WO2018026866A1 - Lipid-substituted amino 1,2-and 1,3-diol compounds as modulators of tlr2 dimerization - Google Patents

Lipid-substituted amino 1,2-and 1,3-diol compounds as modulators of tlr2 dimerization Download PDF

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Publication number
WO2018026866A1
WO2018026866A1 PCT/US2017/044984 US2017044984W WO2018026866A1 WO 2018026866 A1 WO2018026866 A1 WO 2018026866A1 US 2017044984 W US2017044984 W US 2017044984W WO 2018026866 A1 WO2018026866 A1 WO 2018026866A1
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Prior art keywords
alkyl
bis
amino
propyl
tetradecyloxy
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PCT/US2017/044984
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French (fr)
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Wolfgang Wrasidlo
Srinivasa Reddy Natala
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Neuropore Therapies, Inc.
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Priority to JP2019505479A priority Critical patent/JP2019524781A/en
Priority to CN201780048372.3A priority patent/CN109715167A/en
Priority to EP17837574.7A priority patent/EP3493814A4/en
Publication of WO2018026866A1 publication Critical patent/WO2018026866A1/en

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    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C07D211/64—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4 having an aryl radical as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C07D211/66—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4 having a hetero atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes

Definitions

  • the invention relates to a compound of Formula (I):
  • R 1 is H, -C0 2 -Ci_ 8 alkyl, -C0 2 -CHR a -aryl, -C0 2 -CHR a -heteroaryl, -C(0)-Ci_ 4 alkyl, -C(0)aryl, - C(0)-heteroaryl, -C(0)-CHR b -NR c R d , -C(0)-CHR a -heteroaryl, -CHR a -aryl, -CHR a - heteroaryl, -S0 2 -Ci_ 4 alkyl, -S0 2 -aryl, or -S0 2 -heteroaryl;
  • R a is H or Ci-isalkyl
  • R b is H or -Ci_ 5 alkyl-NR e R f ;
  • R c is H or Ci ⁇ alkyl and R d is H, Ci_ 4 alkyl, or -C0 2 Ci_ 4 alkyl;
  • each aryl or heteroaryl is optionally substituted with halo, Ci_ 4 alkyl, Ci_ 4 fluoroalkyl, -OH, - OCi_ 4 alkyl, -OCi_ 4 fluoroalkyl, -CN, phenyl,-OCi_ 4 alkyl-aryl, or -C0 2 Ci_ 4 alkyl;
  • R g is H or Ci_ 4 alkyl
  • R h is H, Ci_ 4 alkyl, or -C0 2 Ci_ 4 alkyl;
  • R m is H, -S0 2 aryl, or -C0 2 Ci_ 4 alkyl
  • R k is H or Ci_ 4 alkyl
  • R 4 is H or Ci_ 4 alkyl
  • R 5 is Cg-i 6 alkyl or C 8 -i 6 ⁇ iIkenyl
  • R 6 is C 8 -i 6 alkyl or C 8 -i 6 alkenyl
  • n 0 or 1 ;
  • n 0 or 1 ;
  • p is 0 or 1 ;
  • n and p are 1 ;
  • the invention relates to a compound of Formula (II):
  • R 21 is H, Ci_ 4 alkyl, or -C0 2 C ⁇ alkyl
  • R 22 is H or Ci_ 4 alkyl
  • R 24 is H or Ci_ 4 alkyl; R is C 8 -i 6 alkyl or C 8 _i 6 alkenyl;
  • R 26 is C 8 _i 6 alkyl or C 8 -i6alkenyl
  • p2 is 0 or 1 ;
  • n2 and p2 are 1 ;
  • the invention relates to a compound of Formula (III):
  • R 31 is phenyl or monocyclic heteroaryl
  • R 32 is H or Ci_ 4 alkyl
  • R 33 is Ci_ 4 alkyl-NR x R y ;
  • R x is H, Ci- 4 alkyl, or -C0 2 -Ci- 4 alkyl
  • R 34 is H or Ci_ 4 alkyl
  • R 35 is Ci 4 _i 8 alkyl or Ci 4 _i 8 alkenyl
  • the invention relates to a compound of Formula (IV):
  • R 41 is H, Ci_ 4 alkyl, or -C0 2 Ci_ 4 alkyl; R 41 is absent, H, or Ci_ 4 alkyl; wherein when R 41 is H or Ci_ 4 alkyl, the nitrogen attached to R has a positive charge;
  • R 42 is H or Ci_ 4 alkyl
  • R 43 is -OCi_i 8 alkyl, -OCi_i 8 alkenyl, -Ci_i 8 alkyl, or -Ci_i 8 alkenyl, each optionally substituted with -OH, -OCi_ 4 alkyl, -C(0)OH, -C(0)OCi_ 4 alkyl, -C(0)NHR 4b , or aryl; and
  • R 44 is -OC 4 _i 8 alkyl or -OC 4 _i 8 alkenyl, each optionally substituted with -OH, -OCi_ 4 alkyl, - C(0)OH, -C(0)OCi_ 4 alkyl, -C(0)NHR 4c , or aryl;
  • R 4b and R 4c are each independently H or Ci_ 4 alkyl
  • the invention relates to a compound of Formula (V):
  • G 3 is -C(O)- or -CH 2 -;
  • R 5b is H, Ci_ 4 alkyl, or -C0 2 Ci_ 4 alkyl;
  • R 52 is H or Ci_ 4 alkyl
  • R 53 is H or Ci_ 4 alkyl
  • r is 0 or 1 ;
  • s is 0 or 1 ;
  • R 54 is C 8 _i 8 alkyl or C 8 _i 8 alkenyl
  • R 55 is C 8 _i 8 alkyl or C 8 _i 8 alkenyl
  • the invention relates to a compound of Formula (VI):
  • R 61 is H, -C0 2 -Ci_ 8 alkyl, -C0 2 -CHR 6a -aryl, -C0 2 -CHR 6a -heteroaryl, -C(0)-Ci_ 4 alkyl, -C(0)aryl, -C(0)-heteroaryl, -C(0)-CHR 6b -NR 6c R 6d , -C(0)-CHR 6a -heteroaryl, -CHR 6a -aryl, -CHR 6a - heteroaryl, -S0 2 -Ci_ 4 alkyl, -S0 2 -aryl, or -S0 2 -heteroaryl;
  • R 6b is H or -Ci_ 5 alkyl-NR 6e R 6f ;
  • R 6c is H or Ci ⁇ alkyl
  • R 6d is H, Ci_ 4 alkyl, or -C0 2 Ci_ 4 alkyl;
  • R 6e is H or Ci ⁇ alkyl
  • R 6f is H, Ci_ 4 alkyl, or -C0 2 C ⁇ alkyl
  • each aryl or heteroaryl is optionally substituted with halo, Ci_ 4 alkyl, Ci_ 4 fluoroalkyl, -OH, -OCi_ 4 alkyl, -OCi_ 4 fluoroalkyl, -CN, phenyl, or -OCi_ 4 alkyl-aryl;
  • R 66 is H, Ci_ 4 alkyl, or -C0 2 C ⁇ alkyl
  • R 6m is H, -S0 2 aryl, or -C0 2 Ci ⁇ alkyl
  • R 64 is H or -OH
  • R 64 is -Ci-i 8 alkyl, -Ci_i 8 alkenyl, -OCi_i 8 alkyl, or -OCi_i 8 alkenyl, each of which is optionally substituted with -OH or -OCi_ 4 alkyl;
  • R 65 is H or -C 4 _ 8 cycloalkyl
  • the invention relates to a pharmaceutical composition comprising at least one compound of Formula (I) or a pharmaceutically acceptable salt thereof. In a further aspect, the invention relates to a pharmaceutical composition comprising at least one compound of Formula (II) or a pharmaceutically acceptable salt thereof. In a further aspect, the invention relates to a pharmaceutical composition comprising at least one compound of Formula (III) or a pharmaceutically acceptable salt thereof. In a further aspect, the invention relates to a pharmaceutical composition comprising at least one compound of Formula (IV) or a
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of Formula (V) or a
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of Formula (VI) or a
  • the invention relates to a pharmaceutical composition comprising at least one compound of any of Tables l-6or a pharmaceutically acceptable salt thereof.
  • Pharmaceutical compositions according to the invention may further comprise a pharmaceutically acceptable excipient.
  • the invention is also a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament.
  • the invention is also a compound of Formula (II) or a pharmaceutically acceptable salt thereof for use as a medicament.
  • the invention is also a compound of Formula (III) or a
  • the invention is also a compound of Formula (IV) or a pharmaceutically acceptable salt thereof for use as a medicament.
  • the invention is also a compound of Formula (V) or a pharmaceutically acceptable salt thereof for use as a medicament.
  • the invention is also a compound of Formula (VI) or a pharmaceutically acceptable salt thereof for use as a medicament.
  • the invention is also a compound of any of Tables 1-6 or a pharmaceutically acceptable salt thereof for use as a medicament.
  • the invention is directed to a method of treating a disease or condition associated with TLR2 heterodimerization, comprising administering to a subject in need of such treatment an effective amount of at least one compound of Formula (I), (II), (III), (IV), (V), or (VI), or a compound of any of Tables 1-6, or a pharmaceutically acceptable salt of any of the foregoing.
  • described herein is a compound or composition for use in treating a disease or condition associated with TLR2 heterodimerization.
  • the invention is directed to a method of treating a disease or medical condition associated with TLR2 heterodimerization, comprising administering to a subject in need of such treatment an effective amount of at least one compound of Formula (I), (II), (III), (IV), (V), or (VI), or a compound of any of Tables 1-6, or a pharmaceutically acceptable salt of any of the foregoing.
  • the invention is also directed to the use of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a compound of any of Tables 1-6, or a pharmaceutically acceptable salt of any of the foregoing for the treatment of, or for the preparation of a medicament for the treatment of, such diseases and medical conditions.
  • the invention relates to a method of interfering with the heterodimerization of TLR2 in a cell, or modulating, preventing, slowing, reversing, or inhibiting TLR2 heterodimerization in a cell, comprising contacting the cell with an effective amount of at least one compound of Formula (I), (II), (III), (IV), (V), or (VI), or a compound of any of Tables 1-6, or a salt of any of the foregoing, and/or with at least one pharmaceutical composition of the invention, wherein the contacting is in vitro, ex vivo, or in vivo.
  • R 1 is H, -C0 2 -Ci_ 8 alkyl, -C0 2 -CHR a -aryl, - C0 2 -CHR a -heteroaryl, -C(0)-Ci_ 4 alkyl, -C(0)aryl, -C(0)-heteroaryl, -C(0)-CHR b -NR c R d , - C(0)-CHR a -heteroaryl, -CHR a -aryl, -CHR a -heteroaryl, -S0 2 -Ci_ 4 alkyl, -S0 2 -aryl, or -S0 2 - heteroaryl; wherein R a is H or Ci_i 5 alkyl; R b is H or -Ci_ 5 alkyl-NR e R f ; where R e is H or Ci_ 4 alkyl and R f is
  • R 1 is H, -C0 2 -Ci- 8 alkyl, -C0 2 -CHR a -aryl, - C0 2 -CHR a -heteroaryl, -C(0)-Ci_ 4 alkyl, -C(0)aryl, -C(0)-heteroaryl, -C(0)-CHR b -NR c R d , - C(0)-CHR a -heteroaryl, -CHR a -aryl, -CHR a -heteroaryl, -S0 2 -Ci_ 4 alkyl, -S0 2 -aryl, or -S0 2 - heteroaryl.
  • R 1 is H, -C0 2 -CHR a -aryl, -C0 2 -CHR a -heteroaryl, -C(0)-Ci_ 4 alkyl, -C(0)aryl, -C(0)-heteroaryl, -C(0)-CHR a -heteroaryl, -CHR a -aryl, -CHR a -heteroaryl, - S0 2 -Ci ⁇ alkyl, -S0 2 -aryl, or -S0 2 -heteroaryl.
  • R 1 is H.
  • R 1 is -C0 2 -Ci_ 8 alkyl.
  • R 1 is -C0 2 -CHR a -aryl or -C0 2 - CHR a -heteroaryl. In other embodiments, R 1 is -C(0)-Ci_ 4 alkyl, -C(0)aryl, or -C(0)-heteroaryl. In other embodiments, R 1 is -C(0)-CHR b -NR c R d . In other embodiments, R 1 is -C(0)-CHR a - heteroaryl. In other embodiments, R 1 is -CHR a -aryl or -CHR a -heteroaryl. In other
  • R 2 and R 3a taken together form C 2 _ 4 alkylene. In some embodiments, R 2 and R 3a taken together form C 3 alkylene.
  • R 3b is H.
  • R 3a and R 3b taken together with the carbon to which they are attached form a 4- to 7-membered heterocycloalkyl, optionally substituted with Ci_ 4 alkyl or -C0 2 Ci ⁇ alkyl.
  • the heterocycloalkyl is pyrrolidine or piperazine.
  • R 3a is substituted or unsubstituted -CH 2 -phenyl.
  • R 3a is -CH 2 -phenyl substituted with benzyloxy, hydroxyl, or phenyl.
  • R 3a is -CH 2 -imidazolyl, optionally substituted with tert-butoxycarbonyl.
  • R 3a is -CH 2 - indolyl.
  • R 3a is -CH 2 -piperidine, optionally substituted with tert-butoxycarbonyl.
  • R 3a is butylamine, optionally substituted with tert-butoxycarbonyl.
  • R 3a is propylamine, optionally substituted with guanidinyl, wherein the guanidinyl is optionally substituted.
  • R 3a is carboxyethyl, optionally substituted with tert-butyl.
  • R 3a is carboxymethyl, optionally substituted with tert-butyl.
  • R 3a and R 3b are both hydrogen.
  • R 4 is H. In some embodiments, R 4 is Ci ⁇ alkyl.
  • R 5 and R 6 are each independently C 8 _i 6 alkyl or C 8 _i 6 alkenyl. In some embodiments, R 5 and R 6 are each independently C 8 _i 6 alkyl. In some embodiments, R 5 and R 6 are the same. In other embodiments, R 5 and R 6 are different. In some embodiments, R 5 and R 6 are unbranched hydrocarbons. In some embodiments, R 5 and R 6 are each Ci 4 alkyl. [0050] In some embodiments, m is 0. In other embodiments, m is 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, p is 0. In other embodiments, p is 1. In some embodiments, n is 1 and p is 0. In other embodiments, n is 0 and p is 1.
  • R 5 and R 6 are each independently Ci 3 _i 6 alkyl or Ci 3 _i 6 alkenyl. In some embodiments, R 5 and R 6 are each independently Cg-nalkyl, Co- ⁇ aLkyl, Cg-nalkenyl, or Ci 3 _i 6 alkenyl.
  • R 5 and R 6 are each independently Cg-iialkyl, Ci 3 _i 6 alkyl, Cs-iialkenyl, or Ci 3 -i 6 alkenyl, and R 1 is H, -C0 2 -Ci_ 8 alkyl, -C0 2 -CHR a -heteroaryl, -C(0)-Ci_ 4alkyl, -C(0)aryl, -C(0)-heteroaryl, -C(0)-CHR b -NR c R d , -C(0)-CHR a -heteroaryl, -CHR a -aryl, - CHR a -heteroaryl, -S0 2 -Ci_ 4 alkyl, -S0 2 -aryl, or -S0 2 -heteroaryl.
  • R 5 and R 6 are each independently C 8 _nalkyl, Ci 3 _i 6 alkyl, C 8 _nalkenyl, or Ci 3 _i 6 alkenyl, and R 3a is H, - C 6 -i 4 alkyl, -CHR g -aryl, -CHR g -heterocycloalkyl, -Ci- 4 alkyl-C0 2 Ci_ 4 alkyl, -Ci_ 4 alkyl-C0 2 H, or - Ci_ 4 alkyl-CONR j R k
  • R 5 and R 6 are each independently Ci 4 alkyl or Ci 4 alkenyl.
  • R 5 and R 6 are each independently C ⁇ alkyl or Ci 6 alkenyl.
  • R 1 is -C0 2 -Ci_ 8 alkyl or -C(0)-CHR b -NR c R d
  • R 3a is -C 6 - i 4 alkyl, -CHR g -aryl, -CHR g -heteroaryl, -CHR g -heterocycloalkyl
  • R 1 is -C0 2 -Ci_ 8 alkyl and R 2 is Ci_ 4 alkyl.
  • the compound of Formula (I) is selected from the group consisting of compounds of Table 1 :
  • the compound is not a compound of Table IX.
  • R 21 is H. In other embodiments, R 21 is Ci_
  • R 21 is -C0 2 Ci_ 4 alkyl. In other embodiments, R 21 is H or -C0 2 - tert-butyl. In some embodiments, R 22 is H. In other embodiments, R 22 is Ci_ 4 alkyl. In some embodiments, R 24 is H. In other embodiments, R 24 is Ci_ 4 alkyl.
  • n2 is 0. In some embodiments, n2 is 1. In some
  • p2 is 0. In other embodiments, p2 is 1. In some embodiments, n2 is 1 and p2 is 0. In other embodiments, n2 is 0 and p2 is 1.
  • the compound of Formula (II) is selected from the group consisting of compounds of Table 2:
  • R is phenyl. In some embodiments, R is monocyclic heteroaryl. In
  • the R heteroaryl is pyrrolyl, imidazolyl, furanyl, or thiophenyl.
  • R is H. In other embodiments, R is Ci_ 4 alkyl.
  • R 33 is Ci_ 4 alkyl-NR x R y .
  • R x is H.
  • R x is Ci_ 4 alkyl.
  • R x is -C0 2 -Ci_ 4 alkyl.
  • R y is H.
  • R y is Ci ⁇ alkyl.
  • R x and R y are both H.
  • R x is -C0 2 -tert-butyl and R y is H.
  • R 35 is Ci 4 _i 8 alkyl. In some embodiments, R 35 is Ci 4 _i 8 alkenyl. In some embodiments, the Ci 4 _i 8 alkenyl has one double bond. In some embodiments, the Ci 4 _ i 8 alkenyl has one cis double bond.
  • the compound of Formula (III) is selected from the group consisting of compounds of Table 3:
  • the compound is of the formula (IVa), (IVb), or (IVc):
  • G 1 is N. In other embodiments, G 1 is CH.
  • R 41 is H. In some embodiments, R 41 is Ci_ 4 alkyl. In some embodiments, R 41 is -C0 2 Ci_ 4 alkyl. In some embodiments,
  • R 41 is absent. In other embodiments, R 41 is H or Ci ⁇ alkyl, wherein the nitrogen attached to R 41 has a positive charge. In some embodiments, R 41 is H. In other embodiments, R 41' is Ci_ 4 alkyl. In some embodiments, R 41 is H, methyl, or tert-butyloxycarbonyl. [0068] In some embodiments of Formula (IV), (IVa), (IVb), or (IVc), R is H. In other embodiments, R is Ci_ 4 alkyl, such as methyl.
  • R 44 is -OC 4 _i 8 alkyl, optionally substituted with -OH, -OCi_ 4 alkyl, -C(0)OH, -C(0)OCi_ 4 alkyl, -C(0)NH 2 , - C(0)NHCi_ 4 alkyl, or aryl.
  • R 44 is -OC 4 _i 8 alkenyl, optionally substituted with -OH, -OCi_ 4 alkyl, -C(0)OH, -C(0)OCi_ 4 alkyl, -C(0)NH 2 , -C(0)NHCi_ 4 alkyl, or aryl.
  • R 43 is -OCi_i 8 alkyl and R 44 is -OC 4 _i 8 alkyl.
  • R 43 is -OCi_i 8 alkenyl and R 44 is -OC 4 _i 8 alkenyl.
  • R 43 is -OCi 3 _i 8 alkyl and R 44 is -OCi 3 _i 8 alkyl.
  • R 43 is -OCi 3 _i 8 alkenyl and R 44 is -OCi 3 _i 8 alkenyl.
  • the compound is selected from the group consisting of compounds of Table 4:
  • G 2 is a bond. In some embodiments, G 2 is - CH 2 -. In some embodiments, G 2 is -CH 2 NH-. In other embodiments, G 2 is -CH 2 NHCH 2 -.
  • R 53 is H. In some embodiments, R 53 is Ci_ 4 alkyl.
  • R 54 is Cg-igalkyl. In some embodiments, R 54 is Cg-igalkenyl. In some embodiments, R 55 is Cg-igalkyl. In some embodiments, R 55 is Cg-igalkenyl. In some embodiments, R 54 and R 55 are each independently Cg-isalkyl or Cg-isalkenyl. In some embodiments, R 54 and R 55 are each independently Cg-isalkyl. In some embodiments, R 54 and R 55 are each independently Cg-igalkenyl. In some embodiments, R 54 and R 55 are the same. In other embodiments, R 54 and R 55 are different. In some embodiments, R 54 and R 55 are unbranched hydrocarbons.
  • R 61 is -C(0)-Ci_ 4 alkyl. In some embodiments, R 61 is -C(0)aryl, or -C(O)- heteroaryl, each optionally substituted with halo, Ci_ 4 alkyl, Ci_ 4 fluoroalkyl, -OH, -OCi_ 4 alkyl, - OCi_ 4 fluoroalkyl, -CN, phenyl, or -OCi_ 4 alkyl-aryl.
  • R 61 is -C(0)-CHR 6b - NR 6c R 6d , where R 6b is H or -Ci_ 5 alkyl-NR 6e R 6f ; R 6e is H or Ci_ 4 alkyl and R 6f is H, C M alkyl, or - C0 2 Ci_ 4 alkyl; R 6c is H or Ci_ 4 alkyl and R 6d is H, Ci_ 4 alkyl, or -C0 2 Ci_ 4 alkyl.
  • R 61 is -C(0)-CHR 6a -heteroaryl, -CHR 6a -aryl, or -CHR 6a -heteroaryl, where R 6a is H or Ci_i 5 alkyl and each aryl or heteroaryl is optionally substituted with halo, Ci_ 4 alkyl, Ci_ 4 fluoroalkyl, -OH, -OCi_ 4 alkyl, -OCi_ 4 fluoroalkyl, -CN, phenyl, or -OCi_ 4 alkyl-aryl.
  • R 61 is -S0 2 -Ci ⁇ alkyl, -S0 2 -aryl, or -S0 2 -heteroaryl. In some embodiments, R 61 is -CHR 6a -aryl, where R 6a is H or Ci-isalkyl and the aryl is optionally substituted with halo, Ci_ 4 alkyl, Ci_ 4 fluoroalkyl, -OH, -OCi_ 4 alkyl, -OCi_ 4 fluoroalkyl, -CN, phenyl, or -OCi_ 4 alkyl-aryl.
  • R 61 is -CHR 6a -heteroaryl, where R 6a is H or Ci-isalkyl and the heteroaryl is optionally substituted with halo, Ci_ 4 alkyl, Ci_ 4 fluoroalkyl, -OH, -OCi_ 4 alkyl, -OCi_
  • R 61 is -CH 2 -phenyl. In some embodiments, R 61 is -CH 2 -napthyl.
  • R 62 is H. In some embodiments, R 62 is Ci_ 4 alkyl.
