compound of Formula (I), (II), (DT), (IV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof wherein the disease, disorder or condition is psoriasis [00178] In one embodiment is a method of treating a disease, disorder or condition m a mammal that would benefit from inhibition of store operated calcium channel activity comprising administering to the mammal a compound of Formula (I), (II), (III), (IV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof wherein the disease, disorder or condition is inflammatory bowel disease [00179] In a further embodiment me inflammatory bowel disease is ulcerative colitis
[00180] In a further embodiment is a method of treating a disease, disorder or condition in a mammal that would benefit from inhibition of store operated calcium channel activity comprising administering to (he mammal a compound of Formula (I), (II), (IH), (IV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof wherein the disease, disorder or condition is organ transplant rejection [00181] In a further embodiment is a method of treating a disease, disorder or condition in a mammal that would benefit from inhibition of store operated calcium channel activity comprising administering to the mammal a compound of Formula (I), (II), (III), (IV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof wherein the disease, disorder or condition is multiple sclerosis
[00182] In yet a further embodiment is a method of treating a disease, disorder or condition in a mammal that would benefit from inhibition of store operated calcium channel activity comprising administering to the mammal a compound of Formula (I), (II), (III), (IV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof further comprising administering to the mammal a second therapeutic agent
[00183] In another embodiment is a method of treating a disease, disorder or condition in a mammal that would benefit from inhibition of store operated calcium channel activity comprising administering to the mammal a compound of Formula (T), (II), (III), (IV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof, wherein the second therapeutic agent is selected from immunosuppressants, glucocorticoids, non-steroidal anti inflammatory drugs, Cox-2-speciftc inhibitors, leflunomide, gold thioglucose, gold thiomalate, aurofin, sulfasalazine, hydroxychloroqumine, minocycline, anti-TNF-α agents, abatacept, anakmra, mterferon-β, interferon-γ, interleukm-2, allergy vaccines, antihistamines, antileukotnenes, beta-agonists, theophylline, and anticholinergics [00184] In yet another embodnnent is a method oftreating a disease, disorder or condition in a mammal that would benefit from inhibition of store operated calcium channel activity comprising administering to the mammal a compound of Formula (I), (II), (III), (TV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof, wherein the second therapeutic agent is selected from tacrolimus, cyclosporin, rapamicin, methotrexate , cyclophosphamide, azathiopnne, mercaptopuπne, mycophenolate, or FTY720, prednisone, cortisone acetate, prednisolone, methylpredmsolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone, aspiπn, salicylic acid, gentisic acid, chohne magnesium salicylate, choline salicylate, chohne magnesium salicylate, chohne salicylate, magnesium salicylate, sodium salicylate, difiumsal, carprofen, fenoprofen, fenøprofen calcium, fluorobiprofen, lbuprofen, ketoprofen, nabutone, ketolorac, ketorolac Iromethamine, naproxen, oxaprozin, diclofenac, etodolac, lndomethacin, suhndac, tolmetin, meclofenamate, meclofenamate sodium, mefenamic acid, piroxicam, meloxicam, celecoxib, rofecoxib, valdecoxib, parecoxib, etoncoxib, lumiracoxib, CS-502, JTE-522, L-745,337 and NS398, leflunomide, gold thioglucose, gold thiomalate, aurofin, sulfasalazine, hydroxychloroquinine, minocycline, infliximab, etanercept, adalimumab, abatacept, anakinra, mterferon-β, interferon-γ, interleukin-2, allergy vaccines, antihistamines, antileukotnenes, beta-agonists, theophylline, and anticholinergics
[0018S] Also described herein is a method of inhibiting store-operated calcium entry (SOCE) activation of nuclear factor of activated T cells (NFAT) m a mammal comprising administering a compound of Formula (I), (II), (IE), (IV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof [00186] In one embodiment is a method of inhibiting store-operated calcium entry (SOCE) activation of nuclear factor of activated T cells (NFAT) m a mammal comprising administering a compound of Formula (I), (II), (III), (TV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof, wherein the compound of Formula (I), (II), (HI), (IV), (V) or (VI) 5 modulates an interaction of, or modulates the level of, or binds to, or interacts with a mammalian STIMl protein, or a mammalian STING protein.
[00187] In another aspect is a method of decreasing cytokine expression by inhibiting the store-operated calcium entry activation of NFAT in a mammal comprising administering a compound of Formula (J), (II), (III), (IV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically 0 acceptable prodrug thereof
[00188] In another embodiment is a method of decreasing cytokine expression by inhibiting the store- operated calcium entry activation of NFAT in a mammal comprising administering a compound of Formula (I), (II), (in), (IV), (V) or (VT) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof wherein the compound of Formula (I), (II), (IH), (IV), (V) or (VI) S modulates an interaction of , or modulates the level of, or binds to, or interacts with a mammalian STIM 1 protein or a mammalian STIM2 protein
[00189] In yet another embodiment is a method of decreasing cytokine expression by inhibiting the store- operated calcium entry activation of NFAT in a mammal comprising administering a compound of Formula (I), (II), (UI), (IV), (V) or (VI) or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or0 pharmaceutically acceptable prodrug thereof wherein the cytokine is selected from IL-2, IL-3, IL-4, IL-S, IL-6, IL-7, IL-8, IL-9, IL-IO, IL-Il, IL-12, IL-13, IL-15, IL-16, IL-17, IL-18, IL-Io, IL-lβ, IL-I RA, granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), oncostaUn M, erythropoietin, leukemia inhibitory factor (LIF), interferons, gamma-interferon (γ-IFN), B7 1 (CD80), B72 (B70, CD86), TNF-α, TNF-β, LT-β, CD40 ligand, Fas ligand, CD27 ligand, CD30 ligand, 4-1BBL, Trail, and5 migration inhibitory factor (MSF) Compounds
[00190] Compounds described herein modulate intracellular calcium and are used m the treatment of diseases, disorders or conditions where modulation of intracellular calcium has a beneficial effect In one embodiment, compounds described herein inhibit store operated calcium entry In one embodiment, compounds0 of Formulas (I), (II), (in), (JY), (V) and (VI) interrupt the assembly of SOCE units In another embodiment, compounds of Formulas Q), (JI), (JJI), (IV), (V) and (VT) alter the functional interactions of proteins that form store operated calcium channel complexes In one embodiment, compounds of Formulas (J), (TL), (IH), (IV), (V) and (VI) alter the functional interactions of STTMl with Orail In other embodiments, compounds of Formulas (I), (II), (HI), (TV), (V) and (VI) are SOC channel pore blockers In other embodiments, compounds of Formulas5 (I), 01), (HI), (JV), (V) and (VT) are CRAC channel pore blockers
[00191] In one aspect, compounds of Formulas (I), (U), (TII), (TV), (V) and (VI) inhibit the electrophysiological current (Isoc) directly associated with activated SOC channels In one aspect, compounds of Formulas (J), (TI), (TTI), (TV), (V) and (VI) inhibit the electrophysiological current (ICRAC) directly associated with activated CRAC channels [00192] In other embodiments, the diseases, conditions or disorders that benefit from modulation of intracellular calcium include, but are not limited to, an immune system-related disease (e g , an autoimmune disease), a disease or disorder involving inflammation (e g , asthma, chrome obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis, neuroinflammatory diseases, multiple 5 sclerosis, and disorders of the immune system), cancer or other proliferative disease, kidney disease and liver disease Ih one embodiment, compounds described herein are used as immunosuppresants to prevent transplant graft rejections, allogeneic or xenogeneic transplantation rejection (organ, bone marrow, stem cells, other cells and tissues), graft-versus-host disease In other embodiments, transplant graft rejections result from tissue or organ transplants In further embodiments, graft-versus-host disease results from bone marrow or stem cell0 transplantation.
[00193] Compounds described herein modulate an activity of, modulate an interaction of, or binds to, or interacts with at least one portion of a protein in the store operated calcium channel complex In one embodiment, compounds described herein modulate an activity of, modulate an interaction of, or binds to, or interacts with at least one portion of a protein in the calcium release activated calcium channel complex In one S embodiment, compounds described herein reduce the level of functional store operated calcium channel complexes In one embodiment, compounds described herem reduce the level of activated store operated calcium channel complexes In one embodiment, store operated calcium channel complexes are calcium release activated calcium channel complexes [00194] Compounds described herem for treatment of a disease or disorder, when administered to a subject0 having a disease or disorder effectively reduces, ameliorates or eliminates a symptom or manifestation of the disease, condition or disorder In other embodiments, compounds described herem also are administered to a subject predisposed to a disease, condition or disorder that does not yet manifest a symptom of the disease, condition or disorder, prevents or delays development of the symptoms In further embodiments, the agent has such effects alone or in combination with other agents, or functions to enhance a therapeutic effect of another5 agent
[00195] In some embodiments, the compounds described herem, pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, or pharmaceutically acceptable solvates thereof, modulate intracellular calcium, and are used to treat patients where modulation of intracellular calcium provides benefit In one embodiment, descπbed herem is a compound of Formula (I), or pharmaceutically acceptable salt,0 pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof
Figure imgf000037_0001
Formula Q), wherein
L is a bond, Q-Qalkyl, Ci-Cβalkenyl, Ci-Cβheteroalkyl, aryl, or heteroaryl, wherein CpQalkyl, CpCealkenyl,5 Ci Cftheteroalkyl, aryl, or heteroaryl is optionally substituted with at least one R5,
V is a bond, O, -(C(R6J2),^ or NR1, W is a bond, Ci-C«alkyl, Ct-Cβalkenyl, Ci-Qjheteroalkyl, wherein when Y is S and X is CR3 then V and W are
X is N or CR3,
Y is O, S or NR3, with the proviso that if Y is S, then X is not CH, R is CO2R1, a carboxylic acid bioisostere, an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl,
R1 is hydrogen, Ci-Cβalkyl, Ct-Cehaloalkyl, or benzyl,
R2 and R4 are independently an aryl, or a heteroaryl, wherein R2 and R4 are independently optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8, Ci-C6alkyl, C3- Cgcycloalkyl, Ci-Cyieteroalkyl, Ci-Qhaloalkyl, tetrazolyl, CrCβheterocycloalleyl, optionally substituted aryl, optionally substituted heteroaryl, -NHSC=O)2R8, -S(O)2N(R"^ -N(R9JS(OJ2N(R9J2, -C(=O)CF3, - CC=O)NHS(O)2R8, -SC=O)2NHCC=O)R8, -N(R9J2, -N(R9JCC=O)R8, -NCR9JC(O)N(R9J2, -N(R9)C(=O)ORS, - CO2R9, -C(=O)R8, -OC(=O)R8, -OC(=O)NCR9)2, -CON(R9J2, -SR8, -S(=O)R8, and -S(O)2R8, n is an integer from 1-6, Rs is selected from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8, C-Cjalkyl, C3-C8cycloalkyl, C,- Csheteroalkyl, Ci-C6haloalkyl, tetrazolyl, C2-Cgheterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(O)2R8, -S(=O)2N(R9)2, -N(R^S(O)2N(R9J2, -C(O)CF3, C(O)NHS(O)2R8, - S(O)2NHC(O)R8, -NCR9J2,
Figure imgf000038_0001
-N(R9JCCO)N(R9J2, -NCR9)C(O)0R8, -CO2R9, -C(O)R8, - OC(O)R8, -OC(O)N(R9J2, -CON(R9J2, -SR8, -S(O)R8, and -S(O)2R8, each R6 is independently hydrogen, F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8, Ci-Qalkyl, C3-
Cjcycloalkyl, Ci-Cβheteroalkyl, Ci-Cjhaloalkyl, tetrazolyl, C2-C8heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(O)2R8, -S(O)2N(R9)2, -N(R9JS(OJ2N(R9J2, -C(O)CF3, - CC=O)NHSC=O)2R8, -SC=OJ2NHCC=O)R8, -N(R9J2, -N(R9JC(OJR8, -N(R9JCC=O)N(R9J2, -N(R9JC(OJOR8, - CO2R9, -C(=O)R8, -OC(O)R8, -OC(O)N(R9J2, -CON(R9J2, SR8, -S(O)R8, and -S(O)2R8, each R8 is independently selected from Ci-Cβalkyl, Ci-C6haloalkyl, C3-C3cycloalkyl, phenyl, and benzyl, each R9 is independently selected from H,
Figure imgf000038_0002
Ci-Cβhaloalkyl, C3-Cgcycloalkyl, phenyl, and benzyl, and R3 is hydrogen, CrC6alkyl, Ci-Cβhaloalkyl, Ci-Csheteroalkyl, C3-C8cycloalkyl, substituted or unsubsαtuted aryl or benzyl [00196] For any and all of the embodiments, substituents are selected from among a subset described herein. For example, in some embodiments, R1 is hydrogen or C,-C6alkyl In other embodiments, R1 is H, methyl, ethyl, n-propyi, iso propyl, n-butyl, sec-butyl, iso butyl, n-pentyl, or hexyl In yet other embodiments, R1 is H, methyl, or ethyl In some embodiments, R1 is H
[00197] In one embodiment is a compound of Formula (I) wherein L is a bond. In another embodiment, L is phenyl In a further embodiment, L is -CH2CH2- In yet another embodiment L is -CH2- [00198] In yet a further embodiment is a compound of Formula CI) wherein V is O or a bond [00199] In one embodiment is a compound of Formula (I) wherein V is NR1
[00200] In another embodiment is a compound of Formula (I) wherein W is C,-C6alkyl In one embodiment, W is a bond In another embodiment, V and W are both bonds [00201] In yet another embodiment is a compound of Formula (I) wherem W is -(CH2Jn, and n is an integer from 1-4 [00202] In yet another embodiment is a compound of Formula (I) wherein n is an integer from 1-2 In a further embodiment, W is d-Qheteroalkyl In yet a further embodiment, W is -(CH^-O- wherein n is 0-6 In another embodiment, n is 1-4
[00203] In some embodiments, R is CO2R1 In other embodiments, R is a carboxylic acid bioisostere In a further embodiment, R is an optionally substituted heteroaryl In yet a further embodiment, R is an optionally substituted heterocycloalkyl
[00204] In some embodiments R4 is a phenyl, optionally substituted with at least one subsbtuent selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3, C-Qalkyl, d-Qsfluoroalkyl, Ci-Csheteroalkyl, C3- Cgcycloalkyl, and Ci-Cβhaloalkyl [00205] In another embodiment R4 is an optionally substituted heterocycle wherein the heterocycle is selected from
O Q CO CO CO ό ύ ύ .ύ.ύ O όό ύ
O O 0 O O 00 co co CO [00206] In a further embodiment R4 is substituted with at least one substituent selected from -NHS(O)2R8, -
S(=O)2N(R')2, -N(R9)S(O)2N(R')2, -N(R9J2, -N(R')C(=O)R8, -N(R9JC(O)N(R9J2,
Figure imgf000039_0001
C(=O)R8, -OC(O)N(R9J2, -CON(R9J2, -SR8, or -S(O)2R8
[00207] In another embodiment R4 ts selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,
2 chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2 bromophenyl, 3 bromophenyl, 4 bromophenyl, 2-iodophenyl, 3-iodophenyl, 4- lodophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 2,3-dimethyhΛenyl, 3,4- dimethylphenyl, 3,5-dimethylphenyl, 2-tnfluromethylphenyl, 3-tnfluromethylphenyl, and 4- tπfluromethylphenyl
[00208] In yet another embodiment R2 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2 -CF3, -OH, -OR8, -OCF3, CrC^alkyl, Ci-Cefluoroalkyl, C-Qheteroalkyl, C3-
Cgcycloalkyl, and Ci-Cβhaloalkyl
[00209J In another embodiment R2 is an optionally substituted heterocycle wherein the heterocycle is selected from
O Q CO CO CO ό ύ O .O.O ύ.ύύ ύ
0 0 0 0 O 00 CO CO 00 100210] In some embodiments R2 is substituted with one or more of the subsutuents selected from -
Figure imgf000040_0001
-N(R9XX=O)R8, N(R9)C(=O)OR8, -CO2R9, -C(=O)R8,
Figure imgf000040_0002
or -S(O)2R* [00211] In another embodiment R2 is selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluoroρhenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4- lodophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dunβthylphenyl, 2,3-dimetliylphenyl, 3,4- dunethylphenyl, 3,5-dunethylphenyl, 2-tπfluromethylphenyl, 3-tπfluromethylphenyl, and 4- tnflυromethylphenyl [00212] In one embodiment X is N and Y is O
[00213] In yet another embodiment X is N and Y is CR3, wherein R3 is selected from H or methyl
[00214] In a further embodiment X is CR3 and Y is O, wherein R3 is selected from H or methyl
[00215] In some embodiments X is CR3 and Y is NR3, wherein each R3 is independently selected from H or methyl [00216] In anomer embodunent. X is N. Y is S. L. V. and W are each a bond. R is COjR' where R1 ^ hydrogen, R4 is a phenyl group substituted with bromine at the para position and R2 is a phenyl group substituted with F at the para position
[00217] In a further embodiment, X is N, Y is S, L, V, and W arc each a bond, R is CO2R1 where R1 is hydrogen, R4 is a phenyl group substituted with bromine at the para position and R2 is a phenyl group substituted with F at the ortho position
[00218] In yet a further embodiment, X is N, Y is S, L, V, and W are each a bond, R is CO2R1 where R1 is hydrogen, R4 is a phenyl group substituted with bromine at the para position and R2 is a phenyl group substituted with F at the para position and a methyl group at the ortho position [00219] In another embodiment, X is N, Y is S, L, V, and W are each a bond, R is CO2R1 where R1 is methyl, R4 is a phenyl group substituted with bromine at the para position and R2 is a phenyl group substituted with F at the para position
[00220] In a further embodiment, X is N, Y is S, L, V, and W are each a bond, R is CO2R1 where R1 is methyl, R4 is a phenyl group substituted with bromine at the para position and R2 is a phenyl group substituted with F at the ortho position. [00221] In a further embodiment, X is N, Y is S, L, V, and W are each a bond, R is CO2R1 where R1 is methyl, R4 is a phenyl group substituted with bromme at the para position and R2 is a phenyl group substituted with methyl at the para position.
[00222] In a further embodiment, X is N, Y is S, L, V, and W are each a bond, R is CO2R1 where R1 is methyl, R4 is a phenyl group substituted with bromme at the para position and R2 is a phenyl group substituted with F at the meta position
[00223] In a further embodiment, X is N, Y is S, L, V, and W are each a bond, R is CO2R-' where R1 is hydrogen, R4 is a phenyl group substituted with bromine at the para position and R2 is a phenyl group substituted with F at the meta position. [00224] Any combination of the groups described above for the various variables is contemplated herein It is understood that substituents and substitution patterns on the compounds provided herein are selected to provide compounds that are chemically stable and that are synthesized by standard techniques, as well as those set forth herein
[00225] In one embodiment, described herein is a compound of Formula (H), or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof
Figure imgf000041_0001
Formula (II), wherein L is a bond, Ci-C6alkyl, Ci-Cβalkenyl, Ci-C6heteroalkyl, aryl, or heteroaryl, wherein Ci-Cjalkyl, Cr
C6alkenyl, Q-Qheteroalkyl, aryl, or heteroaryl is optionally substituted with at least one R5, V is a bond, O, -(CCR'tø.-O or NR1,
W is a bond, CrQplkyl, Q-Qalkenyl, C,-C<jheteroalkyl, X is N or CR3, Y is N or CR3,
R is CO2R1, a carboxyhc acid bioisostere, an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl,
R1 is hydrogen, CrQalkyl, CrC6haloalkyl, or benzyl,
R2 is an aryl, or a benzothienyl, wherein the aryl or benzothienyl is optionally substituted with at least one
R5,
R4 is an aryl, optionally substituted with at least one R5, each R5 is independently selected fiom F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8, Ci-Qplkyl, C3-
C8cycloalkyl, d-Qheteroalkyl, CrC6haloalkyl, tetrazolyl, C2-Cgheterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHSC=O)2R8, -SC=O)2N(Ro)2, N(R9)S(O)2N(R9)J, -CC-O)CFj, -C(O)NHS(O)2R8, -SC=O)2NHC(O)R8, -N(Rj)2, - N(R9)C(O)R8, -N(R9)C(O)N(R9)J, -N(R9)C(O)OR8, -CO2R9, -C(O)R8, -OC(O)R8, - OC(O)N(R9)Z, -CON(R9J2, -SR8, -S(O)R8, and -S(O)2R8, each R6 is independently selected from hydrogen, from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8, Ci-Cβalkyl, C3-C8cycloalkyl, Q-Cyieteroalkyl, Ci-C(jhaloalkyl, tetrazolyl, C2-C8heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(O)2R8,
Figure imgf000041_0002
- N(R9)S(O)2N(R9)2, -CC=O)CF3, -C(O)NHS(O)2R8, -S(O)2NHC(O)R8, -N(R,)2, - N(R9)C(O)R,, -N(R9)C(O)N(R9)J, -N(R9)C(O)ORs, -CO2R9, -C(O)R8, -OC(O)R8, -
0C(O)N(R,)2, -CON(R9)J, -SR8, -S(O)R8, and -S(O)2R8, n is an integer from 1-6, each R8 is independently selected from Ci-C1SaIlCyI, Ci-Cjhaloalkyl, C3-C8cycloalkyl, phenyl, and benzyl, each R* IS independently selected from H, Ci-Qjalkyl, Q-Cjhaloalkyl, C3-C8cycloalkyl, phenyl, and benzyl, and
R3 is hydrogen, Q-Qalkyl, Ci-Cβhaloalkyl, Ci-Qheteroalkyl, substituted or unsubsrxtuted aryl or benzyl 100226] For any and all of the embodiments, substituents are selected from among a subset described herein
For example, in some embodiments, R1 is hydrogen or Ci-C^alkyl In other embodiments, R1 is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, n-pentyl, or hexyl In yet other embodiments, R1 is H, methyl, or ethyl In some embodiments, R1 is H S [00227] In one embodiment is a compound of Formula (II) wherein L is a bond In another embodiment, L is phenyl In a further embodiment, L is -CH2CH2- In yet another embodiment L is -CH2
100228] In yet a further embodiment is a compound of Formula (II) wherein V is O or a bond
[00229] In one embodiment is a compound of Formula (II) wherein V is NR1
[00230] In another embodiment is a compound of Formula (II) wherein W is Ci-Cβalkyl In one embodiment,0 W is a bond In another embodiment, V and W are both bonds
[Θ0231] In yet another embodiment is a compound of Formula (II) wherein W is -(CHi)n, and n is an integer from 1-4
[00232] In yet another embodiment is a compound of Formula (II) wherein n is an integer from 1-2 In a further embodiment, W is Ci-C6heteroalkyl In yet a further embodiment, W is -(CHz)11-O- wherein n is 0-6 In S another embodiment, n is 1 -4
[00233] In some embodiments, R is CO2R1 In other embodiments, R is a carboxylic acid bioisostere In a further embodiment, R is an optionally substituted heteroaryl In yet a further embodiment, R is an optionally substituted heterocycloalkyl
[00234] In some embodiments R4 is a phenyl, optionally substituted with at least one subsutuent selected0 from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3, d-Csalkyl, d-Qfluoroalkyl, Ci-Cfiheteroalkyl, C3-
Cgcycloalkyl, and C,-C6haloalkyl
[00235] In another embodiment R4 is an optionally substituted heterocycle wherein the heterocycle is selected from.
O Q CO CO CO 5 ύ ύ ύ ύ.ύ O όό ύ
[00236] I on a furthoer embodoiment R4o is substiαtuted withc ato least onec subostituento selecoted fromc -NHoS(=O)2R8, -
Figure imgf000042_0001
-N(R9JCX=O)N(R9^1 -CO2R9, - C(=O)R8, -OC(=O)N(R9)2) -CON^, -SR8, or -St=O)2R8 0 [00237] In yet another embodiment R4 is selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4- fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3,4- dichlorophenyl, 3,5-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3- lodophenyl, 4-iodophenyl, 2-methylphenyl, 3-methylphenyl, 4 methylphenyl, 2,4-dimethylphenyl, 2,3- dunethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2-tπfluromethylphenyl, 3-tπfluromethylphenyl, and5 4-tπfluromethylphenyl [00238] In a farther embodiment R2 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3, Ci-C<;alkyl, Ci-C6fluoroalkyl, d-Cβheteroalkyl, C3-
Qcycloalkyl, and Ci-C6haloalkyl
[00239] In another embodiment R2 is an optionally substituted heterocycle wherein the heterocycle is selected from
Figure imgf000043_0001
O 0.0 O O OO 00.00. CCi
[00240] In one embodiment R2 is substituted with one or more of the substituents selected from -
Figure imgf000043_0002
-N(R9J2, -NCR9JCC=O)R8, NCR9JCC=O)OR8, -CO2R9, -C(=O)R8, -OCC=O)N(R9J2, -CON(R9J2, -SR8, or -SC=O)2R8 [00241] In yet another embodiment R2 is selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4- fluorophenyl, 2-chlorophenyI, 3-ehlorophenyl, 4-ohlorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3,4- dichlorophenyl, 3,5-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3- lodophenyl, 4-iodophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 2,3- dunethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2-tπfluromethylphenyl, 3-tπfluromethylphenyl, and
4-tnfhiromethylphenyl
[00242] In an additional embodiment X is N and Y is CR3, wherem R3 is selected from H or methyl
[00243] In a further embodiment X is N and Y is N [00244] In yet another embodiment X is CR3 and Y is CR3, wherein each R3 is independently selected from H or methyl
[00245] In one embodiment X is CR3 and Y is N, wherem R3 is selected from H or methyl [00246] In one embodiment, X is CR3, wherem R3 is H, Y is N, L is a bond, R is CO2R1, wherein R1 is hydrogen, R4 is a phenyl group substituted at the para position with Br, V is a bond, W is a bond, and R2 is a phenyl group substituted at the para position with F
[00247] In another embodiment, described herein is a compound of Formula (III), or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof
Figure imgf000043_0003
Formula (III) wherem
L is a bond, C,-C«alkyl, d-Csalkenyl, Ci-Qheteroalkyl, aryl, or heteroaryl, wherem CpCβalkyl, C1- Qalkenyl, Ci-CsheteroalkyL, aryl, or heteroaryl is optionally substituted with at least one R10, V is a bond, O, -CC(R3J2Jn-O or NR1, W is a bond, Ci-Cølkyl, Ci-C6alkenyl, Ci-Qjheteroalkyl
R is COjR1, a carboxyhc acid bioisostere, an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl,
R1 is hydrogen, Ci-C6alkyl, Ct-Qhaloalkyl, or benzyl, R2 is an aryl, or a benzothienyl, wherein the aryl or benzothienyl is optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8, d-Cj-lkyl, C3- Cscycloalkyl, Ci Qsheteroalkyl, Ci-C6haloalkyl, tetrazolyl, C^-Csheterocyoloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(O)2R8, -S(O)2N(R9)!, - N(R9JS(O)2N(R9J2, -C(O)CF3, -C(O)NHS(O)2R8, -S(O)2NHC(O)R8, -N(R9J2, - N(R')C(O)R8, -N(R9JC(O)N(R9J2, -N(R9JC(O)OR8, -CO2R9, -C(O)R', -OC(O)R', -
OC(O)N(R9J2, -CON(R9J2, -SR8, -S(O)R8, and -S(O)2R8,
R4 is an aryl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, - CF3, -OH, -OR8, -OCF3, C,-C6alkyl, C3-C,cycloallcyl, C-Ofluoroalkyl, Ci-Ceheteroalkyl, C,- Cshaloalkyl, tetrazolyl, C2-C8heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(O)2R8, S(O)2N(R9J2, -N(R9JS(O)2N(R9J2, -C(OJCF3, -C(O)NHS(O)2R8, -
S(O)2NHC(O)R8, -N(R9J2, -N(R9JC(O)R5, -N^JCKW^, -N(R9JC(O)OR8, -CO2R9, - C(O)R8, -OC(O)R8, -OC(O)N(R9J2, -CON(R9)2, -SR8, -S(OJR8, and -S(O)2R8, each R3 is independently selected from hydrogen, from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8,
Ci-Qalkyl, C3-C8cycloalkyl, Ci-Ceheteroalkyl, CpQhaloalkyl, tetrazolyl, C2-C8heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(O)2R8, -S(O)2N(R9J2, -
N(R9)S(OJ2N(R9J2, -C(O)CF3, -C(O)NHS(O)2R8, -S(O)2NHC(OJR8, -N(R9J2, - N(R9JC(O)R^ -N(R9)C(O)N(R9J2, N(R9)C(O)OR8, CO2R9, C(O)R8, OC(O)R8, - OC(OJN(R9J2, CON(R9J2, -SR8, -S(O)R8, and -S(O)2R8, n is an integer from 1 to 6, R10 is independently selected from from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8, Cj-Qalkyl. C3-
C8cycloalkyl, CpCyieteroalkyl, Q-Qhaloalkyl, tetrazolyl, CVCsheterocycIoalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(OJ2R8, -S(O)2N(R^)2, - N(R9)S(OJ2N(R9J2, -C(O)CF3, -C(O)NHS(O)2R8, -S(O)2NHC(O)R8, -N(R9J2, - N(R9)C(O)R8, N(R9)C(O)N(RD)2, N(R9)C(O)OR8, CO2R9, -C(O)R8, -OC(O)R8, - OC(O)N(Rs)2, -CON(R9J2, -SR8, -S(OJR8, and -S(O)2R8, each R8 is independently selected from Ci-C6alkyl, Ci-Qhaloalkyl, C3-C8cycloalkyl, phenyl, and benzyl, each R9 is independently selected from H, Ci-C6alkyl, Ci-C6haloalkyl, C3-C8cycloalkyl, phenyl, and benzyl, and
R5, R6 and R7 are independently selected from a hydrogen, -OH, halogen, Ci-Cjalkyl, CrCyialoalkyl, C1- Cjheteroalkyl, substituted or unsubstituted aryl or benzyl
[00248] For any and all of the embodiments, substituents are selected from among a subset described herein For example, in some embodiments, R1 is hydrogen or Ci-Csalkyl In other embodiments, R1 is H, methyl, ethyl, n-propyl, lso-propyl, n-butyl, sec-butyl, iso-butyl, n-pentyl, or hexyl In yet other embodiments, R1 is H, methyl, or ethyl In some embodiments, R1 is H [00249] In one embodiment is a compound of Formula (in) wherein L is a bond In another embodiment, L is phenyl In a further embodiment, L is -CH2CH2- In yet another embodiment L is -CH2-
[00250] In yet a further embodiment is a compound of Formula (III) wherein V is O or a bond
[002S1] In one embodiment is a compound of Formula (IH) wherein V is NR1 [00252] In another embodiment is a compound of Formula (m) wherein W is Ci-Qalkyl In one embodiment, W is a bond In another embodiment, V and W are both bonds
[00253] In yet another embodiment is a compound of Formula (HI) wherein W is -(CH2),, and n is an integer from 1-4
[00254] In yet another embodiment is a compound of Formula (III) wherein n is an integer from 1-2 In a further embodiment, W is Ci-Cyieteroalkyl In yet a further embodiment, W is -(CH2Jn-O- wherein n is 0-6 In another embodiment, n is 1-4
[00255] In some embodiments, R is CO2R1 In other embodiments, R is a carboxyhc acid bioisostere In a further embodiment, R is an optionally substituted heteroaryl. In yet a further embodiment, R is an optionally substituted heterocycloalkyl [00256] In one embodiment R4 is a phenyl, optionally substituted with at least one substituent selected from
F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3, d-C^alkyl, Cj-Cnfhioroalkyl, d-Osheteroalkyl, C3
Cgcycloalkyl, and CrC6haloalkyl
[00257] In some embodiments R4 is an optionally substituted heterocycle wherein the heterocycle is selected from
ό .ό.ύ .ύ ό.O όό ύ .
0 0 0 0 0 OC) OO CO OO
[00258] In another embodiment R4 is substituted with at least one substituent selected from -NHS(=O)2RB, - S(O)2N(R9);!, -N^S^O^NfR9):,, -N(R9J2, -N(R9)C(=O)R8, -N(R9JC(K))N(R9J2, -N(R9JC(O)OR8, -CO2R9, - C(O)R8, -OC(O)N(R9J2, -CON(R9J2, -SR8, or -S(O)2R8
[00259] In an additional embodiment R4 is selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4- fluorophenyl, 2-chlorophenyI, 3 chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl; 2,3-dichlorophenyl, 3,4- dichlorophenyl, 3,5-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3 iodophenyl, 4-iodophenyl, 2-methylphenyl, 3-methylphenyL, 4-methylphenyl, 2,4-dimethylphenyl, 2,3- dunethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2-tπfluromethylphenyl, 3-tπfluromethylphenyl, and 4-tπfluromethylphenyl
[00260] In some other embodiments R2 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3, d-Qalkyl, Ci-C6fluoroalkyl, C-Qjheteroalkyl, C3-Cgcycloalkyl, and CrC6haloalkyl [00261] In a further embodiment R2 is an optionally substituted heterocycle wherein the heterocycle is selected from. O Q CO CO CO
Figure imgf000046_0001
(00262) O In yet ano Other emb 0odiment O R2 is sub Ostituted w Oith oCn)e or m CoreQ of the su CbstiOtuents se ClecteOd from NHSC=O)2R8, S(O)2N(R")* -NCR9JS(OJ2N(R9J2, -N(R9J2, -NCR9JC(O)R8, -N(R9JCCO)NCR9J2, - N(R9W=O)OR8, -CO2R9, -C(=O)R8, -OCCO)NCR9J2, -CON(R9J2, -SR8, or -S(O)2R8 [00263] In additional embodiments R2 is selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4- fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3,4- dichlorophenyl, 3,5-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3- lodophenyl, 4-iodophenyl, 2-methylphenyl, 3-methylphonyl, 4-methylphenyl, 2,4-dimethylphenyl, 2,3 dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2-tπfluromethylphenyl, 3 tπfluromethylphenyl, and
4-tnfluromethylphenyl
[00264] In one embodiment, described herein is a compound of Formula (IV), or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof
wherein
L is a bond, Ci-Cjalkyl, Ci-C3alkenyl, Ci-Ceheteroalkyl, aryl, or heteroaryl, wherein Ci-C«alkyl, Ci-
C6alkenyl, d-Cϋheteroalkyl, aryl, or heteroaryl is optionally substituted with at least one R10, V is a bond, 0, -(C(R'^ 0 or NR1,
W is a bond, Ci-Csalkyl, Q-C^alkenyl, CpCβheteroalkyl,
X is N or CR3,
Y is O, S, NR3 or -CR5-CR6-,
R2 is an aryl, or a benzothienyl, wherein the aryl or benzothienyl is optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8, C,-C6alkyl, C3-
Cgcycloalkyl, Ci-Ceheteroalkyl, Ci-C6haloalkyl, tetrazolyl, C2-C8heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(O)2R8, -S(O)2N(R9J2, -
Figure imgf000046_0003
-S(O)2NHC(O)R8, -N(R9J2, - N(R9JC(O)R8, -N^CCOJNCR'k, -N(R9JC(O)OR8, -CO2R9, -C(O)R8, -OC(OJR8, - OC(O)NCR9J2, -CONCR9J2, -SR8, -SCO)R8, and -S(O)2R8,
R4 is an aryl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, - CF3, -OH, -OR8, -OCF3, Ci-C6alkyl, C3-CBcycloalkyl, C,-C6fluoroalkyl, CI-C6heteroalkyl, C,- Cfthaloalkyl, tetrazolyl, C2-Cghetorocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(O)2R8, S(O)2N(R9J2, -NCR9JS(OJ2N(R9J2, -C(O)CF3, -C(O)NHS(OJ2R8, - S(O)2NHC(O)R8, -N(R9J2, N(R9XX=O)R8, -N(R9JC(O)N(R9J2, -N(R9JCC=O)OR8, -CO2R9, - C(O)R8, -OC(O)R8, -0C(O)N(R5)2, -CON(R9J2, -SR8, -S(O)R8, and -S(O)2R8, each R7 is independently selected from hydrogen, from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8,
C1-C6HIlCyI, C3-C8cycloalkyl, Q-Qheteroalkyl, Ci-Qhaloalkyl, tetrazolyl, C^-Cgheterooyoloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(O)2R,, -S(O)2N(R9^, -
N(R9)S(O)2N(R9),, -C(O)CF3, -C(O)NHS(O)2R8, -S(O)2NHC(O)R1, -N(R9J2, - N(R9)C(O)R8, -N(R9)C(O)N(R9J2, -N(R9)C(K))OR8, -CO2R9, -C(O)R8, -OC(O)R8, OC(O)N(R9)J, -CON(R9J2, -SR8, -S(O)R8, and -S(O)2R8, n is an integer from 1-6, each R8 is independently selected from Ci-Cδalkyl, Ci-Qhaloalkyl, C3-C8cycloalkyl, phenyl, and benzyl, each R9 is independently selected from H, Ci-C6alkyl, CrC6haloalkyl, C3-C8cycloalkyl, phenyl, and benzyl, R10 is selected from F, Q, Br, T, -CN, -NO2, -CF3, -OH, -OR8, -OCF3, CrC6alkyl, C3-C8cycloalkyl, C,-
Cβfluoroalkyl, Ci-Qfheteroalkyl, Ci-Cshaloalkyl, tetrazolyl, C2-C8heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(O)2R8, -S(O)2N(R9J2, -
N(R9JS(O)2N(R9J2, -C(O)CF3, -C(O)NHS(O)2R8, -S(O)2NHC(OJR8, -N(R9J2, - N(R')C(O)R8, -N(R9JC(O)N(R9J2, -N(R9XXO)OR8, -CO2R9, -C(O)R8, -OC(O)R8, - OC(O)N(R9J2, -CON(R9J2, -SR8, -S(O)R8, and -S(OJ2R8,
R3 is hydrogen, Ci-Qalkyl, Q-Qhaloalkyl, Ci-Qheteroalkyl, substituted or unsubstituted aryl or benzyl, and
Rs and R6 are independently selected from a hydrogen, -OH, halogen,
Figure imgf000047_0001
C6heteroalkyl, substituted or unsubstituted aryl or benzyl
[00265] For any and all of the embodiments, substituents are selected from among a subset described herein. For example, in some embodiments, R1 is hydrogen or Ci-C^alkyl In other embodiments, R1 is H, methyl, ethyl, n-propyl, lso-propyl, n-butyl, sec-butyl, iso-butyl, n-pentyl, or hexyl In yet other embodiments, R1 is H, methyl, or ethyl In some embodiments, R1 is H
[00266] In one embodiment is a compound of Formula (IV) wherein L is a bond In another embodiment, L is phenyl. In a further embodiment, L is -CH2CH2- In yet another embodiment L is -CH2- [00267] In yet a further embodiment is a compound of Formula (IV) wherein V is O or a bond [00268] In one embodiment is a compound of Formula (IV) wherein V is NR1
[00269] In another embodiment is a compound of Formula (IV) wherein W is Ci-C6alkyl In one embodiment, W is a bond. In another embodiment, V and W are both bonds
[00270] In yet another embodiment is a compound of Formula (TV) wherein W is -(CH2Jn, and n is an integer [00271] In yet another embodiment is a compound of Formula (TV) wherein n is an integer from 1-2 In a further embodiment, W is Ci-Cyieteroalkyl In yet a further embodiment, W is -(CH2Jn-O- wherein n is 0-6 In another embodiment, n is 1-4
[00272] In some embodiments R4 is a phenyl, optionally substituted with at least one substrtuent selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3, d-Csalkyl, Ci-Csfluoroalkyl, Ci-Qheteroalkyl, C3- Cjjcycloalkyl, and CrCehaloalkyl [00273] In other embodiments R4 is an optionally substituted heterocycle wherein the heterocycle is selected from.
Figure imgf000048_0001
ό ό O ύ O ύ όύ ό
Figure imgf000048_0002
[00274] In some embodiments R4 is substituted with at least one substituent selected from -NHS^O^R8, -
Figure imgf000048_0003
-N(R9)2, N(R9)C(=O)R8,
Figure imgf000048_0004
-N(R9)C(=OJOR8, CO2R9, -
C(=O)Rβ,
Figure imgf000048_0005
-SR8, or -SJ=O)2R8
[00275] In other embodiments R4 is selected from phenyl, 2 fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2 chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4 dichlorophenyl, 2,3 dichlorophenyl, 3,4 dichlorophenyl,
3,5-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3 lodophenyl, 4- lodophenyl, 2-methylphenyi, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 2,3-dimethylphenyl, 3,4- dimethylphenyl, 3,5-dimethylphenyl, 2-tπfluromethylphenyl, 3-tnfluromethylphenyl, and 4- tπfluromethylphenyl
[00276] In some embodiments R2 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3, Q-Cβalkyl, d-Qjfluoroalkyl, C,-C6heteroalkyl, C3-
Cgcycloalkyl, and C, C6haloalkyl
[00277] In other embodiments R2 is an optionally substituted heterocycle wherein the heterocycle is selected from
Figure imgf000048_0006
ύ ύ.O "ύ ύ O όό ύ
Figure imgf000048_0007
[00278] In some eombodimeonts R2 iso substitutαed with ocne oor more oof theo subsπtouentos selectecd froom -
NHS(=O)2R8, -S(=O)2N(R9)2, -N(R9)S(=O)2N(R9)2I -N(R9J2, -N(R9)C(=O)R8, -N(R9)C(=O)N(R9)2, -
N(R9JCf=O)OR8, -CO2R9, -C(=O)R8, -OC(^)N(R9J2, -CON(R9J2, -SR8, or -8(-OJ2R8
[00279] In other embodiments R2 is selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2- chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 23-dichlorophenyl, 3,4-dichlorophenyl,
3,5 dichlorophenyl, 2 bromophenyl, 3 bromophenyl, 4 bromophenyl, 2 lodophenyl, 3-iodophenyl, 4- lodophenyl, 2-methylphenyl, 3-methylphenyl, 4 methylphenyl, 2,4 dimethylphenyl, 2,3-dimethylphenyl, 3,4- dimethylphenyl, 3 5-dunethylphenyl, 2-tπfluromethylphenyl, 3-tπfluromethylphenyl, and 4- tπfluromethylphenyl
[00280] In another embodiment X is N and Y is S [00281] Ih a further embodiment, described herein is a compound of Formula (V), or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof
Figure imgf000049_0001
Formula (V) wherein
V is a bond, O, (C(R^)-1-O OrNR1, W is a bond, Ci-Csalkyl, Ci-Csalkenyl, CrCjheteroalkyl, n= l or 2, m is an integer from 1-6, R is CO2R1, a carboxylic acid bioisostere, an optionally substituted heteroaryl, or an optionally substituted heterocycloatkyl, R1 is hydrogen, CrCf,alkyl. C,-C6haloalkyl, or benzyl, R2 is an aryl, or a benzothienyl, wherein the aryl or benzothienyl is optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, OR8, C1 C6alkyl, C3 Cgcycloalkyl, Ci-Cδheteroalkyl, Q-Qhaloalkyl, tetrazolyl, C^-Csheterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(=O)2R8, -S(O)2N(R9J2, - N(R9JS(OJ2N(R9J2, -C(=O)CF3, -Ct=O)NHS(O)2R8, -S(=O)2NHC(=O)R', -N(R9J2, - N(R9JC(O)R8, -NCR'jCtOJNfR9^, -N(R9)C(OJOR8, -CO2R9, -C(=O)R8, -OC(=O)R8, - OC(O)N(R9J2, -CON(R9J2, -SR8, -S(=O)R8, and -S(O)2R8, R4 is selected from H, F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3, C,-C6alkyl, C3-Cscycloalkyl, C,-
Qjfluoroalkyl, Ci-Csheteroalkyl, Ci-Cehaloalkyl, tetrazolyl, C2 Ciheterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(O)2R8, -S(O)2N(R9);!, - N(R')S(O)2N(R9)2, -C(O)CF3, -C(O)NHS(O)2R8, -S(O)2NHC(O)R8, -N(R*)2, - N(R')C(O)R8, -N(R9JC(O)N(R9J2, -N(R9JC(O)OR8, -CO2R9, -C(O)R8, -OC(O)R8, - OC(O)N(R9J2, -CON(R9J2, -SR8, -S(O)R8, and -S(O)2R8, each R6 is independently selected from hydrogen, from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8, Ci-Qjalkyl, C3-C8cycloalkyl, CrQsheteroalkyl, Q-Qhaloalkyl, telrazolyl,
Figure imgf000049_0002
optionally substituted aryl, optionally substituted heteroaryl, -NHS(O)2R8, -S(O)2N(R9J2, - N(R9JS(O)2N(Rj)2, -C(O)CF3, -C(O)NHS(O)2R8, -S(O)2NHC(O)R8, N(R9J2, - N(R9)C(O)R8, -N(R9)C(O)N(Rs)2, -N(R9)C(OJOR8, -CO2R9, -C(O)R8, -OC(O)R8, -
OC(O)N(R9J2, -CON(R9J2, -SR8, -S(O)R8, and -S(O)2R8, each R8 is independently selected from C1-C6alkyl, CrC«haloalkyl, C3-C8cycloalkyl, phenyl, and benzyl, and each R9 is independently selected from H, CrC6alkyl, Ci-Cdhaloalkyl, C3-C8cycloalkyl, phenyl, and benzyl
[00282] For any and all of the embodiments, substituents are selected from among a subset described herein. For example, in some embodiments, R1 is hydrogen or Ci-C6alkyl In other embodiments, R1 is H, methyl, ethyl, π-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, n-pentyl, or hexyl In yet other embodiments, R1 is H, methyl, or ethyl In some embodiments, R1 is H
[00283] In yet a farther embodiment is a compound of Formula (V) wherein V is O or a bond.
[00284) In one embodiment is a compound of Formula (V) wherein V is MR1 [00285] In another embodiment is a compound of Formula (V) wherein W is Cj-C6alkyl In one embodiment,
W is a bond. In another embodiment, V and W are both bonds
[00286] In yet another embodiment is a compound of Formula (V) wherein W is -(CH2),,, and n is an integer from 1-4
[00287] In yet another embodiment is a compound of Formula (V) wherein n is an integer from 1 -2 In a further embodiment, W is Ci-Cyieteroalkyl In yet a further embodiment, W is -(CH2)o-O- wherein n is 0-6 In another embodiment, n is 1-4
[00288] In some embodiments, R is CO2R1 In other embodiments R is a carboxylic acid bioisostere In a further embodiment, R is an optionally substituted heteroaryl In yet a further embodiment, R is an optionally substituted heterocycloalkyl [00289] In some embodiments R4 is a substituent selected from H, F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -ORS, -
OCF3, CpCjalkyl, Ci-Qfluoroalkyl, CpCsheteroalkyl, C3-Cacycloalkyl, or CpCβhaloalkyl
[00290] In other embodiments R4 is one or more substituents selected from -NHS(O)2R8, -S(=O)2N(R')2, -
Figure imgf000050_0001
-N(R9JC(O)N(RV -N(R9JC(O)OR8, -CO2R', -C(O)R8, -
OC(O)N(R"),, -CON(R9^, -SR8, or -S(O)2R8 [00291] In some embodiments R2 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, OCF3, CrCjalkyl, CpCsfluoroalkyl, Ci-C6heteroalkyl, C3-
Cscycloalkyl, and Ci-Cehaloalkyl
[00292] In other embodiments R2 is an optionally substituted heterocycle wherein the heterocycle is selected
Figure imgf000050_0002
[00293] I 0n some e 0mbodim.e0nts R2 is O substitut Oed with o Cne oOr more o cf thoe substit CuentOs selecte cd froύm - NHS(O)2R8, -S(O)2N(RV -N(R9JS(O)2N(RV -N(R9J2, -N(R9JC(O)R8, -N(RVXO)N(RV, - N(R*)C(0)OR8, -CO2R9, -C(O)R8, -OC(O)N(R9J2, -CON(RV -SR8, or -S(O)2R8
[00294] In other embodiments R2 is selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2- chlorophenyl, 3-chlorophenyl, 4-chloroρhenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromoρhenyl, 2-iodophenyl, 3-iodophenyl, 4- lodophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 2,3-dimethylphenyl, 3,4- dimethylphenyl, 3,5-dimetiiylphenyl, 2-tπfluromethylphenyl, 3-tπfluromethylphenyl, and 4- tπfluromethylphenyl [00295] In a further embodiment n = 2
[00296] In one aspect is a compound having the structure of Formula (VI)
R4. X J -R2
T z f ϊ
Formula (VI), wherein
Z is Ci-Cβalkyl, Ci-Qjhaloalkyl. Ci-Cyieteroalkyl, wherein C1-C6-USyI and Ci-Qheteroalkyl are independently optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, NO2, -OH, -CF3, -OCF3, -OR8, C-Qsalkyl, C3-C,cycloalkyl, Ci-C6heteroalkyl, d-Cshaloalkyl, tetrazolyl, CrCsheterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, - NHSt=O)2R8, -S(O)2N(R9J2, -N(R9JS(O)2N(R9J2, -C(OJCF3, -C(O)NHS(=0)2R8, -
S(=O)2NHC(=O)R8, -N(R9J2, -N(R9JCt=O)R8, -N(R9JC(O)N(R9J2, -N(R9JCf=O)OR8, -CO2R9, - C(=OJRβ, -OC(=O)R8, -OC(O)N(R9J2, -CON(R9J2, -SR8, -S(=O)R8, and -S(O)2R8 R is CO2R1. a carboxylic acid bioisostere, an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl, R1 is hydrogen, Ci-Cβalkyl, Ci-Cβhaloalkyl, or benzyl;
R2 and R4 are independently an aryl, or a heteroaryl, wherein R2 and R4 are independently optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, - OR8, CrQalkyl, C3-C8cycloalkyl, Ci-Cyieteroalkyl, CrCohaloalkyl, tetrazolyl, C2- Cgheterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(O)2R8, - St=O)2N(R9J2, -N(R9JS(O)2N(R9J2, -C(O)CF3, -C(O)NHS(O)2R8, -S(=O)2NHC(=O)R8, -N(R9J2,
-N(R9)C(=O)R8, -N(R9JC(O)N(R9J2, -N(R*)C(=O)OR8, -CO2R9, -C(O)R8, -OC(O)R8, - OCOOJNtR9)^ -CON(R9J2, -SR8, -S(O)R8, and -S(O)2R8, each R8 is independently selected from Ci-Cβalkyl, C,-C6haloalkyl, C3-C8cycloalkyl, phenyl, and benzyl, and each R9 is independently selected from H, Ci-Qalkyl, Ci-C6haloalkyl, C3-C8cycloalkyl, phenyl, and benzyl.
[00297] In one embodiment is a compound of Formula (VI) wherem Z is CpQalkyl [00298] In another embodiment is a compound of Formula (VI) wherein Z is CH3 [00299] In yet another embodiment is a compound of Formula (VIJ wherem Z is CH2CH3 [00300] In one embodiment is a compound of Formula (VI) wherem Z is substituted with a substituent selected from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8, Ci-C«alkyl, C3-C8cycloalkyl, and C,- Qjheteroalkyl.
[00301] In yet another embodiment is a compound of Formula (VI) wherein the substituent is selected from F, Cl, Br, and I [00302] In some embodiments, subsntuents are selected from among from a subset listed herein. For example, in some embodiments, R1 is hydrogen or CrC^alkyl In other embodiments, R1 is H, methyl, ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, lso-butyl, n-pentyl, or hexyl In yet other embodiments, R1 is H, methyl, or ethyl In some embodiments, R1 is H
[00303] In some embodiments R4 is a phenyl, optionally substituted with at least one substitαent selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3, d-Cjalkyl, Ci-Qfluoroalkyl, C-Qheteroalkyl, C3-
C5cycloalkyl, and Q-Qhaloalkyl
[00304] In another embodiment R4 is an optionally substituted heterocycle wherein the heterocycle is selected from
O Q CO, CO,
Figure imgf000052_0001
SC=O)2N(R9J2, -N(R9JSC=O)2N(R')* -N(R9J2, -N(R9JC(O)R8, -N(R9J(X=O)N(R9J2, -NCR9JC(O)OR8, -CO2R9, -
C(O)R8, -OC(O)N(R9J2, -CON(R9J2, -SR8, or -S(O)2R8
[00306] In another embodiment R4 is selected from phenyl, 2-fluorophenyI, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl,
3,5-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4- lodophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dnnethylphenyl, 2,3-dnnethylρhenyl, 3,4- dimethylphenyl, 3,5-dimethylphenyl, 2-tnfluromethylphenyl, 3-tπfluromethylphenyl, and 4- tπfluromethylphenyl [00307] In yet another embodiment R2 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3, C-Cβalkyl, CrCyiuoroalkyl, Ci-Csheteroalkyl, C3-
Cjcycloalkyl, and Ci-Qhaloalkyl
[00308] In another embodiment R2 is an optionally substituted heterocycle wherein the heterocycle is selected from
O.Q CO,CO,C0. ύ .ύ.ύ .ύ.ύ O όό ύ .
O [00309] o In som.eO embod.imOents R2 O is substit outedo with on Ce orQ more o of theα substitu centso selected from - NHS(O)2R8, S(OJ2N(R9J2, -N(R9JS(OJ2NCR9J2, -NCR9J2, -NCR9JC(O)R8, -NCR9JC(O)N(R9J2, - NCR9JC(O)OR8, -CO2R9, -C(O)R8, -OC(O)N(R9J2, -CONCR9J2, -SR8, or -S(OJ2R8
[00310] In another embodiment R2 is selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-bromophenyl, 3-bromophenyl; 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4- lodophenyl, 2-methylphenyl; 3-methylphenyl, 4-methylphenyl; 2,4-dimethylphenyl; 2,3-dimethylphenyl; 3,4- dimethylphenyl, 3,5-dimethylphenyl; 2-tπfluromethylphenyl; 3-tnfluromethylphenyl; and 4- tnfluromethylphenyl
[00311] Further embodiments of compounds of Formula (VI) described herein include, but are not limited to, compounds m Table 1 Table 1. Representative compounds of Formula (VI).
Figure imgf000053_0001
Compound R2 -R -R4 Z no. 1 4-fluorophenyl -CO2H 4-bromophenyl CH,
2 4-fluorophenyl -CO2H 4-chlorophenyl CH3
3 4-fluorophenyl -CO2H 3 ,4-dichlorophenyl CH3
4 4-fluorophenyl -CO2H 4-tnfluoromethylphenyl CH3
5 4-fluorophenyl -CO2H 2-bromophenyl CH3
6 4-fluorophenyl -CO2H 3,4-dimethylphenyl CH3
7 4-fluorophenyl -CO2H 2-chlorophenyl CH3
8 4-fluorophenyl -CO2H 2,4-dichlorophenyl CH3
9 4-fluorophenyl -CO2H Phenyl CH3
10 4-fluorophenyl -CO2H 4-mefhylphenyl CH3
11 3-fluorophenyl -CO2H 4-chlorophenyl CH3
12 3-Ωuorophenyl -CO2H 2,4-dichlorophenyl CH3
13 3-fluorophenyl -CO2H 3,4-dimethylphenyl CH3
14 3-fluorophenyl -CO2H 3-chlorophenyl CH3
15 3-fluorophenyl -CO2H 4-methylphenyl CH3
16 3-fluorophenyl -CO2H 3,4-dichlorophenyl CH3
17 3-fluorophenyl -CO2H 2-bromophenyl CH3
18 3-fluorophenyl -CO2H 4-tnfluoromethylphenyl CH3
19 4-chlorophenyl -CO2H 4-chlorophenyl CH3
20 4-chlorophenyl -CO2H 4-methylphenyl CH3
21 4-chlorophenyl -CO2H 2,4-dichlorophenyl CH3
22 4-chlorophenyl -CO2H 4-fluorophenyl CH3
23 4-ohlorophenyl -CO2H 3,4-dichlorophenyl CH3
24 4-chlorophenyl -CO2H 3,4-dimethylphenyl CH3
25 4-chlorophenyl -CO2H 4-tnfluoromethylphenyl CH3
26 4-chlorophenyl -CO2H Phenyl CH3
27 4-chlorophenyl -CO2H 2-bromoρhenyl CH3
28 4-chlorophenyl -CO2H 3-chlorophenyl CH3
29 4-bromophenyl -CO2H 4-methylphenyl CH3
30 4-bromophenyl -CO2H 4-chlorophenyl CH3
31 4-bromophenyl -CO2H 4-bromophenyl CH3
32 4-bromophenyl -CO2H 3 ,5-dichlorophenyl CH3
33 4-bromophenyl -CO2H 3-chlorophenyl CH3
34 4-bromophenyl -CO2H 3,4-dimethylphenyl CH3
35 4-bromophenyl -CO2H 4-tnfluoromethylρhenyl CH3
36 4-bromoρhenyl -CO2H 3,4-dichlorophenyl CH3
37 4-bromophenyl -CO2H 2-bromophenyl CH3
38 3-methylphenyl -CO2H 4-chlorophenyl CH3
39 3-methyhjhenyl -CO2H 4-methylphenyl CH3
40 3-methylphenyl -CO2H phenyl CH3
41 3-methyrphenyl -CO2H 2-bromophenyl CH3 Compound R' -R -R Z, no.
42 3-methylphenyl -CO2H 4-fluorophenyl CH3
43 3-methylphenyl -CO2H 3-chlorophenyl CH3
44 3-methylphenyl -CO2H 4-tπfluoromethylphenyl CH3
45 3-methylphenyl -CO2H 2,4-dichlorophenyl CH3
46 3-methylphenyl -CO2H 3,4-dunethylphenyl CH3
47 4-iodobenzamido -CO2H 4-bromophenyl CH3
48 2-chloro,4-fluorophenyl -CO2H 4-bromophenyl CH3
49 3,4difluorophenyl -CO2H 4-bromophenyl CH3
50 2-chloro,4-fluorophenyl -CO2H 4-chlorophenyl CH3
51 2-fluoroρhenyl -CO2H 4-bromophenyl CH3
52 3-fluoro,4- -CO2H 4 bromophenyl CH3 methoxyphenyl
53 4-methylphenyl -CO2H 4-chlorophenyl CH3
54 4-cyanophenyl -CO2H 4-bromophenyl CH3
55 4-ethylphenyl -CO2H 4-chlorophenyl CH3
56 4-tπfluoromethylphenyl -CO2H 4-chlorophenyl CH3
57 3-fluorophenyl -CO2H 4-bromoρhenyl CH3
58 4-chlorophenyl -CO2H 4-bromophenyl CH3
59 4-iodobenzamido -CO2H 2,4-dichlorophenyl CH3
60 3-methylphenyl -CO2H 4-bromophenyl CH3
61 4-fluorophenyl -CO2H 4-bromophenyl CH2CH3
62 4-fluoτophenyl -CO2H 4-chlorophenyl CH2CH3
63 4-fluorophenyl -CO2H 2-bromophenyl CH2CH3
64 4-fluorophenyl -CO2H 2-chlorophenyl CH2CH3
65 4-fluorophenyl -CO2H Phenyl CH2CH3
66 4-chlorophenyl -CO2H 4-fluorophenyl CH2CH3
67 4-chlorophenyl CO2H Phenyl CH2CH3
68 4-chlorophenyl -CO2H 2-bromophenyl CH2CH3
69 4-bromophenyl -CO2H 4-chlorophenyl CH2CH3
70 4-bromophenyl -CO2H 4-bromophenyl CH2CH3
71 4-bromophenyl -CO2H 2-bromophenyl CH2CH3
72 4-chlorophenyl -CO2H 4-bromophenyl CH2CH3
[00312] In one embodiment is a compound of Formula (VI) having the structure
Figure imgf000054_0001
Further Forms of Compounds
[00313] In some embodiments, the compounds described herein exist as diastereomers, enantiomers, or other stereoisomerism forms The compounds presented herein include all diastercomenc, enantiomeric, and epimenc forms as well as the appropriate mixtures (hereof Separation of stereoisomers are performed by chromatography or by the forming diastereomenc and separation by recrystalhzation, or chromatography, or any combination thereof (Jean Jacques, Andre Collet, Samuel H Wilen, "Enantiomers, Racemates and Resolutions", John Wiley
And Sons, Inc , 1981, the separation of stereoisomers as discussed in this reference is herein incorporated) In other embodiments, stereoisomers are obtained by stereoselective synthesis
[00314] In some situations, compounds exist as tautomers All tautomers are included withm the formulas described herein [00315] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs) The compounds described herein are in the form of pharmaceutically acceptable salts As well, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure In addition, in other embodiments, the compounds described herein exist in onsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like The solvated forms of the compounds presented herein are also considered to be disclosed herein
[00316] In some embodiments, compounds described herein are prepared as prodrugs A "prodrug" refers to an agent that is converted into the parent drug in vivo Prodrugs are often useful because, m some situations, they are easier to administer than the parent drug In some other embodiments, the prodrug is bioavailable by oral administration whereas the parent is not In other embodiments, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug An example, without limitation, of a prodrug would be a compound described herein, which is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabohcally hydrolyzed to the carboxyhc acid, the active entity, once mside the cell where water-sotubihty is beneficial In other embodiments, the prodrug is a short peptide (poiyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound
[00317] To produce a prodrug, a pharmaceutically active compound is modified such that the active compound will be regenerated upon in vtvo administration In other embodiments, the prodrug is designed to alter the metabolic stability or (he transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug [00318] Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound of Formulas (I), (II), (III), (TV), (V) or (VI) as set forth herein are included within the scope of the claims hi some cases, some of the herein-described compounds are a prodrug for another derivative or active compound [00319] In some embodiments are prodrugs that are designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues In some embodiments, the design of a prodrug increases the effective water solubility
[00320] In some embodiments, sites on the aromatic πng portion of compounds described herein are susceptible to various metabolic reactions, therefore incorporation of appropriate substituents on the aromatic πng structures, such as, by way of example only, halogens can reduce, minimize or eliminate this metabolic pathway
[00321] In other embodiments, the compounds described herein are labeled isotopically (e g with a radioisotope) or by other means, including, but not limited to, the use of chromophores or fluorescent moieties, biolummescent labels, photoacuvatable or chemiluminescent labels [00322] Compounds described herem include isotopically labeled compounds, which are identical to those recited m the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature In other embodiments are examples of isotopes that are incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorme, such as. for example, 2H, 3H, 13C, 14C, 1SN, 180, 170, 35S, 18F, 36Cl, respectively Certain lsotopically-labeled compounds described herein, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful m drug and/or substrate tissue distribution assays Further, in some other embodiments, substitution with isotopes such as deuterium, i e , 2H, affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements [00323] In further embodiments, the compounds described herein are metabolized upon administration to an organism m need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect
[00324] Compounds described herem are formed as, and/or used as, pharmaceutically acceptable salts The type of pharmaceutical acceptable salts, include, but are not limited to (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphonc acid, and the like, or with an organic acid, such as, for example, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycohc acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumanc acid, tnfluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesuUbnic acid, 1,2-ethanedisulfonic acid, 2-hydroxycthancsulfonic acid, benzenesulfomc acid, toluenesulfonic acid, 2-naphthalenesurfonic acid, 4-methylbicyclo-[2 2 2]oct-2-ene- 1-carboxyhc acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-l-carboxylιc acid), 3- phenylpropiomc acid, tnmethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutync acid, valproic acid, and the like, (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e g , an alkali metal ion (e g lithium, sodium, potassium), an alkaline earth ion (e g magnesium, or calcium), or an aluminum ion In some cases, compounds described herem coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, tnethanolamine, tromethamme, N methylglucamme, dicyclohexylaimne, tris(hydroxymethyl)methylamine In other cases, compounds described herem form salts with ammo acids such as, but not limited to, argmine, lysine, and the like Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like
[00325] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs Solvates contain either stoichiometric or non-stoichiometπc amounts of a solvent, and in some embodiments are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol In some embodiments, solvates of compounds described herem are conveniently prepared or formed during the processes described herem. In other embodiments the compounds provided herein exist in unsolvated as well as solvated forms In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
[00326] In other embodiments, compounds described herein, such as compounds of Formulas (I), (JI), (HI), (IV), (V) and (VI), are in various forms, including but not limited to, amorphous forms, milled forms and nano- particulate forms In addition, compounds described herein include crystalline forms, also known as polymorphs Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, melting points, density, hardness, crystal shape, optical properties, stability, and solubility Various factors such as the recrystalhzation solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate [00327] In further embodiments, the screening and characterization of the pharmaceutically acceptable salts, polymorphs and/or solvates are accomplished using a variety of techniques including, but not limited to, thermal analysis, x-ray diffraction, spectroscopy, vapor sorption, and microscopy Thermal analysis methods address thermo chemical degradation or thermo physical processes including, but not limited to, polymorphic transitions, and such methods are used to analyze the relationships between polymorphic forms, determine weight loss, to find the glass transition temperature, or for excrpient compatibility studies Such methods include, but are not limited to, Differential scanning caloπmetry (DSC), Modulated Differential Scanning Caloπmetry (MDCS), Theπnogravimetπc analysis (TGA), and Theπnogravi-metπc and Infrared analysis (TG/IR) X-ray diffraction methods include, but are not limited to, single crystal and powder diffractometers and synchrotron sources The various spectroscopic techniques used include, but are not limited to, Raman, FTIR, UV-VIS, and NMR (liquid and solid state) The various microscopy techniques include, but are not limited to, polarized light microscopy, Scanning Electron Microscopy (SEM) with Energy Dispersive X-Ray Analysis (EDX), Environmental Scanning Electron Microscopy with EDX (in gas or water vapor atmosphere), IR microscopy, and Raman microscopy Synthesis of Compounds [00328] In some embodiments, the synthesis of compounds described herein are accomplished using means described m the chemical literature, using the methods described herein, or by a combination thereof [00329] The starting materials and reagents used for the synthesis of the compounds described herein are synthesized or are obtained from commercial sources, such as, but not limited to, Sigma Aldπch, FischerScientific (Fischer Chemicals), and AcrosOrgamcs [00330] The compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein as well as other techniques, such as described, for example, in Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc , 1989), March, ADVANCED ORGANIC CHEMISTRY 4* Ed , (Wiley 1992), Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4* Ed , VoIs A and B (Plenum 2000, 2001), and Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3rd Ed , (Wiley 1999) (the synthetic techniques described m the above publications are herein incorporated by reference) General methods for the preparation of compound as disclosed herein are derived from known reactions, and in some embodiments, the reactions are modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formulae as provided herein. As a guide the following synthetic methods are utilized
Formation of Covalent I inlcages bv Reaction of an Electronhilp with a Nucleonhile
[00331] In some embodiments, the compounds described herein are modified using various electrophiles and/or nucleophiles to form new functional groups or subsπtuents Table 2 entitled "Examples of Covalent Linkages and Precursors Thereof lists selected non-hnuting examples of covalent linkages and precursor functional groups which yield the covalent linkages Table 2 is used as guidance toward the variety of electrophiles and nucleophiles combinations available that provide covalent linkages Precursor functional groups are shown as electrophihc groups and nucleophihc groups Table 2: Examples of Covalent Linkages and Precursors Thereof
Figure imgf000058_0001
Use of Protecting Groups [00332] In some embodiments, in the reactions described, it is necessary to protect reactive functional groups, for example hydroxy, amnio, lmino, thio or carboxy groups, where these are desired in the final product, in order to avoid their unwanted participation m reactions Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed In some embodiments, each protective group is removable by a different means Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal [00333) In other embodiments, protective groups are removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and/or oxidative conditions In other embodiments, groups such as tntyl, dimethoxytπtyl, acetal and t-butyldimethylsilyl are acid labile and are used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile In further embodiments, carboxyhc acid and hydroxy reactive moieties are blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as t-butyl carbamate or with carbamates that are both acid and base stable but hydrolybcally removable [00334] In yet further embodiments, carboxyhc acid and hydroxy reactive moieties are blocked with hydrolybcally removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids are blocked with base labile groups such as Fmoc In other embodiments, carboxyhc acid reactive moieties are protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or they are blocked with oxidalively-removable protective groups such as 2,4- dimethoxybenzyl, while co-existmg amino groups are blocked with fluoride labile silyl carbamates [00335] In further embodiments, allyl blocking groups are useful in then presence of acid and base- protectmg groups smce the former are stable and are subsequently removed by metal or pi-acid catalysts For example, an allyl-blocked carboxyhc acid is deprotected with a Pd°-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups Yet another form of protecting group is a resin to which a compound or intermediate is attached As long as the residue is attached to the resin, that functional group is blocked and cannot react Once released from the resin, the functional group is available to react [00336] Typically, in some embodiments, blocking/protecting groups are selected from.