  • R 61 is -CHR 6a -aryl or -CHR 6a -heteroaryl, where R 6a is H or Ci-isalkyl and each aryl or heteroaryl is optionally substituted with halo, Ci_ 4 alkyl, Ci_
  • R 61 is -CH 2 -phenyl or -CH 2 -napthyl; and R 62 is H.
  • R 64 is -OCi_i 8 alkyl or -OCi_i 8 alkenyl, each of which is optionally substituted with -OH or -OCi_ 4 alkyl; and R 65 is -OCi_i 8 alkyl or -OCi_i 8 alkenyl, each of which is optionally substituted with -OH or -OCi_ 4 alkyl.
  • R 64 and R 65 are each -OCi 8 alkenyl.
  • R 64 is -Ci_i 8 alkyl or -Ci_i 8 alkenyl, optionally substituted with -OH or -OCi_ 4 alkyl; and R 65 is H.
  • R 65 is -OCi_i 8 alkyl or -OCi_i 8 alkenyl, optionally substituted with -OH or -OCi_ 4 alkyl; and R 64 is H. In some embodiments, R 65 is -C 4 _ 8 cycloalkyl and R 64 is H.
  • t is 0. In some embodiments, t is 1. In some embodiments, t is 0 and R 65 is -C 4 _ 8 cycloalkyl. In some embodiments, t is 1; R 64 is -OCi_i 8 alkyl or -OCi_ i 8 alkenyl, each of which is optionally substituted with -OH or -OCi_ 4 alkyl; and R 65 is -OCi_ i 8 alkyl or -OCi_i 8 alkenyl, each of which is optionally substituted with -OH or -OCi_ 4 alkyl. In some embodiments, t is 1 and R 64 and R 65 are each -OCi 8 alkenyl.
  • t is 1; R 64 is -Ci-i 8 alkyl or -Ci_i 8 alkenyl, optionally substituted with -OH or -OCi_ 4 alkyl; and R 65 is H. In some embodiments, t is 1; R 65 is -OCi_i 8 alkyl or -OCi_i 8 alkenyl, optionally substituted with - OH or -OCi_ 4 alkyl; and R 64 is H. In some embodiments, t is 0, R 65 is -C 4 _ 8 cycloalkyl, and R 64 is H.
  • the compound of Formula (VI) is selected from the group consisting of compounds of Table 6:
  • any formula or compound given herein such as Formula (I), (II), (III), (IV), (V), or (VI), or compounds of Tables 1-6, is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms.
  • compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof in any ratio, are considered within the scope of the formula.
  • any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof in any ratio.
  • Tables 1-6 is depicted with a particular stereochemical configuration, also provided herein is any alternative stereochemical
  • Any compound of Tables 1-6 is intended to represent a racemate, one or more
  • any formula given herein is intended to refer to hydrates, solvates, and amorphous forms of such compounds, and mixtures thereof, even if such forms are not listed explicitly.
  • the solvent is water and the solvates are hydrates.
  • alkyl refers to a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms in the chain.
  • alkyl groups include methyl (Me), ethyl (Et), n- propyl, isopropyl, butyl, isobutyl, sec -butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.
  • alkenyl refers to a straight- or branched-chain hydrocarbon group having from 2 to 12 carbon atoms in the chain, and having one or more double bonds.
  • alkenyl groups include ethenyl (or vinyl), allyl, and but-3-en-l-yl. Included within this term are cis and trans isomers and mixtures thereof.
  • alkylene refers to a divalent group that is a radical of an alkane.
  • the alkylene can be a straight- or branched-chain divalent alkyl radical.
  • Ci_ 4 alkylene refers to alkylene groups with 1 to 4 carbon atoms.
  • aryl refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (a phenyl group) or a multiple condensed ring (such as napthyl, anthracenyl, or indanyl), in which condensed rings are optionally aromatic, provided that the point of attachment of the aryl group to the parent structure is through an atom of an aromatic ring.
  • Aryl as defined herein encompasses groups such as phenyl and fluorenyl.
  • fluoroalkyl refers to an alkyl group as defined above, substituted with one or more fluoro substituents.
  • fluoroalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, and trifluoroethyl.
  • heteroaryl refers to a monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms per heterocycle.
  • heteroaryl groups include the following entities, in the form of properly bonded moieties:
  • heterocyclic groups include the following entities, in the form of properly bonded moieties:
  • halogen represents chlorine, fluorine, bromine, or iodine.
  • halo represents chloro, fluoro, bromo, or iodo.
  • oxo represents a carbonyl oxygen.
  • a cyclopentyl substituted with oxo is cyclopentanone.
  • Any formula depicted herein is intended to represent a compound of that structural formula as well as certain variations or forms.
  • a formula given herein is intended to include a racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or a mixture thereof.
  • any formula given herein is intended to refer also to a hydrate, solvate, or polymorph of such a compound, or a mixture thereof.
  • any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, U C, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P,
  • Such isotopically labelled compounds are useful in metabolic studies (preferably with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F or 11 C labeled compound may be particularly preferred for PET or SPECT studies.
  • PET and SPECT studies may be performed as described, for example, by Brooks, D.J., "Positron Emission Tomography and Single-Photon Emission Computed Tomography in Central Nervous System Drug Development," NeuroRx 2005, 2(2), 226-236, and references cited therein. Further, substitution with heavier isotopes such as deuterium (i.e., H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • deuterium i.e., H
  • Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.
  • the invention also includes pharmaceutically acceptable salts of the compounds represented by Formula (I), (II), (III), (IV), (V), or (VI) or the compounds of any of Tables 1-6, preferably of those described above and of the specific compounds exemplified herein, and pharmaceutical compositions comprising such salts, and methods of using such salts.
  • Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-l,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,
  • compositions comprising the compounds described herein may further comprise one or more pharmaceutically-acceptable excipients.
  • a pharmaceutically-acceptable excipient is a substance that is non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate administration of the compounds described herein and are compatible with the active ingredient. Examples of pharmaceutically-acceptable excipients include stabilizers, lubricants, surfactants, diluents, antioxidants, binders, coloring agents, bulking agents, emulsifiers, or taste-modifying agents.
  • pharmaceutical compositions according to the invention are sterile compositions. Pharmaceutical compositions may be prepared using compounding techniques known or that become available to those skilled in the art.
  • compositions are also contemplated by the invention, including compositions that are in accord with national and local regulations governing such compositions.
  • compositions and compounds described herein may be formulated as solutions, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers, or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules along with solid carriers according to conventional methods known in the art for preparation of various dosage forms.
  • Pharmaceutical compositions of the invention may be administered by a suitable route of delivery, such as oral, parenteral, rectal, nasal, topical, or ocular routes, or by inhalation.
  • the compositions are formulated for intravenous or oral administration.
  • the compounds the invention may be provided in a solid form, such as a tablet or capsule, or as a solution, emulsion, or suspension.
  • the compounds of the invention may be formulated to yield a dosage of, e.g. , from about 0.01 to about 50 mg/kg daily, or from about 0.05 to about 20 mg/kg daily, or from about 0.1 to about 10 mg/kg daily. Additional dosages include from about 0.1 mg to 1 g daily, from about 1 mg to about 10 mg daily, from about 10 mg to about 50 mg daily, from about 50 mg to about 250 mg daily, or from about 250 mg to 1 g daily.
  • Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents.
  • suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like.
  • Exemplary liquid oral excipients include ethanol, glycerol, water, and the like.
  • Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrating agents.
  • Binding agents may include starch and gelatin.
  • the lubricating agent if present, may be magnesium stearate, stearic acid, or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.
  • Capsules for oral administration include hard and soft gelatin capsules.
  • active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent.
  • Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
  • Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.
  • suspending agents for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethyl
  • inventive compositions may be formulated for rectal administration as a suppository.
  • parenteral use including intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the agents of the invention may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil.
  • Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
  • Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multi- dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation.
  • Illustrative infusion doses range from about 1 to 1000 ⁇ g/kg/minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.
  • inventive pharmaceutical compositions may be administered using, for example, a spray formulation also containing a suitable carrier.
  • the compounds of the present invention are preferably formulated as creams or ointments or a similar vehicle suitable for topical administration.
  • the inventive compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle.
  • Another mode of administering the agents of the invention may utilize a patch formulation to effect transdermal delivery.
  • treatment is an approach for obtaining a beneficial or desired result, including clinical results.
  • beneficial or desired results include, but are not limited to: reducing the severity of or suppressing the worsening of a disease, symptom, or condition, alleviating a symptom and/or diminishing the extent of a symptom and/or preventing a worsening of a symptom associated with a condition, arresting the development of a disease, symptom, or condition, relieving the disease, symptom, or condition, causing regression of the disease, disorder, or symptom (in terms of severity or frequency of negative symptoms), or stopping the symptoms of the disease or condition.
  • Beneficial or desired results can also be slowing, halting, or reversing the progressive course of a disease or condition.
  • beneficial effects may include slowing the progression of Parkinson's disease from an earlier stage (e.g., prodromal stage or stage 1, 2 or 3) to a later stage (e.g., stage 4 or 5), or halting Parkinson's disease at a prodromal or early stage.
  • subject refers to a mammalian patient in need of such treatment, such as a human.
  • a “subject” may be a human, or may be a cat, dog, cow, rat, mouse, horse, or other domesticated mammal.
  • Exemplary diseases that are characterized by protein aggregation include
  • polyneuropathy atopic dermatitis, acne vulgaris, rosacea, non-alcoholic fatty liver disease, nonalcoholic steatohepatisis, corneal wounds, corneal disorders, Stargardt disease (Juvenile macular degeneration), age-related macular degeneration, sepsis, diabetic wounds, herpes simplex virus, and anti-fungal, anti-bacterial, anitviral and antitumor diseases or conditions.
  • the compounds and pharmaceutical compositions of the invention specifically target TLR2 protein dimers.
  • these compounds and pharmaceutical compositions can be used to prevent, reverse, slow, or inhibit dimerization of TLR2 proteins with other natural protein ligands, and are used in methods of the invention to treat neurological and inflammatory diseases related to or caused by such dimerization.
  • methods of treatment target Parkinson's disease, Alzheimer's disease, Lewy body disease, multiple system atrophy, atopic dermatitis, traumatic brain injury, or multiple sclerosis.
  • the compounds, compositions, and method of the present invention are also used to mitigate deleterious effects that are secondary to protein dimerization and/or misfolding, such as neuronal cell death.
  • the compounds, compositions, and methods of the invention are used to inhibit TLR2 dimerization. In alternative aspects, the compounds, compositions, and methods of the invention are used to inhibit TLR2 dimerization with TLR1, or with TLR6, or both.
  • an "effective amount” means an amount sufficient to reduce, slow the progression of, or reverse TLR2 dimerization. Measuring the amount of dimerization may be performed by routine analytical methods such as those described below. Such modulation is useful in a variety of settings, including in vitro assays.
  • the cell is preferably a nerve cell or an HEK or THP cell.
  • the dose may be adjusted for preventative or maintenance treatment.
  • the dosage or the frequency of administration, or both may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained.
  • treatment may cease.
  • Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. Patients may also require chronic treatment on a long-term basis.
  • Combination agents include additional active ingredients are those that are known or discovered to be effective in treating the diseases, disorders, conditions, and symptoms discussed herein, including those active against another target associated with the disease, disorder, or symptom such as but not limited to, a) compounds that address protein misfolding (such as drugs which reduce the production of these proteins, which increase their clearance or which alter their aggregation and/or propagation); b) compounds that treat symptoms of such disorders (e.g., dopamine replacement therapies); and c) drugs that act as neuroprotectants by complementary mechanisms (e.g., those targeting autophagy, those that are anti-oxidants, and those acting by other mechanisms such as adenosine A2A antagonists).
  • a) compounds that address protein misfolding such as drugs which reduce the production of these proteins, which increase their clearance or which alter their aggregation and/or propagation
  • compounds that treat symptoms of such disorders e.g., dopamine replacement therapies
  • drugs that act as neuroprotectants by complementary mechanisms e.g., those targeting autophagy
  • a compound of Formula (I), (I), (III), (IV), (V), or (VI), or a compound of Tables 1, 2, 3, 4, 5, or 6, or a pharmaceutically acceptable salt of any of the foregoing comprising administering to the subject a
  • compositions containing at least one chemical entity as described herein for use in the treatment of a disease or condition associated with TLR2 heterodimerization are provided.
  • the disease or condition is selected from Alzheimer's disease, Parkinson's disease, fronto-temporal dementia, dementia with Lewy bodies (Lewy body disease), Parkinson's disease with dementia, multiple system atrophy, amyotrophic lateral sclerosis, Huntington's disease, inflammatory diseases, asthma, chronic obstructive pulmonary disease (COPD), chronic peptic ulcers, tuberculosis, rheumatoid arthritis, chronic sinusitis, hepatitis, hepatitis B, hepatitis C, gout, lupus, pleurisy, eczema, gastritis, psoriasis, psoriatic arthritis, vasculitis, laryngitis, allergic reactions, multiple sclerosis, Crohn's disease, and traumatic brain injury.
  • Alzheimer's disease Alzheimer's disease
  • Parkinson's disease fronto-temporal dementia
  • dementia with Lewy bodies Lewy body disease
  • Parkinson's disease with dementia dementia with Lew
  • Also provided are methods for interfering with the heterodimerization of TLR2 in a cell, or modulating, preventing, slowing, reversing, or inhibiting TLR2 heterodimerization in a cell which involves contacting the cell with an effective amount of at least one compound of Formula (I), (I), (III), (IV), (V), or (VI), or a compound of Tables 1, 2, 3, 4, 5, or 6, or a pharmaceutically acceptable salt thereof.
  • provided are methods for interfering with the heterodimerization of TLR2 in a cell, or modulating, preventing, slowing, reversing, or inhibiting TLR2 heterodimerization in a cell which involves contacting the cell with an effective amount of at least one chemical entity as described herein.
  • compositions containing at least one chemical entity as described herein for use in interfering with the heterodimerization of TLR2 in a cell, or modulating, preventing, slowing, reversing, or inhibiting TLR2 heterodimerization in a cell.
  • the article of manufacture may comprise a container with a label.
  • Suitable containers include, for example, bottles, vials, and test tubes.
  • the containers may be formed from a variety of materials such as glass or plastic.
  • the container may hold a pharmaceutical composition provided herein.
  • the label on the container may indicate that the pharmaceutical composition is used for preventing, treating or suppressing a condition described herein, and may also indicate directions for either in vivo or in vitro use.
  • kits containing a compound or composition described herein and instructions for use.
  • the kits may contain instructions for use in the treatment of a disease or condition associated with TLR2 heterodimerization in an individual in need thereof.
  • a kit may additionally contain any materials or equipment that may be used in the administration of the compound or composition, such as vials, syringes, or IV bags.
  • a kit may also contain sterile packaging.
  • the compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter (such as the schemes provided in the Examples below).
  • the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to the formulae herein.
  • a particular enantiomer of a compound this may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers.
  • diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g., a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, for example by crystallization and the desired enantiomer recovered. In another resolution process, a racemate may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described.
  • Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.
  • Solvates of a compound provided herein or a pharmaceutically acceptable salt thereof are also contemplated. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
  • PG is a protecting group
  • X is a halogen
  • compounds of the Formula (IV) may be synthesized according to Scheme 4.
  • R , R ,R , R , R , G 2 , G 3 , o, r, and s are as defined for Formula (V), or any variation thereof detailed herein; and R 56 is H or OH.
  • Example 1 tert-Butyl ((2S)-3-(4-(benzyloxy)phenyl)- l-((2,3-bis(tetradecyloxy)propyl)amino)- l-oxopropan-2-yl)carbamate.
  • Step 3 In a 30 mL sealed cap glass vial, 2,3-bis(tetradecyloxy)propan-l-amine hydrochloride (260 mg, 0.5 mmol) was suspended in 1:2 satd. aq. sodium bicarbonate/dioxane (21 mL) and treated with Boc-L-Tyr(0-Bn)-OSu (234 mg, 0.5 mmol), and the resulting mixture was stirred at rt overnight. The mixture was diluted with water and brine, and extracted with ethyl acetate (2 x 25 mL). The combined organic layers were dried over sodium sulfate, and evaporated.
  • Example 7 tert-Butyl ((2S)-l-((2,3-bis(tetradecyloxy)propyl)amino)-3-(4-hydroxyphenyl)-l- oxopropan-2-yl)carbamate.
  • Example 8 (2S)-2-Amino-N-(2.3-bis(tetradecyloxy)propyl)-3-(4-hvdroxyphenyl)propanamide hydrochloride.
  • the title compound was prepared from 2,3 -bis(tetradecyloxy)propan-l -amine hydrochloride (260 mg, 0.5 mmol) and Boc-L-Glu(OtBu)-OSu (200 mg, 0.5 mmol) as described for Example 1 to give a white solid (230 mg, 60% yield).
  • Example 18 -(2,3-Bis(tetradecyloxy)propyl)-2-((4-methylphenyl)sulfonamido)acetamide.
  • Example 50 tert-Butyl ((5S)-5-acetamido-6-((2,3-bis(tetradecyloxy)propyl)amino)-6- oxohexyDcarbamate.
  • the title compound was prepared from N a -acetyl-N e -Boc-L- Lysine (144 mg, 0.5 mmol) and 2,3-bis(tetradecyloxy)propan-l-amine hydrochloride (260 mg, 0.5 mmol) as described for Example 33 to give the title compound as an off-white solid (152 mg, 40% yield).
  • Example 51 (2S)-2-Acetamido-6-amino-N-(2,3-bis(tetradecyloxy)propyl)hexanamide hydrochloride.
  • the title compound was prepared from N a -Fmoc-P-(l-Boc-piperidin-4-yl)-DL- alanine (247 mg, 0.5 mmol) and 2,3-bis(tetradecyloxy)propan-l-amine hydrochloride (260 mg, 0.5 mmol) as described for Example 33 to give the title compound as a gummy solid (130 mg, 27% yield).
  • Example 54 tert-Butyl 4-(((benzyloxy)carbonyl)amino)-4-((2,3- bis(tetradecylox ropyl)carbamoyl)piperidine-l-carboxylate.
  • Example 55 Benzyl (4-((2,3-bis(tetradecyloxy)propyl)carbamoyl)piperidin-4-yl)carbamate hydrochloride.
  • Example 56 tert-Butyl ((5S)-5-((ri J'-biphenyll-4-ylmethyl)amino)-6-((2,3- bis(tetradec loxy)propyl)amino)-6-oxohexyl)carbamate.
  • Step 1 Methyl N2-(riJ'-biphenyll-4-ylmethyl)-N6-(tert-butoxycarbonyl)-L- lysinate.
  • Step 2 N2-(ri,r-Biphenyll-4-ylmethyl)-N6-(tert-butoxycarbonyl)-L-lysine.
  • methyl N2-([l,l'-biphenyl]-4-ylmethyl)-N6-(tert-butoxycarbonyl)-L-lysinate 427 mg, 1.0 mmol
  • 1 THF-MeOH 6 mL
  • LiOH 96 mg, 4.0 mmol
  • the mixture was neutralized by the addition of satd. aq. KHS0 4 (10 mL).
  • Step 3 The title compound was prepared from N2-([l,l'-biphenyl]-4-ylmethyl)-N6- (tert-butoxycarbonyl)-L-lysine (206 mg, 0.5 mmol) and 2,3-bis(tetradecyloxy)propan-l -amine hydrochloride (260 mg, 0.5 mmol) as described for Example 33 to give the title compound as a gummy solid (285 mg, 65% yield).
  • Example 57 (2S)-2-((ri,l , -Biphenyll-4-ylmethyl)amino)-6-amino-N-(2,3- bis(tetradec loxy)propyl)hexanamide dihydrochloride.
  • Example 58 tert-Butyl ((5S)-6-((2.3-bis(tetradecyloxy)propyl)amino)-5-((4- fluorobenzyl)amino)-6-oxohexyl)carbamate.
  • the title compound was prepared from N 6 -(tert-butoxycarbonyl)-N 2 -(4- fluorobenzyl)-L-lysine (176 mg, 0.5 mmol) (synthesized as described in Example 56) and 2,3- bis(tetradecyloxy)propan- 1 -amine hydrochloride (260 mg, 0.5 mmol) as described in Example 33 to give the title compound as a gummy solid (225 mg, 55% yield).
  • Example 59 (2S)-6-Amino-N-(2,3-bis(tetradecyloxy)propyl)-2-((4- fluorobenzyl)amino hexanamide dihydrochloride.
  • the title compound was prepared from N 2 -benzyl-N 6 -(tert-butoxycarbonyl)-L-lysine (168 mg, 0.5 mmol) (synthesized by following the same procedure as in Example 56) and 2,3- bis(tetradecyloxy)propan- 1 -amine hydrochloride (260 mg, 0.5 mmol) as described in Example 33 to give the title compound as a gummy solid (168 mg, 42% yield).
  • the title compound was prepared from N 2 -benzyl-N 6 -(tert-butoxycarbonyl)-D-lysine (168 mg, 0.5 mmol) (synthesized as in Example 56) and 2,3-bis(tetradecyloxy)propan-l -amine hydrochloride (260 mg, 0.5 mmol) as described in Example 33 to give the title compound as a gummy solid (185 mg, 46% yield).
  • Example 65 (c3 ⁇ 4 ' )-4-Amino-N-(2,3-bis(tetradecyloxy)propyl)cyclohexane- 1-carboxamide hydrochloride.
  • Example 66 tert-Butyl ((trans)-4-((2,3- bis(tetradecyloxy)propyl)carbamoyl)cyclohexyl)carbamate.
  • Example 68 Benzyl tert-butyl (6-(octadec-9-en-l-ylamino)-6-oxohexane-l,5-diyl)(R,Z)- dicarbamate.
  • Example 70 Benzyl tert-butyl (6-oxo-6-(tetradecylamino)hexane-l,5-diyl)(R)-dicarbamate.
  • Example 72 tert-butyl 3-((((10S)-2.2-dimethyl-4.11-dioxo-14-(tetradecyloxy)-3.16-dioxa-5.12- diazatriacontan-10- l)amino)methyl)-lH-indole-l-carboxylate
  • Step 1 tert-butyl (S)-3-(((6-((tert-butoxycarbonyl)amino)-l-methoxy-l-oxohexan-2- yl)amino)methyl)-lH-indole-l-carboxylate: A mixture of tert-butyl 3-formyl-lH-indole-l- carboxylate (736 mg, 3.0 mmol) and methyl N 6 -(tert-butoxycarbonyl)-L-lysinate hydrochloride (890 mg, 3.0 mmol) in THF (50 mL) was treated with NaBH(OAc) 3 (763 mg, 3.6 mmol) and the reaction mixture was stirred at room temperature overnight.
  • NaBH(OAc) 3 763 mg, 3.6 mmol
  • Step 2 N 6 -(tert-butoxycarbonyl)-N 2 -((l-(tert-butoxycarbonyl)-lH-indol-3- vPmethvP-L-lysine.
  • methyl N 2 -([l,l'-biphenyl]-4-ylmethyl)-N 6 -(tert- butoxycarbonyl)-L-lysinate (1225 mg, 2.5 mmol)
  • 1 THF-MeOH 15 mL
  • LiOH 180 mg, 7.5 mmol
  • water 8.0 mL
  • Step 3 The title compound was prepared from N 6 -(tert-butoxycarbonyl)-N 2 -((l- (tert-butoxycarbonyl)-lH-indol-3-yl)methyl)-L-lysine (238 mg, 0.5 mmol) and 2,3- bis(tetradecyloxy)propan- 1 -amine hydrochloride (260 mg, 0.5 mmol) as described for Example 33 to give the title compound as a gummy solid (235 mg, 50% yield).
  • Example 74 tert-butyl 3-(2-(((10S)-2,2-dimethyl-4,l l-dioxo-14-(tetradecyloxy)-3,16-dioxa-
  • Step 1 methyl N 6 -(tert-butoxycarbonyl)-N 2 -(2-(5-methoxy-lH-indol-3-yl)acetyl)-L- lysinate.
  • DMAP dimethylaminopyridine
  • Step 4 The title compound was prepared from N 6 -(tert-butoxycarbonyl)-N 2 -(2-(l- (tert-butoxycarbonyl)-5-methoxy-lH-indol-3-yl)acetyl)-L-lysine (267 mg, 0.5 mmol) and 2,3- bis(tetradecyloxy)propan- 1 -amine hydrochloride (260 mg, 0.5 mmol) as described for Example 33 to give the title compound as a white solid (232 mg, 46% yield).
  • Example 76 tert-butyl 5-(benzyloxy)-3-(2-(((10S)-2,2-dimethyl-4,l l-dioxo-14-(tetradecyloxy)- 3 J6-dioxa-5 J2-diazatriacontan-10-yl)amino)-2-oxoethyl)-lH-indole-l-carboxylate
  • the title compound was prepared from N -(2-(5-(benzyloxy)-l-(tert- butoxycarbonyl)-lH-indol-3-yl)acetyl)-N 6 -(tert-butoxycarbonyl)-L-lysine (synthesized as in Example 74) (305 mg, 0.5 mmol) and 2,3-bis(tetradecyloxy)propan-l-amine hydrochloride (260 mg, 0.5 mmol) as described for Example 33 to give the title compound as a white solid (310 mg, 58% yield).
  • Example 78 tert-butyl ((5S)-6-((2,3-bis(tetradecyloxy)propyl)amino)-5-((naphthalen-2- ylmethyl)amino -6-oxohexyl)carbamate
  • Example 80 tert-butyl 4-(3-((2,3-bis(tetradecyloxy)propyl)carbamoyl)phenyl)piperazine-l- carboxylate
  • Example 82 tert-butyl 4-(3-((2,3-bis(tetradecyloxy)propyl)carbamoyl)phenyl)piperidine-l- carboxylate
  • the title compound was prepared from 3-(l-(tert-butoxycarbonyl)piperidin-4- yl)benzoic acid (153 mg, 0.5 mmol) and 2,3-bis(tetradecyloxy)propan-l-amine hydrochloride (260 mg, 0.5 mmol) as described for Example 33 to give the title compound as white solid (280 mg, 73% yield.
  • Step 2 Compound obtained in step 1 (232 mg, 4.0 mmol) was dissolved in methanol (3.0 mL) and methanolic HCl (10 mL) was added and stirred at room temperature for 3 h and the solvent was evaporated to dryness under reduced pressure to get the desired product (100% yield).
  • Step 2 3-(benzyloxy)-2-(dodecyloxy)propan-l-amine hydrochloride : To a stirred solution of compound obtained in step 1 (3 g) in methanol (5 mL) was added methanolic. HC1 (10 mL) and stirring was continued for lh at room temperature. After completion the mixture was concentrated to obtain the desired product as a colorless liquid (100% yield).
  • Step 3 tert-butyl 4-(3-((3-(benzyloxy)-2-
  • reaction mixture was concentrated to dryness.
  • the crude was diluted with water and washed with isopropyl ether.
  • the resulting aqueous phase was acidified to P 2 using 2N HCl and extracted with ethyl acetate.
  • the collected organic layer was concentrated and purified by silica gel column chromatography gradient elution with 5-10% Methanol in dichloromethane to provide desired product as a colorless liquid (900 mg, 82%).
  • ESI-MS m/z [M+H] + calc'd for C 37 H 62 N 2 O 7 , 647; found, 647.
  • Step 2 To a stirred solution of above obtained step 1 product (500 mg) in dichloromethane (4 mL) was added 4N HCl in 1,4-Dioxane (10 mL) slowly and continued to stir for 30 min at room temperature. The resultant reaction mixture was concentrated to furnish the desired product as an off white solid (100% yield).
  • Step 1 tert-butyl 4-(3-((3-((5-amino-5-oxopentyi)oxy)-2- (dodecyloxy)propyl)carbamoyl) phenyl )piperidine- 1-carboxylate:
  • the title compound was prepared from 5-(3-(3-(l-(tert-butoxycarbonyl) piperidin-4-yl)benzamido)-2- (dodecyloxy)propoxy) pentanoic acid (250 mg, O.38mmol) and NH4C1 (46.75 mg, 0.874 mmo) as described for Example 98 to give the desired product as yellow liquid (220 mg, 88%).
  • Step 2 To a stirred solution of above step 1 product (220 mg) in dichloromethane (2 mL) was added HC1 in 1,4-Dioxane (5 mL) and continued to stir for 30 min at room temperature
  • Step 1 tert-butyl 4-(3 -((3 -(octyloxy)propyl)carbamoyl)phenyl)piperidine- 1 - carboxylate:
  • the title compound was prepared from 3-(l-(tert-butoxycarbonyl)piperidin-4- yl)benzoic acid (153 mg, 0.5 mmol) and 3-(octyloxy)propan- l-amine (112 mg, 0.5 mmol) as described for Example 33 to give the title compound as colorless gummy liquid (226 mg, 95% yield).
  • Step 2 The title compound was prepared from above step 1 product (95 mg, 0.2 mmol) as described for Example 1 to give a white solid (100% yield).
  • Step 2 The title compound was prepared from above step 1 product (100 mg, 0.2 mmol) as described for Example 1 to give a white solid (100% yield). 1H NMR (500 MHz,
  • Stepl tert-butyl 4-(3-((3-(2-methoxyethoxy)propyl)carbamoyl)phenyl)piperidine-l- carboxylate:
  • the title compound was prepared from 3-(l-(tert-butoxycarbonyl)piperidin-4- yl)benzoic acid (153 mg, 0.5 mmol) and 3-(2-methoxyethoxy)propan-l-amine (67 mg, 0.5 mmol) as described for Example 33 to give the title compound as colorless liquid (158 mg, 75% yield).
  • ESI-MS m/z [M+H] + calc'd for C 23 H 36 N 2 O 5 , 421; found, 421.
  • Step 2 The title compound was prepared from above step 1 product (84 mg, 0.2 mmol) as described for Example 1 to give a colorless liquid (100% yield).
  • 1H NMR 500 MHz, Chloroform-d
  • Step 1 tert-butyl 4-(3 -((3 -ethoxy-2-hvdroxypropyl)carbamoyl)phenyl)piperidine- 1 - carboxylate:
  • the title compound was prepared from 3-(l-(tert-butoxycarbonyl)piperidin-4- yl)benzoic acid (153 mg, 0.5 mmol) and l-amino-3-ethoxypropan-2-ol (60 mg, 0.5 mmol) as described for Example 33 to give the title compound as colorless liquid (165 mg, 75% yield).
  • Example 104 tert-butyl 4-((2,3-bis(tetradecyloxy)propyl)carbamoyl)-4-phenylpiperidine-l- carboxylate
  • Stepl tert-butyl (3-((2,3-bis(tetradecyloxy)propyl)amino)-3-oxo-2- phenylpropyPcarbamate:
  • the title compound was prepared from 3-((tert- butoxycarbonyl)amino)-2-phenylpropanoic acid (133 mg, 0.5 mmol) and 2,3- bis(tetradecyloxy)propan- 1 -amine hydrochloride (260 mg, 0.5 mmol) as described for Example 33 to give the title compound as colorless liquid (310 mg, 85% yield).
  • Step 2 The title compound was prepared from above step 1 product (146 mg, 0.2 mmol) as described for Example 1 to give a white solid (100% yield).
  • Example 107 tert-butyl 3-benzyl-3-((2,3-bis(tetradecyloxy)propyl)car
  • Step 2 The title compound was prepared from above step 1 product (163 mg, 0.2 mmol) as described for Example 1 to give a light yellow solid (100% yield).
  • Stepl tert-butyl 4-((benzylamino)methyl)-4-((2,3- bis(tetradecyloxy)propyl)carbamoyl) piperidine- 1-carboxylate:
  • the title compound was prepared from 4-((benzylamino)methyl)- l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (174 mg, 0.5 mmol) and 2,3-bis(tetradecyloxy)propan-l-amine hydrochloride (260 mg, 0.5 mmol) as described for Example 33 to give the title compound as yellow liquid (215 mg, 53% yield).
  • Step 2 The title compound was prepared from above step 1 product (163 mg, 0.2 mmol) as described for Example 1 to give a yellow solid (100% yield).
  • Example 112 N-benz l-N,N-dimethyl-2,3-bis(tetradecyloxy)propan-l-aminium iodide
  • Example 113 tert-butyl 4-(3-((2,3-bis(((Z)-tetradec-8-en-l-yl)oxy)propyl)carbamoyl)phenyl) piperidine- 1 -carboxylate
  • Example 113 To a stirred solution of Example 113 (550 mg) in methanol (5 ml) was added Methanolic HCl (10 mL) and stirring was continued for lh at room temperature. The completion of reaction monitored by TLC, the mixture was concentrated and the obtained crude product was purified by Preparative HPLC to furnish desired target product (N-(2,3-bis((Z)-tetradec-8- enyloxy)propyl)-3-(piperidin-4-yl)benzamide hydrochloride as colorless sticky solid (230 mg, 48%).
  • Example 115 tert-butyl 4-(3-((2.3-bis(((9Z.12Z)-octadeca-9.12-dien-l-yl)oxy)propyl) carbamoyl phenvDpiperidine- 1 -carboxylate
  • Example 117 tert-butyl ((5R)-5-(benzylamino)-6-((2,3-bis(((9Z,12Z)-octadeca-9,12-dien-l- yl)oxy)propyl)amino -6-oxohexyl)carbamate
  • the title compound was prepared from N2-benzyl-N6-(tert-butoxycarbonyl)-D- lysine (168 mg, 0.5 mmol) and 2,3-bis(((9Z,12Z)-octadeca-9,12-dien-l-yl)oxy)propan-l-amine hydrochloride (313 mg, 0.5 mmol) as described for Example 33 to give the title compound as colorless oil (410 mg, 90% yield).
  • Step 1 tert-butyl (S)-(5-(benzylamino)-6-oxo-6-(tetradecylamino)hexyl)carbamate: The title compound was prepared from N 2 -benzyl-N 6 -(tert-butoxycarbonyl)-L-lysine (168 mg, 0.5 mmol) and tetradecan-1 -amine (107 mg, 0.5 mmol) as described for Example 33 to give the title compound as gummy solid (155 mg, 58% yield).
  • Step 2 The title compound was prepared from above obtained step 1 product (106 mg, 0.2 mmol) as described for Example 1 to give an off-white solid (100% yield).
  • Stepl tert-butyl (S)-(5-(benzylamino)-6-(decylamino)-6-oxohexyl)carbamate: The title compound was prepared from N 2 -benzyl-N 6 -(tert-butoxycarbonyl)-L-lysine (168 mg, 0.5 mmol) and decyl-l-amine (79 mg, 0.5 mmol) as described for Example 33 to give the title compound as semi solid (158 mg, 66% yield).
  • Step 2 The title compound was prepared from above obtained step 1 product (97 mg, 0.2 mmol) as described for Example 1 to give an off-white solid (100% yield).
  • Step 1 tert-butyl (S)-(5-(benzylamino)-6-((3-ethoxypropyl)amino)-6- oxohexyPcarbamate:
  • the title compound was prepared from N 2 -benzyl-N 6 -(tert- butoxycarbonyl)-L-lysine (168 mg, 0.5 mmol) and 3-ethoxypropan-l-amine (52 mg, 0.5 mmol) as described for Example 33 to give the title compound as semi solid (153 mg, 73% yield).
  • Step 2 The title compound was prepared from above obtained step 1 product (84 mg, 0.2 mmol) as described for Example 1 to give a gummy solid (100% yield).
  • 1H NMR 500 MHz, Chloroform- ) ⁇ 7.86 - 7.31 (m, 8H), 3.68 - 3.54 (m, 3H), 3.50 (m, 3H), 3.25 (s, 5H), 2.04 (m, 2H), 1.81 (m, 2H), 1.52-1.00 (m, 7H).; ESI-MS m/z [M+H] + calc'd for C 18 H 31 N 3 O 2 , 322; found, 322.
  • Step 1 tert-butyl (S)-(5-(benzylamino)-6-((3-(octyloxy)propyl)amino)-6- oxohexyDcarbamate:
  • the title compound was prepared from N 2 -benzyl-N 6 -(tert- butoxycarbonyl)-L-lysine (168 mg, 0.5 mmol) and 3 3-(octyloxy)propan-l -amine (112 mg, 0.5 mmol) as described for Example 33 to give the title compound as semi solid (172 mg, 68% yield).
  • Step 2 The title compound was prepared from above obtained step 1 product (101 mg, 0.2 mmol) as described for Example 1 to give a gummy solid (100% yield).
  • Step 1 tert-butyl (S)-(6-((2-cyclohexylethyl)amino)-5-((naphthalen-2- ylmethyl)amino)-6-oxohexyl)carbamate:
  • the title compound was prepared from N6-(tert- butoxycarbonyl)-N2-(naphthalen-2-ylmethyl)-L- lysine (193 mg, 0.5 mmol) and 2- cyclohexylethan- 1 -amine (82 mg, 0.5 mmol) as described for Example 33 to give the title compound as semi solid (182 mg, 73% yield).
  • Step 2 The title compound was prepared from above obtained step 1 product (100 mg, 0.2 mmol) as described for Example 1 to give an off-white solid (100% yield).
  • 1H NMR 500 MHz, Chloroform- ) ⁇ 9.53 (s, IH), 8.52 (s, IH), 7.62 (m, 10H), 4.09 (m, 5H), 2.93 (m, 2H), 2.21 - 0.51 (m, 19H).; ESI-MS m/z [M+H] + calc'd for C 2 5H 37 N 3 0, 396; found, 396.
  • Step 1 tert-butyl (S)-(6-((2-cyclohexylethyl)amino)-5-((naphthalen-2- ylmethyl)amino)-6-oxohexyl)carbamate:
  • the title compound was prepared from N6-(tert- butoxycarbonyl)-N2-(naphthalen-2-ylmethyl)-L- lysine (193 mg, 0.5 mmol) and methylamine hydrochloride (34 mg, 0.5 mmol) as described for Example 33 to give the title compound as semi solid (156 mg, 78% yield).
  • Step 2 The title compound was prepared from above obtained step 1 product (80 mg, 0.2 mmol) as described for Example 1 to give an off-white gummy solid (100% yield).
  • Step 1 tert-butyl ((5S)-5-(benzylamino)-6-((2,3-bis(heptyloxy)propyl)amino)-6- oxohexyl) carbamate:
  • the title compound was prepared from N 2 -benzyl-N 6 -(tert- butoxycarbonyl)-L-lysine (400 mg, 1.19 mmol) and 2,3 -bis(heptyloxy)propan- 1 -amine (347 mg, 1.19 mmol) as described for Step 3 of Example 93 to give the title compound as semi solid (370 mg, 51% yield).
  • Step 2 The above compound was dissolved in methanol (2 mL) and methanolic HC1 (10 mL) was added and stirred at room temperature for 3 hours and the solvent was concentrated to dryness under vacuum gave title compound (100% yield).
  • Step 1 tert-butyl ((5S)-5-(benzylamino)-6-((2,3-bis((5- methoxypentyl)oxy)propyl)amino)-6-oxohexyl)carbamate:
  • the title compound was prepared from N 2 -benzyl-N 6 -(tert-butoxycarbonyl)-L-lysine (400 mg, 1.19 mmol) and 2,3-bis (5- methoxypentyloxy) prop an- 1- amine.
  • HC1 (476 mg, 1.637 mmol) as described for Step 3 of Example 93 to give the title compound as semi solid (400 mg, 55% yield).
  • Step 2 The above compound was dissolved in methanol (2 mL) and methanolic HC1 (10 mL) was added and stirred at room temperature for 3h and the solvent was concentrated to dryness under vacuum gave title compound (100% yield).
  • Example 127 tert-butyl (S)-(5-(benzylamino)-6-oxo-6-(tetradecylamino)hexyl)carbamate
  • Example 129 tert-butyl (S)-(5-(benzylamino)-6-((3-ethoxypropyl)amino)-6- oxohexyDcarbamate
  • Example 130 tert-butyl (S)-(5-(benzylamino)-6-((3-(octyloxy)propyl)amino)-6-
  • Example 132 tert-butyl (S)-(6-((2-cvclohexylethyl)amino)-5-((naphthalen-2-ylmethyl)amino)-
  • Step 1 tert-butyl ((5S)-6-((3-ethoxy-2-hvdroxypropyl)amino)-5-((naphthalen-2- ylmethvPamino) -6-oxohexyl)carbamate:
  • the title compound was prepared from N 6 -(tert- butoxycarbonyl)-N -(naphthalen-2-ylmethyl)-L-lysine (synthesized as in Example 56) (194 mg, 0.5 mmol) and l-amino-3-ethoxypropan-2-ol (60 mg, 0.5 mmol) as described for Example 33 to give the title compound as yellow liquid (173 mg, 71% yield).
  • Step 2 The title compound was prepared from above obtained step 1 product (98 mg, 0.2 mmol) as described for step 2 of Example 1 to give a yellow solid (100% yield).
  • Step 1 tert-butyl (S)-(5-(benzylamino)-6-((2-(heptyloxy)ethyl)amino)-6- oxohexyDcarbamate: Title compound was prepared from (S)-2-(benzylamino)-6-(tert- butoxycarbonylamino)hexanoic acid (400 mg, 1.19 mmol) and 2-(heptyloxy) ethanamine (189 mg, 1.19 mmol) as described for Step 3 of Example 93 to give the title compound as semi solid (380 mg, 67% yield).
  • Step 2 The above compound was dissolved in methanol (2 mL) and methanolic HC1 (10 mL) was added and stirred at room temperature for 3h and the solvent was evaporated to dryness gave title compound (100% yield).
  • Step 1 tert-butyl ((5S)-5-(benzylamino)-6-((2-(heptyloxy)-3-methoxypropyl)amino)- 6-oxohexyl)carbamate: Title compound was prepared from (S)-2-(benzylamino)-6-(tert- butoxycarbonylamino)hexanoic acid (400 mg, 1.19 mmol) and 2-(heptyloxy)3-methoxypropan- 1 -amine hydrochloride (241 mg, 1.19 mmol) as described for Step 3 of Example 93 to give the title compound as semi solid (350 mg, 56% yield).
  • Step 2 The above compound was dissolved in methanol (2 mL) and methanolic HC1 (10 mL) was added and stirred at room temperature for 3h and the solvent was evaporated to dryness gave title compound (100% yield).
  • 1H NMR 300 MHz, DMSO-d 6 ) ⁇ 9.7 (br s,lH), 9.3 (br s,lH), 8.7 (s, IH), 8.0-7.8 (s, 2H), 7.6-7.3 ( m, 5H), 4.0 (s, 2H), 3.8-3.6 (s, IH), 3.5-3.2 (m, 8H), 2.8-2.6 (m, 3H), 2.9-2.7 (m, 2H), 1.6-1.4 (m, 4H), 1.4-1.1 ( m, 12H), 0.9-0.7 (m, 3H).; ESI- MS m/z [M+H] + calc'd for C2 4 H 43 N 3 0 3 , 422; found, 422.
  • Example 136 N-(l-((2,3-Bis(tetradecyloxy)propyl)amino)- l-oxotetradecan-2-yl)-5-fluoro- 1H- indole-3-carboxamide.
  • Example 137 N-(2,3-Bis(tetradecyloxy)propyl)-2-((l-(5-fluoro-lH-indol-3- yl)tetradecyl)amino)acetamide.
  • Example 138 3-((l-(lH-Indol-3-yl)tetradecyl)amino)-N-(2,3-bis(tetradecyloxy)
  • Example 139 2-Amino-N- l,3-bis(octadecyloxy)propan-2-yl)-3-guanidinopropanamide.
  • the title compound may be prepared from l,3-bis(octadecyloxy)propan-2-amine using methods analogous to those described herein.
  • Example 140 2-Amino-N-(l,3-bis(octadecyloxy)propan-2-yl)-3-(lH-imidazol-5- vPpropanamide.
  • Example 141 2-Amino-N- l,3-bis(octadecyloxy)propan-2-yl)-3-(lH-indol-2-yl)propanamide.
  • Example 142 2 5-Diamino-N-(l,3-bis(octadecyloxy)propan-2-yl)pentanamide.
  • Example 143 2 6-Diamino-N-(l,3-bis(octadecyloxy)propan-2-yl)hexanamide.
  • Example 13 Eight milligrams of Example 13 was dissolved in 1 mL of chloroform. The resulting colorless clear solution was evaporated using a Bueche rotovap apparatus under reduced pressure at 40 °C. [0339] To the resulting uniform nearly-clear coating on the glass walls was added 1 mL of IX PBS buffer at pH 7.3. The vial was vortexed for 3 min, resulting in a turbid suspension of the liposome. The vial was then immersed in a sonication bath for 3 min, followed by probe sonication at 5 second intervals repeatedly five times. The translucent solution was then extruded though a 100 nm membrane filter repeatedly 10 times, and the nearly clear solution was stored at 4 °C. Differential light scattering of this solution using a Wyatt (dynapro) apparatus showed the average particle size to be 120 nm with a dispersion factor of 0.15.
  • Synthetic diacylated lipoprotein (Pam2CSK4, TLR2/6 agonist) and synthetic triacylated lipoprotein (Pam3CSK4, TLR1/2 agonist) were obtained from InvivoGen and were dissolved in endotoxin-free water to a concentration 1 mg/mL, vortexed until complete solubilization, and stored in aliquots at -20 °C.
  • TNFa was obtained from Thermo Fisher Scientific and was used as a counter- screen for specificity to TLR signaling. It was dissolved in endotoxin-free water to a concentration 0.2 mg/ml, and stored in aliquots at -20°C. Prior to addition to cells, an aliquot of the dissolved ligand was vortexed shortly and then was diluted in medium to 25 ng/mL Pam2CSK4, 1000 ng/mL Pam3CSK4 or TNFa. The final top
  • concentration used to determine the agonist EC 50 for each assay run was 5 ng/mL (Pam2CSK4) or 200 ng/mL (Pam3CSK4 or TNFa).
  • Test compounds were solubilized fresh to 3 - 10 mM stocks in 50% DMSO/50% EtOH and sonicated for 5-10 minutes in a water bath sonicator. Serial dilutions were prepared in 50% DMSO/50% EtOH, and then diluted in medium. The final concentration of DMSO used in the assay was 0.5%, and the final concentration of EtOH was 0.5%.