Mfl
Figure imgf000059_0001
[00337] Other protecting groups, plus a detailed description of techniques apphcable to the creation of protecting groups and then- removal are described m Greene and Wuts, Protective Groups m Organic Synthesis, 3rd Ed , John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, the discussion of protecting groups in the above publication is herein incorporated by reference
General Synthesis (00338] In other embodiments, the preparation of compounds of Formulas (I), (II), QB), (TV), (V) and (VI) described herein are accomplished by methods such as described m Beccalli et alJ Org Chem 1985, 50, 2373, Shawah et alJ Heterocyclic Chem 1976, 13, 989, J Heterocyclic Chem 1980, 17, 833, Organic Syntheses 1943, Coll VoI 2, 272, Organic Syntheses 1960, 40, 29, Organic Syntheses 1967, 47, 81, Organic Syntheses 1984, 62, 187, Organic Syntheses 1971, 51, 100, Penning et alJ Med Chem 1997, 40, 1347, Organic Syntheses 1998, 75, 53, Orgamc Syntheses 1970, SO, 104, Organic Syntheses 199S, 72, 163, Sibi et alJ Org Chem , 1995, 60, 5016, Nahm, S , Weinreb, S M Tetrahedron Lett 1981, 22, 3815-3818, Amr et alBworg Med Chem 2006, 14, 5481, the methods describing the preparation of compounds described herein are incorporated by reference [00339] In one embodiment, compounds described herein are prepared by the sequence depicted in Schemes A-H Scheme A. Non-limiting Example of the Synthesis of Compounds of Formula (I)
Figure imgf000060_0001
[00340] Condensation of chlorooxime A-I with cyanoacetate A-2 forms the 5-ammoisoxazole A-3 directly Reaction of 5-aminoisoxazole A-3 with an activated carboxychc acid affords the desired compound A-4 Scheme B. Non-limiting Example of the Synthesis of Compounds of Formula (I)
Figure imgf000060_0002
[00341] Condensation of bromohydrazone B-I with cyanoacetate B-2 forms the 5-aminopyrrazole B-3 directly Reaction of 5-aminopyrrazole B-3 with an activated carboxykc acid affords the desired compound B-4 Scheme C. Non-limiting Example of the Synthesis of Compounds of Formula (I)
Figure imgf000060_0003
[00342] Claisen condensation of cyanoacetate C-I with acid chloride C-2 forms the cyanoketone C-3 Condensation of C-3 with hydrazine yields the 5-aminopyrrazole C-4 Reaction of 5-aminopyrrazole C-4 with an activated carboxylic acid affords the desired compound C-5 Scheme D. Non-limiting Example of the Synthesis of Compounds of Formula (U)
Figure imgf000061_0001
D-1 D-2 D-3
Figure imgf000061_0002
[00343] The synthesis begins with the methyl ester of 3-furan carboxylic acid D-I Oxidation of the fύran with bromine in methanol affords the 2,5-dihydro-2,5-dimetlioxyfuran D-2 which is then reduced by catalytic hydrogenation Treatment of tetrahydrofuran D-3 with a suitable aniline derivative in AcOH yields pyrrole D-4 Hydrolysis of the ester and Curtius rearrangement provides 3-aminopyrrole D-5 Electrophihc substitution of the pyrrole with tnchloroacetyl chloride will give D-6 which is readily cleaved to give ester D-7 Acylation with an appropriate acid chloride gives final product D-8 Scheme E. Non-limiting Example of the Synthesis of Compounds of Formula (D)
Figure imgf000061_0003
[00344] Treatment of nitroketone E-I with dimethylformamide dimethylacetal will provide enamide
£-2 Condensation with a substituted hydrazine yields pyrazole E-3 Reduction of the nitro group and acetylation of the resulting amnio compound affords the desired product E-4. S Scheme F. Non-limiting Example of the Synthesis of Compounds of Formula (IH)
Figure imgf000061_0004
[00345] A palladium-catalyzed cross-coupling reaction between 2-amino-6-brornobenzoic acid derivative F-I and a suitable boronic acid affords product F-2 Reaction of 2-aminobenzoic acid derivatives with an activated carboxylic acid affords the desired compound F-3. Scheme G. Non-limiting Example of the Synthesis of Compounds of Formula (IV)
Figure imgf000062_0001
G-1 G-2
Figure imgf000062_0002
[00346] A palladium-catalyzed cross-coupling reaction between 3-bromo-4-thiophenecarboxylic acid derivative G-I and a suitable boronic acid affords product G-2 Treatment of G-2 with BuLi followed by the Weinreb amide of oxalic acid affords ketone G-3 via the directed metalation intermediate shown. Reaction of G-3 with a suitable Grignard reagent yields the keto acid G-4. Activation of the acid and condensation with hydrazine affords the bicyclic hydrazide G-5. Scheme H. Non-limiting Example of the Synthesis of Compounds of Formula (V)
Figure imgf000062_0003
H-2 H -3 [00347] Condensation of cyclic ketone H-I with cyanoacetate H-2 in the presence of a base and elemental sulfur forms the 5-aminothiophene H-3 directly. Reaction of 5-aminothiophene H-3 with an activated carboxylic acid affords the desired compound H-4.Schemes presented herein are merely illustrative of some methods by which the compounds described herein are synthesized.
Certain Terminoloεv
[00348] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood in the field to which the claimed subject matter belongs. In the event that there is a plurality of definitions for terms herein, those in this section prevail All patents, patent applications, publications and published nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) referred to herein are incorporated by reference. Where reference is made to a URL or other such identifier or address, it is understood that such identifiers can change and particular information on the internet can come and go, but equivalent information is found by searching the internet Reference thereto evidences the availability and public dissemination of such information
[00349] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed In this application, the use of the singular includes the plural unless specifically stated otherwise It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise In this application, the use of "or" means "and/or" unless stated otherwise Furthermore, use of the term "including" as well as other forms, such as "include", "includes," and "included," is not limiting [00350] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described All documents, or portions of documents, cited m the application including, but not limited to, patents, patent applications, articles, books, manuals, and treatises are hereby expressly incorporated by reference for its intended purpose [00351] Definition of standard chemistry terms are found in reference works, including but not limited to, Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4™ ED " VoIs A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HFLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, within the skill of the art are employed [00352] Unless specific definitions are provided, the nomenclature employed in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those known in the art In some embodiments, standard techniques are used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients In other embodiments, standard techniques are used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e g , electroporation, lipotection) In further embodiments, reactions and purification techniques are performed e g , using kits of manufacturer's specifications or as commonly accomplished m the art or as described herein. The foregoing techniques and procedures are generally performed of conventional methods and as described in various general and more specific references that are cited and discussed throughout the present specification [00353] It is to be understood that the methods and compositions described herein are not limited to the particular methodology, protocols, cell hues, constructs, and reagents described herein and as such may vary It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the methods, compounds, compositions descπbed herein. [00354] As used herein, C1-C, includes CrC2, Ci-C3 C1-Cx Cj-C1 refers to the number of carbon atoms mat make up the moiety to which it designates (excluding optional substmients) [00355] An "alkyl" group refers to an aliphatic hydrocarbon group In some embodiments, the alkyl groups include or do not include units of unsaturation In some embodiments, the alkyl moiety is a "saturated alkyl" group, which means that it does not contain any units of unsaturation (i e a carbon-carbon double bond or a carbon-carbon triple bond) In further embodiments, the alkyl group also is an "unsaturated alkyl" moiety, which means that it contains at least one unit of unsaturation In some embodiments, the alkyl moiety, whether saturated or unsaturated, is branched, straight chain, or eye he [00356] In other embodiments, the "alkyl" group has 1 to 6 carbon atoms (whenever it appears herein, a numerical range such as "1 to 6" refers to each integer in the given range, e g , "1 to 6 carbon atoms" means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc , up to and including 6 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated) The alkyl group of the compounds described herein are designated as "Ci-C6 alkyl" or similar designations By way of example only, "Cj-C6 alkyl" indicates that there are one to six carbon atoms m the alkyl chain, i e , the alkyl chain is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, lso-pentyl, neo-pentyl, hexyl, propen-3-yl (allyl), cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl In some embodiments, alkyl groups are substituted or unsubstituted In other embodiments, depending on the structure, an alkyl group is a monoradical or a diradical (i e , an alkylene group)
[00357] An "alkoxy" refers to a "-O-alkyl" group, where alkyl is as defined herein. [00358] The term "alkenyl" refers to a type of alkyl group m which the first two atoms of the alkyl group form a double bond that is not part of an aromatic group That is, an alkenyl group begins with the atoms - C(R)=CR2, wherein R refers to the remaining portions of the alkenyl group, which are the same or different
Non limiting examples of an alkenyl group include -CH=CH2, -C(CHs)=CH2, -CH=CHCH3, CH=C(CH3)2 and The alkenyl moiety are branched, straight chain, or cyclic (in which case, it would also be known as a "cycloalkenyl" group) Alkenyl groups may have 2 to 6 carbons Alkenyl groups are substituted or unsubsr±tuted In some other embodiments, depending on the structure, an alkenyl group is a monoradical or a diradical (i e , an alkenylene group)
[00359] The term "alkynyl" refers to a type of alkyl group m which the first two atoms of the alkyl group form a triple bond That is, an alkynyl group begins with the atoms -C≡C-R, wherein R refers to the remaining portions of the alkynyl group Non- limiting examples of an alkynyl group include -C=CH, -D-CCH3, - C=CCH2CH3 and -C=CCH2CH2CH3 In other embodiments, the "R" portion of the alkynyl moiety is branched, straight chain, or cyclic An alkynyl group can have 2 to 6 carbons Alkynyl groups are substituted or unsubstituted In some embodiments, depending on the structure, an alkynyl group is a monoradical or a diradical (i e , an alkynylene group) [00360] "Ammo" refers to a -NH2 group [00361] The term "alkylamme" or "alkylamino" refers to the -l^alkyl^Hy group, where alkyl is as defined herein and x and y are selected from the group x=l, y=l and x=2, y=0 In some embodiments, when x=2, the alkyl groups, taken together with the nitrogen to which they are attached, optionally form a cyclic ring system "Dialkylamino" refers to a -N(alkyl)2 group, where alkyl is as defined herein.
[00362] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π electrons, where n is an integer In other embodiments, aromatic rings are formed from five, six, seven, eight, nine, or more than nine atoms In some other embodiments, aromatics are optionally substituted. The term "aromatic" includes both aryl groups (e g , phenyl, napthalenyl) and heteroarji groups (e g , pyndinyl, qumohnyl)
[00363] As used herein, the term "aryl" refers to an aromatic nog wherein each of the atoms forming the nng is a carbon atom In further embodiments, aryl rings are formed by five, six, seven, eight, nine, or more than nine carbon atoms In some embodiments, aryl groups are optionally substituted Examples of aryl groups include, but are not limited to phenyl, and naphthalenyl In other embodiments, depending on the structure, an aryl group is a monoradical or a diradical (l e , an arylene group)
[00364] "Carboxy" refers to -CO2H In some cases, oarboxy moieties may be replaced with a "carboxyhc acid bioisostere", which refers to a functional group or moiety that exhibits similar physical and/or chemical properties as a carboxyhc acid moiety Λ carboxyhc acid bioisostere has similar biological properties to that of a carboxyhc acid group A compound with a carboxyhc acid moiety can have the carboxyhc acid moiety exchanged with a carboxyhc acid bioisostere and have similar physical and/or biological properties when compared to the carboxyhc acid-containing compound For example, m one embodiment, a carboxyhc acid bioisostere would ionize at physiological pH to roughly the same extent as a carboxyhc acid group Examples of bioisoteres of a carboxyhc acid include, but are not limited to,
Figure imgf000065_0001
[00365] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the nng (i e skeletal atoms) is a carbon atom In some embodiments, cycloalkyls are saturated, or partially unsaturated In other embodiments cycloalkyls are fused with an aromatic rmg (m which case the cycloalkyl is bonded through a non-aromatic nng carbon atom) Cycloalkyl groups include groups having from 3 to 10 nng atoms Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties
> D O O O O CO O O O O QO, and the like
[00366] The terms "heteroaryl" or, alternatively, "heteroaromatic" refers to an aryl group that includes one or more nng heteroatoms selected from nitrogen, oxygen and sulfur An ΛT-containing "heteroaromatic" or "heteroaryl'* moiety refers to an aromatic group in which at least one of the skeletal atoms of the nng is a nitrogen atom. In some embodiments, polycychc heteroaryl groups are fused or non-fused. Illustrative examples of heteroaryl groups include the following moieties
Figure imgf000065_0002
[00367] A ' heterocycloalkyl" group or "heteroalicyclic" group refers to a cycloalkyl group, wherein at least one skeletal nng atom is a heteroatom selected from nitrogen, oxygen and sulfur In some embodiments, the radicals are fused with an aryl or heteroaryl Illustrative examples of heterocycloalkyl groups, also referred to as non-aromatic heterocycles, include
Δ °6 •&■ ό ό& o
O ύ O ύ > O Q OO CX> 00
Figure imgf000066_0001
and the like The term heteroalicyclic also includes all πng forms of the carbohydrates, including but not limited to the monosaccharides, the disacchandes and the oligosaccharides Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons m the πng It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i e skeletal atoms of the heterocycloalkyl πng)
[00368] The term "halo" or, alternatively, "halogen" means fluoro, chloro, bromo and iodo [00369] The term "haloalkyl" refers to an alkyl group that is substituted with one or more halogens In some embodiments, the halogens are the same or they are different Non-limiting examples of haloalkyls include - CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)3, and the like
[00370] The terms "fluoroalkyl" and "fluoroalkoxy" mclude alkyl and alkoxy groups, respectively, that are substituted with one or more fluorine atoms Non-hmiung examples of fluoroalkyls mclude -CF3, -CHF2, - CH2F, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CF(CKi)3, and the like Non-hmiting examples of fluoroalkoxy groups, include OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCF2CF3, -OCF2CF2CF3, -OCF(CH3)2, and the like [00371] The term "heteroalkyl" refers to an alkyl radical where one or more skeletal chain atoms is selected from an atom other than carbon, e g , oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof In some embodiments, the heteroatom(s) are placed at any ulterior position of the heteroalkyl group Examples mclude, but are not limited to, -CH2-O-CH3, -CH2-CH2-O-CH3, -CH2-NH-CH3, -CH2-CH2-NH-CH3, -CH2- N(CH3)-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH21-S(O)-CH3, -CH2- CH2-S(O)2-CH3, -CH2-NH-OCH3, -CH,-O-Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3 In some embodiments,, up to two heteroatoms are consecutive, such as, by way of example, -CH2-NH-OCH3 and -CH2- 0-Si(CHj)3 Excluding the number of heteroatoms, a "heteroalkyl" may have from 1 to 6 carbon atoms [00372] The term "bond" or "single bond" refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure [00373] The term "moiety" refers to a specific segment or functional group of a molecule Chemical moieties are often recognized chemical entities embedded in or appended to a molecule
[00374] As used herein, the substituent "R" appealing by itself and without a number designabon refers to a substituent selected from among from alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloalkyl [00375] The term "optionally substituted" or "substituted" means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkyisulfone, arylsulfone, -CN, halo, acyl, acyloxy, -CO2H, -Cθ2-alkyl, nitro, haloalkyl, fluoroalkyl, and amino, including mono- and di-substituted amino groups (e g -NH2, -NHR, -N(R)2), and the protected derivatives thereof By way of example, an optional substituents is L'R*, wherein each V is independently selected from a bond, -O-, -C(Oh -S-, -S(O)-, -S(=O)r, -NH , NHC(O)-, -C(O)NH-, S(=0)2NH-, -NHS(O)2, -OC(O)NH , NHC(O)O-, -(Ci-C6alkyl)-, or -(CrCβalkenyl) , and each R* is independently selected from among H, (C,- Qj-lkyl), (C3-C8cycloalkyl), aryl, heteroaryl, heterocycloalkyl, and Ci-C6heteroalkyl In some embodiments, the protecting groups that form the protective derivatives of the above substituents are found in references such as Greene and Wuts, above
[00376] The methods and formulations described herein include the use of crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds having the structure of Formulas (I), (II), (DI), (IV), (V) and (VI), as well as active metabolites of these compounds having the same type of activity In some situations, compounds exist as tautomers All tautomers are included within the scope of the compounds presented herein In some embodiments,, the compounds described herein exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, εthanol, and the like The solvated forms of the compounds presented herein are also considered to be disclosed herein [00377] The terms "kit' and "article of manufacture" are used as synonyms [00378] The term "subject" or "patient" encompasses mammals and non-mammals Examples of mammals include, but are not limited to, any member of the Mammalian class humans, non-human primates such as chimpanzees, and other apes and monkey species, farm animals such as cattle, horses, sheep, goats, swine, domestic animals such as rabbits, dogs, and cats, laboratory animals including rodents, such as rats, mice and guinea pigs, and the like Examples of non-mammals include, but are not limited to, buds, fish and the like In one embodiment of the methods and compositions provided herein, the mammal is a human
[00379] The terms "treat," "treating" or "treatment," as used herein, include alleviating, abating or ameliorating a disease, disorder or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying causes of symptoms, inhibiting the disease, disorder or condition, e g , arresting the development of the disease, disorder or condition, relieving the disease, disorder or condition, causing regression of the disease, disorder or condition, relieving a condition caused by the disease, disorder or condition, or stopping the symptoms of the disease, disorder or condition either prophylactically and/or therapeutically
[00380] As used herein, the term "target protem" refers to a protein or a portion of a protein capable of being bound by, or interacting with a compound described herein, such as a compound of Formulas (I), (II), (III), (IV), (V) or (VI) In certain embodiments, a target protein is a STIM protein In certain embodiments, a target protem is an Oral protem
[00381] As used herein, "STIM protem" includes but is not limited to, mammalian STIM-I, such as human and rodent (e g , mouse) STIM-I, Drosophila melanogaster D-STIM, C elegans C-STIM, Anopheles gambiae STIM and mammalian ST1M-2, such as human and rodent (e g , mouse) STIM-2 As descnbed herein, such proteins have been identified as being involved in, participating m and/or providing for store-operated calcium entry or modulation thereof, cytoplasmic calcium buffering and/or modulation of calcium levels m or movement of calcium into, within or out of intracellular calcium stores (e g , endoplasmic reticulum) 100382] As used herein, an "Oral protein" includes Orail (SEQ ID NO 1 as described in WO 07/081804), Orai2 (SEQ ID NO 2 as described m WO 07/081804), or Orai3 (SEQ ID NO 3 as described in WO 07/081804) Orail nucleic acid sequence corresponds to GenBaok accession number NM_032790, Orai2 nucleic acid sequence corresponds to GenBank accession number BC069270 and Orai3 nucleic acid sequence corresponds to GenBank accession number NM 152288 As used herein, Oral refers to any one of the Oral genes, e g , Orail , Orai2, Orai3 (see Table I of WO 07/081804) As described herein, such proteins have been identified as being involved in, participating m and/or providing for store-operated calcium entry or modulation thereof, cytoplasmic calcium buffering and/or modulation of calcium levels in or movement of calcium into, within or out of intracellular calcium stores (e g , endoplasmic reticulum)
[00383] The term "fragment" or "derivative" when referring to a protein (e g STIM, Oral) means proteins or polypeptides which retain essentially the same biological function or activity in at least one assay as the native protein(s) For example, the fragments or derivatives of the referenced protein maintains at least about 50% of the activity of the native proteins, at least 75%, at least about 95% of the activity of the native proteins, as determined e g by a calcium influx assay
[00384] As used herein, amelioration of the symptoms of a particular disease, disorder or condition by administration of a particular compound or pharmaceutical composition refers to any lessening of seventy, delay m onset, slowing of progression, or shortening of duration, whether permanent or temporary, lasting or transient that are attributed to or associated with administration of the compound or composition
[00385] The term "modulate," as used herein, means to interact with a target protein either directly or indirectly so as to alter the activity of the target protein, including, by way of example only, to inhibit the activity of the target, or to limit or reduce the activity of the target [00386] As used herein, the term "modulator" refers to a compound that alters an activity of a target For example, in some embodiments, a modulator causes an increase or decrease in the magnitude of a certain activity of a target compared to the magnitude of the activity m the absence of the modulator In certain embodiments, a modulator is an inhibitor, which decreases the magnitude of one or more activities of a target In certain embodiments, an inhibitor completely prevents one or more activities of a target [00387] As used herein, "modulation" with reference to intracellular calcium refers to any alteration or adjustment in intracellular calcium including but not limited to alteration of calcium concentration in the cytoplasm and/or intracellular calcium storage organelles, e g , endoplasmic reticulum, and alteration of the kinetics of calcium fluxes into, out of and within cells In aspect, modulation refers to reduction. [00388] The terms "inhibits", "inhibiting", or "inhibitor" of SOC channel activity or CRAC channel activity, as used herein, refer to inhibition of store operated calcium channel activity or calcium release activated calcium channel activity
[00389] The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated [00390] By "pharmaceutically acceptable," as used herein, refers a material, such as a earner or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i e , the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained [00391] The term "pharmaceutical combination" as used herem, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the 5 active ingredients The term "fixed combination" means that one active ingredient, e g a compound of Formulas (I), (II), (III), (TV), (V) or (VI), and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage The term "non-fixed combination" means that one active ingredient, e g a compound of Formulas (I), (II), (III), (IV), (V) or (VI), and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening tune limits, wherein such0 administration provides effective levels of the two compounds m the body of the patient The latter also applies to cocktail therapy, e g the administration of three or more active ingredients
[00392] The term "pharmaceutical composition" refers to a mixture of a compound of Formulas (I), (II), (III), (TV), (V) or (VI) described herem with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients The pharmaceutical composition S facilitates administration of the compound to an organism Multiple techniques of administering a compound exist in the art including, but not limited to intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and topical administration
[00393] The terms "effective amount" or "therapeutically effective amount," as used herem, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more0 of the symptoms of the disease or condition bemg treated. The result is reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of the composition that includes a compound of Formulas (I), (II), (in), (IV), (V) or (VI) described herem required to provide a clinically significant decrease m disease symptoms In some embodiments, an appropriate "effective" amount in any individual case is determined using5 techniques, such as a dose escalation study
[00394] The terms "enhance" or "enhancing," as used herein, means to increase or prolong either in potency or duration a desired effect Thus, in regard to enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong, either m potency or duration, the effect of other therapeutic agents on a system An "enhancing-effective amount," as used herein, refers to an amount adequate to enhance the effect0 of another therapeutic agent in a desired system
[00395] The terms "co-administration" or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are mtended to include treatment regimens m which the agents are administered by the same or different route of administration or at the same or different time [00396] The term "earner," as used herein, refers to relatively nontoxic chemical compounds or agents that5 facilitate the incorporation of a compound into cells or tissues
[00397] The term "diluent" refers to chemical compounds that are used to dilute the compound of interest prior to delivery In some embodiments, diluents are used to stabilize compounds because they provide a more stable environment Salts dissolved in buffered solutions (which also provide pH control or maintenance) are utilized as diluents, including, but not limited to a phosphate buffered saline solution [00398] A "metabolite" of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound that is formed when the compound is metabolized The term "metabolized," as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism Thus, in some embodiments, enzymes produce specific structural alterations to a compound For example, cytochrome P450 catalyzes a variety of oxidative and reductive reactions while undine diphosphate glucuronyltransrerases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups Further information on metabolism are obtained from The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996) Metabolites of the compounds disclosed herein are identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells m vitro and analysis of the resulting compounds
[00399] "Bioavailability" refers to (he percentage of the weight of the compound disclosed herein (e g compound of Formulas (I), (II), (ET), (TV), (V) or (VT)), mat is delivered into the general circulation of the animal or human being studied The total exposure (AUC(O-∞)) of a drug when administered intravenously is usually defined as 100% bioavailable (F%) "Oral bioavailability" refers to the extent to which a compound disclosed herein, is absorbed into the general circulation when the pharmaceutical composition is taken orally as compared to intravenous injection [00400] "Blood plasma concentration" refers to the concentration of a compound of Formulas Q), (U), (III), (IV), (V) or (VT) disclosed herein, in the plasma component of blood of a subject It is understood that the plasma concentration of compounds described herein may vary significantly between subjects, due to variability with respect to metabolism and/or possible interactions with other therapeutic agents In accordance with one embodiment disclosed herein, the blood plasma concentration of the compounds disclosed herein vanes from subject to subject Likewise, in some embodiments, values such as maximum plasma concentration (C1-11) or tune to reach maximum plasma concentration (T101x), or total area under the plasma concentration time curve (AUC(O-∞)) vanes from subject to subject Due to this variability, the amount necessary to constitute "a therapeutically effective amount" of a compound will vary from subject to subject
[00401] As used herein, "calcium homeostasis" refers to the maintenance of an overall balance in intracellular calcium levels and movements, including calcium signaling, within a cell [00402] As used herein, "intracellular calcium" refers to calcium located m a cell without specification of a particular cellular location In contrast, "cytosolic" or "cytoplasmic" with reference to calcium refers to calcium located m the cell cytoplasm.