  • HEK-Blue hTLR2 reporter cells are HEK-293 cells stably expressing both the human TLR2 gene and a secreted embryonic alkaline phosphatase (SEAP) reporter construct downstream of NFKB promotor sites.
  • SEAP embryonic alkaline phosphatase
  • HEK-Blue hTLR2 reporters were cultured according to manufacturer's protocol using Dulbecco's Modified Eagle Medium (DMEM; Gibco) containing IX GlutaMax (Gibco), 10% heat-inactivated Fetal Bovine Serum (Gibco), Pen-Strep (50 U/mL penicillin, 50 ⁇ g/mL streptomycin, Gibco), 100 ⁇ g/mL Normocin
  • Quanti-Blue reagent for detection and quantification of secreted alkaline phosphatase was dissolved in 100 mL of endotoxin-free water, warmed to 37 °C for 30 minutes and then filtered using a 0.2 ⁇ membrane.
  • Example 93 displayed an IC 50 of 10 ⁇ against TNFa.
  • the activities of all other compounds against TNFa are shown in Table 7 and are denoted as (+) for IC 50 values ⁇ 30 ⁇ and (-) for IC 50 values > 30 ⁇ .

Abstract

The present invention relates to lipid-substituted amino 1,2- and 1,3-diol compounds, pharmaceutical compositions comprising such compounds, and use of such compounds in methods of treatment or in medicaments for treatment of inflammatory diseases and certain neurological disorders that are related to inflammatory signaling processes, including but not limited to misfolded proteins.

Description

LIPID-SUBSTITUTED AMINO 1.2- AND 1.3-DIOL COMPOUNDS AS MODULATORS
OF TLR2 DIMERIZATION
Cross -Reference to Related Applications
[0001] This application claims priority to U.S. Provisional Application No. 62/370,637, filed August 3, 2016, which is hereby incorporated by reference in its entirety.
Technical Field
[0002] The present invention relates to lipid-substituted amino 1,2- and 1,3-diol compounds, pharmaceutical compositions comprising such compounds, and use of such compounds in methods of treatment or in medicaments for treatment of inflammatory diseases and certain neurological disorders that are related to inflammatory signaling processes, including but not limited to misfolded proteins.
Background
[0003] Toll-like receptors (TLRs) are sentinel receptors of the immune system. When these receptors are activated on cell surfaces, they initiate recruitment of a family of TIR-domain containing adapter proteins, which induce a signaling cascade that ultimately results in cell-type specific inflammatory responses, resulting in the elevation of pro-inflammatory mediators such as IL1, IL6, IL8 and TNFa. Of the different TLR receptors expressed on mammalian cells, TLR2 forms heterodimers with either TLR1 or TLR6 to initiate inflammatory responses with various microbial derived ligands. Among the various bacterial ligands are lipopolysaccharides (LPS), acylated lipopeptides, lipoglycans, peptidoglycans, porins, glycosylphosphatidyl-inosol anchors, and other bacterial cell wall components such as lipoteichoic acid (LTA) from streptococous pneumonia. In addition to the microbial activation of TLR2, it has also been found that abnormal aggregation of neuron released oligomeric proteins such as alpha- synuclein (aSyn) can induce similar inflammatory responses in animal models of neurodegenerative diseases, including Parkinson's disease (PD), dementia with Lewy bodies, multiple system atrophy (MSA) and Alzheimer's disease (AD). See, e.g., Kim et al., Nat. Commun. 2013, 4, 1562. [0004] The ability of TLR2 to induce signaling via heterodimers allows discrimination between various recognition patterns, which allows for the design of ligands with specific inhibition patterns. Kajava et al., J. Biol. Chem. 2010, 285, 6227. Inhibitors that compete primarily with a specific pathological agonist, such as oligomeric pathogenic alpha-synuclein, but do not affect other ligands involved in pro-inflammatory signaling of bacterial or viral infections, would therefore be useful as potential therapeutic agents. Described herein are compounds that function directly as inhibitors of TLR2 interaction with its heterodimer proteins, rather than as delivery vehicles for other therapeutic agents (such as liposomal delivery of active agents or as targeting agents for delivery of therapeutic moieties covalently bound to the polar heads of the lipid components).
[0005] The function of Toll-like receptors has been linked to various protein folding, protein dimerization, and inflammatory processes and to related diseases such as Alzheimer's disease (Gambuzza, M. et al., "Toll-like receptors in Alzheimer's disease: a therapeutic perspective," CNS Neurol. Disord. Durg Targets 2014, 13(9), 1542-58), Parkinson's disease and Parkinson's disease with dementia (Beraud, D. et ah, "Misfolded a-synuclein and Toll-like receptors:
therapuetic targets for Parkinson's disease," Parkinsonism Relat. Disord. 2012, 18 (Suppl. 1), S 17-20), fronto-temporal dementia, dementia with Lewy bodies (Lewy body disease), multiple system atrophy (Vieira, B. et al., "Neuroinflammation in multiple system atrophy: Response to and cause of a-synuclein aggregation," Front. Cell Neurosci. 2015, 9, 437), amyotrophic lateral sclerosis (Casula, M. et ah, "Toll-like receptor signaling in amyotrophic lateral sclerosis spinal cord tissue," Neuroscience 2011, 179, 233-43), Huntington's disease (Kalathur, R.K.R. et ah, "Huntington's disease and its therapeutic target genes: a global functional profile based on the HD Research Crossroads database," BMC Neurology 2012, 12, 47), inflammatory diseases, asthma and chronic obstructive pulmonary disease (COPD) (Zuo, L. et ah, "Molecular regulation of Toll-like receptors in asthma and COPD," Front. Physiol. 2016, 6, 312), chronic peptic ulcers (Smith, S., "Roll of Toll-like receptors in Helicobacter pylori infection and immunity," World J. Gastrointest. Pathophysiol. 2014, 5(3), 133-146), tuberculosis (Harding, C.V. et al., "Regulation of antigen presentation by Mycobacterium tuberculosis: a role for Tolllike receptors," Nat. Rev. Microbiol. 2010, 8(4), 296-307), rheumatoid arthritis (Huang, Q.-Q. et al., "Roll of Toll like receptors in rheumatoid arthritis," Curr. Rheumatol. Rep. 2009, 11(5), 357-364), chronic sinusitis (Zhang, Q. et al, "Differential expression of Toll-like receptor pathway genes in chronic rhinosinusitis with or without nasal polyps," Acta Otolaryngol. 2013, 133(2), 165-173), hepatitis (including hepatitis B and C) (Zhang, E. et ah, "Toll-like receptor (TLR)-mediated innate immune responses in control of hepatitis B virus (HB V) infection," Med. Microbiol. Immunol. 2015, 204(1), 11-20; Howell, J. et ah, "Toll-like receptors in hepatitis C infection: implications for pathogenesis and treatment," J. Gastroenterol. Hepatol. 2013, 28(5), 766-776), gout, lupus, psoriasis, psoriatic arthritis (Santegoets, K.C.M. et ah, "Toll-like receptors in rheumatic diseases: are we paying a high price for our defense against bugs?" FEBS Letters 2011, 585(23), 3660-3666), vasculitis, laryngitis, pleurisy (Chen, X. et al., "Engagement of Toll-like receptor 2 on CD4(+) T cells facilitates local immune responses in patients with tuberculous pleurisy," J. Infect. Dis. 2009, 200(3), 399-408), eczema (Miller, L.S., "Toll-like receptors in skin," Adv. Dermatol. 2008, 24, 71-87), gastritis (Schmausser, B. et al., "Toll-like receptors TLR4, TLR5 and TLR9 on gastric carcinoma cells: an implication for interaction with Helicobacter pylori," Int. J. Med. Microbiol. 2005, 295(3), 179-85), vasculitis (Song, G.G. et ah, "Toll-like receptor polymorphisms and vasculitis susceptibility: metaanalysis and systematic review," Mol. Biol. Rep. 2013, 40(2), 1315-23), laryngitis (King, S. N. et ah, "Characterization of the Leukocyte Response in Acute Vocal Fold Injury," PLoS One, 2015; 10(10): e0139260), allergic reactions (Gangloff, S.C. et al, "Toll-like receptors and immune response in allergic disease," Clin. Rev. Allergy Immunol. 2004, 26(2), 115-25), multiple sclerosis (Miranda- Hernandez, S. et ah, "Role of toll-like receptors in multiple sclerosis," Am. J. Clin. Exp. Immunol. 2013, 2(1), 75-93), Crohn's disease (Cario, E., "Toll-like receptors in inflammatory bowel diseases: A decade later," Inflamm. Bowel Dis. 2010, 16(9), 1583-1597), and traumatic brain injury (Hua, F. et al., "Genomic profile of Toll-like receptor pathways in traumatically brain-injured mice: effect of exogenous progesterone," J.
Neuroinflammation 2011, 8, 42).
[0006] Patent publications that discuss aminoacid, cationic, and other modified lipids include: U.S. Pat. Publ. Nos. 2015/0030670, 2005/0113345, 2005/0175682, 2011/0091525, 2011/0152251, and 2015/0065414; PCT Publ. Nos. WO2002/0729068, WO2005/039504, WO2009/129385, WO2011/062955, WO2013/030678, and WO2013/135359; and U.S. Patent Nos. 7,803,397, 8,609,663, and 8,936,942. Other publications include: Long, E.M. et al, "A subclass of acylated anti-inflammatory mediators usurp Toll-like receptor 2 to inhibit neutrophil recruitment through peroxisome proliferator-activated receptor," PNAS 2011, 103(39), 16357- 16362; Kang, J.Y. et al, "Recognition of Lipopeptide Patterns by Toll-like Receptor 2-Toll-like Receptor 6 Heterodimer," Immunity 2009, 31(6), 873-884; Kajava, A.V. et al, "A Network of Hydrogen Bonds on the Surface of TLR2 Controls Ligand Positioning and Cell Signaling," . Biol Chem. 2010, 285, 6227-6234; Medel, I. et al "VB-201, an oxidized phospholipid small molecule, inhibits CD 14- and Toll-like receptor-2-dependent innate cell activation and constrains atherosclerosis," Clin. Exp. Immunol. 2014, 175(1), 126-37; Kadi, A. et al,
"Oxidized phospholipid-induced inflammation is mediated by Toll-like receptor 2," Free Radic. Biol. Med. 2011, 51(10), 1903-9.
[0007] Described herein are lipid-substituted amino 1,2- and 1,3-diol compounds that serve as antagonists of TLR2 heterodimer binding with high potency and selectivity.
Summary of the Invention
[0008] In one aspect, the invention relates to a compound of Formula (I):
Figure imgf000005_0001
wherein
R1 is H, -C02-Ci_8alkyl, -C02-CHRa-aryl, -C02-CHRa-heteroaryl, -C(0)-Ci_4alkyl, -C(0)aryl, - C(0)-heteroaryl, -C(0)-CHRb-NRcRd, -C(0)-CHRa-heteroaryl, -CHRa-aryl, -CHRa- heteroaryl, -S02-Ci_4alkyl, -S02-aryl, or -S02-heteroaryl;
wherein Ra is H or Ci-isalkyl;
Rb is H or -Ci_5alkyl-NReRf;
where Re is H or Ci_4alkyl and Rf is H, Ci_4alkyl, or -C02Ci^alkyl;
Rc is H or Ci^alkyl and Rd is H, Ci_4alkyl, or -C02Ci_4alkyl; and
each aryl or heteroaryl is optionally substituted with halo, Ci_4alkyl, Ci_4fluoroalkyl, -OH, - OCi_4alkyl, -OCi_4fluoroalkyl, -CN, phenyl,-OCi_4alkyl-aryl, or -C02Ci_4alkyl;
R2 is H or Ci_4alkyl; R3a is H, -C6-i4alkyl, -CHRg-aryl, -CHRg-heteroaryl, -CHRg-heterocycloalkyl,
Figure imgf000006_0001
-Ci_4alkyl-C02Ci-4alkyl, -Ci_4alkyl-C02H, or -Ci_4alkyl-CONRjRk;
Rg is H or Ci_4alkyl;
Rh is H, Ci_4alkyl, or -C02Ci_4alkyl;
R1 is H, Ci_4alkyl, or -C(=NH)-NHRm;
wherein Rm is H, -S02aryl, or -C02Ci_4alkyl;
RJ is H or Ci_4alkyl; and
Rk is H or Ci_4alkyl;
and wherein each aryl, heteroaryl, and heterocycloalkyl is optionally substituted with -OH, Ci_4alkyl, -C02Ci-4alkyl, phenyl, or benzyloxy;
or R2 and R3a taken together with the atoms to which they are attached form C2_4alkylene;
R3b is H; or R3a and R3b taken together with the carbon to which they are attached form a 4- to 7- membered heterocycloalkyl, optionally substituted with Ci_4alkyl or -C02Ci_4alkyl;
R4 is H or Ci_4alkyl;
R5 is Cg-i6alkyl or C8-i6<iIkenyl;
R6 is C8-i6alkyl or C8-i6alkenyl;
m is 0 or 1 ;
n is 0 or 1 ; and
p is 0 or 1 ;
wherein at least one of n and p is 1 ;
or a pharmaceutically acceptable salt thereof.
[0009] In another aspect, the invention relates to a compound of Formula (II):
Figure imgf000006_0002
wherein
R21 is H, Ci_4alkyl, or -C02C^alkyl;
R22 is H or Ci_4alkyl;
R24 is H or Ci_4alkyl; R is C8-i6alkyl or C8_i6alkenyl;
R26 is C8_i6alkyl or C8-i6alkenyl;
n2 is 0 or 1 ; and
p2 is 0 or 1 ;
wherein at least one of n2 and p2 is 1 ;
or a pharmaceutically acceptable salt thereof.
[0010] In another aspect, the invention relates to a compound of Formula (III):
Figure imgf000007_0001
wherein
R 31 is phenyl or monocyclic heteroaryl;
R32 is H or Ci_4alkyl;
R33 is Ci_4alkyl-NRxRy;
where Rx is H, Ci-4alkyl, or -C02-Ci-4alkyl; and
Ry is H or Ci_4alkyl;
R34 is H or Ci_4alkyl; and
R35 is Ci4_i8alkyl or Ci4_i8alkenyl;
or a pharmaceutically acceptable salt thereof.
[0011] In another aspect, the invention relates to a compound of Formula (IV):
Figure imgf000007_0002
wherein
G is N or CH;
R41 is H, Ci_4alkyl, or -C02Ci_4alkyl; R41 is absent, H, or Ci_4alkyl; wherein when R41 is H or Ci_4alkyl, the nitrogen attached to R has a positive charge;
R42 is H or Ci_4alkyl;
R43 is -OCi_i8alkyl, -OCi_i8alkenyl, -Ci_i8alkyl, or -Ci_i8alkenyl, each optionally substituted with -OH, -OCi_4alkyl, -C(0)OH, -C(0)OCi_4alkyl, -C(0)NHR4b, or aryl; and
R44 is -OC4_i8alkyl or -OC4_i8alkenyl, each optionally substituted with -OH, -OCi_4alkyl, - C(0)OH, -C(0)OCi_4alkyl, -C(0)NHR4c, or aryl;
wherein R4b and R4c are each independently H or Ci_4alkyl;
or a pharmaceutically acceptable salt thereof.
[0012] In another aspect, the invention relates to a compound of Formula (V):
Figure imgf000008_0001
wherein
G2 is a bond, -CH2-,-CH2NH-, or -CH2NHCH2-;
G3 is -C(O)- or -CH2-;
R51 is H, Ci_4alkyl, -C02Ci_4alkyl, heterocycle, or -Ci_4alkyl-NR5aR5b; where R5a is H or Ci_
4alkyl and R5b is H, Ci_4alkyl, or -C02Ci_4alkyl; and
R52 is H or Ci_4alkyl;
or R 51 and R 52 , together with the carbon to which they are attached, form a heterocycloalkyl optionally substituted with -C02Ci_4alkyl;
R53 is H or Ci_4alkyl;
o is 0 or 1 ;
r is 0 or 1 ;
s is 0 or 1 ;
R54 is C8_i8alkyl or C8_i8alkenyl; and
R55 is C8_i8alkyl or C8_i8alkenyl;
or a pharmaceutically acceptable salt thereof.
[0013] In another aspect, the invention relates to a compound of Formula (VI):
Figure imgf000009_0001
wherein
R61 is H, -C02-Ci_8alkyl, -C02-CHR6a-aryl, -C02-CHR6a-heteroaryl, -C(0)-Ci_4alkyl, -C(0)aryl, -C(0)-heteroaryl, -C(0)-CHR6b-NR6cR6d, -C(0)-CHR6a-heteroaryl, -CHR6a-aryl, -CHR6a- heteroaryl, -S02-Ci_4alkyl, -S02-aryl, or -S02-heteroaryl;
where R6a is H or Ci_i5alkyl;
R6b is H or -Ci_5alkyl-NR6eR6f;
R6c is H or Ci^alkyl;
R6d is H, Ci_4alkyl, or -C02Ci_4alkyl;
R6e is H or Ci^alkyl;
R6f is H, Ci_4alkyl, or -C02C^alkyl; and
each aryl or heteroaryl is optionally substituted with halo, Ci_4alkyl, Ci_4fluoroalkyl, -OH, -OCi_4alkyl, -OCi_4fluoroalkyl, -CN, phenyl, or -OCi_4alkyl-aryl;
R62 is H or Ci_4alkyl;
R66 is H, Ci_4alkyl, or -C02C^alkyl;
R67 is H, Ci_4alkyl, or -C(=NH)-NHR6m;
where R6m is H, -S02aryl, or -C02Ci^alkyl;
R63 is H or Ci_4alkyl;
R64 is H or -OH,
or R64 is -Ci-i8alkyl, -Ci_i8alkenyl, -OCi_i8alkyl, or -OCi_i8alkenyl, each of which is optionally substituted with -OH or -OCi_4alkyl;
R65 is H or -C4_8cycloalkyl,
or R65 is -Ci-i8alkyl, -Ci_i8alkenyl, -OCi_i2alkyl, or -OCi_i2alkenyl, each of which is optionally substituted with -OH or -OCi_4alkyl; and
t is 0 or 1 ;
or a pharmaceutically acceptable salt thereof. [0014] In certain embodiments, the compound of Formula (I), (II), (III), (IV), (V), or (VI) is a compound selected from those species described or exemplified herein.
[0015] In a further aspect, the invention relates to a pharmaceutical composition comprising at least one compound of Formula (I) or a pharmaceutically acceptable salt thereof. In a further aspect, the invention relates to a pharmaceutical composition comprising at least one compound of Formula (II) or a pharmaceutically acceptable salt thereof. In a further aspect, the invention relates to a pharmaceutical composition comprising at least one compound of Formula (III) or a pharmaceutically acceptable salt thereof. In a further aspect, the invention relates to a pharmaceutical composition comprising at least one compound of Formula (IV) or a
pharmaceutically acceptable salt thereof. In a further aspect, the invention relates to a pharmaceutical composition comprising at least one compound of Formula (V) or a
pharmaceutically acceptable salt thereof. In a further aspect, the invention relates to a pharmaceutical composition comprising at least one compound of Formula (VI) or a
pharmaceutically acceptable salt thereof. In a further aspect, the invention relates to a pharmaceutical composition comprising at least one compound of any of Tables l-6or a pharmaceutically acceptable salt thereof. Pharmaceutical compositions according to the invention may further comprise a pharmaceutically acceptable excipient. The invention is also a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament. The invention is also a compound of Formula (II) or a pharmaceutically acceptable salt thereof for use as a medicament. The invention is also a compound of Formula (III) or a
pharmaceutically acceptable salt thereof for use as a medicament. The invention is also a compound of Formula (IV) or a pharmaceutically acceptable salt thereof for use as a
medicament. The invention is also a compound of Formula (V) or a pharmaceutically acceptable salt thereof for use as a medicament. The invention is also a compound of Formula (VI) or a pharmaceutically acceptable salt thereof for use as a medicament. The invention is also a compound of any of Tables 1-6 or a pharmaceutically acceptable salt thereof for use as a medicament.
[0016] In another aspect, the invention is directed to a method of treating a disease or condition associated with TLR2 heterodimerization, comprising administering to a subject in need of such treatment an effective amount of at least one compound of Formula (I), (II), (III), (IV), (V), or (VI), or a compound of any of Tables 1-6, or a pharmaceutically acceptable salt of any of the foregoing. In another aspect, described herein is a compound or composition for use in treating a disease or condition associated with TLR2 heterodimerization.
[0017] In another aspect, the invention is directed to a method of treating a disease or medical condition associated with TLR2 heterodimerization, comprising administering to a subject in need of such treatment an effective amount of at least one compound of Formula (I), (II), (III), (IV), (V), or (VI), or a compound of any of Tables 1-6, or a pharmaceutically acceptable salt of any of the foregoing. The invention is also directed to the use of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a compound of any of Tables 1-6, or a pharmaceutically acceptable salt of any of the foregoing for the treatment of, or for the preparation of a medicament for the treatment of, such diseases and medical conditions.
[0018] In yet another aspect, the invention relates to a method of interfering with the heterodimerization of TLR2 in a cell, or modulating, preventing, slowing, reversing, or inhibiting TLR2 heterodimerization in a cell, comprising contacting the cell with an effective amount of at least one compound of Formula (I), (II), (III), (IV), (V), or (VI), or a compound of any of Tables 1-6, or a salt of any of the foregoing, and/or with at least one pharmaceutical composition of the invention, wherein the contacting is in vitro, ex vivo, or in vivo.
[0019] Additional embodiments, features, and advantages of the invention will be apparent from the following detailed description and through practice of the invention.
[0020] For the sake of brevity, the disclosures of publications cited in this specification, including patents, are herein incorporated by reference.
Detailed Description of the Invention
[0021] Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, 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 be limiting, as the scope of the present invention will be limited only by the specification taken as a whole, or by the appended claims. [0022] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, applications, published applications and other publications referred to herein are incorporated by reference in their entireties. If a definition set forth in this section is contrary to or otherwise inconsistent with a definition set forth in a patent, application, or other publication that is herein incorporated by reference, the definition set forth in this section prevails over the definition incorporated herein by reference.
[0023] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely," "only" and the like in connection with the recitation of claim elements, or use of a "negative" limitation.
[0024] As used herein, the terms "including," "containing," and "comprising" are used in their open, non-limiting sense.
[0025] To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term "about". It is understood that, whether the term "about" is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including equivalents and approximations due to the experimental and/or measurement conditions for such given value. Whenever a yield is given as a percentage, such yield refers to a mass of the entity for which the yield is given with respect to the maximum amount of the same entity that could be obtained under the particular stoichiometric conditions. Concentrations that are given as percentages refer to mass ratios, unless indicated differently.
[0026] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.
[0027] Except as otherwise noted, the methods and techniques of the present embodiments are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See, e.g., Loudon, Organic Chemistry, Fourth Edition, New York: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001.
[0028] The nomenclature used herein to name the subject compounds is illustrated in the Examples herein. This nomenclature has generally been derived using the commercially- available ChemBioDraw Ultra software, Version 14.0.
[0029] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to the chemical groups represented by the variables are specifically embraced by the present invention and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcombinations of the chemical groups listed in the embodiments describing such variables are also specifically embraced by the present invention and are disclosed herein just as if each and every such sub -combination of chemical groups was individually and explicitly disclosed herein.
Representative Embodiments
• Formula (I)
[0030] In some embodiments of Formula (I), R1 is H, -C02-Ci_8alkyl, -C02-CHRa-aryl, - C02-CHRa-heteroaryl, -C(0)-Ci_4alkyl, -C(0)aryl, -C(0)-heteroaryl, -C(0)-CHRb-NRcRd, - C(0)-CHRa-heteroaryl, -CHRa-aryl, -CHRa-heteroaryl, -S02-Ci_4alkyl, -S02-aryl, or -S02- heteroaryl; wherein Ra is H or Ci_i5alkyl; Rb is H or -Ci_5alkyl-NReRf; where Re is H or Ci_4alkyl and Rf is H, Ci_4alkyl, or -C02Ci_4alkyl; Rc is H or Ci_4alkyl and Rd is H, Ci_4alkyl, or -C02Ci_ 4alkyl; and each aryl or heteroaryl is optionally substituted with halo, Ci_4alkyl, Ci_4fluoroalkyl, -OH, -OCi_4alkyl, -OCi_4fluoroalkyl, -CN, phenyl, or -OCi_4alkyl-aryl.
[0031] In some embodiments of Formula (I), R1 is H, -C02-Ci-8alkyl, -C02-CHRa-aryl, - C02-CHRa-heteroaryl, -C(0)-Ci_4alkyl, -C(0)aryl, -C(0)-heteroaryl, -C(0)-CHRb-NRcRd, - C(0)-CHRa-heteroaryl, -CHRa-aryl, -CHRa-heteroaryl, -S02-Ci_4alkyl, -S02-aryl, or -S02- heteroaryl. In some embodiments, R1 is H, -C02-CHRa-aryl, -C02-CHRa-heteroaryl, -C(0)-Ci_ 4alkyl, -C(0)aryl, -C(0)-heteroaryl, -C(0)-CHRa-heteroaryl, -CHRa-aryl, -CHRa-heteroaryl, - S02-Ci^alkyl, -S02-aryl, or -S02-heteroaryl. In some embodiments, R1 is H. In other embodiments, R1 is -C02-Ci_8alkyl. In other embodiments, R1 is -C02-CHRa-aryl or -C02- CHRa-heteroaryl. In other embodiments, R1 is -C(0)-Ci_4alkyl, -C(0)aryl, or -C(0)-heteroaryl. In other embodiments, R1 is -C(0)-CHRb-NRcRd. In other embodiments, R1 is -C(0)-CHRa- heteroaryl. In other embodiments, R1 is -CHRa-aryl or -CHRa-heteroaryl. In other
embodiments, R1 is -S02-Ci_4alkyl, -S02-aryl, or -S02-heteroaryl. In some embodiments, the R1 aryl is phenyl. In other embodiments, the R1 aryl is fluorenyl. In some embodiments, the R1 heteroaryl is a bicyclic heteroaryl. In other embodiments, the R1 heteroaryl is indolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, or benzothiazolyl. In other embodiments, the R1 heteroaryl is indolyl. In some embodiments, the R1 aryl or heteroaryl is unsubstituted. In other embodiments, the R1 aryl or heteroaryl is substituted with one or more substituents
independently selected from the group consisting of halo, Ci_4alkyl, Ci_4fluoroalkyl, -OH, -OCi_ 4alkyl, -OCi_4fluoroalkyl, -CN, phenyl, and -OCi-4alkyl-aryl. In other embodiments, the R1 aryl or heteroaryl is substituted with one or more substituents independently selected from the group consisting of halo, Ci_4alkyl, Ci_4fluoroalkyl, -OH, -OCi_4alkyl, -OCi_4fluoroalkyl, -CN, phenyl,- OCi_4alkyl-aryl, and -C02Ci_4alkyl. In some embodiments, the R1 aryl or heteroaryl is substituted with methyl, fluoro, phenyl, or benzyloxy. In some embodiments, the R1 aryl or heteroaryl is substituted with methyl, fluoro, phenyl, benzyloxy, or tert-butyloxycarbonyl. [0032] In some embodiments, R1 is -C02-CH2-fluorenyl, acetyl, or carbobenzyloxy. In some embodiments, R1 is tert-butyloxycarbonyl. In some embodiments, R1 is substituted or unsubstituted benzyl. In some embodiments, R1 is benzyl substituted with halo or phenyl.
[0033] In some embodiments, Ra is H. In other embodiments, Ra is Ci-isalkyl. In other embodiments, Ra is Cio-isalkyl.
[0034] In some embodiments, Rb is H. In some embodiments, Rb is -Ci_5alkyl-NReRf. In some embodiments, Re is H. In other embodiments, Re is Ci_4alkyl. In some embodiments, Rf is
H. In some embodiments, R f is Ci^alkyl. In other embodiments, R f is -C02Ci^alkyl.
[0035] In some embodiments, Rc is H. In some embodiments, Rc is Ci_4alkyl. In some embodiments, Rd is H. In other embodiments, Rd is Ci^alkyl. In other embodiments, Rd is - C02Ci_4alkyl.
[0036] In some embodiments, R 2 is H. In other embodiments, R 2 is Ci_4alkyl.
[0037] In some embodiments, R 1 and R 2 are both hydrogen.
[0038] In some embodiments, R3a is H. In other embodiments, R3a is -C6-14alkyl. In other embodiments, R3a is -CHRg-aryl, -CHRg-heteroaryl, or -CHRg-heterocycloalkyl. In some embodiments, the R3a aryl is phenyl. In some embodiments, the R3a heteroaryl is pyrrolyl, imidazolyl, indolyl, or benzimidazolyl. In other embodiments, the R3a heteroaryl is pyrrolyl or indolyl. In other embodiments, the R3a heterocycloalkyl is a monocyclic heterocycloalkyl. In some embodiments, the R3a heterocycloalkyl is pyrrolidinyl or piperazinyl. In some
embodiments, the R3a aryl, heteroaryl, and heterocycloalkyl are unsubstituted. In other embodiments, the R3a aryl, heteroaryl, and heterocycloalkyl are substituted with -OH, Ci_4alkyl, or -C02Ci_4alkyl. In other embodiments, the R3a aryl and heteroaryl are optionally substituted with phenyl or benzyloxy.
[0039] In some embodiments, R3a is
Figure imgf000015_0001
In other embodiments, R3a is -Ci_ 4alkyl-C02CMalkyl, -Ci_4alkyl-C02H, or -Ci_4alkyl-CONRjRk.
[0040] In some embodiments, Rg is H. In other embodiments, Rg is Ci_4alkyl.
[0041] In some embodiments, Rh is H. In other embodiments, Rh is Ci_4alkyl. In other embodiments, Rh is -C02Ci_4alkyl. [0042] In some embodiments, R1 is H. In other embodiments, R1 is Ci_4alkyl. In further embodiments, R[ is -C(=NH)-NHRm.
[0043] In some embodiments, Rm is H. In some embodiments, Rm is -S02phenyl. In other embodiments, Rm is -C02Ci_4alkyl.
[0044] In some embodiments, RJ is H. In some embodiments, RJ is Ci_4alkyl. In some embodiments, Rk is H. In some embodiments, Rk is Ci^alkyl.
[0045] In some embodiments, R2 and R3a taken together form C2_4alkylene. In some embodiments, R2 and R3a taken together form C3alkylene.
[0046] In some embodiments, R3b is H. In some embodiments, R3a and R3b taken together with the carbon to which they are attached form a 4- to 7-membered heterocycloalkyl, optionally substituted with Ci_4alkyl or -C02Ci^alkyl. In some embodiments, the heterocycloalkyl is pyrrolidine or piperazine.
[0047] In some embodiments, R3a is substituted or unsubstituted -CH2-phenyl. In some embodiments, R3a is -CH2-phenyl substituted with benzyloxy, hydroxyl, or phenyl. In some embodiments, R3a is -CH2-imidazolyl, optionally substituted with tert-butoxycarbonyl. In some embodiments, R3a is -CH2- indolyl. In some embodiments, R3a is -CH2-piperidine, optionally substituted with tert-butoxycarbonyl. In some embodiments, R3a is butylamine, optionally substituted with tert-butoxycarbonyl. In some embodiments, R3a is propylamine, optionally substituted with guanidinyl, wherein the guanidinyl is optionally substituted. In some embodiments, R3a is carboxyethyl, optionally substituted with tert-butyl. In some embodiments, R3a is carboxymethyl, optionally substituted with tert-butyl. In some embodiments, R3a and R3b are both hydrogen.
[0048] In some embodiments, R4 is H. In some embodiments, R4 is Ci^alkyl.
[0049] In some embodiments, R5 and R6 are each independently C8_i6alkyl or C8_i6alkenyl. In some embodiments, R5 and R6 are each independently C8_i6alkyl. In some embodiments, R5 and R6 are the same. In other embodiments, R5 and R6 are different. In some embodiments, R5 and R6 are unbranched hydrocarbons. In some embodiments, R5 and R6 are each Ci4alkyl. [0050] In some embodiments, m is 0. In other embodiments, m is 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, p is 0. In other embodiments, p is 1. In some embodiments, n is 1 and p is 0. In other embodiments, n is 0 and p is 1.
[0051] In some embodiments, R5 and R6 are each independently Ci3_i6alkyl or Ci3_i6alkenyl. In some embodiments, R5 and R6 are each independently Cg-nalkyl, Co-^aLkyl, Cg-nalkenyl, or Ci3_i6alkenyl. In some embodiments, R5 and R6 are each independently Cg-iialkyl, Ci3_i6alkyl, Cs-iialkenyl, or Ci3-i6alkenyl, and R1 is H, -C02-Ci_8alkyl, -C02-CHRa-heteroaryl, -C(0)-Ci_ 4alkyl, -C(0)aryl, -C(0)-heteroaryl, -C(0)-CHRb-NRcRd, -C(0)-CHRa-heteroaryl, -CHRa-aryl, - CHRa-heteroaryl, -S02-Ci_4alkyl, -S02-aryl, or -S02-heteroaryl. In some embodiments, R5 and R6 are each independently C8_nalkyl, Ci3_i6alkyl, C8_nalkenyl, or Ci3_i6alkenyl, and R3a is H, - C6-i4alkyl, -CHRg-aryl, -CHRg-heterocycloalkyl, -Ci-4alkyl-C02Ci_4alkyl, -Ci_4alkyl-C02H, or - Ci_4alkyl-CONRjRk In some embodiments, R5 and R6 are each independently Ci4alkyl or Ci4alkenyl. In some embodiments, R5 and R6 are each independently C^alkyl or Ci6alkenyl.
[0052] In some embodiments, R1 is -C02-Ci_8alkyl or -C(0)-CHRb-NRcRd, and R3a is -C6- i4alkyl, -CHRg-aryl, -CHRg-heteroaryl, -CHRg-heterocycloalkyl,
Figure imgf000017_0001
C02Ci_4alkyl, -Ci_4alkyl-C02H, or -Ci_4alkyl-CONRjRk. In some embodiments, R1 is -C02-Ci_
8alkyl and m is 1. In some embodiments, R 1 is -C02-Ci_8alkyl and R 2 is Ci_4alkyl.
[0053] In other embodiments, the compound of Formula (I) is selected from the group consisting of compounds of Table 1 :
Table 1.
Figure imgf000017_0002
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
(methylamino) acetamide 3 - 3 -
-
Figure imgf000021_0001
-4- -
-4- -
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
yl)carbamate hydrochloride
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
and pharmaceutically acceptable salts thereof.
[0054] In some embodiments, the compound is not a compound of Table IX.
Table IX.
Figure imgf000028_0002
Figure imgf000029_0001
and pharmaceutically acceptable salts thereof.
• Formula (II)
[0055] In some embodiments of Formula (II), R 21 is H. In other embodiments, R 21 is Ci_
4alkyl. In other embodiments, R 21 is -C02Ci_4alkyl. In other embodiments, R 21 is H or -C02- tert-butyl. In some embodiments, R 22 is H. In other embodiments, R 22 is Ci_4alkyl. In some embodiments, R 24 is H. In other embodiments, R 24 is Ci_4alkyl.
[0056] In some embodiments, R25 and R26 are each independently C8_i6alkyl or C8_i6alkenyl. In some embodiments, R25 and R26 are each independently C8_i6alkyl. In some embodiments,
R 25 and R 26o are the same. In other embodiments, R 25 and R 26 are different. In some embodiments, R and R are unbranched hydrocarbons. In some embodiments, R and R are each Ci4alkyl.
[0057] In some embodiments, n2 is 0. In some embodiments, n2 is 1. In some
embodiments, p2 is 0. In other embodiments, p2 is 1. In some embodiments, n2 is 1 and p2 is 0. In other embodiments, n2 is 0 and p2 is 1.
[0058] In other embodiments, the compound of Formula (II) is selected from the group consisting of compounds of Table 2:
Table 2.
Figure imgf000030_0001
and pharmaceutically acceptable salts thereof.
• Formula (III)
31
[0059] In some embodiments of Formula (III), R is phenyl or monocyclic heteroaryl. In
31 31
some embodiments, R is phenyl. In some embodiments, R is monocyclic heteroaryl. In
31
some embodiments, the R heteroaryl is pyrrolyl, imidazolyl, furanyl, or thiophenyl.
32 32
[0060] In some embodiments, R is H. In other embodiments, R is Ci_4alkyl.
[0061] In some embodiments, R33 is Ci_4alkyl-NRxRy. In some embodiments, Rx is H. In some embodiments, Rx is Ci_4alkyl. In some embodiments, Rx is -C02-Ci_4alkyl. In some embodiments, Ry is H. In other embodiments, Ry is Ci^alkyl. In some embodiments, Rx and Ry are both H. In some embodiments, Rx is -C02-tert-butyl and Ry is H.
[0062] In some embodiments, R is H. In some embodiments, RJ 3i4÷ i ·s Ci_4alkyl.
[0063] In some embodiments, R 35 is Ci4_i8alkyl. In some embodiments, R 35 is Ci4_i8alkenyl. In some embodiments, the Ci4_i8alkenyl has one double bond. In some embodiments, the Ci4_ i8alkenyl has one cis double bond.
[0064] In other embodiments, the compound of Formula (III) is selected from the group consisting of compounds of Table 3:
Table 3.
Figure imgf000031_0001
and pharmaceutically acceptable salts thereof. • Formula (IV)
[0065] In some embodiments of Formula (IV), the compound is of the formula (IVa), (IVb), or (IVc):
wherein G1, R41, R41', R42, R43 and R44 are as defined for Formula (IV);
or a pharmaceutically acceptable salt thereof.
[0066] In some embodiments of Formula (IV), (IVa), (IVb), or (IVc), G1 is N. In other embodiments, G1 is CH.
[0067] In some embodiments of Formula (IV), (IVa), (IVb), or (IVc), R41 is H. In some embodiments, R41 is Ci_4alkyl. In some embodiments, R41 is -C02Ci_4alkyl. In some
embodiments, R41 is absent. In other embodiments, R41 is H or Ci^alkyl, wherein the nitrogen attached to R41 has a positive charge. In some embodiments, R41 is H. In other embodiments, R41' is Ci_4alkyl. In some embodiments, R41 is H, methyl, or tert-butyloxycarbonyl. [0068] In some embodiments of Formula (IV), (IVa), (IVb), or (IVc), R is H. In other embodiments, R is Ci_4alkyl, such as methyl.
[0069] In some embodiments of Formula (IV), (IVa), (IVb), or (IVc), R4J is -OCi_i8alkyl or -OCi_i8alkenyl, each optionally substituted with -OH, -OCi_4alkyl, -C(0)OH, -C(0)OCi_4alkyl, -C(0)NHR4b, or aryl. In some embodiments, R43 is -Ci_i8alkyl, or -Ci_i8alkenyl, each optionally substituted with -OH, -OCi_4alkyl, -C(0)OH, -C(0)OCi_4alkyl, -C(0)NHR4b, or aryl.
[0070] In some embodiments of Formula (IV), (IVa), (IVb), or (IVc), R44 is -OC4_i8alkyl, optionally substituted with -OH, -OCi_4alkyl, -C(0)OH, -C(0)OCi_4alkyl, -C(0)NH2, - C(0)NHCi_4alkyl, or aryl. In other embodiments, R44 is -OC4_i8alkenyl, optionally substituted with -OH, -OCi_4alkyl, -C(0)OH, -C(0)OCi_4alkyl, -C(0)NH2, -C(0)NHCi_4alkyl, or aryl.
[0071] In some embodiments of Formula (IV), (IVa), (IVb), or (IVc), R43 is -OCi_i8alkyl and R44 is -OC4_i8alkyl. In some embodiments, R43 is -OCi_i8alkenyl and R44 is -OC4_i8alkenyl. In some embodiments, R43 is -OCi3_i8alkyl and R44 is -OCi3_i8alkyl. In some embodiments, R43 is -OCi3_i8alkenyl and R44 is -OCi3_i8alkenyl. In some embodiments, R43 is -OCi_i2alkyl and R44 is -OC4_i2alkyl. In some embodiments, R43 is -OCi_i2alkenyl and R44 is -OC4_i2alkenyl, wherein R43 and R44 are each optionally substituted with -OH, -OCi_4alkyl,-C(0)OCi_4alkyl, - C(0)NH2, -C(0)NHCi_4alkyl, or aryl. In some embodiments, R43 and R44 are each -OC7alkyl. In some embodiments, R43 and R44 are each -OCi4alkyl or -OCi4alkenyl. In some embodiments, R43 and R44 are each -OCi6alkyl or -OCi6alkenyl. In some embodiments, R43 and R44 are each - OCisalkyl or -OCi8alkenyl.
[0072] In other embodiments, the compound is selected from the group consisting of compounds of Table 4:
Table 4.
x. # Structure Chemical Name
Figure imgf000034_0001
Figure imgf000035_0001
ium iodide
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
and pharmaceutically acceptable salts thereof.
Formula (V) [0073] In some embodiments of Formula (V), G2 is a bond. In some embodiments, G2 is - CH2-. In some embodiments, G2 is -CH2NH-. In other embodiments, G2 is -CH2NHCH2-.
[0074] In some embodiments, G3 is -C(O)-. In other embodiments, G3 is -CH2-.
[0075] In some embodiments, R51 is H. In some embodiments, R51 is Ci_4alkyl. In some embodiments, R51 is -C02Ci_4alkyl. In some embodiments, R51 is a heterocycle, such as pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl. In other embodiments, R51 is -Ci_4alkyl-NR5aR5b; where R5a is H or Ci_4alkyl and R5b is H, Ci_4alkyl, or -C02Ci_4alkyl.
[0076] In some embodiments, R 52 is H. In other embodiments, R 52 is Ci_4alkyl;
[0077] In some embodiments, R 51 and R 52 , together with the carbon to which they are attached, form a heterocycloalkyl; wherein the heterocycloalkyl is optionally substituted with -
C02Ci_4alkyl. In some embodiments, R 51 and R 52 , together with the carbon to which they are attached, form a heterocycloalkyl; wherein the heterocycloalkyl is optionally substituted with tert-butyloxycarbonyl. In some embodiments, R 51 and R 52 , together with the carbon to which they are attached, form a piperidinyl, optionally substituted with -C02Ci_4alkyl, such as tert- butyloxycarbonyl.
[0078] In some embodiments, R 53 is H. In other embodiments, R 53 is Ci_4alkyl.
[0079] In some embodiments, o is 0. In some embodiments, o is 1. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, s is 0. In some embodiments, s is 1.
[0080] In some embodiments, r is 1 and s is 1. In some embodiments, r is 1 and s is 0. In some embodiments, r is 0 and s is 1. In some embodiments G2 is a bond, r is 1, and s is 0. In some embodiments G2 is a bond, r is 1, s is 0, and R 51 and R 52 , together with the carbon to which they are attached, form a heterocycloalkyl; wherein the heterocycloalkyl is optionally substituted with -C02Ci_4alkyl. In some embodiments G2 is -CH2-, r is 1, and s is 0. In some embodiments
G2 is -CH2-, r is 1, s is 0, and R 51 and R 52 , together with the carbon to which they are attached, form a heterocycloalkyl; wherein the heterocycloalkyl is optionally substituted with -C02Ci_ 4alkyl. In some embodiments G2 is -CH2NH-, r is 1, and s is 0. In some embodiments G2 is -
CH2NH-, r is 1, s is 0, and R 51 and R 52 , together with the carbon to which they are attached, form a heterocycloalkyl; wherein the heterocycloalkyl is optionally substituted with -C02Ci_4alkyl. In some embodiments G2 is -CH2NHCH2-, r is 1, and s is 0. In some embodiments G2 is -
CH2NHCH2-, r is 1, s is 0, and R 51 and R 52 , together with the carbon to which they are attached, form a heterocycloalkyl; wherein the heterocycloalkyl is optionally substituted with -C02Ci_ 4alkyl. In some embodiments G2 is -CH2NHCH2-, r is 1, and s is 0. In some embodiments, G2 is -CH2- or -CH2NH-, r is 1, s is 0, and R51 is a heterocycle. In some embodiments, R51 is a heterocycle and R 52 is H.
[0081] In some embodiments, R 53 is H. In some embodiments, R 53 is Ci_4alkyl.
[0082] In some embodiments, R54 is Cg-igalkyl. In some embodiments, R54 is Cg-igalkenyl. In some embodiments, R55 is Cg-igalkyl. In some embodiments, R55 is Cg-igalkenyl. In some embodiments, R54 and R55 are each independently Cg-isalkyl or Cg-isalkenyl. In some embodiments, R54 and R55 are each independently Cg-isalkyl. In some embodiments, R54 and R55 are each independently Cg-igalkenyl. In some embodiments, R54 and R55 are the same. In other embodiments, R54 and R55 are different. In some embodiments, R54 and R55 are unbranched hydrocarbons. In some embodiments, R54 and R55 are each Ci4alkyl. In some embodiments, R54 and R55 are each Ci4alkenyl. In some embodiments, R54 and R55 are each Ci6alkyl or Ci6alkenyl. In some embodiments, R54 and R55 are each Cigalkyl or Cigalkenyl.
[0083] In other embodiments, the compound of Formula (V) is selected from the group consisting of compounds of Table 5:
Table 5.
Figure imgf000040_0001
Figure imgf000041_0001
and pharmaceutically acceptable salts thereof.