[00403] As used herein, an effect on intracellular calcium is any alteration of any aspect of intracellular calcium, including but not limited to, an alteration Ui intracellular calcium levels and location and movement of calcium into, out of or within a cell or intracellular calcium store or organelle For example, in some embodiments, an effect on intracellular calcium is an alteration of the properties, such as, for example, the kinetics, sensitivities, rate, amplitude, and electrophysiological characteristics, of calcium flux or movement that occurs m a cell or portion thereof In some embodiments, an effect on intracellular calcium is an alteration in any intracellular calcium-modulating process, including, store-operated calcium entry, cytosolic calcium buffenng, and calcium levels in or movement of calcium into, out of or within an intracellular calcium store Any of these aspects are assessed in a variety of ways including, but not limited to, evaluation of calcium or other ion (particularly cation) levels, movement of calcium or other ion (particularly cation), fluctuations in calcium or other ion (particularly cation) levels, kinetics of calcium or other ion (particularly cation) fluxes and/or transport of calcium or other ion (particularly cation) through a membrane An alteration is any such S change that is statistically significant Thus, for example, in some embodiments, if intracellular calcium in a test cell and a control cell is said to differ, such differences are a statistically significant difference [00404] As used herein, "involved in" with respect to the relationship between a protein and an aspect of intracellular calcium or intracellular calcium regulation means that when expression or activity of the protein in a cell is reduced, altered or eliminated, there is a concomitant or associated reduction, alteration or elimination0 of one or more aspects of intracellular calcium or intracellular calcium regulation. Such an alteration or reduction in expression or activity can occur by virtue of an alteration of expression of a gene encoding the protein or by altering the levels of the protein A protein involved in an aspect of intracellular calcium, such as, for example, store-operated calcium entry, thus, are one that provides for or participates in an aspect of intracellular calcium or intracellular calcium regulation For example, a protein that provides for store-operated S calcium entry are a STIM protein and/or an Oral protein
[00405] As used herein, a protein that is a component of a calcium channel is a protein that participates in multi-protein complex that forms the channel
[00406] As used herein, "cation entry" or "calcium entry" into a cell refers to entry of cations, such as calcium, into an intracellular location, such as the cytoplasm of a cell or into the lumen of an intracellular0 organelle or storage site Thus, in some embodiments, cation entry is, for example, the movement of cations into the cell cytoplasm from the extracellular medium or from an intracellular organelle or storage site, or the movement of cations into an intracellular organelle or storage site from the cytoplasm or extracellular medium Movement of calcium into the cytoplasm from an intracellular organelle or storage site is also referred to as "calcium release" from the organelle or storage site 5 [00407] As used herein, "protein that modulates intracellular calcium" refers to any cellular protein that is mvolved in regulating, controlling and/or altering intracellular calcium For example, in some embodiments, such a protein is involved in altering or adjusting intracellular calcium m a number of ways, including, but not limited to, through the maintenance of resting or basal cytoplasmic calcium levels, or through involvement in a cellular response to a signal that is transmitted in a cell through a mechanism that includes a deviation m0 intracellular calcium from resting or basal states In the context of a "protein that modulates intracellular calcium," a "cellular" protein is one that is associated with a cell, such as, for example, a cytoplasmic protein, a plasma membrane-associated protein or an intracellular membrane protein Proteins that modulate intracellular calcium include, but are not limited to, ion transport proteins, calcium-binding proteins and regulatory proteins that regulate ion transport proteins 5 [00408] As used herein, "amelioration" refers to an improvement m a disease or condition or at least a partial relief of symptoms associated with a disease or condition
[00409] As used herein, "cell response" refers to any cellular response that results from ion movement into or out of a cell or within a cell In some embodiments, the cell response is associated with any cellular activity that is dependent, at least in part, on ions such as, for example, calcium. Such activities may include, for example,0 cellular activation, gene expression, endocytosis. exocytosis, cellular trafficking and apoptotic cell death [004101 As used herein, "immune cells" include cells of the immune system and cells that perform a function or activity in an immune response, such as, but not limited to, T-cells, B-cells, lymphocytes, macrophages, dendritic cells, neutrophils, eosinophils, basophils, mast cells, plasma cells, white blood cells, antigen presenting cells and natural killer cells [00411] As used herein, 'cytokine" refers to small soluble protems secreted by cells that in some embodiments, alter the behavior or properties of the secreting cell or another cell Cytokines bmd to cytokine receptors and trigger a behavior or property within the cell, for example, cell proliferation, death or differentiation Exemplary cytokines include, but are not limited to, interleukins (e g , lL-2, lL-3, IL-4, 1L-5, IL- 6, IL-7, IL-8, IL-9, IL-10, IL-Il, IL-12, IL-13, IL-15, IL-16, IL-17, IL-18, IL-lα, IL-lβ, and IL-I RA), granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), oncostabn M, erythropoietin, leukemia inhibitory factor (LIF), interferons, B7 1 (also known as CD80), B72 (also known as B70, CD86), TNF family members (TNF-α, TNF-β, LT-β, CD40 ligand, Fas ligand, CD27 ligand, CD30 ligand, 4-1BBL, Trail), and MIF [00412] "Store operated calcium entry" or "SOCE" refers to the mechanism by which release of calcium ions from intracellular stores is coordinated with ion influx across the plasma membrane
[00413] "Selective inhibitor of SOC channel activity" means that the inhibitor is selective for SOC channels and does not substantially affect the activity of other types of ion channels
[00414] "Selective inhibitor of CRAC channel activity" means that the inhibitor is selective for CRAC channels and does not substantially affect the activity of other types of ion channels and/or other SOC channels Examples of Pharmaceutical Compositions and Methods of Administration
[00415] Pharmaceutical compositions are formulated m a conventional manner using one or more physiologically acceptable earners including excipients and auxiliaries which facilitate processing of the active compounds into preparations which are used pharmaceutically Proper formulation is dependent upon the route of administration chosen. In some embodiments, any of the well-known techniques, carriers, and excipients are used as suitable In some embodiments, a summary of pharmaceutical compositions described herein are found, for example, in Remington The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa Mack Publishing Company, 1995), Hoover, John E , Remington's Pharmaceutical Sciences, Mack Publishing Co , Easton, Pennsylvania 1975, Liberman, H A. and Lachman, L , Eds , Pharmaceutical Dosage Forms, Marcel Decker, New York, N Y , 1980, and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed (Lippincott Williams & Wukmsl999), the pharmaceutical compositions described in the above publications are herein incorporated by reference
[00416] A pharmaceutical composition, as used herein, refers to a mixture of a compound of Formulas (I), (II), (IE), (TV), (V) or (VI) described herein, with other chemical components, such as earners, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients The pharmaceutical composition facilitates administration of the compound to an organism In practicing the methods of treatment or use provided herein, therapeutically effective amounts of compounds described herein are administered in a pharmaceutical composition to a mammal having a disease, disorder, or condition to be treated In some embodiments, the mammal is a human In some embodiments, a therapeutically effective amount vanes widely depending on the seventy of the disease, the age and relative health of the subject, the potency of the compound used and other factors In some embodiments, the compounds of Formulas (I), (II), (III), (TV), (V) and (VI) are used singly or in combination with one or more therapeutic agents as components of mixtures (as m combination therapy)
[00417] In further embodiments, the pharmaceutical formulations described herein are administered to a subject by multiple administration routes, including but not limited to, oral, parenteral (e g , intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes Moreover, in some embodiments, the pharmaceutical compositions described herein, which include a compound of Formulas (I), (II), (III), (IV), (V) or (VI) described herein, are formulated into any suitable dosage form, including but not limited to, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, aerosols, controlled release formulations, fast melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations
[00418] In some embodiments, the compounds and/or compositions are administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ or tissue, often m a depot preparation or sustained release formulation In other embodiments, such long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection Furthermore, in some embodiments, the drug is administered in a targeted drug delivery system, for example, in a liposome coated with organ-specific antibody The liposomes will be targeted to and taken up selectively by the organ. In some embodiments, the drug is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
[00419] In some embodiments, pharmaceutical compositions including a compound described herein is manufactured m a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes [00420] The pharmaceutical compositions will include at least one compound of Formulas (I), (II), (III), (TV), (V) or (VI) described herein, as an active ingredient in free-acid or free-base form, or in a pharmaceutically acceptable salt form. In addition, the methods and pharmaceutical compositions described herein include the use of crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity [00421] In certain embodiments, compositions provided herem also mclude one or more preservatives to inhibit microbial activity Suitable preservatives mclude quaternary ammonium compounds such as benzalkomum chloride, cetyltπmethylammonium bromide and cetylpyπdimum chloride [00422] In some embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein (e g compounds of Formulas (I), (II), (III), (IV), (V) and (VI)), optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets, pills, or capsules Suitable excipients mclude, for example, fillers such as sugars, including lactose, sucrose, mamutol, or sorbitol, cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystallme cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate In other embodiments,, disintegrating agents are added, such as die cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or algiruc acid or a salt thereof such as sodium alginate
[00423] Dragee cores are provided with suitable coatings For this purpose, in some embodiments, concentrated sugar solutions are used, which optionally contain gum arable, talc, polyvinylpyrrolidone, carbopol 5 gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures In some embodiments, dyestuffs or pigments are added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses
[00424] In further embodiments, pharmaceutical preparations that are used orally include push fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol Ih0 some embodiments, he push-fit capsules contain the active ingredients m admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers In some embodiments, are soft capsules, wherein the active compounds are dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols In some embodiments,, stabilizers are added S [00425] In some embodiments, the solid dosage forms disclosed herein are in the form of a tablet, (including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid-disintegration tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder), a capsule (including both soft or hard capsules, e g , capsules made from ammal-denved gelatin or plant-denved HPMC, or "sprinkle capsules"), solid dispersion, solid solution, bioerodible dosage0 form, controlled release formulations, pulsatile release dosage forms, multiparticulate dosage forms, pellets, granules, or an aerosol. In other embodiments, the pharmaceutical formulation is in the form of a powder In still other embodiments, the pharmaceutical formulation is in the form of a tablet, including but not limited to, a fast- melt tablet Additionally, pharmaceutical formulations of the compounds described herein are administered as a single capsule or m multiple capsule dosage form In some embodiments, the pharmaceutical formulation is5 administered m two, or three, or four, capsules or tablets
[00426] In some embodiments, solid dosage forms, e g , tablets, effervescent tablets, and capsules, are prepared by mixing particles of a compound of Formulas (I), (II), (III), (IV), (V) or (VI) described herein, with one or more pharmaceutical excipients to form a bulk blend composition When referring to these bulk blend compositions as homogeneous, it is meant that the particles of the compound of Formulas (I), (IT), (1C), (IV),0 (V) or (VI) described herein, are dispersed evenly throughout the composition so that the composition are readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules In some embodiments, the individual unit dosages also mclude film coatings, which disintegrate upon oral ingestion or upon contact with diluent In further embodiments, these formulations are manufactured by conventional pharmacological techniques 5 [00427] In some embodiments, the pharmaceutical solid dosage forms described herein include a compound of Formulas (I), (U), (III), (IV), (V) or (VI) described herein, and one or more pharmaceutically acceptable additives such as a compatible earner, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant, diluent, solubdizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one0 or more combination thereof In still other embodiments, usmg standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000), a film coating is provided around the formulation of the compound described herein In one embodiment, some or all of the particles of the compound described herein are coated In another embodiment, some or all of the particles of the compound described herein are microencapsulated In still another embodiment, the particles of the compound described herein are not microencapsulated and are uncoated
[00428] Suitable carriers for use in the solid dosage forms described herein include, but are not limited to, acacia gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextπn, glycerine, magnesium silicate, sodium casemate, soy lecithin, sodium chloride, rπcalcram phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceπde, diglycende, pregelaunized starch, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol and the like
[00429] Suitable filling agents for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatmized starch, hydroxypropylmethycellulose (HPMC), hyάroxypropylmemycellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lacntol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like
[00430] In order to release the compound of Formulas (I), (II), (III), (IV), (V) or (VI) from a solid dosage form matrix as efficiently as possible, disintegrants are often used in the formulation, especially when the dosage forms are compressed with binder Disintegrants help rupturing the dosage form matrix by swelling or capillary action when moisture is absorbed into the dosage form Suitable disintegrants for use in the solid dosage forms described herein include, but are not limited to, natural starch such as com starch or potato starch, a pregelatmized starch such as National 1551 or Amijelβ, or sodium starch glycolate such as Promogel® or Explotab®, a cellulose such as a wood product, methylcrystalline cellulose, e g , Avicel", Avicel* PHlOl, Avicel® PH102, Avicel" PH105, Elcema® PlOO, Emcocel® Vivacef, Ming Tiaφ, and Solka-Floc®, methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol®), cross-linked carboxymethylcellulose, or cross-linked croscarmellose, a cross-bilked starch such as sodium starch glycolate, a cross-linked polymer such as crospovidone, a cross-linked polyvinylpyrrolidone, alginate such as alginic acid or a salt of alguuc acid such as sodium alginate, a clay such as Veegum* HV (magnesium aluminum silicate), a gum such as agar, guar, locust bean, Karaya, pectin, or tragacanth, sodium starch glycolate, bentomte, a natural sponge, a surfactant, a resin such as a cation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate m combination starch, and the like [00431] Binders impart cohesiveness to solid oral dosage form formulations for powder filled capsule formulation, they aid in plug formation that m some embodiments, are filled mto soft or hard shell capsules and for tablet formulation, they ensure the tablet remaining intact after compression and help assure blend uniformity prior to a compression or fill step Materials suitable for use as binders in the solid dosage forms described herein mclude, but are not limited to, carboxymethylcellulose, methylcellulose (e g , Methocel®), hydroxypropylmethylcellulose (e g Hypromellose USP Pharmacoat-603, hydroxypropylmethylcellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethylcellulose, hydroxypropylcelhilose (e g , Klucel®), ethylcellulose (e g , Ethocel®), and microcrystalline cellulose (e g , Avicel®), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonites, gelatin, polyvinylpyrrohdone/vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextπn, a sugar, such as sucrose (e g , Dipac®), glucose, dextrose, molasses, lnanmtol, sorbitol, xylitol (e g , Xylitab®), lactose, a natural or synthetic gum such as acacia, tragacanth, ghatti gum, mucilage of isapol husks, starch, polyvinylpyrrolidone (e g , Povidone® CL, Kollidon® CL, Polyplasdone® XL-IO, and Povidone® K-12), larch arabogalactan, Veegum®, polyethylene glycol, waxes, sodium alginate, and the like
[00432] In general, binder levels of about 20to about 70% are used in powder-filled gelatin capsule formulations In some embodiments, binder usage level in tablet formulations vanes whether direct compression, wet granulation, roller compaction, or usage of other excipients such as fillers which itself act as moderate binder In some embodiments, are tablet formulations comprising binder usage levels of up to about 70%
[00433] Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, com starch, sodium stearyl ftimcratc, alkali-metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zmc, steaπc acid, sodium stearates, magnesium stearate, zinc stearate, waxes, Stearowet®, bone acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol or a methoxypolyethylene glycol such as CaIbOWaX111, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate, and the like [00434] Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextπns and the like
[00435] Suitable wetting agents for use m the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, tnethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e g , Polyquat 10s), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, tπacetin, vitamin E TPGS and the like
[00436] Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e g , Phironic® (BASF), and the like [00437] Suitable suspending agents for use m the solid dosage forms described here include, but are not limited to, polyvinylpyrrolidone, e g , polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol, e g , in some embodiments, the polyethylene glycol has a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 5400 to about 7000, vinyl pyrrohdone/vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxy-propyhnethylcellulose, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as, e g , gum tragacanth and gum acacia, guar gum, xanthans, including xanthan gum, sugars, cellulosics, such as, e g , sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropyhnethylcellulose, hydroxyethylcellulose, ρolysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone and the like [00438] Suitable antioxidants for use in the solid dosage forms described herein include, for example, e g , butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol
[00439] It should be appreciated that there is considerable overlap between additives used in the solid dosage forms described herein Thus, the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that are included in solid dosage forms of the pharmaceutical compositions described herein
[00440] In other embodiments, one or more layers of the pharmaceutical formulation are plasncized Illustratively, a plastcizer is generally a high boiling point solid or liquid In some embodiments, suitable plasncizers are added from about 0 01% to about 50% by weight (w/w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycendes, tπacetin, polypropylene glycol, polyethylene glycol, tnethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil
[00441] Compressed tablets are solid dosage forms prepared by compacting the bulk blend of the formulations described above In various embodiments, compressed tablets which are designed to dissolve in the mouth will include one or more flavoring agents In other embodiments, the compressed tablets will include a film surrounding the final compressed tablet In some embodiments, the film coating provides a delayed release of the compounds of Formulas (I), (S), (Ul), (TV), (V) or (VI) described herein from the formulation In other embodiments, the film coating aids in patient compliance (e g , Opadry" coatings or sugar coating) Film coatings including Opadry® typically range from about 1% to about 3% of the tablet weight In other embodiments, the compressed tablets include one or more excipients
[00442] In some embodiments, a capsule is prepared, for example, by placing the bulk blend of the formulation of the compound described above, inside of a capsule In some embodiments, the formulations (non-aqueous suspensions and solutions) are placed in a soft gelatin capsule In other embodiments, the formulations are placed in standard gelatin capsules or non-gelatin capsules such as capsules comprising HPMC In other embodiments, the formulation is placed in a sprinkle capsule, wherein the capsule is swallowed whole or the capsule is opened and the contents sprinkled on food prior to eating In some embodiments, the therapeutic dose is split into multiple (e g , two, three, or four) capsules In some embodiments, the entire dose of the formulation is delivered in a capsule form [00443] In various embodiments, the particles of the compound of Formulas (I), (II), (TII), (IV), (V) or (VI) described herein and one or more excipients are dry blended and compressed into a mass, such as a tablet, having a hardness sufficient to provide a pharmaceutical composition that substantially disintegrates within less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes, after oral administration, thereby releasing the formulation into the gastrointestinal fluid [00444] In another formulation, dosage forms include microencapsulated formulations In some embodiments, one or more other compatible materials are present m the microencapsulation material Exemplary materials include, but are not limited to, pH modifiers, erosion facilitators, ana-foaming agents, antioxidants, flavoring agents, and earner materials such as binders, suspending agents, disintegration agents, filling agents, surfactants, solubilrzers, stabilizers, lubricants, wetting agents, and diluents [00445] Materials useful for the microencapsulation described herein include materials compatible with compounds described herein, which sufficiently isolate the compound from other non-compatible excipients Materials compatible with compounds of Formulas (I), (II), (III), (IV), (V) and (VI) described herein are (hose that delay the release of the compounds of Formulas (I), (II), (III), (IV), (V) and (VI) m vivo [00446] Exemplary microencapsulation materials useful for delaying the release of the formulations including compounds described herein, include, but are not limited to, hydroxypropyl cellulose ethers (HFC) such as Klucel® or Nisso HPC, low-substituted hydroxypropyl cellulose ethers (L-HPC), hydroxypropyl methyl cellulose ethers (HPMC) such as Seppifilm-LC, Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PπmaFlo, Benecel MP824, and Benecel MP843, methylcellulose polymers such as Methocelβ-A, hydroxypropymiethylcellulose acetate stearate Aqoat (HF-LS, HF-LG.HF-MS) and Metolose®, Ethylcelluloses (EC) and mixtures thereof such as E461, Ethocel® Aqualonφ-EC, Surelease®, Polyvinyl alcohol (PVA) such as Opadry AMB, hydroxyethylcelluloses such as Natrosole, carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) such as Aqualonφ-CMC, polyvinyl alcohol and polyethylene glycol copolymers such as Kolhcoat IR9, monoglyceπdes (Myvcrol), tπglycendes (KLX), polyethylene glycols, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers such as Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 3OD Eudragit® L100-55, Eudragit*1 LlOO, Eudragit® SlOO, Eudragit® RDlOO, Eudragit® ElOO, Eudragit® L12 5, Eudragit® S12 5, Eudragit® NE30D, and Eudragit® NE 4OD, cellulose acetate phthalate, sepifilms such as mixtures of HPMC and stearic acid, cyclodextπns, and mixtures of these materials [00447] In still other embodiments, plasticizers such as polyethylene glycols, e g , PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, and tπacctin are incorporated into (he microencapsulation material In other embodiments, the microencapsulating material useful for delaying the release of the pharmaceutical compositions is from the USP or the National Formulary (NF) In yet other embodiments, the microencapsulation material is Klucel In still other embodiments, the microencapsulation material is methocel
[00448] Microencapsulated compounds of Formulas (I), (H), (IH), (IV), (V) and (VI) described herein are formulated by methods which in some embodiments, include, e g , spray drying processes, spinning disk-solvent processes, hot melt processes, spray chilling methods, fluidized bed, electrostatic deposition, centrifugal extrusion, rotational suspension separation, polymerization at hquid-gas or solid-gas interface, pressure extrusion, or spraymg solvent extraction bath In addition to these, in some other embodiments, several chemical techniques, e g , complex coacervaUon, solvent evaporation, polymer-polymer incompatibility, interfacial polymerization in liquid media, in situ polymerization, m-liquid drying, and desolvation in liquid media are used Furthermore, m other embodiments, other methods such as roller compaction, extrosion/spheromzation, coacervation, or nanoparucle coating also are used [00449] In still other embodiments, effervescent powders are also prepared m accordance with the present disclosure Effervescent salts have been used to disperse medicines in water for oral administration. Effervescent salts are granules or coarse powders containing a medicinal agent in a dry mixture, usually composed of sodium bicarbonate, citnc acid and/or tartaric acid When such salts are added to water, the acids and the base react to liberate carbon dioxide gas, thereby causing "effervescence " Examples of effervescent salts include, e g , the following ingredients sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, citnc acid and/or tartaric acid Any acid-base combination that results in the liberation of carbon dioxide are used in place of the combination of sodium bicarbonate and citnc and tartaric acids, as long as the ingredients were suitable for pharmaceutical use and result in a pH of about 6 0 or higher [00450] In other embodiments, the formulations described herein, which include a compound described S herein, are solid dispersions In still other embodiments, the formulations described herein are solid solutions Solid solutions incorporate a substance together with the active agent and other excrpients such that heating the mixture results in dissolution of the drug and the resulting composition is then cooled to provide a solid blend which is further formulated or directly added to a capsule or compressed into a tablet [00451] The pharmaceutical solid oral dosage forms including formulations described herein, which include a0 compound of Formulas (T), (U), (in), (IV), (V) or (VI) described herein, are further formulated to provide a controlled release of the compound of Formulas (I), (II), (JS), (W), (V) or (VI) Controlled release refers to the release of the compound of Formulas (I), (II), (HI), (IV), (V) or (VI) described herein from a dosage form in which it is incorporated according to a desired profile over an extended period of tune Controlled release profiles include, for example, sustained release, prolonged release, pulsatile release, and delayed release S profiles In contrast to immediate release compositions, controlled release compositions allow delivery of an agent to a subject over an extended period of time according to a predetermined profile In some embodiments, such release rates provide therapeutically effective levels of agent for an extended period of tune and thereby provide a longer period of pharmacologic response while minimizing side effects as compared to conventional rapid release dosage forms Such longer periods of response provide for many inherent benefits that are not0 achieved with the corresponding short acting, immediate release preparations
[00452] In some embodiments, the solid dosage forms described herein are formulated as enteric coated delayed release oral dosage forms, i e , as an oral dosage form of a pharmaceutical composition as described herem which utilizes an enteπc coating to affect release m the small intestine of the gastrointestinal tract In further embodiments, the enteric coated dosage form is a compressed or molded or extruded tablet/mold (coated5 or uncoated) containing granules, powder, pellets, beads or particles of the active ingredient and/or other composition components, which are themselves coated or uncoated In other embodiments, the enteric coated oral dosage form is also a capsule (coated or uncoated) containing pellets, beads or granules of the solid carrier or the composition, which are themselves coated or uncoated [00453] The term "delayed release" as used herein refers to the delivery so that the release is accomplished at0 some generally predictable location in the intestinal tract more distal to that which would have been accomplished if there had been no delayed release alterations In some embodiments the method for delay of release is a coating Any coatings should be applied to a sufficient thickness such that the enure coating does not dissolve in the gastrointestinal fluids at pH below about S, but does dissolve at pH about S and above In some embodiments, coatings are made from 5 [00454] Acrylic polymers In some embodiments, the performance of acrylic polymers (primarily their solubility in biological fluids) vary based on the degree and type of substitution Examples of suitable acrylic polymers include methacryhc acid copolymers and ammonium methacrylate copolymers The Eudragit series E, L, S, RL, RS and NE (Rohm Pharma) are available as solubihzed in organic solvent, aqueous dispersion, or dry powders The Eudragit seπes RL, NE, and RS are insoluble in the gastrointestinal tract but are permeable and are used primarily for colonic targeting The Eudragit series E dissolve in the stomach The Eudragit series L, T - 3OD and S are insoluble m stomach and dissolve in the intestine,
[00455] Cellulose Derivatives Examples of suitable cellulose derivatives are ethyl cellulose, reaction mixtures of partial acetate esters of cellulose with phthalic anhydride In other embodiments, the performance varies based on the degree and type of substitution Cellulose acetate phfhalate (CAP) dissolves m pH > about 6 Aquatenc (FMC) is an aqueous based system and is a spray dried CAP pseudolatex with particles <1 μm In other embodiments, other components m Aquatenc include pluronics, Tweens, and acetylated monoglycendes Other suitable cellulose derivatives include cellulose acetate tnmellitate (Eastman), methylcellulose (Phaπnacoat, Methocel), hydroxypropylmethyl cellulose phthalate (HPMCP), hydroxypropylmethyl celhilose succinate (HPMCS), and hydroxypropyknethylcellulose acetate succinate (e g , AQOAT (Shin Etsu)) In further embodiments, the performance vanes based on the degree and type of substitution. For example, HPMCP such as, HP-50, HP-55, HP-55S, HP-55F grades are suitable In other embodiments, the performance vanes based on the degree and type of substitution For example, suitable grades of hydroxypropylmethylcellulose acetate succinate include, but are not limited to, AS LG (LF), which dissolves at pH about 5, AS-MG (MF), which dissolves at pH about S S, and AS-HG (HF), which dissolves at higher pH These polymers are offered as granules, or as fine powders for aqueous dispersions,
[00456] Poly Vinyl Acetate Phthalate (PVAP) PVAP dissolves in pH > about 5, and it is much less permeable to water vapor and gastric fluids [00457] In some embodiments, the coating contains a plasticizcr and possibly other coating excipients such as colorants, talc, and/or magnesium stearate Suitable plasticizers include tnethyl citrate (Citroflex 2), tπacetin (glyceryl triacetate), acetyl tnethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycendes, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate In some embodiments, anionic carboxyhc acrylic polymers contain about 10 to about 25% by weight of a plasucizer, especially dibutyl phthalate, polyethylene glycol, tnethyl citrate and tnacetm Conventional coating techniques such as spray or pan coating are employed to apply coatings The coating thickness must be sufficient to ensure that the oral dosage form remains intact until the desired site of topical delivery in the intestinal tract is reached
[00458] In some embodiments, colorants, detackifiers, surfactants, antifoaming agents, lubricants (e g , carnuba wax or PEG) are added to the coatings besides plasticizers to solubihze or disperse the coating material, and to improve coating performance and the coated product
[00459] In other embodiments, the formulations descnbed herein, which include a compound of Formulas (I), (C), (in), (IV), (V) or (VI) descnbed herein, are delivered using a pulsatile dosage form. A pulsatile dosage form is capable of providing one or more immediate release pulses at predetermined time points after a controlled lag tune or at specific sites In further embodiments, pulsatile dosage forms are administered usmg a variety of pulsatile formulations
[00460] Examples of such delivery systems include, e g , polymer-based systems, such as polylactic and polyglycolic acid, polyanhydndes and polycaprolactone, porous matrices, nonpolymer-based systems that are lipids, including sterols, such as cholesterol, cholesterol esters and tatty acids, or neutral fats, such as mono-, di- and tπglycendes, hydrogel release systems, silastic systems, peptide-based systems, wax coatings, bioerodible dosage forms, compressed tablets using conventional binders and the like [00461] In some embodiments, pharmaceutical formulations are provided that include particles of the compounds described herein, e g compounds of Formulas (I), (H), (HI), (IV), (V) and (VI), and at least one dispersing agent or suspending agent for oral administration to a subject In some embodiments, the formulations are a powder and/or granules for suspension, and upon admixture with water, a substantially 5 uniform suspension is obtained
[00462] In some embodiments, liquid formulation dosage forms for oral administration are aqueous suspensions selected from the group including, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups [00463] In other embodiments, the aqueous suspensions and dispersions described herein remain m a
10 homogenous state, as defined in The USP Pharmacists' Pharmacopeia (200S edition, chapter 905), for at least 4 hours The homogeneity should be determined by a sampling method consistent with regard to determining homogeneity of the entire composition In one embodiment, an aqueous suspension is re-suspended into a homogenous suspension by physical agitation lasting less than about 1 minute In another embodiment, an aqueous suspension is re-suspended into a homogenous suspension by physical agitation lasting less than about
15 45 seconds In yet another embodiment, an aqueous suspension is re-suspended into a homogenous suspension by physical agitation lasting less than about 30 seconds In still another embodiment, no agitation is necessary to maintain a homogeneous aqueous dispersion. [00464] [00465] In some embodiments, the pharmaceutical formulations described herein are self-emulsifying drug
20 delivery systems (SEDDS) Emulsions are dispersions of one immiscible phase in another, usually in the form of droplets Generally, emulsions are created by vigorous mechanical dispersion. SEDDS, as opposed to emulsions or microemulsions, spontaneously form emulsions when added to an excess of water without any external mechanical dispersion or agitation An advantage of SEDDS is that only gentle mixing is required to distribute fhe droplets throughout the solution. Additionally, in other embodiments, water or the aqueous phase
25 is added just prior to administration, which ensures stability of an unstable or hydrophobic active ingredient Thus, the SEDDS provides an effective delivery system for oral and parenteral delivery of hydrophobic active ingredients In further embodiments, SEDDS provides improvements in the bioavailability of hydrophobic active ingredients [00466] It is to be appreciated that there is overlap between the above-listed additives used m the aqueous
30 dispersions or suspensions described herein, since a given additive is often classified differently by different practitioners m the field, or is commonly used for any of several different functions Thus, in other embodiments, the above-listed additives are taken as merely exemplary, and not limiting, of the types of additives that are included in formulations described herein [00467] In some embodiments, formulations that include a compound described herein, are prepared
35 according to these and other techniques are prepared as solutions m saline, employing benzyl alcohol or other suitable preservatives, fluorocarbons, and/or other solubilizrng or dispersing agents In other embodiments, are compositions and formulations prepared with suitable nontoxic pharmaceutically acceptable ingredients In farther embodiments, these ingredients are found m REMINGTON THE SCIENCE AND PRACTICE OF PHARMACY, 21st edition, 2005 The choice of suitable earners is highly dependent upon the exact nature of
40 the nasal dosage form desired, e g , solutions, suspensions, ointments, or gels Nasal dosage forms generally contain large amounts of water in addition to the active ingredient Minor amounts of other ingredients such as pH adjusters, emulsiflers or dispersing agents, preservatives, surfactants, gelling agents, or buffering and other stabilizing and solubilrzing agents may also be present In other embodiments, the nasal dosage form is isotonic with nasal secretions [00468] In some embodiments, for administration by inhalation, the compounds described herein are in a form as an aerosol, a mist or a powder Pharmaceutical compositions described herein are conveniently delivered m the form of an aerosol spray presentation from pressurized packs or a nebuhser, with the use of a suitable propellent, e g , dichlorodifluoromethane, tnchlorofhioromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas In further embodiments, are pressurized aerosols, wherein the dosage unit is determined by providing a valve to deliver a metered amount Capsules and cartridges of, such as, by way of example only, gelatin for use m an inhaler or insufflator are formulated containing a powder mix of the compound described herein and a suitable powder base such as lactose or starch. [00469] In other embodiments, are buccal formulations that include compounds described herein are administered using a variety of formulations In some embodiments, the buccal dosage forms described herein further include a bioerodible (hydrolysable) polymeric earner that also serves to adhere the dosage form to the buccal mucosa The buccal dosage form is fabricated so as to erode gradually over a predetermined time period, wherem the delivery of the compound is provided essentially throughout Buccal drug delivery, avoids the disadvantages encountered with oral drug administration, e g , slow absorption, degradation of the active agent by fluids present in the gastrointestinal tract and/or first-pass lnactivation in the liver With regard to the bioerodible (hydrolysable) polymeric carrier, it will be appreciated that virtually any such earner is used, so long as the desired drug release profile is not compromised, and the carrier is compatible with the compound of Formulas (I), (II), (III), (IV), (V) or (VI) described herein, and any other components that are present m the buccal dosage unit Generally, the polymeric carrier comprises hydrophilic (water-soluble and water-swellable) polymers that adhere to the wet surface of the buccal mucosa Examples of polymeric carriers useful herein include acrylic acid polymers and co, e g , those known as "carbomers" (Carbopol®, which are obtained from BJ5 Goodnch, is one such polymer) In further embodiments are components incorporated into the buccal dosage forms described herein mclude, but are not limited to, disintegrants, diluents, binders, lubricants, flavoring, colorants, preservatives, and the like In yet further embodiments, are buccal or sublingual administration, wherem the compositions take the form of tablets, lozenges, or gels formulated in a conventional manner
[00470] In further embodiments, are transdermal formulations described herein administered using a variety of devices
[00471J In other embodiments the transdermal dosage forms described herein incorporate certain pharmaceutically acceptable excipients In one embodiment, the transdermal formulations described herein include at least three components (1) a formulation of a compound of Formulas (I), (II), (HI), (IV), (V) or (VI), (2) a penetration enhancer, and (3) an aqueous adjuvant In addition, transdermal formulations mclude additional components such as, but not limited to, gelling agents, creams and ointment bases, and the like In some embodiments, the transdermal formulation further includes a woven or non-woven backing material to enhance absorption and prevent the removal of the transdermal formulation from the skin In other embodiments, the transdermal formulations described herein maintains a saturated or supersaturated state to promote diffusion into the skin
[00472] In other embodiments, formulations suitable for transdermal administration of compounds described herein employ transdermal delivery devices and transdermal delivery patches and are lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive Such patches are constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents Still further, in some embodiments, transdermal delivery of the compounds described herein are accomplished by means of iontophorebc patches and the like Additionally, in other embodiments, transdermal patches provide controlled delivery of the compound of Formulas (I), (K), (HI), (IV), (V) or (VI) described herein. In further embodiments, the rate of absorption is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel Conversely, in yet further embodiments, absorption enhancers are used to increase absorption An absorption enhancer or earner includes absorbable pharmaceutically acceptable solvents to assist passage through the skin. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with earners, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged penod of tune, and means to secure the device to the skin
100473] In further embodiments, formulations suitable for intramuscular, subcutaneous, or intravenous injection include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution mto sterile injectable solutions or dispersions Examples of suitable aqueous and non-aqueous earners, diluents, solvents, or vehicles including water, ethanol, polyols
(propyleneglycol, polyethylene-glycol, glycerol, cremophor and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate In some embodiments, proper fluidity is maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants In further embodiments, formulations suitable for subcutaneous injection also contain additives such as preserving, wetting, emulsifying, and dispensing agents Prevention of the growth of microorganisms is ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like Prolonged absorption of the injectable pharmaceutical form are brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin. [00474] In some embodiments, are intravenous injections, compounds formulated in aqueous solutions, in some embodiments, in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer For transmucosal administration, penetrants appropriate to the barrier to be permeated are used m the formulation For other parenteral injections, appropriate formulations may include aqueous or nonaqueous solutions, in other embodiments, with physiologically compatible buffers or excipients [00475] In some embodiments, parenteral injections mvolve bolus injection or continuous infusion In other embodiments, formulations for injection are presented m unit dosage form, e g , in ampoules or in multi-dose containers, with an added preservative In some embodiments, the pharmaceutical compositions described herein are in a form suitable for parenteral injection as a sterile suspensions, solutions or emulsions m oily or aqueous vehicles, and contain formulatory agents such as suspending, stabilizing and/or dispersing agents Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds m water-soluble form. Additionally, in other embodiments, suspensions of the active compounds are prepared as appropriate oily injection suspensions Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes In further embodiments, aqueous injection suspensions contain substances which increase the viscosity of die suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran In some embodiments, the suspension also contains suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions In other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, e g , sterile pyrogen-free water, before use [00476] In certain embodiments, delivery systems for pharmaceutical compounds are employed, such as, for example, liposomes and emulsions In certain embodiments, compositions provided herein can also include an mucoadhesive polymer, selected from among, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), polymethylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran [00477] In some embodiments, the compounds described herem are administered topically and are formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments Such pharmaceutical compounds contain for example, solubihzers, stabilizers, tonicity enhancing agents, buffers and preservatives
[00478] In some embodiments, the compounds described herem are also formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycendes, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like In suppository forms of the compositions, a low- melting wax such as, but not limited to, a mixture of fatty acid glycendes, optionally m combination with cocoa butter is first melted [00479] Generally, an agent, such as a compound of Formulas (I), (II), (IH), (TV), (V) or (VI), is administered man amount effective for amelioration of, or prevention of the development of symptoms of, the disease, condition or disorder (i e , a therapeutically effective amount) Thus, m some embodiments, a therapeutically effective amount is an amount that is capable of at least partially preventing or reversing a disease, condition or disorder In other embodiments, the dose required to obtain an effective amount varies depending on the agent, formulation, disease, condition or disorder, and individual to whom the agent is administered. [00480] In other embodiments, determination of effective amounts also involves in vitro assays in which varying doses of agent are administered to cells in culture and the concentration of agent effective for ameliorating some or all symptoms is determined m order to calculate the concentration required m vtvo Effective amounts are also based on in vivo animal studies [00481] In other embodiments, an agent is administered prior to, concurrently with and subsequent to the appearance of symptoms of a disease, condition or disorder In some embodiments, an agent is administered to a subject with a family history of the disease, condition or disorder, or who has a phenotype that indicates a predisposition to a disease, condition or disorder, or who has a genotype which predisposes the subject to the disease, condition or disorder [00482] In some embodiments, the particular delivery system used depends on a number of factors, including, for example, the intended target and the route of administration, e g , local or systemic Targets for delivery are specific cells which are causing or contributing to a disease, condition or disorder, including, for example, cells that have altered intracellular calcium or calcium deregulation or dyshomeostasis, and cells that do not have altered intracellular calcium but that in some embodiments, have some alteration, defect or deficiency mat is, at least in part, compensated, counteracted, reversed or alleviated or eliminated by altering intracellular calcium of the cell Particular cells include, for example, immune cells (e g , lymphocytes, T cells, B cells, white blood cells), fibroblasts (or cells deπved from a fibroblast), epidermal, dermal or skin cells (e g , a keratuiocytes), blood cells, kidney or renal cells (e g , mesangial cells), muscle cells (e g , a smooth muscle cell such as an airway (tracheal or bronchial) smooth muscle cell) and exocrine or secretory (e g , salivary, including parotid acinar and submandibular gland) cells For example, m some embodiments, a target cell is a resident or infiltrating cells m the lungs or airways that contribute to an asthmatic illness or disease, resident or infiltrating cells m the nervous system contributing to a neurological, neurodegenerative or demyelinating disease, condition or disorder, resident or infiltrating cells involved in rejection of a kidney graft, grafted cells that when activated lead to graft-versus-host disease, resident or infiltrating cells involved in rejection of a kidney graft, resident or infiltrating cells, activation of which contributes to inflammation, e g , in arthritis, resident or infiltrating cells m the kidney or renal system (e g , mesangial cells) involved in neuropathy and glomerulonephritis and resident or infiltrating cells m exocrine glands (e g , salivary and lacrimal glands) involved in autoimmune disorders (e g , Sjogren's disease) In some embodiments, an agent is coupled to an antibody, ligand to a cell surface receptor or a toxin, or is contained in a particle that is selectively internalized into cells, e g , liposomes or a virus in which the viral receptor binds specifically to a certain cell type, or a viral particle lacking the viral nucleic acid, or are administered locally Examples of Methods of Dosing and Treatment Regimens
[00483] In some embodiments, the compounds described herein are used in the preparation of medicaments for the modulation of intracellular calcium, or for the treatment of diseases, disorders or conditions that would benefit, at least in part, from modulation of intracellular calcium. In addition, a method for treating any of the diseases, disorders or conditions described herein in a subject in need of such treatment, involves administration of pharmaceutical compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject [00484] In other embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments In therapeutic applications, the compositions are administered to a patient already suffering from a disease, disorder or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease, disorder or condition Amounts effective for this use will depend on the seventy and course of the disease, disorder or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician [00485] In prophylactic applications, compositions containing the compounds described herem are administered to a patient susceptible to or otherwise at nsk of a particular disease, disorder or condition Such an amount is defined to be a "prophylactically effective amount or dose " In this use, the precise amounts also depend on the patient's state of health, weight, and the like When used in a patient, effective amounts for this use will depend on the seventy and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician [00486] In some embodiments wherein the patient's condition does not improve, upon the doctor's discretion the administration of the compounds is administered chronically, that is, for an extended period of tune, including throughout the duration of the patient's life m order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.
5 [00487] In other embodiments, wherein the patient's status does improve, upon the doctor's discretion the administration of the compounds are given continuously, alternatively, the dose of drug bemg administered is temporarily reduced or temporarily suspended for a certain length of tune (i e , a "drug holiday") In other embodiments, the length of the drug holiday vanes between about 2 days and about 1 year, including by way of example only, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 10 days,
10 about 12 days, about 15 days, about 20 days, about 28 days, about 35 days, about 50 days, about 70 days, about 100 days, about 120 days, about 150 days, about 180 days, about 200 days, about 250 days, about 280 days, about 300 days, about 320 days, about 350 days, or about 365 days In some embodiments, the dose reduction during a drug holiday is from about 10% to about 100%, including, by way of example only, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about
15 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%
[00488] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary Subsequently, in other embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the unproved disease, disorder or condition is retained. In other embodiments, patients, however, require intermittent treatment on a long-term basis upon any
20 recurrence of symptoms
[00489] In other embodiments, the amount of a given agent vanes depending upon factors such as the particular compound, disease, disorder or condition and its seventy, the identity (e g , weight) of the subject or host in need of treatment, but is nevertheless determined in a manner according to the particular circumstances surrounding the case, including, e g , the specific agent bemg administered, the route of administration, the
25 condition being treated, and the subject or host bemg treated In some embodiments, doses employed for adult human treatment are typically m the range of about 0 02 to about 5000 mg per day, m other embodiments, about 1 to about 1500 mg per day In further embodiments, the desired dose is convemently presented in a smgle dose or as divided doses administered simultaneously (or over a short period of tune) or at appropriate intervals, for example as two, three, four or more sub-doses per day
30 [00490] In other embodiments, the pharmaceutical composition described herein is m unit dosage forms suitable for smgle administration of precise dosages In unit dosage form, the formulation is divided into unit doses containing appropnatc quantities of one or more compound. In further embodiments, the unit dosage is in the form of a package containing discrete quantities of the formulation Non-limiting examples are packaged tablets or capsules, and powders m vials or ampoules In other embodiments, aqueous suspension compositions
35 are packaged in single-dose non-reclosable containers In further embodiments, multiple-dose reclosable containers are used, m which case it is typical to include a preservative in the composition By way of example only, formulations for parenteral injection are presented in unit dosage form, which include, but are not limited to ampoules, or m multi-dose containers, with an added preservative [00491] The daily dosages appropriate for the compounds described herein described herein are from about
40 0 01 mg/kg to about 20 mg/kg In one embodiment, the daily dosages are from about 0 1 mg/kg to about 10 mg/kg An indicated daily dosage in the larger mammal, including, but not limited to, humans, is m the range from about 0 5 mg to about 1000 mg, conveniently administered in a single dose or in divided doses, including, but not limited to, up to four times a day or in extended release form Suitable unit dosage forms for oral administration include from about 1 to about 500 mg active ingredient In one embodiment, the unit dosage is about 1 mg, about 5 mg, about, 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 250 mg, about 400 mg, or about 500 mg The foregoing ranges are merely suggestive, as the number of variables in regard to an individual treatment regime is large, and considerable excursions from these recommended values are not uncommon In some embodiments, such dosages are altered depending on a number of variables, not limited to the activity of the compound used, the disease, disorder or condition to be treated, the mode of administration, the requirements of the individual subject, the seventy of the disease, disorder or condition being treated, and the judgment of the practitioner
[00492] In further embodiments, toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population) The dose ratio between the toxic and therapeutic effects is the therapeutic mdex and it are expressed as the ratio between LD50 and ED50 In other embodiments, are compounds exhibiting high therapeutic indices In other embodiments, the data obtained from cell culture assays and animal studies are used in formulating a range of dosage for use in human In some other embodiments, the dosage of such compounds lies withm a range of circulating concentrations that include the ED90 with minimal toxicity In further embodiments, the dosage varies within this range depending upon the dosage form employed and the route of administration utilized. Combination Treatments
100493] In other embodiments, the compounds of Formulas (I), (II), (III), (TV), (V) and (VI), and compositions thereof, are also used in combmation with other therapeutic agents that are selected for their therapeutic value for the condition to be treated. In general, the compositions described herein and, m embodiments where combinational therapy is employed, other agents do not have to be administered m the same pharmaceutical composition, and in some embodiments, because of different physical and chemical characteristics, have to be administered by different routes [00494] In certain instances, it is appropriate to administer at least one compound of Formulas (I), (H), (III), (TV), (V) or (VT) described herein m combination with another therapeutic agent By way of example only, if one of the side effects experienced by a patient upon receiving one of the compounds herein, such as a compound of Formulas (I), (II), (III), (IV), (V) or (VI), is nausea, then it is appropriate to administer an antinausea agent in combination with the initial therapeutic agent Or, by way of example only, the therapeutic effectiveness of one of the compounds described herem is enhanced by administration of an adjuvant (i e , by itself the adjuvant has minimal therapeutic benefit, but in combmation with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced) Or, by way of example only, the benefit experienced by a patient is increased by administering one of the compounds described herem with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit In any case, m other embodiments, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient is simply be additive of the two therapeutic agents or the patient experiences a synergistic benefit [00495] In other embodiments, the particular choice of compounds used depends upon the diagnosis of the attending physicians and then- judgment of the condition of the patient and the appropriate treatment protocol In further embodiments, the compounds are administered concurrently (e g , simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending upon the nature of the disease, disorder, or condition, the condition of the patient, and the actual choice of compounds used
[00496] In some embodiments, therapeutically-effective dosages vary when die drugs are used in treatment combinations Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient [00497] In some embodiments, combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease, disorder or condition being treated and so forth In addition, when co-admmistered with one or more biologically active agents, the compound provided herein is administered either simultaneously with the biologically active agent(s), or sequentially In some embodiments, if administered sequentially, the attending physician decides on the appropriate sequence of administering protein in combination with the biologically active agent(s)
[00498] In some embodiments, the multiple therapeutic agents (one of which is a compound of Formulas (I), (H), (in), (IV), (V) or (VT) described herein) are administered in any order or even simultaneously In other embodiments, if simultaneously, the multiple therapeutic agents are provided in a single, unified form, or m multiple forms (by way of example only, either as a single pill or as two separate pills) In other embodiments, one of the therapeutic agents are given in multiple doses, or both are given as multiple doses If not simultaneous, the tuning between the multiple doses vary from more than zero weeks to less than about four weeks In addition, the combination methods, compositions and formulations are not to be limited to the use of only two agents, the use of multiple therapeutic combinations are also envisioned (00499] It is understood that the dosage regimen to treat, prevent, or ameliorate the conditions) for which relief is sought, is modified in accordance with a variety of factors These factors include the disorder, disease or condition from which the subject suffers, as well as the age, weight, sex, diet, and medical condition of the subject Thus, in other embodiments, the dosage regimen actually employed vanes widely and therefore can deviate from the dosage regimens set forth herein [00500] In other embodiments, the pharmaceutical agents who make up the combination therapy disclosed herein are in a combined dosage form or in separate dosage forms intended for substantially simultaneous administration In other embodiments, the pharmaceutical agents that make up the combmation therapy are also administered sequentially, with either therapeutic compound being administered by a regimen calling for two step administration. In yet other embodiments, the two-step administration regimen calls for sequential administration of the active agents or spaced-apart administration of the separate active agents In further embodiments, the time period between the multiple administration steps range from, a few minutes to several hours, depending upon the properties of each pharmaceutical agent, such as potency, solubility, bioavailability, plasma half-life and kinetic profile of the pharmaceutical agent In other embodiments, circadian variation of the target molecule concentration also determines the optimal dose interval [00501] In addition, the compounds described herein also are used m combination with procedures that m some embodiments, provide additional or synergistic benefit to the patient By way of example only, patients are expected to find therapeutic and/or prophylactic benefit in the methods descnbed herein, wherein pharmaceutical composition of a compound disclosed herein and /or combinations with other therapeutics are combined with genetic testing to determine whether that individual is a earner of a mutant gene that is known to be correlated with certain diseases or conditions [00502] In further embodiments, the compounds described herein and combination therapies are administered before, during or after the occurrence of a disease, disorder or condition, and the tuning of administering the composition containing a compound vanes Thus, for example, the compounds are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions, disorders or diseases in order to prevent the occurrence of the disease, disorder or condition In other embodiments, the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms In other embodiments, the administration of the compounds are initiated within the first 48 hours of the onset of the symptoms, m some embodiments, within the first 48 hours of the onset of the symptoms, in yet other embodiments within the first 6 hours of the onset of the symptoms, and m other embodiments within 3 hours of the onset of the symptoms In further embodiments, the initial administration is via any route practical, such as, for example, an intravenous injection, a bolus injection, infusion over about 5 minutes to about 5 hours, a pill, a capsule, transdermal patch, buccal delivery, and the like, or combination thereof In other embodiments, a compound is administered as soon as is practicable after the onset of a disease, disorder or condition is detected or suspected, and for a length of time necessary for the treatment of the disease, such as, for example, from about 1 day to about 3 months In other embodiments, the length of treatment varies for each subject, and the length is determined using the known criteria For example, the compound or a formulation containing the compound is administered for at least 2 weeks, in some embodiments about 1 month to about 5 years InhlMtnrs nf SnrF
[00503] In one aspect, compounds of Formulas (I), (H), (III), (TV), (V) and (VI) are administered or used m conjunction with other inhibitors of SOCE In one embodiment, the inhibitors of SOCE are non-selective inhibitors In one embodiment, the inhibitors of SOCE are selective inhibitors
[00504] A variety of inhibitors of SOCE have been descnbed Inhibitors of SOCE include a) Cations, which include lanthanide cations, such as for example, Gd3+, La3+, b) P-450 inhibitors, which include econazole, miconazole, clotrimazole, ketoconazole, c) Cyclooxygenase inhibitors, which include niflumic acid, flufenamic acid, tenidap, d) Lipoxygenase inhibitors, which mclude nordihydroguaiaretic acid, eicosatetraynoic acid, e) Compounds that are channel blockers, which include SK&F 96365, SC38249, LU52396, L-651,582, tetrandnne, 2-APB, f) Compounds that inhibit SOCE not by an action on the SOC channels themselves, which include U73122 (phospholipase C inhibitor), wortmannin (phosphahdyhnositol kinase inhibitor) [00505] Some ofthese inhibitors ofSOCE have non-specific actions andor multiple mcκles of action tliat contribute to the inhibition of SOCE, which include blocking (he pore of the SOC channel (Channel blockers), inhibition of mitochondrial ATP synthesis that appears to support SOCE, disturbances of cytoplasmic pH (, as well as inhibiting the activation of SOC channels Immunosuppressants [00506} In one embodiment, compounds of Formulas (I), (U), (IU), (IV), (V) and (VI) are administered as single agents in immunosuppressive therapy to reduce, inhibit, or prevent activity of the immune system. Immunosuppressive therapy is clinically used to prevent the rejection of transplanted organs and tissues (e g bone marrow, heart, kidney, liver), treatment of autoimmune diseases or diseases that are most likely of autoimmune origin (e g rheumatoid arthritis, myasthenia gravis, systemic lupus erythematosus, Crohn's disease, and ulcerative colitis), and treatment of some other non-autoimmune inflammatory diseases (e g long term allergic asthma control)
(00507] In some embodiments, a compound of Formulas (I), (H), (HT), (IV), (V) or (VI) is administered with other immunosuppresants selected from among Calcineurm inhibitors (such as, but not limited to, cyclosporin, tacrolimus). niTOR inhibitors (such as, but not limited to, sirolimus, everohmus), antiproliferatives (such as, but not limited to, azathioprine, mycophenohc acid), corticosteroids (such as, but not hunted to, prednisone, cortisone acetate, prednisolone, methylpredmsolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone, hydrocortisone), antibodies (such as, but not limited to, monoclonal anti-IL-2Rα receptor antibodies (basiliximab, daclizumab), polyclonal anti-T-cell antibodies (anti-fhymocyte globulin (ATG), anti-lymphocyte globulin (ALG)))
[00508] Other immunosuppresants include, but are not limited to glucocorticoids (alclometasone, aldosterone, amcinomde, beclometasone, betamethasone, budesonide, ciclesonide, clobetasol, clobetasone, clocortolone, cloprednol, cortisone, cortivazol, deflazacort, deoxycorticosterone, desomde, desoximetasone, desoxycortone, dexamethasone, diflorasone, diflucortolone, difluprednate. fluclorolone, Fludrocortisone, fludroxycortide, flumetasone, flunisohde, fluocmolone acetonide, fluocinomde, fluocortin, fluocortolone, fluorometholone, fluperolone, flupredmdene, fluticasone, formocortal, halcinomde, halometasone, hydrocortisone/Cortisol, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone butyrate, loteprednol, medrysone, mepredmsone, methylpredmsolone, methylpredmsolone aceponate, mometasone fαroate, paramethasone, prednicarbate, prednisone, prednisolone, prednylidene, nmexolone, tixocortol, triamcinolone, ulobetasol), cyclophosphamide, nitrosoureas, cisplatm, carboplatm, oxaliplatm, methotrexate, azathioprine, mercaptopuπne, pyπmidine analogues, protein synthesis inhibitors, methotrexate, azathiopnne, mercaptopuπne, dactinomycin, anthracyclmes, mitomycin C, bleomycin, mithramycin, Atgam1"', Thymoglobuhne", OKT3®, basiliximab, daclizumab, cyclosporin, tacrolimus, sirohmus, Interferons (IFN-β, IFN-γ), opioids, TNF binding proteins (infliximab, etanercept, adalimumab, golimumab), mycophenohc acid, mycophenolate mofetil, FTY720, as well as those listed in US 7,060,697 Agents for Treating Autoimmune Diseases, Inflammatory Diseases
[00509] In some embodiments, where the subject is suffering from or at πsk of suffering from an autoimmune disease, disorder or condition, or an inflammatory disease, disorder or condition, a compound of Formulas (I), (II), (III), (TV), (V) or (VI) is administered in any combination with one or more of the following therapeutic agents immunosuppressants (e g , tacrolimus, cyclosporin, rapamicin, methotrexate , cyclophosphamide, azathiopnne, mercaptopunne, mycophenolate, or FTY720), glucocorticoids (e g , prednisone, cortisone acetate, prednisolone, methylpredmsolone, dexamethasone, betamethasone triamcinolone, beclometasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone), non-steroidal antiinflammatory drugs (e g , salicylates, arylalkanoic acids, 2-arylpropiomc acids, N-arylanthramlic acids, oxicams, coxibs, or sulphonamlides), Cox-2-specific inhibitors (e g , valdecoxib, etoπcoxib, lumiracoxib, celeccxib, or rofecoxib), leflunomide, gold thioglucose, gold thiomalate, aurofin, sulfasalazuie, hydroxychloroquinine, minocycline TNF-α binding proteins (e g , infliximab, etanercept, or adalimumab), abatacept, anakinra, interferon-β, interferon-γ, interleukin-2, antileukotnenes, theophylline, or anticholinergics [00510] In one embodiment, compounds of Formulas (I), (II), (IH), (TV), (V) and (VI) described herein, are S administered in combination with inhibitors of NFAT-calcineunn pathway In one embodiment, the inhibitors of NFAT-calcineunn pathway include, but are not limited to, Cyclosporin A (CsA) and tacrolimus (FK506) [00511] In one embodiment, a compound of Formulas (I), (II), (III), (IV), (V) or (VI), or compositions and medicaments that include a compound of Formulas (I), (II), (III), (IV), (V) or (VI), are administered to a patient ni combination with an anti-inflammatory agent including, but not limited to, non-steroidal anti inflammatory0 drugs (NSAIDs) and corticosteroids (glucocorticoids)
[00512] NSAIDs include, but are not limited to aspiπn, salicylic acid, gentisic acid, choline magnesium salicylate, choline salicylate, choline magnesium salicylate, choline salicylate, magnesium salicylate, sodium salicylate, diflunisal, carprofen, fenoprofen, fenoprofen calcium, flurobrprofen, lbuprofen, ketoprofen, nabutone, ketolorac, ketorolac tromethamine, naproxen, oxaprozin, diclofenac, etodolac, lndomethacin, sulindac, tolmeun, S meclofenamate, mcclofcnamate sodium, mefenamic acid, prroxicam, meloxicam, COX-2 specific inhibitors (such as, but not limited to, celecoxib, rofccoxib, valdecoxib, parecoxib, etoncoxib, lumiracoxib, CS-S02, JTE- 522, 1/745,337 and NS398)
[00513] Combinations with NSAIDs, which are selective COX-2 inhibitors, are contemplated herein Such compounds melude, but are not limited to those disclosed m U S Patent No 5,474,995, U S Patent No0 5,861,419, U S PatentNo 6,001,843, U S PatentNo 6,020,343, U S Patent No 5,409,944, U S PatentNo 5,436,265, U S PatentNo 5,536,752, U S PatentNo 5,550,142, U S PatentNo 5,604,260, U S PatentNo 5,698,584, U S PatentNo 5,710,140, WO 94/15932, U S PatentNo 5,344,991, U S PatentNo 5,134,142, U S PatentNo 5,380,738, U S PatentNo 5,393,790, U S PatentNo 5,466,823, U S PatentNo 5,633,272, U S Patent No 5,932,598 and 6,313,138, the disclosure of NSAIDs which are herein incorporated by reference5 [00514] Compounds that have been described as selective COX-2 inhibitors and are therefore useful in the methods or pharmaceutical compositions described herein include, but are not limited to, celecoxib, rofecoxib, lumiracoxib, etoncoxib, valdecoxib, and parecoxib, or a pharmaceutically acceptable salt thereof [00515] Corticosteroids, include, but are not limited to betamethasone, prednisone, alclorαetasone, aldosterone, amcinonide, beclometasone, betamethasone, budesonide, ciclesomde, clobetasol, clobetasone,0 clocortolone, cloprednoL cortisone, cortivazol, deflazacort, deoxycorticosterone, desomde, desoximetasone, desoxycortone, dexamethasone, diflorasone, diflucortolone, difluprednate, fluclorolone, fludrocortisone, fludroxycornde, flumetasone, flumsohde, fluocmolone acetomde, fluocmomde, fluocortm, fluocortolone, fluorometholone, fluperolone, fliipredmdene, fluticasone, formocortal, halcmomde, halometasone, hydrocortisone/cortisol, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone butyrate,5 loteprednol, medrysone, meprednisone, methylprednisolone, methylpredmsolone aceponate, mometasone furoate, paramethasone, predmcarbate, prednisone/prednisolone, πmexolone, tixocortol, triamcinolone, and ulobetasol
[00516] Other agents used as anti-imflammatones include those disclosed m U S patent publication 2005/0227929, the disclosure of antiinflammatories which is herein incorporated by reference [00517] Some commercially available anb-inflammatones include, but are not limited to Arthrotec* (diclofenac and misoprostol), Asacolβ(S-aminosahcyclic acid), Salofelk® (S-aminosalicychc acid), Auralgan® (antipyπne and benzocaine), Azulfϊdine® (sulfasalazine), Daypro® (oxaprozin), Lodmeβ(etodolac), Ponstan® (mefenamic acid), Solumedrol® (methylprednisolone), Bayerφ(aspiπn), Buffeπn® (aspirin), Indocin® 5 (lndomethacin), Vioxx® (rofecoxib), Celebrex® (celecoxib), Bextra" (valdecoxib), Arcoxia® (etoπcoxib), Prexige® (lumπacoxib), Advil®, Motrin* (ibuprofen), Voltarenφ(diclofenac), Orudisβ(ketoprofen), Mobicβ(meloxicam), Relafen* (nabumetone), Aleve*, Naprosyn* (naproxen), Feldene*(piroxicam) [00518] In one embodiment, compounds of Formulas (I), (II), (in), (IV), (V) and (VI) are administered in combination with leukotnene receptor antagonists including, but are not limited to, BAY u9773 (see EP
10 00791576, published 27 Aug 1997), DUO-LT (Tsuji e/ al, Org Biomol Chan , 1, 3139-3141, 2003), zafirlukast (Accolate®), montelukast (Singulair®), praπkulast (Onon®), and deπvatives or analogs thereof Kits/ Articles of Manufacture
[00519] For use in the therapeutic applications described herein, kits and articles of manufacture are also described herein. In some embodiments, such kits include a carrier, package, or container mat is
1 S compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the containers) including one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes In other embodiments, the containers are formed from a variety of materials such as glass or plasbc [00520] The articles of manufacture provided herein contain packaging materials Examples of
20 pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment A wide array of formulations of the compounds and compositions provided herein are contemplated as are a variety of treatments for any disease, disorder, or condition that would benefit by inhibition of CRAC channel activity
25 [00521] For example, m some embodiments, the containers) includes one or more compounds described herein, optionally in a composition or in combination with another agent as disclosed herein. The contamer(s) optionally have a sterile access port (for example the container is an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle) Such kits optionally comprising a compound with an identifying description or label or instructions relating to its use ui the methods described herein
30 [00522] In some other embodiments, a kit includes one or more additional containers, each with one or more of various materials (such as reagents, optionally m concentrated form, and/or devices) desirable from a commercial and user standpoint for use of a compound described herein. Non-limiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes, earner, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use In
35 other embodiments, a set of instructions is also included
[00523] In further embodiments, is a label on or associated with the container In other embodiments, the label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself, a label is associated with a container when it is present within a receptacle or earner that also holds the container, e g , as a package insert. In some embodiments, a label is used to indicate that the contents are to be used for a specific therapeutic application In yet other embodiments, the label also indicates directions for use of the contents, such as in the methods described herein
[00524] In certain embodiments, die pharmaceutical compositions are presented m a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein In other embodiments, the pack contains metal or plastic foil, such as a blister pack. In other embodiments, the pack or dispenser device is accompanied by instructions for administration In still other embodiments, the pack or dispenser also accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration Such notice, for example, is the labeling approved by the U S Food and Drug Administration for prescription drugs, or the approved product insert. Compositions containing a compound provided herein formulated m a compatible pharmaceutical carrier are also prepared, placed m an appropriate container, and labeled for treatment of an indicated condition Assays [00525] In some embodiments, several techniques are used to evaluate store operated calcium entry and calcium signaling m cells Such techniques include, but are not limited to, patch clamp eleclrophysiology (measurement of calcium ions or other ions across cell membranes, such as plasma membranes), capacitance measurements (allows exocytosis to be followed at the level of single cells), calcium imaging using fluorescent dyes allows patterns of calcium movement within the cytoplasm to be tracked, fluorescence resonance energy transfer (FRET) enables protein-protein interactions to be evaluated, and molecular biology methods allow for the manipulation of the levels of expression of proteins of interest
[00526] In other embodiments, a wide variety of assay methods are used to examine the modulation of intracellular calcium by compounds of Formulas (I), (II), (III), (IV), (V) and (VI) Such assays include in vitro cell based assays as well as in vivo animal models In some embodiments, are assays that detect, monitor or measure an effect on intracellular calcium, including calcium entry-mediated events Such assays include, but are not limited to, assays monitoring, measuring and/or detecting intracellular calcium levels, modulation of calcium levels, and movement of calcium into, out of or within cells and intracellular organelles In other embodiments are assays winch also include monitoring, measuring and/or detecting calcium entry-mediated events and molecules involved in calcium entry-mediated events such as, but not limited to, signal transduction molecules, transcription factors, secreted molecules and other molecules that are affected by changes m calcium homeostasis Assays mclude, but are not limited to, those described herein and those described m US patent publication no 2007/0031814 and WO 07/081804, herein incorporated by reference CeBs and CeU Models
[00527] For in vitro testing of the modulation of intracellular calcium by compounds of Formulas (I), 01), (HI), (FV), (V) and (VI), a wide variety of cell types for such assays are available In one embodiment, the cell is one in which store-operated calcium entry occurs or that is manipulated such that store-operated calcium entry occurs in the cell In other embodiments, the cell contains one or more proteins involved in modulating intracellular calcium (and, m particular, is involved m, participates m and/or provides for store-operated calcium entry, movement of calcium into, out of or within an intracellular organelle or calcium store, modulation of calcium levels in an intracellular organelle or calcium store (e g , endoplasmic reticulum) and/or calcium buffering), such as those provided herein In further embodiments, the protein(s) mclude a STIM proteins (including STIMI, STΪM2, DSTIM and CSTIM protein) and/or Oral proteins (Orail, Oπu2, Oπu3) The cell may endogenously express the protein(s) or recombinantly express the protein(s)
[00528] In some embodiments, cells for use in the methods are of any species In one embodiment, the cells are eukaryotic cells In one embodiment, the cells are yeast, insect (e g , Drosophila or Anopheles), or mammalian cells Mammalian cells mclude, but are not limited to, rodent (e g , mouse, rat and hamster), primate, monkey, dog, bovine, rabbit and human cells A variety of cell types are used in the methods, including, for example, neuronal, nervous system, brain, immune system cells, e g , T lymphocytes and B cells, primary cells, blood and hematopoietic cells, stromal cells, myeloid cells, lymphoid cells, and a variety of tumor and cancer cells Particular cells mclude Drosophila Schneider 2 or S2 cells, human embryonic kidney (HEK293) cells, rat basophilic leukemia (RBL-2H3) cells, Jurkat cells, epithelial cells, rhabdomyosarcoma cells, rhabdoid cells, retinoblastoma cells, neuroepithelioma cells, neuroblastoma cells, osteosarcoma cells, fibroblasts, bone marrow stroma cells, erythroleukemia cells and lymphoblast cells Other cell hues include HEK 293 and 293T, CHO (including CHO-Kl), LTK-, N2A, H6, and HGB Many such cells and cell lines are available through cell depositories such as, for example, the American Type Culture Collection (ATCC, Manassas, Va) In further embodiments, primary cells are obtained by isolation from tissue sources The generation, maintenance and use of such cells and cell lines is well known
[00529] In other embodiments, cells from a known cell line are used, such as neuroblastoma SH SYSY cells, pheochromocytoma PC12 cells, neuroblastoma SK-N-BE(2)C or SK-N-SH cells, human SK-N-MC neuroepithelioma cells, SMS-KCNR cells, human LAN-5 neuroblastoma cells, human GI-CA-N neuroblastoma cells, human GOTO neuroblastoma cells, mouse Neuro 2a (N2A) neuroblastoma cells and/or human IMR 32 neuroblastoma cells, chronic myeloid leukemia cells (e g , human KS62 cells), promyelocyte leukemia cells (e g , HL60 cells) and histiocytic lymphoma cells (e g , U937 cells), Burkitt's lymphoma cells (e g , CA46 cells), B-cells (e g , NALM6), acute lymphoblastic leukemia cells (e g , MOLT4 cells), T cells (e g Jurkat cells) and early T-ALL (e g , DU528) cells [00530] The choice of a cell for use in an m vitro assay to test the modulation of intracellular calcium by compounds of Formulas (I), (II), (ID), (IV), (V) and (VI) involve several considerations, including, for example, a particular protein that is being used in the method and a particular aspect or activity of intracellular calcium modulation that is being monitored or assessed m the method [00531] In one embodiment, the modulation of intracellular calcium by a compound of Formulas (I), (II), (in), (TV), (V) or (VI) is examined by monitoring or assessing the effect on store-operated calcium entry Cells typically used in such methods exhibit store-operated calcium entry either naturally or through manipulation of the cells In other embodiments, cells that endogenously exhibit store-operated calcium entry mclude some excitable cells and most non-excitable cells and are identified using methods described herein [00532] In one embodiment, it is desirable to utilize a cell that contains components of signaling and messenger systems that effects release of calcium from intracellular stores For example, cells containing components of receptor-mediated phosphohpase C (PLC) activation systems are used for physiological activation (via generation of IP3) of store depletion to facilitate monitoring of store-operated calcium entry Receptor mediated PLC activation occurs through distinct coupling mechanisms PLC-β activation by G protein-coupled receptors (GPCRs) and PLC^y activation by tyrosine kinase receptors and nonreceptor tyrosine kinases Thus, cells containing a receptor-mediated PLC-actvation system are monitored or assessed for store- operated calcium entry upon agonist activation of one or more receptors known to participate in the system [00533] In another embodiment, an assessment of intracellular calcium after treatment with a compound of Formulas (I), (II), (HI), (IV), (V) or (VI) is made under a variety of conditions Conditions are selected to evaluate the effect of test agent on a specific aspect of intracellular calcium. For example, reagents and conditions are known, and are used, for specifically evaluating store-operated calcium entry, resting cytosolic calcium levels, calcium buffering, and calcium levels of and calcium uptake by or release from intracellular organelles in further embodiments, resting cytosolic calcium levels, intracellular organelle calcium levels and cation movement are assessed using any of the methods described herein Such methods of assessing modulation m intracellular calcium include, but are not limited to, calcium-sensihve indicator-based measurements, such as fluo-3, mag-fiira 2 and ER-targeted aequoπn, labeled calcium (such as 45Ca2+)-based measurements, and electrophysiological measurements Particular aspects of ion flux that are assessed include, but are not limited to, a reduction (including elimination) in the amount of ion flux, altered biophysical properties of the ion current, and altered sensitivities of the flux to activators or inhibitors of calcium flux processes, such as, for example, store-operated calcium entry Reagents and conditions for use m specifically evaluating receptor-mediated calcium movement and second messenger-operated calcium movement are also available
Evaluation of Store-Operated Calcium Entry [00534] In one aspect, compounds of Formulas (I), (II), (III), (IV), (Y) and (VI) are added to cells under conditions that permit store-operated calcium entry to occur m order to assess the effects of compounds of Formulas (I), (II), (HI), (TV), (V) and (VI) on store-operated calcium entry
[00535] For example, m one method cells are treated to reduce the calcium levels of intracellular calcium stores and then analyzed for evidence of ion (e g , calcium) influx m response thereto in the presence of a compound of Formulas (I), (IT), (IE), (IV), (V) or (VI) Techniques for reducing calcium levels of intracellular stores and for analyzing cells for evidence of ion (e g , calcium) influx are described herein.