• Formula (VI)
[0084] In some embodiments of Formula (VI), R61 is H. In some embodiments, R61 is -C02- Ci-galkyl. In some embodiments, R61 is -C02-CHR6a-aryl or -C02-CHR6a-heteroaryl, where R6a is H or Ci-i5alkyl and the aryl or heteroaryl is optionally substituted with halo, Ci_4alkyl, Ci_ 4fluoroalkyl, -OH, -OCi_4alkyl, -OCi_4fluoroalkyl, -CN, phenyl, or -OCi_4alkyl-aryl. In some embodiments, R61 is -C(0)-Ci_4alkyl. In some embodiments, R61 is -C(0)aryl, or -C(O)- heteroaryl, each optionally substituted with halo, Ci_4alkyl, Ci_4fluoroalkyl, -OH, -OCi_4alkyl, - OCi_4fluoroalkyl, -CN, phenyl, or -OCi_4alkyl-aryl. In some embodiments, R61 is -C(0)-CHR6b- NR6cR6d, where R6b is H or -Ci_5alkyl-NR6eR6f; R6e is H or Ci_4alkyl and R6f is H, CMalkyl, or - C02Ci_4alkyl; R6c is H or Ci_4alkyl and R6d is H, Ci_4alkyl, or -C02Ci_4alkyl. In some embodiments, R61 is -C(0)-CHR6a-heteroaryl, -CHR6a-aryl, or -CHR6a-heteroaryl, where R6a is H or Ci_i5alkyl and each aryl or heteroaryl is optionally substituted with halo, Ci_4alkyl, Ci_ 4fluoroalkyl, -OH, -OCi_4alkyl, -OCi_4fluoroalkyl, -CN, phenyl, or -OCi_4alkyl-aryl. In some embodiments, R61 is -S02-Ci^alkyl, -S02-aryl, or -S02-heteroaryl. In some embodiments, R61 is -CHR6a-aryl, where R6a is H or Ci-isalkyl and the aryl is optionally substituted with halo, Ci_ 4alkyl, Ci_4fluoroalkyl, -OH, -OCi_4alkyl, -OCi_4fluoroalkyl, -CN, phenyl, or -OCi_4alkyl-aryl. In some embodiments, R61 is -CHR6a-heteroaryl, where R6a is H or Ci-isalkyl and the heteroaryl is optionally substituted with halo, Ci_4alkyl, Ci_4fluoroalkyl, -OH, -OCi_4alkyl, -OCi_
4fluoroalkyl, -CN, phenyl, or -OCi-4alkyl-aryl. In some embodiments, R61 is -CH2-phenyl. In some embodiments, R61 is -CH2-napthyl.
[0085] In some embodiments, R62 is H. In some embodiments, R62 is Ci_4alkyl.
[0086] In some embodiments, R61 is -CHR6a-aryl or -CHR6a-heteroaryl, where R6a is H or Ci-isalkyl and each aryl or heteroaryl is optionally substituted with halo, Ci_4alkyl, Ci_
4fluoroalkyl, -OH, -OCi_4alkyl, -OCi_4fluoroalkyl, -CN, phenyl, or -OCi_4alkyl-aryl; and R62 is H or methyl. In some embodiments, R61 is -CH2-phenyl or -CH2-napthyl; and R62 is H.
[0087] In some embodiments, R66 is H. In some embodiments, R66 is Ci_4alkyl. In other embodiments, R66 is -C02Ci_4alkyl. In some embodiments, R67 is H. In some embodiments, R67 is Ci_4alkyl. In some embodiments, R67 is -C(=NH)-NHR6m, where R6m is H, -S02aryl, or - C02Ci_4alkyl. In some embodiments, R66 is -C02Ci_4alkyl and R67 is H. In some embodiments, R66 is H and R67 is C^alkyl or -C(=NH)-NHR6m, where R6m is H, -S02aryl, or -C02Cwalkyl. In some embodiments, R66 and R67 are both H. [0088] In some embodiments, R is H. In some embodiments, R is Ci_4alkyl. In some embodiments, R 62 and R 63 are both H. In other embodiments, one of R 6o2 and R 63 is H and the other is Ci_4alkyl.
[0089] In some embodiments, R64 is H. In some embodiments, R64 is -OH. In some embodiments, R64 is -Ci_i8alkyl or -Ci_i8alkenyl, each optionally substituted with -OH or -OCi_ 4alkyl. In some embodiments, R64 is -OCi_i8alkyl or -OCi_i8alkenyl, each optionally substituted with -OH or -OCi_4alkyl. In some embodiments, R65 is H. In some embodiments, R65 is -C4_ 8cycloalkyl. In some embodiments, R65 is -Ci_i8alkyl or -Ci_i8alkenyl, each of which is optionally substituted with -OH or -OCi_4alkyl. In some embodiments, R65 is -OCi_i8alkyl or - OCi_i8alkenyl, each of which is optionally substituted with -OH or -OCi_4alkyl.
[0090] In some embodiments, R64 is -OCi_i8alkyl or -OCi_i8alkenyl, each of which is optionally substituted with -OH or -OCi_4alkyl; and R65 is -OCi_i8alkyl or -OCi_i8alkenyl, each of which is optionally substituted with -OH or -OCi_4alkyl. In some embodiments, R64 and R65 are each -OCi8alkenyl. In some embodiments, R64 is -Ci_i8alkyl or -Ci_i8alkenyl, optionally substituted with -OH or -OCi_4alkyl; and R65 is H. In some embodiments, R65 is -OCi_i8alkyl or -OCi_i8alkenyl, optionally substituted with -OH or -OCi_4alkyl; and R64 is H. In some embodiments, R65 is -C4_8cycloalkyl and R64 is H.
[0091] In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 0 and R65 is -C4_8cycloalkyl. In some embodiments, t is 1; R64 is -OCi_i8alkyl or -OCi_ i8alkenyl, each of which is optionally substituted with -OH or -OCi_4alkyl; and R65 is -OCi_ i8alkyl or -OCi_i8alkenyl, each of which is optionally substituted with -OH or -OCi_4alkyl. In some embodiments, t is 1 and R64 and R65 are each -OCi8alkenyl. In some embodiments, t is 1; R64 is -Ci-i8alkyl or -Ci_i8alkenyl, optionally substituted with -OH or -OCi_4alkyl; and R65 is H. In some embodiments, t is 1; R65 is -OCi_i8alkyl or -OCi_i8alkenyl, optionally substituted with - OH or -OCi_4alkyl; and R64 is H. In some embodiments, t is 0, R65 is -C4_8cycloalkyl, and R64 is H.
[0092] In other embodiments, the compound of Formula (VI) is selected from the group consisting of compounds of Table 6:
Table 6.
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
and pharmaceutically acceptable salts thereof.
[0093] Any formula or compound given herein, such as Formula (I), (II), (III), (IV), (V), or (VI), or compounds of Tables 1-6, is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms. In particular, compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof in any ratio, are considered within the scope of the formula. Thus, any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof in any ratio. Where a compound of Tables 1-6 is depicted with a particular stereochemical configuration, also provided herein is any alternative stereochemical
configuration of the compound, as well as a mixture of stereoisomers of the compound in any ratio. Any compound of Tables 1-6 is intended to represent a racemate, one or more
enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof in any ratio. Furthermore, certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers. Additionally, any formula given herein is intended to refer to hydrates, solvates, and amorphous forms of such compounds, and mixtures thereof, even if such forms are not listed explicitly. In some embodiments, the solvent is water and the solvates are hydrates.
Chemical Definitions
[0094] The term "alkyl" refers to a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms in the chain. Examples of alkyl groups include methyl (Me), ethyl (Et), n- propyl, isopropyl, butyl, isobutyl, sec -butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.
[0095] The term "alkenyl" refers to a straight- or branched-chain hydrocarbon group having from 2 to 12 carbon atoms in the chain, and having one or more double bonds. Examples of alkenyl groups include ethenyl (or vinyl), allyl, and but-3-en-l-yl. Included within this term are cis and trans isomers and mixtures thereof.
[0096] The term "alkylene" refers to a divalent group that is a radical of an alkane. The alkylene can be a straight- or branched-chain divalent alkyl radical. "Ci_4 alkylene" refers to alkylene groups with 1 to 4 carbon atoms.
[0097] The term "aryl" refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (a phenyl group) or a multiple condensed ring (such as napthyl, anthracenyl, or indanyl), in which condensed rings are optionally aromatic, provided that the point of attachment of the aryl group to the parent structure is through an atom of an aromatic ring. "Aryl" as defined herein encompasses groups such as phenyl and fluorenyl.
[0098] The term "fluoroalkyl" refers to an alkyl group as defined above, substituted with one or more fluoro substituents. Examples of fluoroalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, and trifluoroethyl.
[0099] The term "heteroaryl" refers to a monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms per heterocycle. Illustrative examples of heteroaryl groups include the following entities, in the form of properly bonded moieties:
Figure imgf000049_0001
[0100] The term "heterocycloalkyl" refers to a saturated or partially unsaturated group having a single ring or multiple condensed rings, including fused, bridged, or spiro ring systems, and having from 3 to 20 ring atoms, including 1 to 10 heteroatoms. These ring atoms are selected from the group consisting of carbon, nitrogen, sulfur, or oxygen. In certain
embodiments, the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for N-oxide, -S(O)-, or -S02- moieties. Illustrative examples of
heterocyclic groups include the following entities, in the form of properly bonded moieties:
Figure imgf000050_0001
[0101] The term "halogen" represents chlorine, fluorine, bromine, or iodine. The term "halo" represents chloro, fluoro, bromo, or iodo.
[0102] The term "oxo" represents a carbonyl oxygen. For example, a cyclopentyl substituted with oxo is cyclopentanone.
[0103] Those skilled in the art will recognize that the species listed or illustrated above are not exhaustive, and that additional species within the scope of these defined terms may also be selected.
[0104] The term "substituted" means that the specified group or moiety bears one or more substituents. The term "unsubstituted" means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted by one or more substituents. Where the term "substituted" is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system.
[0105] Any formula depicted herein is intended to represent a compound of that structural formula as well as certain variations or forms. For example, a formula given herein is intended to include a racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or a mixture thereof. Additionally, any formula given herein is intended to refer also to a hydrate, solvate, or polymorph of such a compound, or a mixture thereof.
[0106] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2H, 3H, UC, 13C, 14C, 15N, 180, 170, 31P, 32P,
35 S, 18 F, 36 CI, and 125 I, respectively. Such isotopically labelled compounds are useful in metabolic studies (preferably with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an 18 F or 11 C labeled compound may be particularly preferred for PET or SPECT studies. PET and SPECT studies may be performed as described, for example, by Brooks, D.J., "Positron Emission Tomography and Single-Photon Emission Computed Tomography in Central Nervous System Drug Development," NeuroRx 2005, 2(2), 226-236, and references cited therein. Further, substitution with heavier isotopes such as deuterium (i.e., H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.
[0107] The nomenclature "Ci_j" with j > i, when applied herein to a class of substituents, is meant to refer to embodiments of this invention for which each and every one of the number of carbon members, from i to j including i and j, is independently realized. By way of example, the term Ci_3 refers independently to embodiments that have one carbon member (CO, embodiments that have two carbon members (C2), and embodiments that have three carbon members (C3).
[0108] Any disubstituent referred to herein is meant to encompass the various attachment possibilities when more than one of such possibilities are allowed. For example, reference to disubstituent -A-B-, where A≠ B, refers herein to such disubstituent with A attached to a first substituted member and B attached to a second substituted member, and it also refers to such disubstituent with A attached to the second substituted member and B attached to the first substituted member.
[0109] The invention also includes pharmaceutically acceptable salts of the compounds represented by Formula (I), (II), (III), (IV), (V), or (VI) or the compounds of any of Tables 1-6, preferably of those described above and of the specific compounds exemplified herein, and pharmaceutical compositions comprising such salts, and methods of using such salts.
[0110] A "pharmaceutically acceptable salt" is intended to mean a salt of a free acid or base of a compound represented herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response. A compound described herein may possess a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
[0111] Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-l,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,
hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates,
propylsulfonates, besylates, xylenesulfonates, naphthalene- 1- sulfonates, naphthalene-2- sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ- hydroxybutyrates, glycolates, tartrates, and mandelates. Lists of other suitable pharmaceutically acceptable salts are found in Remington's Pharmaceutical Sciences, 17th Edition, Mack
Publishing Company, Easton, Pa., 1985.
[0112] For a compound of Formula (I), (II), (III), (IV), (V), or (VI) or a compound of any of Tables 1-6 that contains a basic nitrogen, a pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, or ethanesulfonic acid, or any compatible mixture of acids such as those given as examples herein, and any other acid and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology.
[0113] The invention also relates to pharmaceutically acceptable prodrugs of the compounds of Formula (I), (II), (III), (IV), (V), or (VI), or the compounds of any of Tables 1-6, and treatment methods employing such pharmaceutically acceptable prodrugs. The term "prodrug" means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the formula compound). A "pharmaceutically acceptable prodrug" is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
[0114] The present invention also relates to pharmaceutically active metabolites of compounds of Formula (I), (II), (III), (IV), (V), or (VI), or the compounds of any of Tables 1-6, and uses of such metabolites in the methods of the invention. A "pharmaceutically active metabolite" means a pharmacologically active product of metabolism in the body of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or the compounds of any of Tables 1-6, or a salt of any of the foregoing. Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini et al., J. Med. Chem. 1991, 40, 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86 (7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984, 13, 255-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991). Pharmaceutical Compositions
[0115] For treatment purposes, pharmaceutical compositions comprising the compounds described herein may further comprise one or more pharmaceutically-acceptable excipients. A pharmaceutically-acceptable excipient is a substance that is non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate administration of the compounds described herein and are compatible with the active ingredient. Examples of pharmaceutically-acceptable excipients include stabilizers, lubricants, surfactants, diluents, antioxidants, binders, coloring agents, bulking agents, emulsifiers, or taste-modifying agents. In preferred embodiments, pharmaceutical compositions according to the invention are sterile compositions. Pharmaceutical compositions may be prepared using compounding techniques known or that become available to those skilled in the art.
[0116] Sterile compositions are also contemplated by the invention, including compositions that are in accord with national and local regulations governing such compositions.
[0117] The pharmaceutical compositions and compounds described herein may be formulated as solutions, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers, or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules along with solid carriers according to conventional methods known in the art for preparation of various dosage forms. Pharmaceutical compositions of the invention may be administered by a suitable route of delivery, such as oral, parenteral, rectal, nasal, topical, or ocular routes, or by inhalation. Preferably, the compositions are formulated for intravenous or oral administration.
[0118] For oral administration, the compounds the invention may be provided in a solid form, such as a tablet or capsule, or as a solution, emulsion, or suspension. To prepare the oral compositions, the compounds of the invention may be formulated to yield a dosage of, e.g. , from about 0.01 to about 50 mg/kg daily, or from about 0.05 to about 20 mg/kg daily, or from about 0.1 to about 10 mg/kg daily. Additional dosages include from about 0.1 mg to 1 g daily, from about 1 mg to about 10 mg daily, from about 10 mg to about 50 mg daily, from about 50 mg to about 250 mg daily, or from about 250 mg to 1 g daily. Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrating agents.
Binding agents may include starch and gelatin. The lubricating agent, if present, may be magnesium stearate, stearic acid, or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.
[0119] Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
[0120] Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.
[0121] The inventive compositions may be formulated for rectal administration as a suppository. For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the agents of the invention may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multi- dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Illustrative infusion doses range from about 1 to 1000 μg/kg/minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.
[0122] For nasal, inhaled, or oral administration, the inventive pharmaceutical compositions may be administered using, for example, a spray formulation also containing a suitable carrier.
[0123] For topical applications, the compounds of the present invention are preferably formulated as creams or ointments or a similar vehicle suitable for topical administration. For topical administration, the inventive compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle. Another mode of administering the agents of the invention may utilize a patch formulation to effect transdermal delivery.
[0124] As used herein, "treatment" or "treating" is an approach for obtaining a beneficial or desired result, including clinical results. For purposes of this invention, beneficial or desired results include, but are not limited to: reducing the severity of or suppressing the worsening of a disease, symptom, or condition, alleviating a symptom and/or diminishing the extent of a symptom and/or preventing a worsening of a symptom associated with a condition, arresting the development of a disease, symptom, or condition, relieving the disease, symptom, or condition, causing regression of the disease, disorder, or symptom (in terms of severity or frequency of negative symptoms), or stopping the symptoms of the disease or condition. Beneficial or desired results can also be slowing, halting, or reversing the progressive course of a disease or condition. For example, beneficial effects may include slowing the progression of Parkinson's disease from an earlier stage (e.g., prodromal stage or stage 1, 2 or 3) to a later stage (e.g., stage 4 or 5), or halting Parkinson's disease at a prodromal or early stage.
[0125] As used herein, "delaying" development of a disease or condition means to defer, hinder, slow, retard, stabilize and/or postpone development of the disease or condition. This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease or condition. For example, a method that "delays" development of Parkinson's disease (e.g., in a prodromal individual) is a method that reduces probability of disease development in a given time frame and/or reduces extent of the disease in a given time frame, when compared to not using the method.
[0126] The term "subject" refers to a mammalian patient in need of such treatment, such as a human. A "subject" may be a human, or may be a cat, dog, cow, rat, mouse, horse, or other domesticated mammal.
[0127] Exemplary diseases that are characterized by protein aggregation include
Alzheimer's disease, Parkinson's disease, fronto-temporal dementia, dementia with Lewy bodies (Lewy body disease), Parkinson's disease with dementia, multiple system atrophy, amyotrophic lateral sclerosis, and Huntington's disease, as well inflammatory diseases, such as asthma, chronic obstructive pulmonary disease (COPD), chronic peptic ulcers, tuberculosis, rheumatoid arthritis, chronic sinusitis, hepatitis (such as hepatitis B or C), gout, lupus, pleurisy, eczema, gastritis, psoriasis, psoriatic arthritis, vasculitis, laryngitis, allergic reactions, multiple sclerosis, Crohn's disease, traumatic brain injury, CIDP (chronic inflammatory demyelinating
polyneuropathy), atopic dermatitis, acne vulgaris, rosacea, non-alcoholic fatty liver disease, nonalcoholic steatohepatisis, corneal wounds, corneal disorders, Stargardt disease (Juvenile macular degeneration), age-related macular degeneration, sepsis, diabetic wounds, herpes simplex virus, and anti-fungal, anti-bacterial, anitviral and antitumor diseases or conditions.
[0128] In one aspect, the compounds and pharmaceutical compositions of the invention specifically target TLR2 protein dimers. Thus, these compounds and pharmaceutical compositions can be used to prevent, reverse, slow, or inhibit dimerization of TLR2 proteins with other natural protein ligands, and are used in methods of the invention to treat neurological and inflammatory diseases related to or caused by such dimerization. In preferred embodiments, methods of treatment target Parkinson's disease, Alzheimer's disease, Lewy body disease, multiple system atrophy, atopic dermatitis, traumatic brain injury, or multiple sclerosis. The compounds, compositions, and method of the present invention are also used to mitigate deleterious effects that are secondary to protein dimerization and/or misfolding, such as neuronal cell death. [0129] In some aspects, the compounds, compositions, and methods of the invention are used to inhibit TLR2 dimerization. In alternative aspects, the compounds, compositions, and methods of the invention are used to inhibit TLR2 dimerization with TLR1, or with TLR6, or both.
[0130] In the inhibitory methods of the invention, an "effective amount" means an amount sufficient to reduce, slow the progression of, or reverse TLR2 dimerization. Measuring the amount of dimerization may be performed by routine analytical methods such as those described below. Such modulation is useful in a variety of settings, including in vitro assays. In such methods, the cell is preferably a nerve cell or an HEK or THP cell.
[0131] In treatment methods according to the invention, an "effective amount" means an amount or dose sufficient to generally bring about the desired therapeutic benefit in subjects needing such treatment. Effective amounts or doses of the compounds of the invention may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the infection, the subject's health status, condition, and weight, and the judgment of the treating physician. An exemplary dose is in the range of about 1 μg to 2 mg of active agent per kilogram of subject's body weight per day, preferably about 0.05 to 100 mg/kg/day, or about 1 to 35 mg/kg/day, or about 0.1 to 10 mg/kg/day. In alternative embodiments an exemplary dose is in the range of about 1 mg to about 1 g per day, or about 1-500, 1-250, 1-100, 1-50, 50-500, or 250-500 mg per day. The total dosage may be given in single or divided dosage units (e.g., BID, TID, QID).
[0132] Once improvement of the patient's disease has occurred, the dose may be adjusted for preventative or maintenance treatment. For example, the dosage or the frequency of administration, or both, may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained. Of course, if symptoms have been alleviated to an appropriate level, treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. Patients may also require chronic treatment on a long-term basis. Drug Combinations
[0133] The inventive compounds described herein may be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients in the treatment of neurodegenerative disorders. Further additional active ingredients for cancer applications include other cancer therapeutics or agents that mitigate adverse effects of cancer chemotherapeutic agents. Such combinations may serve to increase efficacy, ameliorate other disease symptoms, decrease one or more side effects, or decrease the required dose of an inventive compound. The additional active ingredients may be administered in a separate pharmaceutical composition from a compound of the present invention or may be included with a compound of the present invention in a single pharmaceutical composition. The additional active ingredients may be administered simultaneously with, prior to, or after administration of a compound of the present invention.
[0134] Combination agents include additional active ingredients are those that are known or discovered to be effective in treating the diseases, disorders, conditions, and symptoms discussed herein, including those active against another target associated with the disease, disorder, or symptom such as but not limited to, a) compounds that address protein misfolding (such as drugs which reduce the production of these proteins, which increase their clearance or which alter their aggregation and/or propagation); b) compounds that treat symptoms of such disorders (e.g., dopamine replacement therapies); and c) drugs that act as neuroprotectants by complementary mechanisms (e.g., those targeting autophagy, those that are anti-oxidants, and those acting by other mechanisms such as adenosine A2A antagonists).
[0135] For example, compositions and formulations of the invention, as well as methods of treatment, can further comprise other drugs or pharmaceuticals, e.g., other active agents useful for treating or palliative for a neurological or inflammatory diseases related to or caused by TLR2 dimerization, e.g., Parkinson's disease, Alzheimer's Disease (AD), Lewy body disease (LBD) and multiple system atrophy (MSA), or related symptoms or conditions. For example, the pharmaceutical compositions of the invention may additional comprise one or more of such active agents, and methods of treatment may additionally comprise administering an effective amount of one or more of such active agents. In certain embodiments, additional active agents may be antibiotics (e.g., antibacterial or bacteriostatic peptides or proteins), e.g., those effective against gram positive or negative bacteria, fluids, cytokines, immunoregulatory agents, antiinflammatory agents, complement activating agents, such as peptides or proteins comprising collagen-like domains or fibrinogen-like domains (e.g., a ficolin), carbohydrate-binding domains, and the like and combinations thereof. Additional active agents include those useful in such compositions and methods include dopamine therapy drugs, catechol-O-methyl transferase (COMT) inhibitors, monamine oxidase inhibitors, cognition enhancers (such as
acetylcholinesterase inhibitors or memantine), adenosine 2A receptor antagonists, beta- secretase inhibitors, or gamma- secretase inhibitors. In particular embodiments, at least one compound of the present invention may be combined in a pharmaceutical composition or a method of treatment with one or more drugs selected from the group consisting of: tacrine (Cognex), donepezil (Aricept), rivastigmine (Exelon) galantamine (Reminyl), physostigmine, neostigmine, Icopezil (CP- 118954, 5,7-dihydro-3-[2-[l-(phenylmethyl)-4-piperidinyl]ethyl]-6H-pyrrolo-[4,5- f- ]-l,2-benzisoxazol-6-one maleate), ER-127528 (4-[(5,6-dimethoxy-2-fluoro-l-indanon)-2- yl]methyl-l-(3-fluorobenzyl)piperidine hydrochloride), zanapezil (TAK-147; 3-[l- (phenylmethyl)piperidin-4-yl]-l-(2,3,4,5-tetrahydro-lH-l-benzazepin- 8-yl)-l -propane fumarate), Metrifonate (T-588; (-)-R-.alpha.-[[2-(dimethylamino)ethoxy]methyl]
benzo[b]thiophene-5-methanol hydrochloride), FK-960 (N-(4-acetyl-l-piperazinyl)-p- fluorobenzamide-hydrate), TCH-346 (N-methyl-N-2-pyropinyldibenz[b,f]oxepine- 10- methanamine), SDZ-220-581 ((S)-alpha-amino-5-(phosphonomethyl)-[l,l'-biphenyl]-3-propionic acid), memantine (Namenda/Exiba) and 1,3,3,5,5-pentamethylcyclohexan-l-amine
(Neramexane), tarenflurbil (Flurizan), tramiprosate (Alzhemed), clioquinol, PBT-2 (an 8- hydroxyquinilone derivative), l-(2-(2-Naphthyl)ethyl)-4-(3-trifluoromethylphenyl)-l, 2,3,6- tetrahydropyridine, Huperzine A, posatirelin, leuprolide or derivatives thereof, ispronicline, (3- aminopropyl)(n-butyl)phosphinic acid (SGS-742), N-methyl-5-(3-(5-isopropoxypyridinyl))-4- penten-2- amine (ispronicline), 1-decanaminium, N-(2-hydroxy-3-sulfopropyl)-N-methyl-N- octyl-, inner salt (zt-1), salicylates, aspirin, amoxiprin, benorilate, choline magnesium salicylate, diflunisal, faislamine, methyl salicylate, magnesium salicylate, salicyl salicylate, diclofenac, aceclofenac, acemetacin, bromfenac, etodolac, indometacin, nabumetone, sulindac, tolmetin, ibuprofen, carprofen, fenbufen, fenoprofen, flurbiprofen, ketoprofen, ketorolac, loxoprofen, naproxen, tiaprofenic acid, suprofen, mefenamic acid, meclofenamic acid, phenylbutazone, azapropazone, metamizole, oxyphenbutazone, sulfinprazone, piroxicam, lornoxicam, meloxicam, tenoxicam, celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, valdecoxib, nimesulide, arylalkanoic acids, 2-arylpropionic acids (profens), N-arylanthranilic acids (fenamic acids), pyrazolidine derivatives, oxicams, COX-2 inhibitors, sulphonanilides, essential fatty acids, and Minozac (2-(4-(4-methyl-6-phenylpyridazin-3-yl)piperazin-l-yl)pyrimidine dihydrochloride hydrate), or a combination thereof.
Methods of Use
[0136] The compounds and pharmaceutical compositions herein may be used to treat or prevent a disease or condition in an individual. In some embodiments, provided are methods of treating a disease or condition associated with TLR2 heterodimerization, comprising
administering to the individual in need thereof a compound of Formula (I), (I), (III), (IV), (V), or (VI), or a compound of Tables 1, 2, 3, 4, 5, or 6, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, provided are methods of treating a disease or condition associated with TLR2 heterodimerization comprising administering to the subject a
therapeutically effective amount of at least one chemical entity as described herein.
[0137] In some embodiments, provided are compositions containing one or more
compounds of Formula (I), (I), (III), (IV), (V), or (VI), or a compound of Tables 1, 2, 3, 4, 5, or 6, or a pharmaceutically acceptable salt of any of the foregoing, for use in the treatment of a disease or condition associated with TLR2 heterodimerization. In some embodiments, provided are compositions containing at least one chemical entity as described herein for use in the treatment of a disease or condition associated with TLR2 heterodimerization.
[0138] Also provided herein is the use of a compound of Formula (I), (I), (III), (IV), (V), or (VI), or a compound of Tables 1, 2, 3, 4, 5, or 6, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treatment of a disease or condition associated with TLR2 heterodimerization. In some embodiments, provided is the use of at least one chemical entity as described herein in the manufacture of a medicament for treatment of a disease or condition associated with TLR2 heterodimerization. [0139] In some embodiments, the disease or condition is selected from Alzheimer's disease, Parkinson's disease, fronto-temporal dementia, dementia with Lewy bodies (Lewy body disease), Parkinson's disease with dementia, multiple system atrophy, amyotrophic lateral sclerosis, Huntington's disease, inflammatory diseases, asthma, chronic obstructive pulmonary disease (COPD), chronic peptic ulcers, tuberculosis, rheumatoid arthritis, chronic sinusitis, hepatitis, hepatitis B, hepatitis C, gout, lupus, pleurisy, eczema, gastritis, psoriasis, psoriatic arthritis, vasculitis, laryngitis, allergic reactions, multiple sclerosis, Crohn's disease, and traumatic brain injury.
[0140] Also provided are methods for interfering with the heterodimerization of TLR2 in a cell, or modulating, preventing, slowing, reversing, or inhibiting TLR2 heterodimerization in a cell which involves contacting the cell with an effective amount of at least one compound of Formula (I), (I), (III), (IV), (V), or (VI), or a compound of Tables 1, 2, 3, 4, 5, or 6, or a pharmaceutically acceptable salt thereof. In some embodiments, provided are methods for interfering with the heterodimerization of TLR2 in a cell, or modulating, preventing, slowing, reversing, or inhibiting TLR2 heterodimerization in a cell which involves contacting the cell with an effective amount of at least one chemical entity as described herein.
[0141] Also provided herein are compositions containing one or more compounds of Formula (I), (I), (III), (IV), (V), or (VI), or a compound of Tables 1, 2, 3, 4, 5, or 6, or a pharmaceutically acceptable salt of any of the foregoing, for use in interfering with the heterodimerization of TLR2 in a cell, or modulating, preventing, slowing, reversing, or inhibiting TLR2 heterodimerization in a cell. In some embodiments, provided are compositions containing at least one chemical entity as described herein for use in interfering with the heterodimerization of TLR2 in a cell, or modulating, preventing, slowing, reversing, or inhibiting TLR2 heterodimerization in a cell.
[0142] Additionally provided herein is the use of at least one chemical entity as described herein, such as a compound of Formula (I), (I), (III), (IV), (V), or (VI), or a compound of Tables 1, 2, 3, 4, 5, or 6, or a pharmaceutically acceptable salt of any of the foregoing in the
manufacture of a medicament for interfering with the heterodimerization of TLR2, or modulating, preventing, slowing, reversing, or inhibiting TLR2 heterodimerization. Kits
[0143] Also provided are articles of manufacture and kits containing any of the compounds or pharmaceutical compositions provided herein. The article of manufacture may comprise a container with a label. Suitable containers include, for example, bottles, vials, and test tubes. The containers may be formed from a variety of materials such as glass or plastic. The container may hold a pharmaceutical composition provided herein. The label on the container may indicate that the pharmaceutical composition is used for preventing, treating or suppressing a condition described herein, and may also indicate directions for either in vivo or in vitro use.
[0144] In one aspect, provided herein are kits containing a compound or composition described herein and instructions for use. The kits may contain instructions for use in the treatment of a disease or condition associated with TLR2 heterodimerization in an individual in need thereof. A kit may additionally contain any materials or equipment that may be used in the administration of the compound or composition, such as vials, syringes, or IV bags. A kit may also contain sterile packaging.
General Synthetic methods
[0145] The compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter (such as the schemes provided in the Examples below). In the following process descriptions, the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to the formulae herein.
[0146] Where it is desired to obtain a particular enantiomer of a compound, this may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers. Thus, for example, diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g., a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, for example by crystallization and the desired enantiomer recovered. In another resolution process, a racemate may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described.
[0147] Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.
[0148] Solvates of a compound provided herein or a pharmaceutically acceptable salt thereof are also contemplated. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
[0149] In some embodiments, compounds of the Formula (I) may be synthesized according to Scheme 1.
Scheme 1.
Figure imgf000064_0001
thereof detailed herein; PG is a protecting group, and X is a halogen.
[0150] In some embodiments, compounds of the Formula (II) may be synthesized according to Scheme 2.
Scheme 2.
Figure imgf000064_0002
wherein R , R , R , R , R , n2, and p2 are as defined for Formula (II), or any variation thereof detailed herein; PG is a protecting group, and X is a halogen.
[0151] In some embodiments, compounds of the Formula (III) may be synthesized according to Scheme 3.
Scheme 3.
Figure imgf000065_0001
wherein R , R , R , R , and R are as defined for Formula (III), or any variation thereof detailed herein.
[0152] In some embodiments, compounds of the Formula (IV) may be synthesized according to Scheme 4.
Scheme 4.
Figure imgf000065_0002
wherein R41, R41 ,R42, R43, R44, and Gi are as defined for Formula (IV), or any variation thereof detailed herein.
[0153] In some embodiments, compounds of the Formula (V) may be synthesized according to Scheme 5.
Scheme 5.
Figure imgf000065_0003
wherein R , R ,R , R , R , G2, G3, o, r, and s are as defined for Formula (V), or any variation thereof detailed herein; and R56 is H or OH.
[0154] In some embodiments, compounds of the Formula (VI) may be synthesized according to Scheme 6.
Scheme 6.
Figure imgf000066_0001
wherein R , R ,R , R , R , R , R , and t are as defined for Formula (VI), or any variation thereof detailed herein.
Chemical Synthesis
[0155] Exemplary chemical entities useful in methods of the invention will now be described by reference to the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Furthermore, one of skill in the art will recognize that the transformations shown in the schemes below may be performed in any order that is compatible with the functionality of the particular pendant groups. Each of the reactions depicted in the general schemes is preferably run at a temperature from about 0 °C to the reflux temperature of the organic solvent used. Isotopically labeled compounds as described herein are prepared according to the methods described below, using suitably labeled starting materials. Such materials are generally available from
commercial suppliers of radiolabeled chemical reagents. Examples
[0156] The following examples are offered to illustrate but not to limit the invention. One of skill in the art will recognize that the following synthetic reactions and schemes may be modified by choice of suitable starting materials and reagents in order to access other compounds of Formula (I), (II), (III), (IV), (V), or (VI). The compounds are prepared using the general methods described above.
Example 1 : tert-Butyl ((2S)-3-(4-(benzyloxy)phenyl)- l-((2,3-bis(tetradecyloxy)propyl)amino)- l-oxopropan-2-yl)carbamate.
Figure imgf000067_0001
[0157] Step 1: tert-Butyl (2,3-bis(tetradecyloxy)propyl)carbamate. In a 50 mL sealed cap glass vial, a mixture of tert-butyl (2,3-dihydroxypropyl)carbamate (1.15 g, 6.0 mmol) in toluene (6.0 mL) was treated sequentially with 1-bromotetradecane (10.71 mL, 36 mmol), sodium hydroxide (50% aq.; 6.0 mL) and tetrabutylammonium bisulfate (1.02 g, 3.0 mmol). The vial was sealed and heated at 65 °C with vigorous stirring overnight. The mixture was cooled to room temperature (rt) and extracted with toluene (2 x 25 mL). The combined organic layers were washed with water, dried over sodium sulfate, and evaporated. The resulting colorless liquid was purified by silica gel column chromatography (hexane-ethyl acetate (0-25%)) to give the title compound as a colorless liquid (1.52 g, 44% yield). 1H NMR (500 MHz, Chloroform-d) δ 4.88 (s, 1H), 3.57 (dt, J = 9.3, 6.7 Hz, 1H), 3.52 - 3.29 (m, 7H), 3.17 (dt, J = 12.1, 5.7 Hz, 1H), 1.63 - 1.48 (m, 5H), 1.44 (s, 9H), 1.25 (s, 44H), 0.88 (t, J = 6.9 Hz, 6H); ESI-MS m z
[M+H]+ calc'd for C36H73N04, 585; found, 585.
[0158] Step 2: 2,3-Bis(tetradecyloxy)propan-l-amine. A solution of tert-butyl (2,3- bis(tetradecyloxy) propyl) carbamate (1.50 g, 2.57 mmol) was dissolved in tetrahydrofuran (10 mL) was treated with HCl (4 N in dioxane; 10 mL) and the resulting mixture was stirred at rt for 5 h. The mixture was concentrated, and then re-concentrated twice with 1: 1 dichloromethane- diethyl ether. The resulting solid was lyophilized to obtain the title compound as a white powder (100% yield). 1H NMR (500 MHz, Chloroform- ) δ 8.29 (s, 3H), 4.00 - 3.63 (m, 2H), 3.63 - 3.27 (m, 7H), 3.24 (s, 1H), 3.11 (s, 1H), 1.75 - 1.43 (m, 4H), 1.26 (s, 44H), 0.88 (t, = 6.9 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for C31H65NO2, 485; found, 485.
[0159] Step 3. In a 30 mL sealed cap glass vial, 2,3-bis(tetradecyloxy)propan-l-amine hydrochloride (260 mg, 0.5 mmol) was suspended in 1:2 satd. aq. sodium bicarbonate/dioxane (21 mL) and treated with Boc-L-Tyr(0-Bn)-OSu (234 mg, 0.5 mmol), and the resulting mixture was stirred at rt overnight. The mixture was diluted with water and brine, and extracted with ethyl acetate (2 x 25 mL). The combined organic layers were dried over sodium sulfate, and evaporated. The residue was purified by silica gel column (hexane-ethyl acetate (0-100%)) to give the title compound as a white solid (205 mg, 49% yield). 1H NMR (500 MHz, Chloroform- d) δ 7.39 (dt, / = 14.8, 7.6 Hz, 4H), 7.32 (t, = 7.1 Hz, 1H), 7.18 - 7.06 (m, 2H), 6.90 (d, = 8.4 Hz, 2H), 6.12 (d, = 21.0 Hz, 1H), 5.03 (d, = 2.0 Hz, 2H), 4.25 (s, 1H), 3.47 (tdd, = 10.9, 6.6, 3.3 Hz, 2H), 3.43 - 3.27 (m, 6H), 3.23 (dt, / = 12.8, 5.6 Hz, 1H), 2.98 (q, = 12.9, 12.0 Hz, 2H), 1.50 (dq, = 14.7, 6.7 Hz, 4H), 1.41 (s, 9H), 1.25 (s, 44H), 0.88 (t, = 6.9 Hz, 6H); ESI- MS m/z [M+Na]+ calc'd for C52H88N206, 860; found, 860.
Example 2: (2S)-2-Amino-3-(4-(benzyloxy)phenyl)-N-(2,3- bis(tetradecyloxy)propyl)propanamide hydrochloride.
Figure imgf000068_0001
[0160] The title compound was prepared from tert-butyl ((2S)-3-(4-(benzyloxy)phenyl)-l- ((2,3-bis(tetradecyloxy)propyl) amino)- l-oxopropan-2-yl)carbamate (167.5 mg, 0.2 mmol) as in Example 1, Step 2, to give an off-white solid (150 mg, 100% yield). 1H NMR (500 MHz, DMSO- e) δ 8.35 (dt, J = 11.5, 5.8 Hz, 1H), 8.17 (s, 3H), 7.53 - 7.24 (m, 6H), 7.15 (d, J = 8.2 Hz, 2H), 7.03 - 6.87 (m, 2H), 5.06 (d, = 3.0 Hz, 2H), 3.95 (t, / = 7.1 Hz, 1H), 3.81 - 3.68 (m, 1H), 3.69 - 3.59 (m, 1H), 3.44 (t, / = 6.5 Hz, 1H), 3.32 (m, 3H), 3.13 (dd, = 10.6, 5.9 Hz, 1H), 3.04 (dt, / = 13.5, 5.2 Hz, 1H), 2.94 (tt, = 13.0, 6.9 Hz, 2H), 2.01 - 1.67 (m, 1H), 1.44 (dq, = 12.0, 6.5 Hz, 4H), 1.34 - 1.06 (m, 44H), 0.85 (t, = 6.8 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for C47H8oN204, 738; found, 738.
Example 3: tert-Butyl ((2S)-l-((2,3-bis(tetradecyloxy)propyl)amino)-3-(lH-indol-3-yl)-l- oxopropan-2-yl)carbamate.
Figure imgf000069_0001
[0161] The title compound was prepared from 2,3-bis(tetradecyloxy) propan-1 -amine hydrochloride (260 mg, 0.5 mmol) and activated Boc-L-Trp-OSu (201 mg, 0.5 mmol) as in Example 1, Step 3, to give a gummy solid (265 mg, 69% yield). 1H NMR (500 MHz,
Chloroform-d) δ 8.05 (s, 1H), 7.66 (dd, J = 8.0, 3.9 Hz, 1H), 7.34 (dd, J = 8.2, 1.8 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.06 (d, J = 2.3 Hz, 1H), 6.06 (d, J = 25.0 Hz, 1H), 5.13 (s, 1H), 4.41 (s, 1H), 3.39 (dt, J = 9.3, 6.7 Hz, 2H), 3.34 - 3.20 (m, 5H), 3.16 (dd, J = 14.1, 8.2 Hz, 3H), 1.66 - 1.45 (m, 4H), 1.42 (s, 9H), 1.25 (s, 44H), 0.88 (t, J = 6.8 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for C47H83N305, 771; found, 771.
Example 4 : (2S )-2- Amino-N-(2,3 -bis(tetradecyloxy)propyl)-3 -( 1 H-indol-3 -yPpropanamide hydrochloride.
Figure imgf000070_0001
[0162] The title compound was prepared from tert-butyl ((2S)-l-((2,3- bis(tetradecyloxy)propyl)amino)-3-(lH-indol-3-yl)-l-oxopropan-2-yl)carbamate (154 mg, 0.2 mmol) as described in Example 1 to give a gummy solid (100% yield). 1H NMR (500 MHz, DMSO- e) δ 11.02 (s, 1H), 8.49 (t, J = 6.0 Hz, 1H), 8.23 - 8.04 (m, 3H), 7.65 (d, J = 7.9 Hz, 1H), 7.35 (d, = 8.1 Hz, 1H), 7.20 (d, = 2.2 Hz, 1H), 7.08 (ddd, = 8.1, 6.9, 1.1 Hz, 1H), 7.00 (t, = 7.4 Hz, 1H), 3.98 (d, = 6.5 Hz, 1H), 3.78 - 3.50 (m, 6H), 3.48 - 3.36 (m, 2H), 3.24 - 2.96 (m, 3H), 1.54 - 1.31 (m, 4H), 1.34 - 1.12 (m, 44H), 0.85 (t, = 6.8 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for Q2H75N3O3, 671; found, 671.
Example 5: tert-Butyl (2S)-2-((2,3-bis(tetradecyloxy)propyl)carbamoyl) pyrrolidine- 1- carboxylate.
Figure imgf000070_0002
[0163] The title compound was prepared from 2,3 -bis(tetradecyloxy)propan-l -amine hydrochloride (260 mg, 0.5 mmol) and Boc-L-Pro-OSu (156 mg, 0.5 mmol) as in Example 1 to give a colorless liquid (252 mg, 74% yield). 1H NMR (500 MHz, Chloroform- ) δ 4.39 - 4.12 (d, 1H), 3.56 (m, 1H), 3.52 - 3.35 (m, 7H), 3.32 (s, 1H), 2.08 (t, / = 19.9 Hz, 2H), 1.99 - 1.78 (m, 2H), 1.67 - 1.50 (m, 6H), 1.45 (s, 11H), 1.25 (s, 42H), 0.88 (t, = 6.8 Hz, 6H); ESI-MS m/z [M+Na]+ calc'd for C4iH8oN205, 704; found, 704.
Example 6: (2S)-N-(2,3-Bis(tetradecyloxy)propyl)pyrrolidine-2-carboxamide hydrochloride.
Figure imgf000071_0001
[0164] The title compound was prepared from tert-butyl (2S)-2-((2,3- bis(tetradecyloxy)propyl)carbamoyl)pyrrolidine-l-carboxylate (136.2 mg, 0.2 mmol) as in Example 1 to give a white solid (100% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.46 (s, 1H), 4.14 (dd, J = 10.2, 3.9 Hz, 1H), 3.79 - 3.69 (m, 3H), 3.68 - 3.57 (m, 2H), 3.56 - 3.34 (m, 4H), 3.28 - 3.14 (m, 2H), 1.93 - 1.80 (m, 3H), 1.53 - 1.39 (m, 4H), 1.24 (s, 44H), 0.88 (t, J = 6.8 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for C36H72N2O3, 582; found, 582.
Example 7: tert-Butyl ((2S)-l-((2,3-bis(tetradecyloxy)propyl)amino)-3-(4-hydroxyphenyl)-l- oxopropan-2-yl)carbamate.
Figure imgf000071_0002
[0165] The title compound was prepared from 2,3 -bis(tetradecyloxy)propan-l -amine hydrochloride (260 mg, 0.5 mmol) and Boc-L-Tyr-OSu (189 mg, 0.5 mmol) as in Example 1 to give a white solid (163 mg, 44% yield). 1H NMR (500 MHz, Chloroform- ) δ 7.10 - 7.00 (m, 2H), 6.80 - 6.65 (m, 2H), 6.16 (d, J = 18.5 Hz, 1H), 5.25 (s, 1H), 5.01 (s, 1H), 4.25 (s, 1H), 3.56 - 3.28 (m, 8H), 3.23 (d, J = 14.3 Hz, 1H), 2.97 (s, 2H), 1.51 (dp, J = 13.8, 7.0, 6.6 Hz, 4H), 1.41 (s, 9H), 1.25 (s, 44H), 0.88 (t, J = 6.9 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for C45H82N206, 748; found, 748.
Example 8: (2S)-2-Amino-N-(2.3-bis(tetradecyloxy)propyl)-3-(4-hvdroxyphenyl)propanamide hydrochloride.
Figure imgf000072_0001
[0166] The title compound was prepared from tert-butyl ((2S)-l-((2,3- bis(tetradecyloxy)propyl)amino)-3-(4-hydroxyphenyl)-l-oxopropan-2-yl)carbamate (149.5 mg, 0.2 mmol) as for Example 1 to give a white solid (100% yield). 1H NMR (500 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.39 (dt, 7 = 11.2, 5.4 Hz, 1H), 8.15 (s, 3H), 7.15 - 6.90 (m, 2H), 6.81 - 6.53 (m, 2H), 3.91 (t, J = 6.8 Hz, 1H), 3.45 (t, = 6.5 Hz, 1H), 3.40-3.11 (m, 7H), 3.06 (dt, / = 13.6, 5.4 Hz, 1H), 2.91 (m, = 7.4, 7.0 Hz, 1H), 2.85 (ddd, = 13.8, 7.1, 3.7 Hz, 1H), 1.54 - 1.36 (m, 4H), 1.23 (d, = 3.1 Hz, 44H), 0.85 (t, = 6.8 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for
C40H74N2O4, 648; found, 648.
Example 9: (9H-Fluoren-9-yl)methyl tert-butyl ((5S)-6-((2,3-bis(tetradecyloxy)propyl)amino)-
6-oxohexane- 1 5-diyl)dicarbamate.