[00536] In other methods, electrophysiological analysis of currents across a cell-detached plasma membrane patch or an outside-out membrane vesicle are used to detect or monitor store-operated channel currents (e g , Isoc, ICRAC) in the presence of a compound of Formulas (I), (II), (III), (IV), (V) or (VI) Evaluation of Calcium Entry-Mediated Events [00537] A number of molecules involved in calcium-regulated pathways are known. Evaluation of molecules involved in calcium-entry mediated events are used to monitor intracellular calcium, and are used, for example m screening assays described herein to monitor the effects of compounds of Formulas (I), (II), (HI), (IV), (V) and (VI) Examples of assays include but are not limited to assays which detect, or determine the presence, levels, alteration of levels, production, modification (such as phosphorylation and dephosphorylation), translocation, degradation and activity of molecules involved in calcium-entry mediated events (see for example, Trevillyan et al (200I) J BIoI Chem 276 48118-26) In some embodiments, the assays described herein are used with cells that have been treated with or contacted with a compound of Formulas (I), (II), (III), (IV), (V) or (VT), or that express an altered amount of a test molecule (such as a protein involved in calcium regulation, including a STIM protein, Oral protein), or with control cells In other embodiments, the assays are also conducted in cells that have been stimulated with a physiological or non-physiological activator, or in unstimulated cells The following are representative assays for molecules involved in calcium-entry mediated events and are meant to be exemplary only Other assays for these molecules and assays for other molecules involved in calcium-entry mediated events are also employed in any of the screening and/or modulation methods described herein. S B-Hexosaιninidgse Release
[00538] In mast cells, Ca2+ influx results m degranulation and release of inflammatory mediators such as heparin, histamine and enzymes such as β-hexosaminidase In further embodiments, detecting and/or measuring release of such molecules is used to monitor intracellular calcium. For example, in other embodiments, media from mast cells are collected In further embodiments, suitable substrate for β-hexosamimdase (e g p-
10 mtrophenyl-acetyl-gtucosamide) is then added and the absorbance of the resulting mixture assessed to measure the relative amount of β-hexosamimdase activity in the samples
Culcium/Calniodulin-Depeiident CaN Phosphatase Activity
[00539] The phosphatase calcineunn (CaN) dephosphorylates various proteins, affecting then- activity and localization In other embodiments, CaN activity is assessed by incubating purified CaN and a CaN substrate,
15 for example a radiolabeled peptide corresponding to a sequence m the Ru subunit of c AMP dependent kinase, either with or without a compound of Formulas (I), (II), (III), (IV), (V) or (VT) (see, Trevillyan et al (2001) J BmI Chem 27648118-26) In further embodiments, the level of radiolabeled peptide and/or the amount of free inorganic phosphate released is measured to assess CaN dephosphorylation activity NFAT Transcriptional Activity
20 [00540] The NFAT (nuclear factor of activated T cells) transcription factor regulates a number of genes in response to intracellular calcium levels For example, NFAT proteins regulate the transcription of cytokine genes mvolved m the immune response In other embodiments, promoters from NFAT-reguIated genes, and/or regulatory regions and elements from these genes, are used to monitor NFAT regulated expression and thereby monitor intracellular calcium In further embodiments, reporter gene fusions are constructed with NFAT
25 regulated promoters or NFAT-regulated elements operably linked to a reporter gene such as hiciferase, β- galactosidase, green fluorescent protein (GFP) or any other known reporter (see for example, Published U S Application no 2002-0034728) The amount of reporter protein or activity is a measure of NFAT activity
NFAT Phosphorylation [00541] NFAT activation is regulated primarily through its phosphorylation, which in turn regulates its
30 subcellular localization. In unstimulated cells, NFAT is a hyperphosphorylated cytosolic protein An elevation in intracellular Ca2*, induced by a variety of mechanisms, increases the activity of the Ca^-calmoduhn- dependent phosphatase, calcineunn. Activated calcineunn dephosphorylates multiple serine residues within the regulatory region of the NFAT molecule NFAT is rephosphorylated m response to decreases in Ca2+ levels or CaN inhibition
35 [00542] The phosphorylation state of NFAT is monitored for example, by expressing a detectably tagged NFAT protein m cells, such as a His6 tagged-NFAT Tagged NFAT is purified from cells using Ni2+ chromatography and subjected to gel electrophoresis and staining or western blotting More highly phosphorylated forms of NFAT are distinguished by their slower migration In further embodiments, the state of phosphorylated NFAT is used as a measure of NFAT activation (see, Trevillyan et al (2001) / BwI Chem
40 27648118-26) NFAT Nuclear Localization
[00543] NFAT localization between the cytoplasm and nucleus is regulated by the phosphorylation state of NFAT Phosphorylation of NFAT prevents nuclear localization by masking the nuclear localization sequence NFAT nuclear localization are monitored, for example, by expressing fluorescently tagged NFAT, for example, 5 GFP-NFAT, in cells In further embodimente, confocal microscopy is used to monitor nuclear localization of the tagged NFAT (see, Trevillyan e/ α/ (2001)7 BwI Chem 27648118-26)
Cytokine Secretion
[00544] In some embodiments, cytokine secretion, such as IL-2 secretion, is monitored using protein detection assays For example, supernatant is collected from immune cells In other embodiments, an ELISA0 assay or other suitable format with IL-2 antibodies is used to detect and/or measure the amount of IL-2 secreted as compared to control cells Secretion of other cytokines, for example, TNF-α, is also detected in similar assays
Cytokine Expression [00545] Expression of cytokines, such as, but not limited to IL-2, are assessed either directly or indirectly in S cells For example, in indirect methods, an IL-2 promoter are operably linked to a reporter gene such as luciferase or β-galactosidase, and the reporter construct introduced into cells In further embodiments, reporter gene expression is monitored and compared to gene expression in control cells (see, Trevillyan et al (2001) J BwI Chem 27648118-26) In other embodiments, expression of endogenous or recombinant IL-2 mRNA or protein is assessed 0 T Cell Proliferation
[00546] Cytokines such as IL-2 are necessary for T-cell proliferation in response to mitogen or alloantigen stimulation, and thus T-cell proliferation is altered by changes in cytokine expression or secretion. In some embodiments, T cells are induced, such as with cσncanavalin A or alloreacbve lymphocytes and T cell proliferation measured, for example, by subjecting cells to a pulse of 3H- thymidine and measuring 3H-thymidine5 incorporation (see, Trevillyan et al (2001) J Biol Chem 27648118-26)
[00547] In further embodiments, the modulation (e g inhibition or reduction) of SOCE by compounds of Formulas (I), (II), (HI), (IV), (V) and (VI) is determined by evaluation of any of the following criteria a. there is direct inhibition of increased [Ca2+]I as measured by a calcium indicator, b there is a direct inhibition OfI80C or ICRAC as measured by patch clamp, 0 c there is inhibition of downstream signaling functions such as calcmeurm activity, NFAT subcellular localization, NFAT phosphorylation, and/or cytokine, e g , IL-2, production, or d. there are modifications m activation-induced cell proliferation, differentiation and/or apoptoπc signaling
Animal Models 5 [00548] Animal models that are used in embodiments of the methods further include animals, such as, but not limited to non-human animals, which have, m at least some of their cells, an alteration or defect in, or aberrant functioning of, a cellular process which relies on or is regulated by intracellular calcium Cellular processes that rely on or are regulated by intracellular calcium include, for example, cellular activation, gene expression, cellular trafficking, and apoptosis In some embodiments, are diseases/disorders that involve defects that are at0 least partially compensated for by modulation of intracellular calcium include, but are not limited to autoimmune disorders, including rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome (cytokines associated with lymphocyte invasion of salivary epithelial cells can reduce calcium mobilization in parotid cells, also, T-cell activation, including activation of transcription factors, cytokine gene expression and cell proliferation, depends on sustained elevation of intracellular calcium level provided by store-operated calcium influx), asthma (store-operated calcium entry also plays an important role in mediating bronchial chonstnction and bronchial smooth muscle cell proliferation), glomerulonephritis and glomerular inflammation (changes in intracellular calcium, such as by store-operated calcium entry, signal monocyte adhesion m a co- culture model of glomerular inflammation) 100549] Types of animal models include, but are not limited to, non-human animals, such as non-human invertebrates and vertebrates and non-human mammals, rodents (e g , mice, rat and hamster), cows, chickens, pigs, goats, dogs, sheep, insects, Drosophila, nematodes, worms, C elegans, monkeys, gorillas, and other primates
[00550] Animal models include transgenic and non-transgenic animals One example of such an animal model that are used in particular embodiments of the methods is a rodent model of airway hyperresponsiveness (AHR), a characteristic of asthma This model are generated, for example, by sensitization through immunization with ovalbumin followed by exposure to aerosolized ovalbumin and challenge by cholinergic stimulation (e g , via administration of methacholine or acetylcholine) (see, e g , Xu et al (2002) J Appl Physiol 93 1833-1840, Humbles etal (2002) Proc Nad Acad Sa 99 1479-1484) Airway hyperresponsiveness (which in some embodiments are evaluated using methods such as, for e g , using barometric plethysmography to record respiratory pressure curves and through measurement of pulmonary parameters such as pulmonary conductance and pulmonary compliance) are assessed and compared in animals treated and not treated with a compound of Formulas (I), (II), (IH), (TV), (V) or (VI) A further example of an animal model that is used in embodiments of the methods is a rodent model of mesangial proliferative glomerulonephritis, which is generated, for example, by administration of anu-Thyl 1 antibody (see, e g , Jefferson and Johnson (1999) J Nephrol 12 297-307) Any number of parameters indicative of glomerulonephritis or renal dysfunction (e g , mesangial cell proliferation, blood pressure, urinary protein excretion, creatinine clearance, glomerulosclerosis index and other parameters) are in some embodiments, evaluated and compared m animals treated with and not treated with test agent The non-obese diabetic (NOD) mouse, an inbred mouse strain that spontaneously develops an autoimmune diabetes that shares many immunogenetic features with Type 1 diabetes melhtus, is another example of an animal model that is used in one embodiment of the methods These mice also manifest many characteristics of autoimmune exocrmopathy (such as Sjorgen's syndrome) including declining exocrine tissue secretory function (see, e g , Humphreys-Beher and Peck (1999) Arch OralBwl 44 Suppl 1 S21-25 and Brayer ef α/ (2000) J Rheumatol 27 1896-1904) Characteristics relevant to Sjorgen's syndrome (e g , lymphocytic infiltrates m exocrine glands (e g , salivary and lacrimal glands), presence of dendritic cells and macrophages in submandibular glands, integrity of the lacrimal gland by measurement of basal and stimulated tear secretion, saliva flow rates and amylase activity) are evaluated and compared m animals treated with and not treated with a compound of Formulas (I), (JJ), (IE), (IV), (V) or (VI) In further embodiments, an animal (e g , rodent) model of autoimmune disease is also used in particular embodiments of the methods Such animals include rat models available through the National Institutes of Health (NIH) Autoimmune Rat Model Repository and Development Center (Bethesda, Md , accessible at www ors od nih gov/dirs/vrp/ratcenter) One rat model of rheumatoid arthritis (RA) and related chronic/inflammatory autoimmune diseases is the collagen-induced arthritis (CIA) model (see, e g , Griffiths and Remmers (2001) Immunol Rev 184 172-183) Characteπstic phenotjpes of autoimmune disease (e g altered levels of immune reactivity to self-antigens, chronic inflammation of autoantigen-expressmg target organs, and activation and participation of invading mononuclear cells and tissue fibroblasts in organ damage) are in some embodiments, evaluated and compared m animals treated with and not treated with a compound of Formulas (I), (π), (III), (TV), (V) or (VI) In other embodiments, an animal (e g , rodent) model of neuropathic or inflammatory pain is also used m one embodiment of the methods For example, one rat model of neuropathic pain mvolves development of tactile allodynia (exaggerated response to otherwise innocuous stimuli) after ligation of lumbar spinal nerves (see, e g , Chaplan et al (1994) J Neurosci Methods 53 55-63 and Luo et al (2001) J Neurosci 21 1868-1875) Tactile allodynia, one characteristic feature of neuropathic pain, are evaluated (e g , by evaluating paw withdrawal threshold in response to application of pressure) and compared m animals treated and not treated with a compound of Formulas (I), (H), (HI), (IV), (V) or (VI)
EXAMPLES
[00551] These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein The starting materials and reagents used for the synthesis of the compounds described herem are synthesized or are obtained from commercial sources, such as, but not limited to, Sigma- Aldnch, Acros Organics, Fluka, and Fischer Scientific Example IA: General Synthesis of Compounds of the Formula IA
Figure imgf000099_0001
Formula IA
[00552] Compounds of the Formula IA are synthesized according to Scheme IA Scheme IA
Figure imgf000099_0002
CO2H
NaOH, H2O
O 1-5
[00553] Step / Following the procedure of Beccalli et al (J Org Chem 1985, 50, 2373) hydroxamic acid chloride 1-1 is condensed with nitπle 1-2 m the presence of base to give 5-aminooxazole 1-3 Step 2 Treatment of oxazole 1-3 with benzoyl chloride will afford oxazole 1-4 Step 3 Hydrolysis of the ester in compound 1-4 will give acid 1-5 Examples 1B-1M
(00554] Compounds 1B-1M are synthesized as described in Example IA using the appropriate starting materials and intermediates with selective protection and deprotection when necessary.
Figure imgf000100_0001
Figure imgf000101_0001
Example 2A: General Synthesis of Compounds of the Formula 2A
Figure imgf000101_0002
Formula 2A
[00555) Compounds of the Formula 2A are synthesized according to Scheme 2A Scheme 2A
Figure imgf000101_0003
[00556] Step / Following the procedure of Shawah et sύ (J Heterocyclic Chem 1976, 13, 989, J
Heterocyclic Chem 1980, 17, 833) hydrazonyl bromide 2-1 is condensed with nitπle 2-2 in the presence of base to give 5-aminopyrazole 2-3 Step 2 Treatment of pyrazole 2-3 with benzoyl chloride will afford pyrazole 2-4
Step 3 Hydrolysis of the ester in compound 2-4 will give acid 2-5
Examples 2B-2M
[00557] Compounds 2B-2M are synthesized as described in Example 2A using the appropriate starting materials and intermediates with selective protection and deprotection when necessary
Figure imgf000102_0001
Figure imgf000103_0001
Example 3A: General Synthesis of Compounds of the Formula 3A
Figure imgf000103_0002
Formula 3A
[00558] Compounds of the Formula 3 A are synthesized according to Scheme 3 A. Scheme 3A
Figure imgf000103_0003
[00559] Step 1. Claisen condensation {Organic Syntheses 1943, Coll VoI 2, 111) between ester 3-1 and acid chloride 3-2 will give ketoester 3-3. Step 2- Condensation of ketoester 3-3 with hydrazine will be performed by heating ketoester 3-3 in ethanol with excess hydrazine hydrate Step 3 Reaction of aminoprazole 3-4 with an acid chloπde will provide pyrazole 3-5 Step 4. Hydrolysis of the ester in compound 3-5 will give acid 3-6 Examples 3B-3M
[00560] Compounds 3B-3M are synthesized as described in Example 3A using the appropriate starting materials and intermediates with selective protection and deprotection when necessary
Figure imgf000105_0001
Figure imgf000106_0001
Example 4A: General Synthesis of Compounds of the Formula 4A
Figure imgf000106_0002
Formula 4A
[00561] Compounds of the Formula 4A are synthesized according to Scheme 4A Scheme 4A
Br2 H2, Pd-C PhNH2
MeO.
MeOH MβOχ AcOH
O^ MeOH
O2Me cry n- ιc,uo2*Mθ *" 9^ y-CO2Me
MeO MeO-* — '
4-1 4-2 4-3
Figure imgf000106_0003
[00562] Step 1 Following the procedure of Burness (Organic Syntheses 1960, 40, 29) the methyl ester of 3- iuran carboxylic acid is oxidized with bromine in methanol to give the 2,5-dihydro-2,5-dimethoxyfuran 4-2 Step 2 Reduction of 4-2 by hydrogenation with palladium-on-carbon will afford tetrahydrofiiran 4-3 Step 3 Condensation of aniline with 4-3 according to the procedure of Josey (Organic Syntheses 1967, 47, 81) will yield substituted pyrrole 4-4 Step 4 Hydrolysis of the methyl ester followed by Curtius rearrangement with diphenylphosphorylazidate (Organic Syntheses 1984, 62, 187) gives the 3-aminopyrrole 4-5 Step 5 Acylation of pyrrole 4-5 with tnchloroacetyl chloπde according to the procedure of Bailey et al (Organic Syntheses 1971, 5/, 100) produces the pyrrole 4-6 Step 6 Hydrolysis of 4-6 will give amino acid 4-7 Step 7 Acylation of 4-7 provides the desired target compound 4-8 Examples 4B-4M
[00563] Compounds 4B-4M are synthesized as described in Example 4A using the appropriate starting materials and intermediates with selective protection and deprotection when necessary
Figure imgf000108_0001
Figure imgf000109_0001
Example SA: General Synthesis of Compounds of the Formula 5A
Figure imgf000109_0002
Formula 5A
[00564] Compounds of the Formula 5A are synthesized according to Scheme 5 A. Scheme SA
Figure imgf000109_0003
[005651 Step /: Following the procedure of Penning (J. Med. Chem. 1997, 40, 1347) nitro ketone 5-1 is condensed with dimethylformamide to provide the enamide 5-2. Step 2: Reaction of phenyl hydrazine hydrochloride with enamide 5-2 in methanol gives pyrazole 5-3. Step 3: Reduction of nitro compound 5-3 according to (he procedure of Penning (J. Med. Chem. 1997, 40, 1347) will yield the aminopyrazole which is acetylated with benzoyl chloride to give compound 5-4. Step 4: Hydrolysis of the meβiyl ester gives the compound 5-5. Examples 5B-5M
[00566] Compounds 5B-SM are synthesized as described in Example 5A using the appropriate starring S materials and intermediates with selective protection and deprotection when necessary.
Figure imgf000111_0001
Figure imgf000112_0001
Example 6A: General Synthesis of Compounds of the Formula 6A
Figure imgf000112_0002
Formula 6A [00567] Compounds of the Formula 6A are synthesized according to Scheme 6 A Scheme 6A
Figure imgf000112_0003
[00568] Step I BromoanthraiuUc acid derivative 6-1 is subjected to a palladium-catalyzed cross-coupling reaction (Organic Syntheses 1998 75, 53) with phenyl boronic acid to give amino ester 6-2 Step 2 Reaction of 6-2 with benzoyl chloride will give amide 6-3 Step 3 Hydrolysis of the methyl ester gives the compound 6-3 Examples 6B-6M
[00569] Compounds 6B-6M are synthesized as described in Example 6A using the appropriate starting materials and intermediates with selective protection and dcprotection when necessary.
Ill
Figure imgf000114_0001
Figure imgf000115_0001
Example 7A: General Synthesis of Compounds of the Formula 7 A
Figure imgf000115_0002
Formula 7A
[00570] Compounds of the Formula 7A are synthesized according to Scheme 7 A. Scheme 7A
Figure imgf000115_0003
[00571] Step 1 Bromothiophene derivative 7-1 is subjected to a palladium-catalysed cross-coupling reaction (Organic Syntheses 1998, 75, 53) with phenyl boronic acid to give acid 7-2 Step 2 Treatment of 7-2 with butyl lithium will result in metalation of the thiophene nng at the 2 -position with the carboxylate group serving to direct metalation as shown in intermediate 7-2a (See Organic Syntheses 1970, 50, 104, Organic Syntheses 1995, 72, 163) Addition of the Weinreb's amide derived from oxalic acid (Sibi et alJ Org Chem , 1995, 60, 5016, Nahm, S , Weinreb, S M Tetrahedron Lett 1981, 22, 3815-3818) to this lithium species will afford ketone 7-3 Step 3 Treatment of amide 7-3 with phenyl magnesium bromide yields ketone 7-4 Activation of the acid in 7-4 and condensation with hydrazine affords hydraztde 7-5 Examples 7B-7M
[00572] Compounds 7B-7M are synthesized as described m Example 7A using the appropriate starting S materials and intermediates with selective protection and deprotection when necessary
Figure imgf000117_0001
Figure imgf000118_0001
Example 8A: General Synthesis of Compounds of the Formula 8A
T IT 7-NHcoR2
Formula 8A [00573] Compounds of the Formula SA are synthesized according to Scheme 8 A. Scheme 8A
Figure imgf000118_0002
[00574] Step 1 Tetralone 8-1 is subjected to thiophene annulation according to the procedure of Amr et al (Bioorg Med Chem 2006, 14, 5481) wherein methyl cyanoacetate is added to the ketone in the presence of elemental sulphur and diethyl amine to give the tricyclic thiophene 8-3 Step 2 Treatment of 8-3 with benzoyl chloride affords amide 8-4 Step 3 Hydrolysis of the ester in 8-4 will be performed with aqueous sodium hydroxide to give acid 8-5 Examples 8B-8M
[00575] Compounds SB-8M are synthesized as described m Example 8A using the appropriate starting materials and intermediates with selective protection and deprolecuon when necessary
Figure imgf000120_0001
Figure imgf000121_0001
Biological Examples
In Vitro Examples
Example 9: In Vitro Screening for Agents that Modulate Intracellular Calcium Levels
[00576] Fluorescence-based assays are used for screening the compounds described herein, such as compounds of Formulas (I), (II), (HI), (TV), (V) and (VI)1 which modulate intracellular calcium
A. Assay Protocol
[00577] RBL-2H3 cells plated m 384-well plates are loaded for 45 mm with FLUO-4-AM (2 μM final concentration) m a Hanks-buffered salt solution Cells are washed and placed m a nominally Ca2+- and Mg2+- free Hanks solution. One minute later, a test agent or vehicle is added After a IS minute incubation period, 1 μM thapsigargin (Tg) is added to inhibit the ER Ca2+ pump and discharge intracellular Ca2+ stores Fifteen minutes after addition of Tg, store-operated calcium entry is initiated by adding external Ca2+ to a final concentration of 1 8 mM and the cells monitored for a further 10-15 minutes Calcium levels are monitored throughout the assay using a FLIPR384 (Molecular Devices fluorimetnc imaging plate reader for high throughput screening) [00578] In an alternative screening assay procedure, one minute after washing out the FLUO-4-AM, 1 μM Tg is added to the SH-SY5Y cells Fifteen minutes after addition of Tg, test compound or vehicle is added, followed by another 15 minute incubation in Ca2+-free buffer Store-operated calcium entry is then initiated by adding external Ca2+ to a final concentration of 1 S mM and the response monitored for a further 10-15 minutes [00579] A similar screening assay procedure is used with HEK293 and RBL-2H3 cells
[00580] In some embodiments, the screening assay alternatively uses external Ba2+ (final concentration of 10 mM) in place of external Ca2+ In this case, thapsigargin- induced store-operated Ba2+ entry serves as a surrogate for store-operated Ca2+ entry
B. Data Analysis [00581] The kinetic data from the FLIPR384 are analyzed and stored in a relational database (AcuvityBase,
IDBS) Ten quantitative parameters are calculated dial define various aspects of the store-operated calcium entry response These parameters are as follows
Mean Basal: basal fluorescence (relative fluorescence units, RFU) readings averaged over 30 seconds prior to addition OfCa2+ to initiate store-operated calcium entry Up slope: linear regression of the increase m RFU from 2 to 30 sec after addition OfCa2+
Up rate constant (Up IQ the rate constant derived from first-order association of RFUs from 2 seconds to peak response
Peak: me peak RFU (single point) achieved after addition of Ca2+
Time to peak: the tune at which the peak RFU is achieved. Peak/Basal the difference between peak and mean basal RFU
Decay slope: linear regression of the decrease in RFU from the peak to the end of the measurement period Decay rate constant (Decay K): the rate constant derived from first-order decay of RFUs from the peak to the end of the measurement peπod Area under the curve (AUC): area under the curve from the addition OfCa2+ to the end of the measurement peπod
[00582] Combinations of these parameters are used to characterize the compounds of Formulas (I), (II), (III), (IV), (V) and (VI) Compounds are retested under identical conditions to confirm their activity Compounds with confirmed activity are then analyzed for concentration-dependent effects, and subsequently, those compounds displaying concentration-dependent effects are categorized as compounds that modulate intracellular calcium
[00583] Please provide data, if any, from this assay
Example 10: In Vitro Effects of Agents that Modulate Intracellular Calcium on Degranulation and
Cytokine Release in RBL-2H3 Cells.
[00584] To assess degranulation and cytokine release, RBL-2H3 cells are plated and stimulated with 20 nM thapsigargm/20 nM TPA for 20 hr in the presence or absence of compound of Formulas (I), (II), (HI), (IV), (V) or (VI) Media is collected and assayed for the release of the inflammatory mediator β-hexosammidase or for the release of the cytokine TNF-α The β-hexosaminidase enzymatic assay is performed by adding 200 μL 1 mM p- mtrophenyl-acetyl-glucosamide substrate (Sigma #N9376) in 0 OSM sodium citrate (pH 4 5) to 50 μL of conditioned medium, incubating for 60 mm at 37 0C, then adding 500 μL 005M sodium carbonate, 0 05M sodium bicarbonate pH 10 5, mixing thoroughly, and reading the absorbance at 405 nm in a BioRad plate reader The TNF-Ot release assay is performed using the Rat Tumor Necrosis Factor-α Ultrasensitive ELISA Kit from BioSource
Example 11: Modulation of Intracellular Calcium by a SOCl Inhibitor in STIMl-Overexpressing Cells [00585] Store-operated calcium entry is sensitive to the inhibitor 2-aminoethoxydiphenyl borate (2-APB) To test whether the Ca2+ entry pathway consutuuvely activated by STIM 1 overexpression is pharmacologically similar to endogenous SOCE, HEK[STIMl] cells are pre-incubated with increasing doses of 2-APB and STIMl-induced Ca2+ entry is measured. Thapsigargin-mediated store depletion of both HEK-Zeo control cells and HEKf STIMl] cells followed by readdraon of external calcium results in inhibition by 2-APB with similar ICj0 values of 11 8 μM and 10 5 μM, respectively Treatment OfHEK[STIMl] cells with 2-APB and examining calcium entry in the absence of store depletion results in a biphasic effect of 2-APB on calcium entry The constitutive calcium entry is inhibited with an IC30 value of 10 8 μM, similar to that reported for endogenous SOCE However, at lower concentrations of 2-APB, calcium entry is potentiated The ability to both potentiate and inhibit calcium entry is a property of 2-APB that has previously been shown to occur with the calcium release activated calcium (CRAC) channel [00586] Thus, overexpression of STIMl m HEK293 cells confers a CRAC-like property to constitutive Ca2+ entry measured in HEK293 cells Accordingly, assays to identify agents that modulate intracellular calcium can optionally be performed in cells overexpressing STIMl in the absence of intracellular calcium depletion protocols Example 12: In Vitro Effects of Agents that Modulate Intracellular Calcium on IL-2 Secretion from Jurkat T Cells.
[00587] To measure IL-2 secretion from Jurkat T cells, cells are plated in a 96 well plate at a density of 1 5 x 10s cells/well Cells are stimulated with 2 5 μg/ml PHA lectin + 80 nM TPA for 20 hr m the presence or absence of a compound of Formulas (I), (II), (HI), (TV), (V) or (VI) The medium is then collected and analyzed for IL-2 levels by ELISA (BioSource) according to the manufacturer's protocols In Vivo Examnles
Example 13. Dose-Response Effects of Test Compound, CSA or Rapamycin in Mouse Footpad DTH [00588] Purpose Determine dose-response effects of Test Compound on mBSA induced DTH response in foot pads when dosmg is done during the sensitization as well as induction phase [00589] Animals 61 Male Swiss Webster Mice approx 20-25 grams at start of study [00590] Materials Methylated BSA (Sigma) Freund's complete adjuvant (Difco) phis supplemental M tuberculosis H37 RA (Difco) [00591] General Study Design.
[00592] Mice are anesthetized with Isoflurane and given intradermal antigen injections of 0 1 ml at the base of the tail (DO, D07) Antigen is prepared by making a 4 mg/ml solution in sterile water Equal volumes of antigen and Freund's complete adjuvant to which 4 mg/ml MTB are added (sonicate for 5 minutes after adding MTB to oil), are emulsified by hand mixing until a bead of this materia! holds its form when placed m water Treatment is initiated on day 0, qd (24 hr intervals) and continued through day 10 when challenge is done [00593] On day 10 ammals are injected into the right hind footpad with 20μl of lOmg/ml mBSA Five unsensitized males are injected with mBSA into the footpad Twenty-four hours later (day 11) the right and left hind paws are transected at the medial and lateral malleolus and weighed and the weight difference induced by injection of antigen is determined
[00594] Statistical Analysis Paw weights (mean±SE) for each group are analyzed for differences using a Student's t test or ANOVA with Dunnett's post test Statistical significance is set at p ≤) 05 Table 1. Treatment Groups Males
Group N Treatment 10 ml/kg qd, po
1 S Normal controls (no sensitization) Inject mBSA into right only
2 8 DTH+Vehicle (70% PEG400/30%Water)
3 8 DTH+ Test Compound (50 mg/kg, po, qd)
4 8 DTH+ Test Compound (100 mg/kg, po, qd)
5 8 DTH+ Test Compound (200 mg/kg, po, qd)
6 8 DTH+ Test Compound (300 mg/kg, po, qd)
7 8 DTH+ CSA (100 mg/kg qd, φ)
8 8 DTH+Rapamycin (5 mg/kg qd, iρ)
Example 14: Effect of Test Compound in Rat Collagen Induced Arthritis (CIA) model
[00595] Purpose Determine efficacy of Test Compound administered by oral dosing qd, in inhibiting the inflammation, cartilage destruction and bone resorption of developing type II collagen arthritis in rats [00596] Animals: 44 Female Lewis rats (Charles River#7246950), weighing 125-150 g at the start of the study 40 rats are injected with collagen to get 40 solid responders on days 10,11 for 4 groups of 10 Four nommmiimzed animals serve as normal controls
[00597] Materials: Test Compound (sodium salt), PEG400 as liquid, Type II collagen, Freund's incomplete adjuvant, acetic acid. Test Compound is prepared at a concentration of up to 100 mg/ml in 70% PEG400 / 30% water Collagen is prepared by making a 4 mg/ml solution m 00 IN Acetic acid Equal volumes of collagen and Freund's incomplete adjuvant, are emulsified by hand mixing until a bead of this material holds its form when placed in water
[00598] General Study Design: Animals (10 rats/group for arthritis, 4 rats/group for normal control) [00599] Animals in groups 2-5 are anesthetized with isoflurane and given collagen injections (DO), each animal gets 300 μl of the mixture spread over 3 subcutaneous sites on the back. On Day 6 (D6) the animals are anesthetized again and given a second collagen injection, as before
[0O600] Oral dosing of Test Compound at 24 hour intervals (qd) is initiated on Day 0 using a dose volume of 5 ml/kg for oral solutions Rats are weighed on Days 0, 3, 6, and 9-17 of arthritis, and caliper measurements of ankles taken every day beginning on Day 9 Final body weights are taken on Day 17 of arthritis On Day 17, all animals are anesthetized for terminal blood draw and then euthanized Subsequently, hmd paws and knees are removed, the hind paws are weighed and then (with knees) placed m formalin for processing for microscopy Livers, spleen and thymus and kidneys are also removed, tπmmed of extraneous tissue and weighed Kidneys are retained in formalin for histopathology [006*01] Sampling will occur over 1 day and involves groups 2-5 with samples retained from all groups This results m all animals being treated similarly and is important for clinical parameters and final liver weights
Example 15: Effect of compounds of Formulas (I), (II), (HI), (TV), (V) and (Vl) on DNBS-Induced Colitis in Rats
[006*02] Procedure Male Wistar rats weighing 200 * 20 g are fasted for 24 hours pπor to use Distal colitis is induced by mtra-colonic instillation of DNBS (2,4-dinotrobenzene sulfonic acid, 20 nig in 0 5 ml ethanol 30%) with a catheter of 12 cm in length, followed by gentle injection of air (2 ml) through the catheter to ensure that the solution remain in the colon The animals are divided into groups of 5 each Test substance and vehicle are administered either daily or twice daily by appropriate route of administration 24 hour and 1 hour before DNBS instillation and then for 6 consecutive days thereafter One normal control group is treated with 0 9% NaCl alone without DNBS challenge The animals are sacrificed 12 hours after the final bid dose and 24 hours after the final daily dose and the colon is removed and weighed During the experiment, body weight, fecal occult blood and stool consistency are monitored daily Furthermore, when the abdominal cavity is opened before removal of the colon, adhesions between the colon and other organs are noted as is the presence of colonic ulceration after removal and weighing of each colon (a macroscopic damage score is recorded according to established score criteria) The colon-to-body weight ratio is calculated according to the formula Colon (g)/BW x 100 The "Net" increase in ratio of Vehicie-control + DNBS group relative to Vehicle-control group is used as a base for comparison with individual treated groups and expressed as "Dec (%)" (percent decrease) A 30% or more ( -80%) reduction in colon-to-body weight ratio, relative to the vehicle treated control group, is considered significant [00603] Sulfasalazine is used the standard test agent (Hogaboam CM, et al , An orally active non-selective endothelin receptor antagonist, bosentan, markedly reduces injury in a rat model of colitis Ew J Pharmacol 309 261-269, 1996, Yue G, et al , In some embodiments, the 21-aminosteroid tinlazid mesylate ameliorates inflammatory bowel disease in rats J Pharmacol Exp Ther 276 265-270, 1996 ) Example 16: Phase II Clinical Trial of the Safety and Efficacy of Compounds of Formula (I), (II), (TII), (IV), (V) or (VI) in Patients with Active Rheumatoid Arthritis.
[00604] The purpose of this phase II trial is to investigate the safety, tolerability, PK, PD, and efficacy of single and repeat intravenous infusions of a compound of Formula (I), (II), (IU), (IV), (V) or (VI) m patients with active rheumatoid arthritis [00605] Patients Eligible subiects will be men and women between the ages of 18 and 75 [00606] Criteria Inclusion Criteria.
• All subjects must use acceptable contraception to ensure that no pregnancies occur during the course of the study and for at least 12 weeks after dosing for males and for 32 weeks after dosing for females, • Body mass index within the range 18 5 - 35 kg/m2 mclusive, m addition to a weight range of 55 - 95kg,
• The subject must be capable of giving informed consent and can comply with the study requirements and timetable,
• The subject must have a diagnosis of RA according to (he revised 1987 criteria of the American College of Rheumatology (ACR), • The subject must have a DAS28 disease activity score of greater than 42 at screening and pie-dose,
• The subject must have a CRP serum level of >/05mg/dl or an ESR level 28mm/hour at screening and pre-dose,
• The subject has NOT received any biological therapy in the past, including biologicals for the treatment of rheumatoid arthritis, • The subject must have liver function tests including alanine transaminase (ALT) and aspartate transaminase (AST) within 1 5 times the upper limit of normal (ULN) and alkaline phosphatase (ALP) within 3 times ULN at screening The patient must also have total bilirubin Within the ULN at screening, • The subject must have received at least 3 months of methotrexate and must be on a stable dose of methotrexate (up to 25 mg/week) for at least 8 weeks prior to screening and be willing to remain on this dose throughout the study,
• If sulfasalazine is being taken in addition to methotrexate, the subject must be on a stable dose for at least 4 weeks prior to screening and be willing to remain on this dose throughout the study,
• If hydroxychloroquine or chloroquine is being taken in addition to methotrexate, the subject must be on a stable dose for at least 3 months prior to screening and be willing to remain on this dose throughout the study,
• Those subjects on other oral anti-rheumatic therapies, which may include Non Steroidal Anti Inflammatory Drugs (NSAIDs), COX-2 inhibitors, oral glucocorticoids e g prednisolone (~10mg/day) must be on stable dosing regimens for at least 4 weeks pπor to screening and be willing to remain on this regime throughout the study Subjects receiving intramuscular glucocorticoids e g methylpredmsolone (-120 mg/month) must be on a stable dosing regimen for at least 3 months pπor to screening and be willing to remain on this regimen throughout the study, • The subject must be on a stable dose of folate supplements (5 mg/week) for at least 4 weeks pπor
Exclusion Criteria
• Any clinically relevant abnormality identified on the screening medical assessment, laboratory examination (e g haematology parameter outside the normal limits), or ECG (12 Lead or Hotter),
• The subject has a positive Hepatitis B surface antigen or Hepatitis C antibody result at screening, • The subject has a history of elevated liver function tests on more than one occasion (ALT, AST and
AU > 3 x Upper Limit of Normal (ULN), total bilirubin > 1 5 x ULN) in the past 6 months,
• Previous exposure or past infection caused by Mycobacterium tuberculosis,
• The subject has an acute infection,
• The subject has a history of repeated, chrome or opportunistic infections that, in the opinion of the investigator and/or GSK medical monitor, places the subject at an unacceptable risk as a participant in this trial,
• The subject has a history of malignancy, except for surgically cured basal cell carcinoma or females with cured cervical carcinoma (> 2 yrs pπor),
• The subject has a history of human immunodeficiency virus (HIV) or other immunodeficiency disease, * The subject whose calculated creatinine clearance is less than 50ml/min,
• The subject has significant cardiac, pulmonary, metabolic, renal, hepatic or gastrointestinal conditions that, ui the opinion of the investigator and/or GSK medical monitor, places the subject at an unacceptable risk as a participant m this trial,
• The subject has taken cyclospoπne, leflonomide, cyclophophamide or azathioprine within 1 month of screening Subjects that have taken cyclospoπne, leflonomide, cyclophophamide or azathioprine in the past must have recovered from all drug related adverse events,
• The subject has taken gold salts or d-penicillamine within 1 month pπor to screening Subjects that have taken gold salts or d-penicillamine in the past must have recovered from all drug related adverse events, • The subject has received ultra-articular glucocorticoids within 1 month of screening,
• Recent history of bleedmg disorders, anaemia, peptic ulcer disease, haematemesis or gastrointestinal bleeding,
• Subjects with a history of haematological disease or acquired platelet disorders, including drug-induced thrombocytopaenia, acute idiopathic thrombocytopaenia or von Willebrand's disease, • Subjects with a known risk of lntra-crarual haemorrhage including Central Nervous System (CNS) surgery within the last 12 months, arterial vascular malformations, aneurysms, significant closed head trauma within 6 months or any other incident the investigator and/or medical monitor considers to be relevant,
• The subject has Hb <10 g/decihter (dL) and platelet count < 150 x 109/Liter (L), • Donation ofblood m excess of 500 ml within a 56 day penod prior to dosing,
• An unwillingness of male subjects to abstain from sexual intercourse with pregnant or lactatmg women, or an unwillingness of the male subject to use a condom with spermicide in addition to having their female partner use another form of contraception such as an mteruteπne device (IUD), diaphragm with spermicide, oral contraceptives, injectable progesterone, subdermal implants of levonorgestrel or a tubal ligation if the woman could become pregnant for at least 12 weeks after dosing,
• An unwillingness of female subject of child bearing potential to use adequate contraception, as defined in the study restriction section If necessary, women of non-child bearing potential (i.e postmenopausal or surgically steπle e g tubal ligation or hysterectomy or bilateral oophorectomy) will be confirmed Postmenopausal status will be confirmed by serum follicle stimulating hormone (FSH) and oestradiol concentrations at screening Surgical sterility -will be defined as females who have had a documented hysterectomy, tubal ligation or bilateral oophorectomy,
• The subject has a history of use of drugs of abuse within 12 months pπor to screening, • History of regular alcohol consumption exceeding average weekly intake of greater than 21 units or an average daily intake of greater than 3 units (males) or an average weekly intake of greater than 14 units or an average daily intake of greater than 2 units (females) Subjects who regularly consume more than 12 units of alcohol in a 24h period will also be excluded 1 unit is equivalent to a half-pint (220ml) of beer/lager or 1 (25ml) measure of spirits or 1 glass (125ml) of wine, • Positive pregnancy test or lactatuig at screening,
• Participation in a trial with any investigational drug within 3 months or 5 balf-Uves (whichever is longer) before
[00607] Study Design. This is a randomized, double-blinded, placebo-controlled adaptive, dose finding study to investigate the safety, tolerabihty, PK, PD and efficacy of single and repeat intravenous infusions of a compound of Formula (I), (II), (in), (IV), (V) or (VI) in patients with active rheumatoid arthritis The study is divided into 2 parts Part A is an adaptive, dose finding phase which will provide safety, tolerabihty, PK and PD on single intravenous infusions Part B is a repeat dose phase which will provide safety, tolerabihty, PK, PD and efficacy following repeat intravenous infusions of a selected dose level
Figure imgf000127_0001
• Safety and Tolerabihty following single ascending doses of a compound of Formula (I), (II), (HI), (FV),
(V) or (VT) at 1 month and following 3 repeat doses of a compound of Formula (I), (II), (III), (IV), (V) or (VI) at 3 months Clinical Efficacy (DAS28 score) of a compound of Formula (I), (II), (HI), (TV), (V) or (VI) at 1 month [00609] Secondary Outcome Measures • Weighted mean DAS28 after single and repeat intravenous doses
• Plasma PK parameters of a compound of Formula (I), (IT), (IH), (TV), (V) or (VT) after single and repeat intravenous doses including free, and bound a compound of Formula (I), (II), (in), (IV), (V) or (VT) (serum) concentrations, AUC,^,, Cm clearance, volume of distribution and accumulation ratio
• DAS28 and EULAR response criteria after single and repeat intravenous doses • ACR20/ACR50/ACR70 response after single and repeat intravenous doses
• Number of swollen joints assessed using 28-jomt counts
• Number of tender/painful joints assessed using 28-jomt counts
• Subject's pain assessment
• Physician's global assessment of arthritis condition • Patients' global assessment of arthritis condition
• Functional disability mdex (Health Assessment Questionnaire)
• C-reactve Protein (CRP)
• ESR
• Global Fatigue Index • HAQ disability index
• Pharmacodynamic biomarkers after single and repeat intravenous doses
• Characteristic AUC50 and EC50 for clinical endpoint changes with plasma exposure model, as assessed by sigmoid E011x and indirect response "PKfPO models • Immunogemcity (Human anti-compound of Formula (I), (II), (III), (IV), (V) or (VI) antibodies) Phase II Clinical Trial of the Safety and Efficacy of Compounds of Formula (I), (D), (ID), (IV), (V) or (VI) in Patients with Severe, Recalcitrant, Plaque-type Psoriasis.
[00610] The purpose of this phase II trial is to investigate the safety, efficacy, and tolerability of a compound of Formula (I), (II), (IH), (IV), (V) or (VI) in patients with severe, recalcitrant, plaque-type psoriasis [00611] Patients Eligible subjects will be men and women between the ages of 18 and 75 [00612] Criteria Inclusion Criteria
• The patient has severe, recalcitrant, plaque-type psoriasis and has failed at least 1 systemic therapy (for the purposes of this study psoralen with ultraviolet light A is considered to be a systemic therapy),
• The patient has psoriatic involvement of at least 10% of BSA,
• The patient has a PSGA score of 4 or greater;
• The patent, if a woman, is surgically sterile or 2 years postmenopausal, or if of childbeanng potential is currently using a medically accepted method of contraception, and agrees to continue use of this method for the duration of the study (and for 30 days after participation in the study) Acceptable methods of contraception include abstinence, steroidal contraceptive (oral, transdermal, implanted, or injected) m conjunction with a barrier method, or intrauterine device (IUD),
• The patient, if a main, is surgically sterile, or if capable of producing offspring, is currently using an approved method of birth control, and agrees to continued use of this method for the duration of the study (and for 60 days after taking the last dose of a compound of Formula (I), (II), (IH), (IV), (V) or
(VI) because of the possible effects on spermatogenesis),
• The patient must be willing and able to comply with study procedures and restrictions and willing to return to the clinic for the follow-up evaluation as specified in this protocol
Exclusion Criteria • The patient has received treatment with systemic psoriasis treatments (specifically, retinoids, methotrexate, cyclospoπne A, etanercept, efalizumab, other biological agents or other lmmunomodulators) within 4 weeks, or UV based therapy within 2 weeks, or alefacept within 6 weeks of the planned 1st day of study treatment,
• The patient has received treatment with potent CYP3A4 inhibitors including cyclosporme, clotrimazole, fluconazole, itraconazole, ketoconazole, voπconazole, erythromycin, clarithromycin, and troleandomycin, human immunodeficiency virus (HIV) protease inhibitors, or nefazodone within 1 week (7 days) of the planned 1st day of study treatment,
• The patient is currently receiving warfarin,
• The patient has hypersensitivity to a compound of Formula (I), (E), (III), (IV), (V) or (Vl) or any component of a compound of Formula (I), (H), (IH), (IV), (V) or (VT),
• The patient has one or more of the following serum chemistry values as determined at the screening visit (visit 1)
• bilirubin levels greater than 2 tunes the upper limit of normal (ULN),
• ALT or AST levels greater than 2 tunes the ULN, • serum creatinine levels or more than 2mg/dL,
• The patient requires current treatment for HIV with protease inhibitors,
• The patient is taking medication for a clinical diagnosis of gastrointestinal ulceration or has expeπenced melena or hematoemesis in the previous 3 weeks,
• The patient is a woman who is pregnant or lactating, • The patient has received treatment with an investigation drug within 4 weeks of the planned 1 st day of study treatment [00613] Study Design This is an exploratory, open-label, nonrandomized, dose-escalation study of the efficacy, safety, and tolerability of a compound of Formula (I), (II), (HI), (IV), (V) or (VI) m patients with severe, recalcitrant, plaque-type psoriasis Phase π Clinical Trial of the Safety and Efficacy of Compounds of Formula (I), TO, (m), (IV), (V) or (VT) for Prophylaxis of Acute Rejection after Renal Transplantation [00614] The standard immunosuppressive treatment after renal transplantation is a combination of tacrolimus, mycophenolate mofetil, and prednisolone With this regimen the incidence of acute rejection within the first six months after transplantation can drop to about 20% The main challenge at present remains to improve long-term outcome by preventing chronic allograft nephropathy (CAN) Since acute rejection is a strong predictor of CAN, a further decrease in the incidence of acute rejection can improve the long-term graft survival The purpose of this phase II clinical trial is to investigate the effectiveness and safety of a compound of Formula (I), (II), (III), (IV), (V) or (VT) for prophylaxis of acute rejection after renal transplantation [00615] Patients Eligible subjects will be men and women ages 18 and older [00616] Cfltejia: Inclusion Criteria.
• Renal transplant recipients,
• Signed, dated, and witnessed IRB approved informed consent, Exclusion Criteria.
• Pregnancy, • Living donor, who is HLA identical,
• Hemolytic uremic syndrome as original kidney disease,
• Focal segmental glomerulosclerosis that had recurred in a previous graft,
• More than two previously failed grafts and/or PRA > 85%,
• Diabetes melhtus that is currently not treated with insulin, • Total white blood cell count <3,000/mm3 or platelet count <75,000/mm3,
• Active infection with hepatitis B, hepatitis C, or HIV,
• History of tuberculosis
[00617] Study Design. This is a randomized, double blind, placebo controlled intervention study on the efficacy and safety of the prophylactic use of a compound of Formula (I), (II), (III), (TV), (V) or (VI) One group will receive a single dose of a compound of Formula (I), (U), (III), (IV), (V) or (VI) intravenously at the time of transplantation, and the other group receives a placebo infusion [00618] Primary Outcome
• To determine the incidence and seventy of biopsy-confirmed acute rejection within the first six months after transplantation [00619] Secondary Outcomes
• Renal function as estimated by the endogenous creatinine clearance at 6 months
• Occurrence of chrome allograft nephropathy at 6 months
• Cumulative incidence of infections and malignancies at 6 months
• Medical costs during the first 6 months after transplantation • Patient and graft survival
Phase II Clinical Trial of the Safety and Tolerability of a compound of Formula (I), (II), (ID), (TV), (V) or (VI) in Patients with Active Ulcerative CoUtIs (CC)
[00620] The purpose of this phase II trial is to investigate the safety, tolerabihty of a compound of Formula (I), (II), (HI), (IV), (V) or (VI) regimen in patients with active ulcerative colitis [00621] Patients Eligible subjects will be men and women aged 18 and older [00622] Cπteπa
Inclusion Criteria
• Active UC on 5-ASA therapy and also treated with 6-MP and/or corticosteroids or who have previously been treated with AZA, 6-MP or corticosteroids and could not tolerate them, • Mayo score of 6 to 10 points with moderate to severe disease on endoscopy (Mayo score of at least
2) performed ≤14 days of study drug administration,
• Subjects on the following medications may be enrolled into the study if the medications were according to the following schedules prior to study drug administration and if no changes are anticipated during the study, o prednisolone ≤20 mg daily (or equivalent) (dose must be stable for at least 2 weeks prior to study drug administration), o 5-ASA (dose must be stable for at least 4 weeks pπor to study drug administration), o AZA or 6-MP (dose must be stable for at least 3 months pπor to study drug administration), o Rectal steroids or 5-ASA (must have been stable for at least 4 weeks pπor to study drug),
• Subjects usmg rectal medications must have visible disease on sigmoidoscopy at ≥20 cm,
• Screening laboratory values must meet certain cπteπa o Women must be postmenopausal (> 12 months without menses) or surgically sterile (e g , by hysterectomy and/or bilateral oophorectomy) or must be using effective contraception (e g , oral contraceptives, intrauterine device (IUD), double barrier method of condom and spermicidal) for at least 4 weeks pπor to study drug administration and agree to continue contraception for the duration of their participation m the study, and o Sexually active male subjects must use a barrier method of contraception during the duration of the study Exclusion Cπteπa
• Anti-TNF therapy within 8 weeks before study drug administration,
• Any experimental therapy more therapy ≤4 weeks before study drug administration,
• Pπor treatment with any monoclonal antibody or lmmunoglobulin-based fusion proteins ≤S weeks pπor to study treatment, • Presence of Cushmg's syndrome,
• Toxic megacolon or fulminant disease likely to require colectomy,
• Contraindication to colonoscopy or sigmoidoscopy,
• Primary or secondary immunodeficiency,
• Autoimmune disease besides UC, with the exceptions of Sjogren's syndrome or hypothyroidism, • History of malignancy, excluding adequately treated and cured basal or squamous cell of the skin, or cervical carcinoma in situ,
• Major psychiatπc disease (subjects with stable depression receiving appropπate management will be permitted in the study),
• Evidence of acute or chrome infection as evidenced by • stool culture positive for pathogens and/or Clostridium difficile toxni,
• findings on Screening chest radiography such as pulmonary infiltrate(s) or adenopathy,
• current treatment for tuberculosis infection, clinical or radiological evidence of active TB, or for subjects m North Amenca, a positive PPD without pnor prophylaxis,
• Herpes zoster ≤3 months pπor to study drug administration, • active infectious disease requiring i v antibiotics within 4 weeks pnor to study treatment or oral antibiotics at the time of enrollment,
• HIV or AIDS,
• positive tests for HBV, or HCV indicating active or chronic infection,
• Clinically significant cardiac disease requiring medication, unstable angina, myocardial within 6 months, or congestive heart failure,
• Arrhythmia requiring active therapy, with the exception of clinically insignificant or minor conduction abnormalities,
• History of cerebrovascular disease requiring medication/treatment,
• Anticoagulation therapy or a known bleeding disorder, • Seizure disorder requiring active therapy,
• Known drug or alcohol abuse, • Pregnant or nursing,
• Any underlying medical condition that in the Principal Investigator's opinion will make the study drug hazardous to the subject or would obscure the interpretation of treatment efficacy or safety, or
• Inability or unwillingness to return for Follow-up visits and comply with study protocol [00623] PπrfifllΥ Outcome Measures.
• Change m Mayo score at Day 57 compared with Screening [00624] Secondary Outcome Measures.
• Remission rate
[00625] Study Design This is a phase II, double-blind, placebo-controlled, randomized, multi-dose study of a compound of Formula (I), (II), (HI), (TV), (V) or (VI) m subjects with active UC experiencing flare All subjects will have active disease while on a 5-ASA containing medication and are either on stable doses of corticosteroids and/or azathiopπne or 6-mercaptopunne, or who have previously been on these medications but could not tolerate them. Flare is defined as a Mayo score of 6 to 10 with moderate to severe disease activity on endoscopy (Mayo endoscopic subscore of at least 2) within 2 weeks of receiving study drug administration Doses of permitted concomitant medications (corticosteroids, azathiopπne (AZA), 6-mercaptopuπne (6-MP), and 5-aminosalicylates (5-ASA) containing compounds) should remain constant during the course of the study Subjects will be randomized to receive placebo or a compound of Formula (I), (II), (ID), (IV), (V) or (VI) intravenously on Days 1, 15, 29, and 43 All subjects will be seen in the clinic at regular intervals up to Day 85 for safety, efficacy, pharmacokinetic, and/or pharmacodynamic assessments AU subjects will be contacted 70 days after the last dose of study drug Assessment of safety will be determined by vital sign measurements, cluneal laboratory tests, physical examinations, immunogenicity assessments, chest x-ray, electrocardiograms, and the incidence and seventy of treatment emergent adverse events The primary clinical assessment of activity will be determined by the change m Mayo score at Day 57 compared with Screening Secondary endpoints include determination of remission rate by the mayo score at Day 57, evaluation of mucosal healing and change from baseline in the IBDQ score
Phase π Clinical Trial of the Safety and Efficacy of Compounds of Formula (I), (II), (IH), (IV), (V) or (VI) in Patients with Multiple Sclerosis
[00626] The purpose of this phase II trial is to investigate the safety, efficacy and tolerability of a compound of Formula (I), (II), (III), (IV), (V) or (VI) in patients with Relapsing Remitting Multiple Schlerosis [00627] Patients Eligible subjects will be men and women between the ages of 18 and 65 [00628] Criteria
Inclusion Criteria
• Have a definite diagnosis of Relapsing remitting Multiple Sclerosis
• Have a history of at least 1 of the following a. A minimum of 2 relapses of MS within the previous 2 years but not withm the 1-month period prior to screening b A relapse of MS within the previous 6 months but not within the 1-monthpeπod prior to screening Exclusion Criteria
• Have a CNS disease (e g , CNS lymphoma, systemic lupus erythematous)
• Have significant bulbar involvement of MS or other neurologic deficits • Have a decubitus ulcer
• Have received immunomodulatory therapies within 3 months of screenmg [00629] TMIΠUΠΎ Outcome Measures.
• The cumulative number of newly Gd-enhancing T 1 -weighted lesions on cranial MRIs through week 23
[00630] Secondary Outcome Measures
• The total number of relapses of MS through week 23, change from baseline in Expanded Disability Status Scale (EDSS) score at week 23
[00631] Study Design This is a phase II, double-bhnd, placebo-controlled, randomized, dose-ranging study of multiple subcutaneous injections of a compound of Formula Q), (II), (HI), (IV), (V) or (VI) m patients with relapsing-remitting multiple sclerosis Patients will receive subcutaneous injections of a compound of Formula
10 (I), Qi), (IH), (IV), (V) or (VI) or placebo at weeks 0, 1, 2, 3, 7, 11, 15, and 19 or 100 Pharmaceutical Compositions
Parenteral Composition
[00632] To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of a compound of Formulas (I), (II), (HI), (IV), (V) or (VI) is dissolved in DMSO and then mixed with 10 mL of
15 0 9% stenle saline The mixture is incorporated into a dosage unit form suitable for administration by injection [00633] In another embodiment, the following ingredients are mixed to form an injectable formulation
Ingredient Amount
Compound of Formulas (I), Ql), (III), (TV), (V) or (VI) 1 2 g sodium acetate buffer solution (04 M) 2 O mL
HCl (I N) OrNaOH (I M) q s to suitable pH water (distilled, sterile) q s to 20 mL
[00634] All of the above ingredients, except water, are combined and stirred and if necessary, with slight heating if necessary A sufficient quantity of water is then added
Oral Composition
20 [00635] To prepare a pharmaceutical composition for oral delivery, 100 mg of a compound of Formulas Q), (II), (III), QV), (V) or (VI) is mixed with 750 mg of starch. The mixture is incorporated into an oral dosage unit, such as a hard gelatin capsule, which is suitable for oral administration. [00636] In another embodiment, die following ingredients are mixed intimately and pressed into single
Ingredient Quantity per tablet, mg compound of Formulas Q), (H), (HT), (IV), (V) or (VI) 200 Cornstarch 50 croscarmellose sodium 25 Lactose 120 magnesium stearate 5
25
[00637] In yet another embodiment, the following ingredients are mixed intimately and loaded into a hardshell gelatin capsule
Ingredient Quantity per tablet, mg compound of Formulas (I), Ql), QU), QY), (V) or (VI) 200 lactose, spray-dried 148 magnesium stearate 2
[00638] In yet another embodiment, the following ingredients are mixed to form a solution/suspension for oral administration.
Ingredient Amount Compound of Formulas (I), Ql), (Ql), (IV), (V) or (VI) I g
Anhydrous Sodium Carbonate O l g
Ethanol (200 proof), USP 1O mL
Purified Water, USP 9O mL
Aspartame 0003g
Sublingual (Hard Lozenge) Composition
[00639] To prepare a pharmaceutical composition for buccal delivery, such as a hard lozenge, mix 100 mg of a compound of Formulas (I), (ID, (IH), (IV), (V) or (VT) with 420 mg of powdered sugar mixed with 1 6 mL of light corn syrup, 24 mL distilled water, and 042 mL mint extract The mixture is gently blended and poured into a mold to form a lozenge suitable for buccal administration
Inhalation Composition
[00640] To prepare a pharmaceutical composition for inhalation delivery, 20 mg of a compound of Formulas (I), (H), (HI), (TV), (V) or (VI) is mixed with 50 mg of anhydrous citnc acid and 100 mL of 09% sodium chloride solution The mixture is incorporated into an inhalation delivery unit, such as a nebulizer, which is suitable for inhalation administration
Rectal Gel Composition
[00641] To prepare a pharmaceutical composition for rectal delivery, 100 mg of a compound of Formulas (I), (II), (III), (TV), (V) or (VI) is mixed with 2 5 g of methyicelluose (1500 mPa), 100 mg of methylparapen, 5 g of glycerin and 100 mL of purified water The resulting gel mixture is chen incorporated into rectal delivery units, such as syringes, which are suitable for rectal administration
Suppository Formulation
[00642] A suppository of total weight 2 5 g is prepared by mixing a compound of Formulas (I), (II), (III), (IV), (V) or (VI) with Witepsol™ H- 15 (triglycerides of saturated vegetable fatty acid, Riches-Nelson, Inc , New York), and has the following composition
Ingredient Quantity per suppository, mg compound of Formulas (I), (π), (IH), (TV), (V) or (VI) 500
Witepsol*H-15 balance
Topical Gel Composition
[00643] To prepare a pharmaceutical topical gel composition, 100 mg of a compound of Formulas (I), (II), (III), (TV), (V) or (VI) is mixed with 1 75 g of hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of isopropyl mynstate and 100 mL of purified alcohol USP The resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topical administration
Ophthalmic Solution Composition
[00644] To prepare a pharmaceutical opthaknic solution composition, 100 mg of a compound of Formulas (I), (II), (πi), (TV), (V) or (VI) is mixed with 0 9 g of NaCl in 100 mL of purified water and filtered using a 0 2 micron filter The resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration.
|0064S] The examples and embodiments described herein are for illustrative purposes only and m some embodiments, various modifications or changes are to be included within the purview of disclosure and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference.

Claims

WHAT IS CLAIMED IS:
1. A compound of Formula (I), or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:
Figure imgf000135_0001
Formula (I) wherein:
L is a bond, CrC6alkyl, Ci-Qalkenyl, Ci-Qheteroalkyl, aryl, or heteroaryl; wherein C1-QaUCyI, CrC6aIkenyl, Ci-Qheteroalkyl, aryl, or heteroaryl is optionally substituted with at least one R5;
V is a bond, O5 -(C(R6J2Jn-O or NR1; W is a bond, C]-C6alkyl, CrC6alkenyi, CrC6heteroalkyl; wherein when Y is S and X is CR3 then V and W are absent; X is N or CR3;
Y is O, S or NR3, with the proviso that if Y is S, then X is not CH;
R is CO2R1, a carboxylic acid bioisostere, an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl;
R1 is hydrogen, Ci-C6alkyl, C]-C6haloalkyl, or benzyl;
R2 and R4 are independently an aryl, or a heteroaryl, wherein R2 and R4 are independently optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8, Ci-C6alkyl, C3- Cjcycloalkyl, CrC6heteroalkyl, CrC6haloalkyl, tetrazolyl, C2-C8heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(=O)2R8, -SC=O)2N(R9J2, -N(R9)S(=O)2N(R9)2, -C(=O)CF3, -
C(=O)NHS(=O)2RS, -S(=O)2NHC(=O)R8, -N(R9)2, -N(R9JCf=OJR8, -N(R9)C(=O)N(R9)2, -N(R9)C(=O)OR8, -
CO2R9, -C(=O)R8, -OC(=O)R8, -OC(=O)N(R9)2, -CONfR9J2, -SR8, -S(K))R8, and -Sf=O)2R8; n is an integer from 1 -6;
R5 is selected from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8, CrC6alkyl, CrC8cycloalkyl, C,- Cfiheteroalkyl, Ci-Cβhaloalkyl, tetrazolyl, C2-C8heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(=O)2R8, -St=O)2N(R9J2, -N(R9)S(=O)2N(R9)2, -C(=O)CF3, -C(=O)NHS(=O)2R8, - S(=O)2NHC(=O)R8, -N(R9J2, -N(R9JCf=O)R8, -N(R9)C(=O)N(R9)2, -N(R9JCf=O)OR8, -CO2R9, -C(=OJR8, - OC(=O)R8, -OC(=OJN(R9)2, -CON(R9)2) -SR8, -S(=O)R8, and -Sf=O)2R8; each R6 is independently hydrogen, F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8, CrC6alkyl, C3- C8cycloalkyl, Q-Cgrieteroalkyl, CpQhaloalkyl, tetrazolyl, C2-C8heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(=O)2R8, -S(-O)2N(R9)2, -N(R9)S(=O)2N(R9)2, -C(=O)CF3, - C(=O)NHS(=O)2R8, -S(=OJ2NHCf=O)R8, -N(R9J2, -N(R9)C(=O)R8, -N(R9)C(=O)N(R9)2, -N(R9)C(=O)OR8, - CO2R9, -Cf=O)R8, -OCf=O)R8, -0C(=0)N(R% -CON(R9J2, -SR8, -S(=O)R8, and -S(=O)2R8; each R8 is independently selected from CrC6alkyl, CpCehaloalkyl, C3-C3cycloalkyl, phenyl, and benzyl; each R9 is independently selected from H, CrC6alkyl, Ci-Qjbaloalkyl, C3-C8cycloalkyl, phenyl, and benzyl; and R3 is hydrogen, Ci-C6alkyl,
Figure imgf000135_0002
CrC6heteroalkyl, CrCgcycloalkyl, substituted or unsubstituted aryl or benzyl.
2. The compound of claim 1 , wherein:
R1 is hydrogen, methyl, ethyl, n-propyl or wo-propyl.
3. The compound of claim 1 or 2, wherein:
R4 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, - CF3, -OH, -OR8, -OCF3, CrC6alkyl, CrC6fluoroalkyl, CrC6heteroalkyl, C3-C8cycloalkyl, and Cr C6haloalkyl.
4. The compound of claim 1 or 2, wherein:
R4 is an optionally substituted heterocycle wherein the heterocycle is selected from:
Figure imgf000136_0001
5. The compound of any of claims 1 , 2 , or 4, wherein:
R4 is substituted with at least one substituent selected from -NHS(^O)2R8, -S(=O)2N(R9)2; -
N(R9)S(=O)2N(R9)2, -N(R9)2τ -N(R^Cf=O)R8, -N(R9)C(=O)N(R9)2, -N(R9JCC=O)OR8, -CO2R9, -
Figure imgf000136_0002
or -S(=O)2R8.
6. The compound of claim 1 , wherein:
R4 is selected from phenyl; 2-fluoroρhenyl; 3-fluoroρhenyl; 4-fluorophenyl; 2-chloroρhenyl; 3- chlorophenyl; 4-chlorophenyl; 2,4-dichloroρhenyl; 2,3-dichloroρhenyl; 3,4-dichlorophenyI; 3,5- dichlorophenyl; 2-bromoρhenyl; 3-bromophenyl; 4-bromophenyl; 2-iodoρhenyl; 3-iodophenyl; 4-0 iodophenyl; 2-methyIρhenyl; 3-methylphenyI; 4-methylphenyl; 2,4-dimethylρhenyl; 2,3- dimethylphenyl; 3,4-dimethylρhenyl; 3,5-dimethylphenyl; 2-trifluromethylρhenyl; 3- trifluromethylphenyl; and 4-trifluromethylphenyl.
7. The compound of claims 1-6, wherein:
R2 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2,5 CF3, -OH, -OR8, -OCF3, C]-C6alkyl, Ci-C6fluoroalkyl, Q-Csheteroalkyl, C3-C8cycloalkyl, and C1-
Qihaloalkyl.
8. The compound of any claims 1-6, wherein:
R2 is an optionally substituted heterocycle wherein the heterocycle is selected from:
Figure imgf000136_0003
0
Figure imgf000136_0004
,0 w //,0 w // .0 r'x 0,
Figure imgf000136_0005
9. The compound of any of claims 1 -6 and 8 , wherein: R2 is substituted with one or more of the substituents selected from -NHS(=O)2R8, -S(=O)2N(R9)2, - N(R9)S(=O)2N(R9)2, -N(R9)2, -N(R9)C(=O)RS, -N(R»)C(=O)N(R9)2) -N(R9)C(=O)OR8 ; -CO2R9, - C(=O)R8, -OC(=O)N(R9)2, -CONtRV -SR8, or -Sf=O)2R8.
10. The compound of claim 1, wherein: R2 is selected from phenyl; 2-fluorophenyl; 3-fluorophenyl; 4-fluorophenyl; 2-chlorophenyl; 3- chlorophenyl; 4-chlorophenyl; 2,4-dichlorophenyl; 2,3-dichlorophenyl; 3,4-dichlorophenyl; 3,5- dichlorophenyl; 2-bromophenyl; 3-bromophenyl; 4-bromophenyl; 2-iodophenyl; 3-iodophenyl; 4- iodophenyl; 2-methylρhenyl; 3-methylρhenyl; 4-methylρhenyl; 2,4-dimethylρhenyl; 2,3- dimethylphenyl; 3,4-dimethylphenyI; 3,5-dimethylphenyl; 2-trifluromethyiρhenyl; 3- trifluromethylphenyl; and 4-trifluromethylphenyl.
11. The compound of any of claims 1-10, wherein: R1 is hydrogen.
12. The compound of any of claims 1-11, wherein: X is N and Y is O.
13, The compound of any of claims 1-11, wherein:
X is N and Y is CR3, wherein R3 is selected from H or methyl.
14. The compound of any of claims 1-11, wherein:
X is CR3 and Y is O, wherein R3 is selected from H or methyl.
15. The compound of any of claims 1-11, wherein: X is CR3 and Y is NR3, wherein each R3 is independently selected from H or methyl.
16. A compound of Formula (II), or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:
Figure imgf000137_0001
Formula (II) wherein:
L is a bond, CrC6alkyl, CrC6alkenyl, CrC6heteroalkyl, aryl, or heteroaryl; wherein C]-Cealkyl, Cr C6alkenyl, Ci-C6heteroalkyl, aryl, or heteroaryl is optionally substituted with at least one R5;
V is a bond, O, -(C(R6)2)π-O or NR1;
W is a bond, CrC6alkyl, CrC6alkenyl, CrC6heteroalkyl; X is N or CR3;
Y is N or CR3;
R is CO2R1, a carboxylic acid bioisostere, an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl;
R1 is hydrogen, Ci-C6alkyl, Ci-C6haloalkyl, or benzyl; R2 is an aryl, or a benzothienyl, wherein the aryl or benzothienyl is optionally substituted with at least one
R5;
R+ is an aryl, optionally substituted with at least one R5; each R5 is independently selected from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8, C,-C6alkyl, C3- Cgcycloalkyl, Ci-Csheteroalkyl, Ci-C6haloalkyl, tetrazolyl, CrC8heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl,
Figure imgf000138_0001
- N(R9)SC=O)2N(R9K -C(=O)CF3, -Cf=O)NHSt=O)2R8, -Sf=O)2NHCf=O)R8, -N(R9J2, - N(R9)Cf=O)R8, -N(R9)Cf=O)N(R9J2, -N(R9)Cf=O)OR8, -CO2R9, -Cf=O)R8, -OCf=O)R8, -
Figure imgf000138_0002
-CON(R9)2, -SR8, -Sf=OJR8, and -S(=O)2R8; each R6 is independently selected from hydrogen, from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8, Ci-C6alkyl, C3-C8cycloalkyl, Ci-Qheteroalkyl, Ci-C^haloalkyl, tetrazolyl, C2-C8heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -
Figure imgf000138_0003
NHSt=O)2R8, - N(R9)S(=O)2N(R9)2, -Cf=O)CF3, -Ct=O)NHSf=O)2R8, -Sf=O)2NHCf=O)R8, -NfR9),, -
N(R9)Cf=O)R8, -N(R9)Cf=O)N(R9J2, -N(R9)Cf=O)OR8, -CO2R9, -Cf=O)R8, -OCf=O)R8, - OC(=O)N(R9)2, -CON(R9J2, -SR8, -S(=O)Rgj and -Sf=OJ2R8; n is an integer from 1-6; each R8 is independently selected from Ci-Qalkyl, Ci-Qhaloalkyl, C3-C8cycloalkyl, phenyl, and benzyl; each R9 is independently selected from H, d-C^alkyl, Ci-Cghaloalkyl, C3-C8cycloalkyl, phenyl, and benzyl; and
R3 is hydrogen, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6heteroalkyl, substituted or unsubstituted aryl or benzyl.
17. The compound of claim 16, wherein:
R1 is hydrogen, methyl, ethyl, n-propyl or isσ-propyl.
18. The compound of claim 16 or 17, wherein:
R4 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, - CF3, -OH, -OR8, -OCF3, CrQalkyl, Ci-C6fiuoroalkyl, Cj-Ceheteroalkyl, C3-C8cycloalkyl, and C1- Cehaloalkyl.
19. The compound of claim 16 or 17, wherein: R4 is an optionally substituted heterocycle wherein the heterocycle is selected from:
Figure imgf000138_0004
20. The c oompou.nod of any. oOf claim.so 16, 17,. aond 19, w .hCereiOn: - Co. co.oα. R4 is substituted with at least one substituent selected from -NHS(=O)2R8, -S(=O)2N(R9)2j -
N(R^Sf=O)2N(R9);,, -N(R9J2, -N(R9)C(=O)R8, -N(R9)C(=O)NfR9)2, -NfR9)C(=O)OR8, -CO2R9, - Cf=O)R8, -OC(=O)N(R9)2, -CONfR9),, -SR8, or -Sf=O)2R8.
21. The compound of claim 16, wherein:
R4 is selected from phenyl; 2-fluoroρhenyl; 3-fluorophenyl; 4-fluorophenyl; 2-chlorophenyl; 3- chlorophenyl; 4-chlorophenyl; 2,4-dichloroρhenyl; 2,3-dichlorophenyl; 3,4-dichloroρhenyI; 3,5- dichlorophenyl; 2-bromophenyl; 3-bromophenyl; 4-bromophenyl; 2-iodoρhenyI; 3-iodophenyl; 4- iodophenyl; 2-methylphenyl; 3-methylphenyl; 4-methylphenyl; 2,4-dimethylphenyl; 2,3- dimethylphenyl; 3,4-dimethylphenyI; 3,5-dimethylphenyl; 2-trifluromethylphenyl; 3- trifluromethylphenyl; and 4-trifluromethylphenyl.
22. The compound of any of claims 16-21, wherein:
R2 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, CF3, -OH, -OR8, -OCF3, CrQalkyl, CrC6fluoroalkyl, CrC6heteroalkyl, C3-C8cycloalkyl, and Cr C6haloalkyl.
23. The compound of any of claims 16-21, wherein:
R2 is an optionally substituted heterocycle wherein the heterocycle is selected from:
Figure imgf000139_0001
24. The compound of any of claims 16-21 and 23, wherein:
R2 is substituted with one or more of the substituents selected from -NHS(=O)2R8, -S(=O)2N(R9)2, - N(R9)S(=O)2N(R9)2 , -N(R^)2, -N(R9)C(=O)RS, -NCR^C^N^, -N(R9)C(=O)OR8, -CO2R9, -
C(=O)R8, -OC(=O)N(R9)2, -CON(R9J2, -SR8, or -Sf=O)2R8.
25. The compound of claim 16, wherein:
R2 is selected from phenyl; 2-fluoroρhenyl; 3-fluoroρhenyl; 4-fluoroρhenyl; 2-chlorophenyl; 3- chlorophenyl; 4-chloroρhenyI; 2,4-dichloroρhenyl; 2,3-dichlorophenyl; 3,4-dichlorophenyl; 3,5- dichlorophenyl; 2-bromophenyl; 3-bromoρhenyl; 4-bromoρhenyl; 2-iodophenyl; 3-iodophenyl; 4- iodophenyl; 2-methylphenyl; 3-methylphenyl; 4-methylphenyl; 2,4-dimethylphenyl; 2,3- dimethylphenyl; 3,4-dimethylphenyl; 3,5-dimethylphenyI; 2-trifluromethylphenyl; 3- trifluromethylphenyl; and 4-trifluromethylphenyl.
26. The compound of any of claims 16-25, wherein; R1 is hydrogen.
27. The compound of any of claims 16-26, wherein:
X is N and Y is CR3, wherein R3 is selected from H or methyl.
28. The compound of any of claims 16-26, wherein: X is N and Y is N.
29. The compound of any of claims 16-26, wherein:
X is CR3 and Y is CR3, wherein each R3 is independently selected from H or methyl.
30. The compound of any of claims 16-26, wherein:
X is CR3 and Y is N, wherein R3 is selected from H or methyl.
31. A compound of Formula (III), or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:
Figure imgf000140_0001
Formula (III) wherein:
L is a bond, Ci-Cgalkyl, Ci-Cealkenyl, Ci-Cβheteroalkyl, aryl, or heteroaryl; wherein Ci-C6alkyl, Cr Cgalkenyl,
Figure imgf000140_0002
aryl, or heteroaryl is optionally substituted with at least one R10;
V is a bond, O, -(C(R3)2)n-O or NR1; W is a bond, CrC6alkyl, CrC6alkenyl, CrC6heteroalkyl R is CO2R1, a carboxylic acid bioisostere, an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl; R1 is hydrogen, Cj-Qalkyl, Ci-Qhaloalkyl, or benzyl;
R2 is an aryl, or a benzothienyl, wherein the aryl or benzothienyl is optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8, CrC6alkyl., C3- Cgcycloalkyl, Ci-Csheteroalkyl, Ci-C6haloalkyl, tetrazolyl, C2-C8heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHSf=O)2R8, -S(=O)2N(R9)2, - N(R^)Sf=O)2NfR9J2, -Cf=O)CF3, -C(=O)NHS(=O)2R8, -Sf=O)2NHCf=O)R8, -N(R9J2, -
N(R9M=O)R8, -N(R9JCt=O)N(R9);,, -N(R9JCf=O)OR8, -CO2R9, -Cf=O)R8, -OC(=O)R8, - OC(=O)N(R9)2, -CON(R9)2, -SR8, -S(=O)R8, and -Sf=O)2R8; R4 is an aryl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, -
CF3, -OH, -OR8, -OCF3, CrC6alkyl, CrC8cycloalkyl, CrC6fluoroaIkyl, Q-Cβheteroalkyl, C1- Cfihaloalkyl, tetrazolyl, C2-C8heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHSf=O)2R8, -S(=O)2N(R9)2, -N(R9)S(=O)2N(R9)2) -Cf=O)CF3, -Cf=O)NHSf=O)2R8, - Sf=O)2NHCf=O)R8, -N(R9)2, -N(R9JCt=O)R8, -N(R9)C(=O)N(R9)2) -N(R9)C(=O)OR8, -CO2R9, - Cf=O)R8, -OC(=O)R8, -OC(=0)N(R9)2, -CON(R9)2, -SR8, -Sf=O)R8, and -Sf=O)2R8; each R3 is independently selected from hydrogen, from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8, Ci-C6alkyl, CrCgcycloalkyl, Cj-Ceheteroalkyl, CrC6haloalkyl, tetrazolyl, C2-C8heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHSf=O)2R8, -Sf=O)2N(Rs)2, - N(R9)Sf=O)2N(R9K -Cf=O)CF3, -Cf=O)NHSf=O)2R8, -Sf=O)2NHCf=O)R8, -N(R9),, - N(R9)Cf=O)R8, -N(R9)Cf=O)N(Rs)2, -N(R9)Ct=O)OR8, -CO2R9, -Cf=O)R8, -OCt=O)R8, - OC(=O)NfR9)2, -CONfR9);,, -SR8, -St=O)R8, and -Sf=O)2R8; n is an integer from 1 to 6;
R10 is independently selected from from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8, C,-C6alkyl, C3- Cgcycloalkyl, Ci-C6heteroalkyl, CrC6haloa3kyl, tetrazolyl, Qj-Qheterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl,
Figure imgf000140_0003
-
Figure imgf000140_0004
-NfR9J2, - N(R9)Cf=O)R5, -N(R9)C(=O)N(R9)2, -N(R9)Cf=O)OR8, -CO2R9, -C(=O)RS, -Oq=O)R8, -
OCf=O)N(R9J2, -CON(R9J2, -SR8, -Sf=O)R8, and -S(=O)2Rg; each R8 is independently selected from CrC6alkyl, Cj-Qhaloalkyl, C3-C8cycloalkyl5 phenyl, and benzyl; each R9 is independently selected from H, Ci-C6alkyl, Ci-Qhaloalkyl, C3-C8cycloalkyl, phenyl, and benzyl; and
R5, R6 and R7 are independently selected from a hydrogen, -OH, halogen, Cj-Qalkyl, Ci-C6haloalkyl, Cr Ceheteroalkyl, substituted or unsubstituted aryl or benzyl.
32. The compound of claim 31 , wherein:
R1 is hydrogen, methyl, ethyl, n-propyl or rsσ-propyl.
33. The compound of claim 31 or 32, wherein:
R4 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, - CF3, -OH, -OR8, -OCF3, Q-Cealkyl, CrC6fluoroalkyl, CrCβheteroalkyl, C3-C3cycloalkyl, and C1-
Cehaloalkyl.
34. The compound of claim 31 or 32, wherein:
R4 is an optionally substituted heterocycle wherein the heterocycle is selected from:
Figure imgf000141_0001
35. The compound of any of claims 31, 32, and 34, wherein:
R4 is substituted with at least one substituent selected from -NHS(=O)2R8, -S(=O)2N(R9)2, -
N(R9)S(=O)2N(R9)2, -N(R9)2, -N(R9)C(=O)R8, -N(R9)C(=O)N(R9)2, -N(R9)C(=0)ORS, -CO2R9, - Cf=O)R8, -OC(=O)N(R9)2, -CON(R9)2, -SR8, or -S(=O)2R8.
36. The compound of claim 31 , wherein:
R4 is selected from phenyl; 2-fluoroρhenyl; 3-fluoroρhenyl; 4-fluorophenyl; 2-chloroρhenyl; 3- chlorophenyl; 4-chlorophenyi; 2,4-dichlorophenyl; 2,3-dichlorophenyl; 3,4-dichlorophenyl; 3,5- dichlorophenyl; 2-bromoρhenyl; 3-bromoρhenyl; 4-bromophenyl; 2-iodophenyl; 3-iodoρhenyl; 4- iodophenyl; 2-methylphenyl; 3-methylρhenyl; 4-methylphenyl; 2,4-dimethylphenyl; 2,3- dimethylphenyl; 3,4-dimethylρhenyl; 3,5-dimethylρhenyl; 2-trifluromethylphenyl; 3- trifluromethylphenyl; εaid 4-trifluromethylphenyl.
37. The compound of any of claims 31-36, wherein:
R2 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, - CF3, -OH, -OR8, -OCF3, CrC6alkyl, d-Cβfluoroalkyl, C[-C6heteroalkyl, C3-C8cycloalkyl, and C1-
Cβhaloalkyl.
38. The compound of any of claims 31-36, wherein:
R2 is an optionally substituted heterocycle wherein the heterocycle is selected from:
Figure imgf000141_0002
Figure imgf000142_0001
39. The compound of any of claims 31-36 and 37, wherein:
R2 is substituted with one or more of the substituents selected from -NHSt=O)2R8, -S(=O)2N(R9)2, - N(R9)S(=O)2N(R9)2, -N(R9)2, -N(R9JCf=O)R8, -N(R9)C(=O)N(R9)2j -N(R9JCf=O)OR8, -CO2R9, -
C(=O)R8, -OC(=O)N(R9)2, -CON(R9J2, -SR8, or -Sf=O)2R8.
40. The compound of claim 31 , wherein:
R2 is selected from phenyl; 2-fluorophenyl; 3-fluorophenyl; 4-fluorophenyl; 2-chlorophenyl; 3- cbJorophenyl; 4-chloroρhenyl; 2,4-dichloroρhenyl; 2,3-dichloroρhenyl; 3,4-dichlorophenyl; 3,5- dichlorophenyl; 2-bromoρhenyl; 3-bromophenyl; 4-bromophenyl; 2-iodophenyl; 3-iodophenyl; 4- iodophenyl; 2-methylρhenyl; 3-methylρhenyl; 4-methylphenyl; 2,4-dimethylphenyl; 2,3- dimethylphenyl; 3,4-dimethylphenyl; 3,5-dimethylphenyl; 2-trifluromethylphenyJ; 3- trifluromethylphenyl; and 4-trifluromethylphenyl.
41. The compound of any of claims 31-40, wherein: R1 is hydrogen.
42. A compound of Formula (IV), or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:
Figure imgf000142_0002
wherein:
L is a bond, C1-QaIlCyI, CrC6alkenyl, CrC6heteroalkyl, aryl, or heteroaryl; wherein CrC6alkyl, Ci- C6alkenyl, CrCfjheteroalkyl, aryl, or heteroaryl is optionally substituted with at least one R10;
V is a bond, O, -(C(R7)2)n-O or NR1;
W is a bond, C,-C6alkyl, d-Cgalkenyl, C,-C6heteroalkyl; X is N or CR3;
Y is O, S, NR3 or -CR5=CR6-;
R2 is an aryl, or a benzothienyl, wherein the aryl or benzothieny! is optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8, CrC6aIkyl, C3- C8cycloalkyl, Ci-Ceheteroalkyl, Ci-Cehaloalkyl, tetrazolyl, C2-C8heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(=O)2R8, -Sf=O)2N(R9^, -
N(R9JSt=O)2N(R9J2, -C(=O)CF3, -C(=O)NHS(=O)2R8, -S(=O)2NHC(=O)R8, -N(R9J2, - N(R9JCt=O)R8, -N(R9)C(=OJN(R9J2, -N(R9)C(=OJOR8 3 -CO2R9, -C(=O)R8, -OC(=O)R8, - OCt=O)N(R9J2, -CON(R9J2, -SR8, -S(=O)R8, and -St=O)2R8;
R4 is an aryl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, - CF3, -OH, -OR8, -OCF3, CrC6alkyl, C3-C8cycloalkyl, Cj-Qfluoroalkyl, CrC6heteroalkyl, C,- Cfihaloalkyl, tetrazolyl, C2-C8heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHSf=O)2R8, -Sf=O)2N(R9J2, -N(R^Sf=O)2N(R9J2, -C(=O)CF3, -C(=O)NHS(=O)2R8, - Sf=O)2NHCf=O)R8, -N(R9J2, -N(R9)C(=O)R8, -N(R9JCf=O)NfR9J2, -N(R9JCf=O)OR8, -CO2R9, - C(=0)R8, -OC(=O)R8, -OCf=OJN(R9J2, -CON(R9)2, -SR8, -S(=O)R8, and -Sf=O)2R8; each R7 is independently selected from hydrogen, from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8,
Ci-C6alkyl, C3-C8cycloalkyl, Ci-Ceheteroalkyl, C1-C6HaIOaIlCyI, tetrazolyl, C2-C8heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -
Figure imgf000143_0001
NHSf=O)2R8, -
Figure imgf000143_0002
-N(R9)2, -
Figure imgf000143_0003
-OCf=O)R8, - OC(O)N(R9J2, -CON(R9)2, -SR8, -Sf=O)R8, and -Sf=O)2R8; n is an integer from 1-6; each R8 is independently selected from Ci-Qalkyl, CpCβhaloalkyl, C3-C8cycloalkyl, phenyl, and benzyl; each R9 is independently selected from H, CrC6alkyl, Ci-C^haloalkyl, C3-Cgcycloalkyl, phenyl, and benzyl; R10 is selected from F5 Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3, CrC6alkyl, C3-C8cycloalkyl, Cr
Qfluoroalkyl, Ci-Ctheteroalkyl, Q-Cshaloalkyl, tetrazolyl, C2-C8heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHSf=O)2R8, -Sf=O)2NfR9J2, - NfR9)S(=O)2N(R9)2, -Cf=O)CF3, -Cf=O)NHSf=O)2R8, -Sf=O)2NHCf=O)R8, -N(R9J2, - NfR9JCf=O)R8, -N(R9JCf=O)N(R9J2, -N(R9JCf=O)OR8, -CO2R9, -Cf=O)R8, -OCf=O)R8, - OC(=O)N(R9)2, -CON(R9J2, -SR8, -S(=O)RB, and -Sf=OJ2R8;
R3 is hydrogen, Ci-C6alkyl, Ci-C6haloalkyl, Q-Cglieteroalkyl, substituted or unsubstituted aryl or benzyl; and
R5 and R6 are independently selected from a hydrogen, -OH, halogen, Ct-C6alkyl, Ct-C6haloalkyl, Q-
Cβheteroalkyl, substituted or unsubstituted aryl or benzyl.
43. The compound of claim 42, wherein:
R! is hydrogen, methyl, ethyl, n-propyl or iso-propyl.
44. The compound of claim 42 or 43 , wherein:
R4 is a phenyl, optionally substituted with at least one substituent selected from F, Ci, Br, I, -CN, -NO2, -
CF3, -OH, -OR8, -OCF3, C|-C6alkyl, C,-C6fluoroalkyl, C,-C6heteroalkyl, C3-C3cycloalkyl, and Cr Cfihaloalkyl.
45. The compound of claim 42 or 43, wherein:
R4 is an optionally substituted heterσcycle wherein the heterocycle is selected from:
Figure imgf000143_0004
46. The compound of any of claims 42, 43, and 45, wherein: R4 is substituted with at least one substituent selected from -NHS(=O)2R8, -S(=O)2N(R9)2, -
N(R9JSf=O)2N(R9);,, -N(R9J2, -N(R9)C(=O)R8, -N(R9)C(=O)N(R9)2) -N(R9JCf-OJOR8, -CO2R9, - C(=O)R8, -OCf=O)N(R9J2, -CON(R9J2, -SR8, or -S(=O)2R8.
47. The compound of claim 42, wherein: R4 is selected from phenyl; 2-fluoroρhenyl; 3-fIuoroρhenyl; 4-fluoroρhenyl; 2-chloroρhenyl; 3- chlorophenyl; 4-chloroρhenyl; 2,4-dichloroρhenyl; 2,3-dichloroρhenyl; 3,4-dichloroρhenyl; 3,5- dichlorophenyl; 2-bromoρhenyl; 3-bromoρhenyl; 4-bromoρhenyl; 2-iodoρhenyl; 3-iodoρhenyl; 4- iodophenyl; 2-methylρhenyl; 3-methylρhenyl; 4-methylρhenyl; 2,4-dimethylρhenyl; 2,3- dimethylphenyl; 3,4-dimethylphenyl; 3,5-dimethylphenyI; 2-trifluromethylphenyl; 3- trifluromethylphenyl; and 4-trifluromethylphenyl.
48. The compound of any of claims 42-47, wherein:
R2 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, - CF3, -OH, -OR8, -OCF3, Ci-Qalkyl, CrQfluoroalkyl, Ci-Csheteroalkyl, C3-C8cycloalkyl, and C1- Qjhaloalkyl.
49. The compound of any of claims 42-47, wherein:
R2 is an optionally substituted heterocycle wherein the heterocycle is selected from:
Figure imgf000144_0001
50. The c 0ompou.n0d of any. o0f claim.s042-47 a.n0d 49, wh .e0rein0: CO- oα. co.
R2 is substituted with one or more of the substituents selected from -NHS(=O)2R8, -S(=O)2N(R9)2, - N(R9)S(=O)2N(R9)2, -N(R9J2, -N(R9W=O)R8, -N(R9JCf=O)N(R9J2, -N(R9JCt=OJOR8, -CO2R9, - Cf=O)R8, -OC(=O)N(R9)2, -CON(R9J2, -SR8, or -S(=O)2R8.
51. The compound of claim 42, wherein: R2 is selected from phenyl; 2-fluorophenyl; 3 -fluorophenyl; 4-fluorophenyl; 2-chloroρhenyl; 3- chlorophenyl; 4-chlorophenyl; 2,4-dichlorophenyl; 2,3-dichlorophenyl; 3,4-dichlorophenyl; 3,5- dichlorophenyl; 2-bromophenyl; 3-bromophenyl; 4-bromoρhenyl; 2-iodophenyl; 3-iodophenyl; 4- iodophenyl; 2-methylρhenyl; 3-methylρhenyl; 4-methylphenyl; 2,4-dimethylρhenyl; 2,3- dimethylphenyl; 3,4-dimethylphenyl; 3,5-dimethylρhenyl; 2-trifluromethylphenyl; 3- trifluromethylphenyl; and 4~trifluromethylphenyl.
52. The compound of any of claims 42-51 , wherein: R1 is hydrogen.
53. The compound of any of claims 42-51 , wherein:
X is N and Y is S.
54. A compound of Formula (V), or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:
Figure imgf000145_0001
Formula (V) wherein:
V is a bond, O, -fC(R6)2)m-O or NR1; W is a bond, CrC6alkyl, CrC6alkenyl, d-Qheteroalkyl; n = 1 or 2; m is an integer from 1-6; R is CO2R1, a carboxylic acid bioisostere, an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl; R1 is hydrogen, (VCgalkyl, Ci-C6haloalkyl, or benzyl;
R2 is an aryl, or a benzothienyl, wherein the aryl or benzothienyl is optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8, CrC6alkyl, C3- Cgcycloalkyl, Ci-C6heteroalkyl, Ci-Cβhaloalkyl, tetrazolyl, C2-C8heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(=O)2R8, -S(=O)2N(R9)2, - N(R9)S(=O)2N(R9)2, -Cf=O)CF3, -Cf=O)NHSf=O)2R8, -Sf=O)2NHCf=O)R8, -N(R9)2, -
N(R9)C(=O)R8, -N(R9)C(=O)N(R9)2j -N(R^Cf=O)OR8, -CO2R9, -Cf=O)R8, -OCf=O)R8, - OC(=0)N(R9)2, -CON(R9)2) -SR8, -Sf=O)R8, and -Sf=O)2R8; R4 is selected from H, F, Cl, Br, I, -CN5 -NO2, -CF3, -OH, -OR8, -OCF3, CrQalkyl, C3-C8cycloalkyl, C,-
C6fluoroalkyl, Ci-Cβheteroalkyl, Ci-Cβhaloalkyl, tetrazolyl, C2-C8heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHSf=O)2R8, -Sf=O)2N(R9J2, -
N(R9)S(=O)2N(R9)2, -C(=O)CF3, -Cf=O)NHSf=O)2R8, -Sf=O)2NHCf=O)R8, -N(R9),, - N(R9)C(=O)R8, -N(R9)C(=O)N(R9)2, -N(R9JCf=O)OR8, -CO2R9, -Cf=O)R8, -OCf=O)R8, - OC(=O)N(R9)2, -CON(R9);,, -SR8, -S(=O)R8, and -Sf=O)2R8; each Rs is independently selected from hydrogen, from F, Cl, Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8, C rC6alfcyl, C3-C3cycloalkyl, C rC6heteroalkyl, d -Cβhaloalkyl, tetrazolyl, C2-C8heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -
Figure imgf000145_0002
NHSf=O)2Rs, - NfR9)Sf=O)2NfR9),, -Cf=O)CF3, -Cf=O)NHSf=O)2R8, -Sf=O)2NHCf=O)R,, -N(R9),, - N(R9)Cf=O)R8, -N(R9)Cf=O)N(R.,),, -N(R9)Ct=O)OR8, -CO2R9, -Cf=O)R8, -OCf=O)R8, - OCf=O)NfRs)2, -CON(R9);,, -SR8, -Sf=O)R8, and -Sf=O)2R8; each R8 is independently selected from Ci-C6alkyl, Ci-C6haloalkyl, C3-C8cycloalkyl, phenyl, and benzyl; and each R9 is independently selected from H, Ci-C6alkyl, CrC6haloalkyl, C3-C8cycloalkyl, phenyl, and benzyl.
55. The compound of claim 54, wherein: R1 is hydrogen, methyl, ethyl, n-propyl or jso-propyl.
56. The compound of claim 54 or 55, wherein: R4 is a substituent selected from H, F, Cl, Br, I, -CN, -NO2, -CF3, -OH, -OR8, -OCF3, CrC6alkyl, Cr Cfifluoroalkyl, Ci-Qheteroalkyl, Cj-Cjcycloalkyl or Cj-Qhaloalkyl.
57. The compound of any of claims 54 or 55, wherein:
R4 is one or more substituents selected from -NHS(^O)2R8, -S(=O)2N(R9)2, -N(R9)S(=O)2N(R9)2, -N(R9J2, -N(R9)C(=O)RS, -N(R9JCf=O)N(R9J2, -N(R9)C(=O)OR8, -CO2R9, -C(=0)R8, -OC(=O)N(R9J2, -
CON(R9J2, -SR8, or -S(=O)2R8.
58. The compound of any of claims 54-57, wherein:
R2 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, -
CF3, -OH, -OR8, -OCF3, Ci-C6alkyl, CrC6fluoroalkyl, Ci-Qheteroalkyl, C3-C8cycloalkyl, and Cr Qhaloalkyl.
59. The compound of any of claims 54-57, wherein:
R2 is an optionally substituted heterocycle wherein the heterocycle is selected from:
Figure imgf000146_0001
60. The compound of any of claims 54-57 and 59, wherein:
R2 is substituted with one or more of the substituents selected from -NHS(=O)2R8, -S(=O)2N(R9)2, - N(R9)S(=O)2N(R9)2, -N(R9J2, -N(R9)C(=O)R8, -N(R9)C(=O)N(R9)2, -N(R9JCt=O)OR8, -CO2R9, - C(=O)R8, -OC(=O)N(R9)2, -CON(R9J2, -SR8, or -Sf=O)2R8.
61. The compound of claim 54, wherein:
R2 is selected from phenyl; 2-fluoroρhenyl; 3-fluorophenyl; 4-fluoroρhenyl; 2-chloroρhenyl; 3- chlorophenyl; 4-chlorophenyl; 2,4-dichlorophenyl; 2,3-dichlorophenyl; 3,4-dichlorophenyl; 3,5- dichlorophenyl; 2-bromophenyl; 3-bromophenyl; 4-bromoρhenyl; 2-iodophenyl; 3-iodophenyl; 4- iodophenyl; 2-methylρhenyl; 3-methylρhenyl; 4-methylphenyl; 2,4-dimethylρhenyl; 2,3- dimethylphenyl; 3,4-dimethylρhenyl; 3,5-dimethylphenyl; 2-trifluromethylρhenyl; 3- trifluromethylphenyl; and 4-trifluromethylρhenyl.
62. The compound of any of claims 54-61 , wherein R1 is hydrogen.
63. The compound of any of claims 54-62, wherein n=2.
64. A method of modulating store-operated calcium (SOC) channel activity comprising contacting the store- operated calcium (SOC) channel complex, or portion thereof, with a compound of any of claims 1 ,
16, 31, 42 or 54, or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
65. The method of claim 64, wherein contacting occurs in vitro.
66. The method of claim 64, wherein contacting occurs in vivo.
67. The method of any of claims 64-66, wherein the compound of any of claims 1 , 16, 31, 42 or 54 modulates an activity of, modulates an interaction of, or modulates the level of, or binds to, or interacts with at least one portion of the store operated calcium channel complex selected from stromal interaction molecules (STIM) family of proteins.
68. The method of claim 67, wherein the compound of any of claims 1, 16, 31, 42 or 54 modulates an activity of, modulates an interaction of, or modulates the level of, or binds to, or interacts with at least one portion of STIMl or STIM2.
69. The method of any of claims 64-68, wherein modulating store operated calcium channel activity with a compound of any of claims 1, 16, 31, 42 or 54 inhibits store-operated calcium entry (SOCE).
70. The method of any of claims 64-69, wherein the store operated calcium channel complex is calcium- release activated calcium (CRAC) channel complex.
71. The method of claim 70, wherein modulating calcium release activated calcium (CRAC) activity with a compound of any of claims 1, 16, 31, 42 or 54 inhibits the electrophysiological current (ICRAC) associated with activated CRAC channels.
72. A method of modulating calcium release activated calcium channel (CRAC) activity in a mammal comprising administering a compound of any of claims 1, 16, 31, 42 or 54, or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
73. The method of claim 72, wherein the compound of any of claims 1 , 16, 31 , 42 or 54 modulates an activity of, modulates an interaction of, or modulates the level of, or binds to, or interacts with at least one component of the calcium release activated (CRAC) channel complex selected from stromal interaction molecules (STIM) family of proteins.
74. The method of claim 73, wherein the compound of any of claims 1, 16, 31, 42 or 54 modulates an activity of, modulates an interaction of, or modulates the level of, or binds to, or interacts with STIMl or STIM2.
75. The method of any of claims 72-74 wherein modulating calcium release activated calcium (CRAC) channel activity with a compound of any of claims 1, 16, 31, 42 or 54 inhibits store-operated calcium entry (SOCE).
76. The method of any of claims 72-75, wherein modulating calcium release activated calcium (CRAC) channel activity with a compound of any of claims 1, 16, 31, 42 or 54 inhibits the electrophysiological current (ICRAC) directly associated with activated CRAC channels.
77. The method of any of claims 72-76, wherein the compound of any of claims 1, 16, 31, 42 or 54 inhibits SOCE with an IC50 below about 10 μM.
78. The method of any of claims 72-77, wherein the compound of any of claims 1, 16, 31, 42 or 54 inhibits electrophysiological current (ICRAC) associated with activated CRAC channels at a concentration below about 10 μM.
79. A method of treating a disease, disorder or condition in a mammal that would benefit from inhibition of store operated calcium channel activity comprising administering to the mammal a compound of any of claims 1 , 16, 31 , 42 or 54, or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
80. The method of claim 79, wherein the compound of any of claims 1 , 16, 31 , 42 or 54 modulates the activity of, modulates an interaction of, or binds to, or interacts with a mammalian STIMI protein, or a mammalian STIM2 protein.
81. The method of claim 79 or claim 80 , wherein the disease, disorder or condition in a mammal is selected from diseases/disorders involving inflammation, glomerulonephritis, uveitis, hepatic diseases or disorders, renal diseases or disorders, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, vasculitis, dermatitis, osteoarthritis, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, organ transplant rejection, allogeneic or xenogeneic transplantation, graft rejection, graft- versus-host disease, lupus erythematosus, type I diabetes, pulmonary fibrosis, dermatomyositis, thyroiditis, myasthenia gravis, autoimmune hemolytic anemia, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis, hepatitis and atopic dermatitis, asthma, psoriasis, multiple sclerosis, Sjogren's syndrome, and autoimmune diseases or disorders.
82. The method of claim 81 wherein the disease, disorder, or condition is rheumatoid arthritis.
83. The method of claim 81 wherein the disease, disorder, or condition is psoriasis.
84. The method of claim 81 wherein the disease, disorder, or condition is organ transplant rejection.
85. The method of claim 81 wherein the disease, disorder, or condition is multiple sclerosis.
86. The method of claim 81 wherein the disease, disorder, or condition is inflammatory bowel disease.
87. The method of claim 86 wherein the inflammatory bowel disease is ulcerative colitis.
88. The method of any of claims 79-87, further comprising administering to the mammal a second therapeutic agent.
89. The method of claim 88, wherein the second therapeutic agent is selected from immunosuppressants, glucocorticoids, non-steroidal anti-inflammatory drugs, Cox-2-sρecifϊc inhibitors, leflunomide, gold thioglucose, gold thiomalate, aurofin, sulfasalazine, hydroxychloroquinine, minocycline, anti-TNF-α agents, abatacept, anakinra, interferon-β, interferon-γ, interleukin-2, allergy vaccines, antihistamines, antileukotrienes, beta-agonists, theophylline, and anticholinergics.
90. The method of claim 89, wherein the second therapeutic agent is selected from tacrolimus, cyclosporin, rapamicin, methotrexate , cyclophosphamide, azathioprine, mercaptopurine, mycophenolate, or
FTY720, prednisone, cortisone acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone, aspirin, salicylic acid, gentisic acid, choline magnesium salicylate, choline salicylate, choline magnesium salicylate, choline salicylate, magnesium salicylate, sodium salicylate, diflunisal, carprofen, fenoprofen, fenoprofen calcium, flurobiprofen, ibuprofen, ketoprofen, nabutone, ketolorac, ketorolac tromethamine, naproxen, oxaprozin, diclofenac, etodolac, indomethacin, sulindac, tolmetin, meclofenamate, meclofenamate sodium, mefenamic acid, piroxicara, meloxicam, celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib, lumiracoxib, CS-502, JTE-522, L-745,337 and NS398, leflunomide, gold thioglucose, gold thiomalate, aurofin, sulfasalazine, hydroxychloroquinine, minocycline, infliximab, etanercept, adalimumab, abatacept, anakinra, interferon-β, interferon-γ, interleukin-2, allergy vaccines, antihistamines, antileukotrienes, beta- agonists, theophylline, and anticholinergics.
91. A method of inhibiting store-operated calcium entry (SOCE) activation of nuclear factor of activated T cells (NFAT) in a mammal comprising administering a compound of any of claims 1, 16, 31, 42 or 54, or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
92. The method of claim 91 , wherein the compound of any of claims 1 , 16, 31 , 42 or 54 modulates an interaction of, or modulates the level of, or binds to, or interacts with a mammalian STIMl protein, or a mammalian STIM2 protein.
93. A method of decreasing cytokine expression by inhibiting the store-operated calcium entry activation of
NFAT in a mammal comprising administering a compound of any of claims 1 , 16, 31, 42 or 54, or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
94. The method of claim 93 , wherein the compound of any of claims 1, 16, 31, 42 or 54 modulates an interaction of, or modulates the level of, or binds to, or interacts with a mammalian STIMl protein or a mammalian STIM2 protein.
95. The method of claim 94, wherein the cytokine is selected from IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8,
IL-9, IL-IO, IL-11, IL-12, IL-13, IL-15, IL-16, IL-17, DL-18, IL-lα, IL-lβ, IL-I RA, granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), oncostatin M, erythropoietin, leukemia inhibitory factor (LIF), interferons, gamma-interferon (γ- IFN), B7.1 (CD80), B7.2 (B70, CD86), TNF-α, TNF-β, LT-β, CD40 ligand, Fas ligand, CD27 ligand, CD30 ligand, 4-1BBL, Trail, and migration inhibitory factor (MIF).
96. A pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient or binder, and a compound of any of claims 1 , 16, 31 , 42 or 54, or pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof.
97. Use of a compound of any of claims 1 , 16, 31 , 42 or 54, or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof, for the formulation of a medicament for the modulation of store operated calcium (SOC) channel activity in a subject or for the treatment of a disease or condition in a subject that would benefit from the modulation of store operated calcium (SOC) channel activity.
98. The use of claim 97, wherein the compound of any of claims 1 , 16, 31 , 42 or 54 inhibits store operated calcium entry (SOCE).
99. The use of claim 97 or claim 98, wherein the store operated calcium channel activity is calcium release activated calcium channel activity.
100. An article of manufacture, comprising packaging material, a compound of any of claims 1, 16, 31, 42 or
54, or composition, or pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, which is effective for inhibiting calcium release- activated calcium (CRAC) channel activity, or for the treatment, prevention or amelioration of one or more symptoms of a disease or condition that would benefit from the inhibition of calcium release- activated calcium (CRAC) channel activity, within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used for the inhibition of calcium release- activated calcium (CRAC) channel activity, or for the treatment, prevention or amelioration of one or more symptoms of a disease or condition that would benefit from the inhibition of calcium release- activated calcium (CRAC) channel activity.
101. The article of manufacture of claim 100, wherein the compound of any of claims 1, 16, 31, 42 or 54 inhibits store operated calcium entry (SOCE).
102. The compound of claim 1 having the structure of Formula (VI):
Figure imgf000150_0001
Formula (VI) wherein:
Z is Ci-C6alkyl, Ci-Qhaloalkyl, Ci-Cgheteroalkyl; wherein CrC6alkyl and Ci-C6heteroaikyl are independently optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -
NO2, -OH, -CF3, -OCF3, -OR8, CrC6alkyl, Q-Cgcycloalkyl, Ci-Ceheteroalkyl, Cj-Cehaloalkyl, tetrazolyl, C2-C3heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, - NHS(=O)2R8, -St=O)2N(R9J2, -N(R9JS(O)2N(R9J2, -C(O)CF3, -C(=O)NHS(=O)2R8, - S(O)2NHC(O)R8, -N(R9J2, -N(R9JC(O)R8, -N(R9)C(=O)N(R9)2, -N(R9)C(0)OR8, -CO2R9, - C(=O)R8, -OC(=O)R8, -OC(=O)N(R9)2> -CON(R9J2, -SR8, -S(O)R8, and -S(O)2R8.
R is CO2R1, a carboxylic acid bioisostere, an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl;
R1 is hydrogen, Ct-Qalkyl, Ci-C6haloalkyl, or benzyl;
R2 and RA are independently an aryl, or a heteroaryl, wherein R2 and R4 are independently optionally substituted with at least one substituent selected from F, Cl, Br, I, -CN, -NO2, -OH5 -CF3, -OCF3, -
OR8, CrC6alkyl, Cj-Qcycloalkyl, CrC6heteroalkyl, Ci-C5haloalkyl, tetrazolyl, C2- Cgheterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -NHS(=O)2R8, - S(=O)2N(R9)2, -N(R9)S(O)2N(R9)2, -C(O)CF3, -C(=O)NHS(=O)2R8, -S(=O)2NHC(=O)R8, -N(R9J2, -N(R9)C(O)R8, -N(R9)C(=O)N(R9)2, -N(R9JC(O)OR8, -CO2R9, -C(O)R8, -OC(O)R8, - OC(O)N(R9J2, -CON(R9J2, -SR8, -S(OJR8, and -S(OJ2R8; each R8 is independently selected from CrC6alkyl, Ci-C6haloalkyl, C3-C8cycloalkyl, phenyl, and benzyl; and each R9 is independently selected from H, Ci-Qalkyl, Ci-C6haloalkyl, C3-C8cycloalkyl, phenyl, and benzyl.
103. The compound of claim 102 wherein X is Ci -Cβalkyl.
104. The compound of claim 103 wherein X is CH3.
105. The compound of claim 103 wherein X is CH2CH3.
106. The compound of any of claims 102-105 wherein X is substituted with a substituent selected from F, Cl,
Br, I, -CN, -NO2, -OH, -CF3, -OCF3, -OR8, C,-C6alkyl, C3-C8cycloalkyl, and Q-Cβheteroalkyl.
107. The compound of any of claims 102-106 wherein the substituent is selected from F, Cl, Br, and I.
108. The compound of claim 102 having the structure
Figure imgf000151_0001
109. A pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient or binder, and a compound of any of claims 102-108 or pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof.
110. A method of modulating store-operated calcium (SOC) channel activity comprising contacting the store- operated calcium (SOC) channel complex, or portion thereof, with a compound of any of claims 102- 109 or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
111. A method of modulating calcium release activated calcium channel (CRAC) activity in a mammal comprising administering a compound of any of claims 102- 109 or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
112. A method of treating a disease, disorder or condition in a mammal that would benefit from inhibition of store operated calcium channel activity comprising administering to the mammal a compound of any of claims 102-109 or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
113. A method of inhibiting store-operated calcium entry (SOCE) activation of nuclear factor of activated T cells (NFAT) in a mammal comprising administering a compound of any of claims 102-109 or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
114. A method of decreasing cytokine expression by inhibiting the store-operated calcium entry activation of NFAT in a mammal comprising administering a compound of any of claims 102-109 or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
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