Figure imgf000072_0002
[0167] The title compound was prepared from 2,3 -bis(tetradecyloxy)propan-l -amine hydrochloride (260 mg, 0.5 mmol) and Na-Fmoc-Ne-Boc-L-Lys-OSu (283 mg, 0.5 mmol) as described in Example 1 to give a white solid (152 mg, 33% yield). 1H NMR (500 MHz, Chloroform- ) δ 7.76 (d, = 7.6 Hz, 2H), 7.59 (d, = 7.4 Hz, 2H), 7.40 (t, = 7.5 Hz, 2H), 7.31 (t, = 7.5 Hz, 2H), 6.33 (s, 1H), 5.49 (s, 1H), 4.59 (s, 1H), 4.43 - 4.31 (m, 2H), 4.21 (t, = 7.0 Hz, 1H), 4.11 (d, = 6.9 Hz, 1H), 3.69 - 3.23 (m, 9H), 3.19 - 2.95 (m, 2H), 1.85 (s, 1H), 1.61 (s, 2H), 1.52 (dq, J = 14.0, 6.4, 5.7 Hz, 4H), 1.43 (s, 9H), 1.25 (q, = 6.8, 5.5 Hz, 47H), 0.88 (t, = 6.8 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for C57H95N3O7, 935; found, 935.
Example 10: (9H-Fluoren-9-yl)methyl ((2S)-6-amino-l-((2,3-bis(tetradecyloxy)propyl)amino)- l-oxohexan-2- l)carbamate hydrochloride.
Figure imgf000073_0001
[0168] The title compound was prepared from (9H-fluoren-9-yl)methyl tert-butyl ((5S)-6- ((2,3-bis(tetradecyloxy)propyl)amino)-6-oxohexane-l,5-diyl)dicarbamate (94 mg, 0.1 mmol) as described for Example 1 to give a white solid (100% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.89 (d, = 7.5 Hz, 2H), 7.84 - 7.74 (m, 4H), 7.71 (t, = 7.8 Hz, 2H), 7.50 (dd, = 8.4, 3.6 Hz, 1H), 7.41 (t, = 7.4 Hz, 2H), 7.32 (t, = 7.4 Hz, 2H), 4.32 - 4.12 (m, 3H), 3.95 (tt, = 9.3, 5.3 Hz, 1H), 3.42 (qd, = 6.9, 2.9 Hz, 3H), 3.34 (s, 4H), 3.11 (ddt, = 34.7, 13.1, 6.5 Hz, 2H), 2.74 (s, 2H), 1.61 (d, = 9.6 Hz, 1H), 1.57 - 1.47 (m, 3H), 1.46 - 1.34 (m, 4H), 1.21 (s, = 4.8 Hz, 46H), 0.84 (t, = 6.9 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for CsiH^NsOs, 835; found, 835.
[0169] Example 11: (9H-Fluoren-9-yl)methyl ((2S)-l-((2,3-bis(tetradecyloxy)
propyl)amino)-3-(lH-indol-3-yl)-l-oxopropan-2-yl)carbamate.
Figure imgf000074_0001
[0170] The title compound was prepared from 2,3 -bis(tetradecyloxy)propan-l -amine hydrochloride (260 mg, 0.5 mmol) and Fmoc-L-Trp-OSu (262 mg, 0.5 mmol) as described for Example 1 to give a white solid (185 mg, 42% yield). 1H NMR (500 MHz, Chloroform-d) δ 8.05 (d, = 3.0 Hz, 1H), 7.76 (d, = 7.6 Hz, 2H), 7.70 (s, 1H), 7.55 (t, = 8.2 Hz, 2H), 7.45 - 7.33 (m, 3H), 7.30 (td, = 7.5, 3.1 Hz, 2H), 7.17 (dt, = 30.1, 7.5 Hz, 2H), 7.08 - 7.00 (m, 1H), 5.99 (d, = 22.3 Hz, 1H), 5.52 (s, 1H), 4.54 - 4.27 (m, 3H), 4.20 (t, = 7.1 Hz, 1H), 3.51 - 3.21 (m, 6H), 3.21 - 3.07 (m, 3H), 1.46 (q, = 6.7 Hz, 2H), 1.37 (q, = 7.0 Hz, 2H), 1.33 - 1.06 (m, 44H), 0.88 (t, = 6.9 Hz, 6H); ESI-MS m/z [M+Na]+ calc'd for C57H85N305, 915; found, 915.
Example 12: tert-Butyl ((2R)-l-((2,3-bis(tetradecyloxy)propyl)amino)-3-(lH-indol-3-yl)-l- oxopropan-2-yl)carbamate.
Figure imgf000074_0002
[0171] The title compound was prepared from 2,3 -bis(tetradecyloxy)propan-l -amine hydrochloride (260 mg, 0.5 mmol) and Boc-D-Trp-OSu (262 mg, 0.5 mmol) as described for Example 1 to give a white solid (175 mg, 46% yield). 1H NMR (500 MHz, Chloroform- ) δ 8.06 (s, 1H), 7.66 (dd, = 8.0, 3.9 Hz, 1H), 7.34 (dd, = 8.2, 1.9 Hz, 1H), 7.23 - 7.16 (m, 1H), 7.12 (t, = 7.4 Hz, 1H), 7.06 (d, = 2.3 Hz, 1H), 6.06 (d, = 24.9 Hz, 1H), 5.13 (s, 1H), 4.41 (s, 1H), 3.47 - 3.04 (m, 11H), 1.48 (q, = 6.6 Hz, 2H), 1.42 (s, 11H), 1.26 (s, 44H), 0.88 (t, = 6.9 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for C47H83N305, 771; found, 771. Example 13: (2R)-2-Amino-N-(2,3-bis(tetradecyloxy)propyl)-3-(lH-indol-3-yl)propanamide hydrochloride.
Figure imgf000075_0001
[0172] The title compound was prepared from tert-butyl ((2R)-l-((2,3- bis(tetradecyloxy)propyl)amino)-3-(lH-indol-3-yl)-l-oxopropan-2-yl)carbamate (154 mg, 0.2 mmol) as described for Example 1 to give a gummy solid (100% yield). 1H NMR (500 MHz, Chloroform- ) δ 9.42 (s, 3H), 8.01 (s, 1H), 7.26 (s, 3H), 7.17 - 6.71 (m, 2H), 4.55 - 4.04 (m, 1H), 3.33 (s, 11H), 1.45 (d, = 20.1 Hz, 4H), 1.24 (t, J = 6.9 Hz, 44H), 0.88 (t, = 6.8 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for Q2H75N3O3, 671 ; found, 671.
Example 14: tert-Butyl (4S)-5-((2,3-bis(tetradecyloxy)propyl)amino)-4-((tert- butoxyc arbonyl) amino - 5 -oxopentanoate .
Figure imgf000075_0002
[0173] The title compound was prepared from 2,3 -bis(tetradecyloxy)propan-l -amine hydrochloride (260 mg, 0.5 mmol) and Boc-L-Glu(OtBu)-OSu (200 mg, 0.5 mmol) as described for Example 1 to give a white solid (230 mg, 60% yield). 1H NMR (500 MHz, Chloroform-d) δ 6.51 (t, = 5.4 Hz, 1H), 5.26 (s, 1H), 4.09 (s, 1H), 3.62 - 3.21 (m, 9H), 2.39 (dtd, = 16.7, 7.3, 2.6 Hz, 1H), 2.28 (dt, = 16.5, 7.0 Hz, 1H), 2.08 (dtd, = 14.1, 7.1, 4.9 Hz, 1H), 1.96 - 1.78 (m, 1H), 1.56 (d, = 8.2 Hz, 4H), 1.44 (d, = 6.8 Hz, 18H), 1.26 (s, 44H), 0.88 (t, J = 6.9 Hz, 6H); ESI-MS m/z [M+Na]+ calc'd for C45H88N2O7, 792; found, 792. Example 15: (4S)-4-Amino-5-((2,3-bis(tetradecyloxy)propyl)amino)-5-oxopentanoic acid hydrochloride.
Figure imgf000076_0001
[0174] The title compound was prepared from tert-butyl (4S)-5-((2,3- bis(tetradecyloxy)propyl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoate (154 mg, 0.2 mmol) as described for Example 1 to give a white solid (100% yield). 1H NMR (500 MHz, Chloroform- ) δ 8.48 - 7.93 (m, 4H), 4.01 - 3.13 (m, 9H), 2.65 (s, 2H), 1.87 (dddd, = 18.6, 15.0, 10.6, 5.6 Hz, 2H), 1.72 (ddd, = 14.6, 10.8, 6.4 Hz, 1H), 1.54 (s, 4H), 1.25 (s, 44H), 0.88 (t, = 6.8 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for C36H72N2O5, 614; found, 614.
Example 16: tert-Butyl (2R)-2-((2,3-bis(tetradecyloxy)propyl)carbamoyl)pyrrolidine-l- carboxylate.
Figure imgf000076_0002
[0175] The title compound was prepared from 2,3 -bis(tetradecyloxy)propan-l -amine hydrochloride (260 mg, 0.5 mmol) and Boc-D-Pro-OSu (156 mg, 0.5 mmol) as described for Example 1 to give a white solid (275 mg, 81% yield). 1H NMR (500 MHz, Chloroform- ) δ 4.45 - 4.10 (m, 1H), 3.67 - 3.16 (m, 12H), 2.47 - 2.00 (m, 2H), 1.86 (s, 2H), 1.54 (q, = 6.9 Hz, 4H), 1.46 (s, 9H), 1.25 (s, 44H), 0.88 (t, = 6.9 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for C4iH8oN205, 682; found, 682.
Example 17: (2R)- -(2,3-Bis(tetradecyloxy)propyl)pyrrolidine-2-carboxamide hydrochloride.
Figure imgf000076_0003
[0176] The title compound was prepared from tert-butyl (2R)-2-((2,3- bis(tetradecyloxy)propyl)carbamoyl)pyrrolidine-l-carboxylate (204 mg, 0.3 mmol) as described for Example 1 to give a white solid (100% yield). 1H NMR (500 MHz, Chloroform- ) δ 11.37 (s, 1H), 7.62 (d, = 97.3 Hz, 2H), 3.94 - 3.21 (m, 11H), 2.63 - 2.42 (m, 1H), 2.22 - 1.95 (m, 2H), 1.95 - 1.61 (m, 2H), 1.62 - 1.45 (m, 4H), 1.25 (s, 44H), 0.87 (t, = 6.8 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for C36H72N2O3, 582; found, 582.
Example 18: -(2,3-Bis(tetradecyloxy)propyl)-2-((4-methylphenyl)sulfonamido)acetamide.
Figure imgf000077_0001
[0177] The title compound was prepared from 2,3 -bis(tetradecyloxy)propan-l -amine hydrochloride (260 mg, 0.5 mmol) and Tosyl-Gly-OSu (163 mg, 0.5 mmol) as described for Example 1 to give a white solid (115 mg, 33% yield). 1H NMR (500 MHz, Chloroform- ) δ 7.87 - 7.68 (m, 2H), 7.31 (d, = 8.0 Hz, 2H), 6.50 (t, = 5.6 Hz, 1H), 5.14 (t, = 5.9 Hz, 1H), 3.66 - 3.13 (m, 11H), 2.43 (s, 3H), 1.56 (tt, = 11.3, 7.1 Hz, 4H), 1.26 (s, 44H), 0.88 (t, = 6.9 Hz, 6H); ESI-MS m/z [M+Na]+ calc'd for C4oH74N205S, 718; found, 718.
Example 19: tert-Butyl 4-((2S)-3-((2,3-bis(tetradecyloxy)propyl)amino)-2-((tert- butoxycarbon l)amino)-3-oxopropyl)- lH-imidazole- 1-carboxylate.
Figure imgf000077_0002
[0178] The title compound was prepared from 2,3 -bis(tetradecyloxy)propan-l -amine hydrochloride (260 mg, 0.5 mmol) and Boc-L-His(Boc)-OSu (226 mg, 0.5 mmol) as described for Example 1 to give a white solid (245 mg, 60% yield). 1H NMR (500 MHz, Chloroform- ) δ 8.01 (t, = 1.7 Hz, 1H), 7.17 (d, = 1.9 Hz, 1H), 6.89 (s, 1H), 6.11 (s, 1H), 4.43 (s, 1H), 3.61 - 3.15 (m, 9H), 3.09 (s, 1H), 2.94 (dd, = 14.9, 5.5 Hz, 1H), 1.60 (s, 9H), 1.53 (q, = 7.1 Hz, 4H), 1.44 (s, 9H), 1.34 - 1.16 (m, 44H), 0.88 (t, J = 6.9 Hz, 6H); ESI-MS m/z [M+Na]+ calc'd for C47H88N407, 844; found, 844.
Example 20: (2S)-2-Amino-N-(23-bis(tetradecyloxy)propyl)-3-( lH-imidazol-4- vPpropanamide dihydrochloride.
Figure imgf000078_0001
[0179] The title compound was prepared from tert-butyl 4-((2S)-3-((2,3- bis(tetradecyloxy)propyl)amino)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)-lH-imidazole-l- carboxylate (164 mg, 0.2 mmol) as described for Example 1 to give a white solid (100% yield). 1H NMR (500 MHz, Chloroform-d) δ 8.89 (s, 1H), 8.21 (s, 4H), 7.62 (s, 1H), 4.70 (d, = 41.4 Hz, 1H), 3.87 - 3.18 (m, 9H), 2.61 - 2.15 (m, 2H), 1.72 - 1.45 (m, 4H), 1.24 (d, = 7.3 Hz, 44H), 0.88 (t, = 6.8 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for C37H72N403, 622; found, 622.
Figure imgf000078_0002
[0180] The title compound was prepared from 2,3 -bis(tetradecyloxy)propan-l -amine hydrochloride (260 mg, 0.5 mmol) and Boc-P-Ala-OSu (143 mg, 0.5 mmol) as described for Example 1 to give a white solid (255 mg, 78% yield). 1H NMR (500 MHz, Chloroform-d) δ 5.97 (t, = 5.6 Hz, 1H), 5.21 (s, 1H), 3.68 - 3.35 (m, 10H), 3.30 (dt, = 13.7, 5.2 Hz, 1H), 2.37 (t, = 6.0 Hz, 2H), 1.63 - 1.47 (m, 4H), 1.43 (s, 9H), 1.25 (s, 44H), 0.88 (t, = 6.9 Hz, 6H); ESI-MS m/z [M+Na]+ calc'd for C39H78N205, 678; found, 678.
Example 22: 3-Amino-N-(2,3-bis(tetradecyloxy)propyl)propanamide hydrochloride.
Figure imgf000079_0001
[0181] The title compound was prepared from tert-butyl (3-((2,3- bis(tetradecyloxy)propyl)amino)-3-oxopropyl)carbamate (196.5 mg, 0.3 mmol) as described for Example 1 to give a white solid (100% yield). 1H NMR (500 MHz, Chloroform- ) δ 8.43 (s, 3H), 6.54 (s, 1H), 3.60 - 3.19 (m, 11H), 2.76 (s, 2H), 1.96 (s, 2H), 1.55 (t, = 6.6 Hz, 4H), 1.25 (s, 44H), 0.88 (t, = 6.9 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for C34H7oN203, 556; found, 556.
Example 23: tert-Butyl (3S)-4-((2,3-bis(tetradecyloxy)propyl)amino)-3-((tert- butox carbonyl)amino)-4-oxobutanoate.
Figure imgf000079_0002
[0182] The title compound was prepared from 2,3 -bis(tetradecyloxy)propan-l -amine hydrochloride (260 mg, 0.5 mmol) and Boc-L-Asp(OtBu)-OSu (193 mg, 0.5 mmol) as described for Example 1 to give a white solid (160 mg, 42% yield). 1H NMR (500 MHz, Chloroform- ) δ 6.79 (q, = 5.2 Hz, 1H), 5.63 (d, = 8.6 Hz, 1H), 4.43 (s, 1H), 3.63 - 3.21 (m, 9H), 2.89 (dd, = 16.9, 4.7 Hz, 1H), 2.59 (dd, / = 16.9, 6.1 Hz, 1H), 1.56 (td, = 14.2, 12.7, 5.7 Hz, 4H), 1.44 (d, = 5.1 Hz, 18H), 1.25 (s, 44H), 0.88 (t, = 6.9 Hz, 6H); ESI-MS m/z [M+Na]+ calc'd for C44H86N2O7, 778; found, 778.
Example 24: (3S)-3-Amino-4-((2,3-bis(tetradecyloxy)propyl)amino)-4-oxobutanoic acid hydrochloride.
Figure imgf000079_0003
[0183] The title compound was prepared from tert-butyl (3S)-4-((2,3- bis(tetradecyloxy)propyl)amino)-3-((tert-butoxycarbonyl)amino)-4-oxobutanoate (151 mg, 0.2 mmol) as described for Example 1 to give a white solid (100% yield). 1H NMR (499 MHz, Chloroform- ) δ 8.09 (d, = 111.7 Hz, 4H), 3.92 - 3.20 (m, 10H), 3.08 (s, 2H), 1.55 (s, 4H), 1.26 (s, 44H), 0.88 (t, = 6.8 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for C35H70N2O5, 600; found, 600.
[0184] Example 25: tert-Butyl (2-((2,3-bis(tetradecyloxy)propyl)amino)-2-oxoethyl) (methyl)carbamate.
Figure imgf000080_0001
[0185] The title compound was prepared from 2,3 -bis(tetradecyloxy)propan-l -amine hydrochloride (260 mg, 0.5 mmol) and Boc-Sar-OSu (Sar = N-methylglycine; 143 mg, 0.5 mmol) as described for Example 1 to give a white solid (220 mg, 67% yield). 1H NMR (500 MHz, Chloroform-d) δ 6.41 (s, 1H), 3.87 (s, 2H), 3.66 - 3.20 (m, 9H), 2.92 (s, 3H), 1.55 (td, / : 7.2, 3.7 Hz, 4H), 1.46 (s, 9H), 1.25 (s, 44H), 0.88 (t, = 6.9 Hz, 6H); ESI-MS m/z [M+Na]+ calc'd for C39H78N2O5, 678; found, 678.
Example 26: N-(2, -bis(tetradecyloxy)propyl)-2-(methylamino)acetamide hydrochloride.
Figure imgf000080_0002
[0186] The title compound was prepared from tert-butyl (2-((2,3- bis(tetradecyloxy)propyl)amino)-2-oxoethyl) (methyl)carbamate (196.5 mg, 0.3 mmol) as described for Example 1 to give a white solid (100% yield). 1H NMR (499 MHz, Chloroform- ) δ 9.42 (s, 2H), 7.45 (d, = 12.9 Hz, 1H), 3.88 (s, 2H), 3.72 - 3.19 (m, 9H), 2.82 (s, 3H), 1.54 (q, = 6.8 Hz, 4H), 1.25 (s, 44H), 0.88 (t, = 6.9 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for
C34H7oN203, 556; found, 556. Example 27: tert-Butyl (3S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-((2,3- bis(tetradecyloxy)propyl)amino)-4-oxobutanoate.
Figure imgf000081_0001
[0187] The title compound was prepared from 2,3 -bis(tetradecyloxy)propan-l -amine hydrochloride (260 mg, 0.5 mmol) and Fmoc-L-Asp(OtBu)-OSu (254 mg, 0.5 mmol) as described for Example 1 to give a white solid (280 mg, 64% yield). 1H NMR (499 MHz, Chloroform-d) δ 7.76 (d, J = 7.6 Hz, 2H), 7.58 (d, J = 7.5 Hz, 2H), 7.40 (t, J = 7.5 Hz, 2H), 7.31 (t, J = 7.5 Hz, 2H), 6.89 - 6.64 (m, 1H), 5.96 (d, J = 8.4 Hz, 1H), 4.50 (s, 1H), 4.40 (tt, J = 18.4, 9.0 Hz, 2H), 4.22 (t, J = 7.2 Hz, 1H), 3.62 - 3.22 (m, 9H), 2.92 (dd, J = 17.0, 4.4 Hz, 1H), 2.61 (dd, J = 17.1, 6.6 Hz, 1H), 1.67 - 1.49 (m, 4H), 1.45 (s, 9H), 1.25 (q, J = 7.3, 5.2 Hz, 44H), 0.88 (t, J = 6.9 Hz, 6H); ESI-MS m z [M+H]+ calc'd for C54H88N207, 878; found, 878.
Example 28: (3S)-3-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-4-((2,3- bis(tetradecyloxy)propyl)amino)-4-oxobutanoic acid.
Figure imgf000081_0002
[0188] The title compound was prepared from tert-butyl (3S)-3-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-4-((2,3-bis(tetradecyloxy) propyl)amino)-4-oxobutanoate (175.4 mg, 0.2 mmol) as described for Example 1 to give an off-white solid (100% yield). 1H NMR (499 MHz, Chloroform-d) δ 7.76 (dd, = 7.6, 3.0 Hz, 2H), 7.58 (d, = 7.3 Hz, 2H), 7.40 (td, = 7.5, 2.5 Hz, 2H), 7.31 (td, J = 7.5, 2.4 Hz, 2H), 6.85 (dd, / = 38.1, 6.0 Hz, 1H), 5.96 (d, = 8.9 Hz, 1H), 4.66 - 4.28 (m, 3H), 4.21 (q, = 7.1 Hz, 1H), 3.77 (q, = 4.7, 3.8 Hz, 2H), 3.64 (dt, = 7.4, 5.0 Hz, 2H), 3.58 - 3.19 (m, 6H), 3.15 - 2.81 (m, 1H), 2.82 - 2.48 (m, 1H), 1.53 (p, / = 6.7 Hz, 4H), 1.38 - 1.11 (m, 44H), 0.88 (t, = 6.9 Hz, 6H); ESI-MS m/z [M-H]+ calc'd for C50H80N2O7, 820; found, 820.
Example 29: tert-Butyl (4S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-((2,3- bis(tetradecylox ropyl)amino)-5-oxopentanoate.
Figure imgf000082_0001
[0189] The title compound was prepared from 2,3 -bis(tetradecyloxy)propan-l -amine hydrochloride (260 mg, 0.5 mmol) and Fmoc-L-Glu(OtBu)-OSu (261 mg, 0.5 mmol) as described for Example 1 to give a white solid (265 mg, 60% yield). 1H NMR (499 MHz, Chloroform- ) δ 7.76 (d, = 7.5 Hz, 2H), 7.59 (d, = 7.5 Hz, 2H), 7.40 (t, = 7.5 Hz, 2H), 7.31 (t, = 7.4 Hz, 2H), 6.54 (s, 1H), 5.74 (s, 1H), 4.52 - 4.27 (m, 2H), 4.21 (t, = 7.2 Hz, 2H), 3.71 - 3.13 (m, 9H), 2.43 (d, J = 16.7 Hz, 1H), 2.35 - 2.19 (m, 1H), 2.09 (dd, = 14.3, 7.0 Hz, 1H), 1.93 (dd, = 14.7, 7.4 Hz, 1H), 1.65 - 1.49 (m, 4H), 1.46 (s, 9H), 1.25 (q, = 7.5, 5.7 Hz, 44H), 0.88 (t, = 6.9 Hz, 6H); ESI-MS m/z [M+Na]+ calc'd for C55H90N2O7, 914; found, 914.
[0190] Example 30: (4S)-4-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-5-((2,3- bis(tetradecyloxy)propyl)amino)-5-oxopentanoic acid.
Figure imgf000083_0001
[0191] The title compound was prepared from tert-butyl (4S)-4-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-5-((2,3-bis(tetradecyloxy)propyl)amino)-5-oxopentanoate (178 mg, 0.2 mmol) as described for Example 1 to give an off-white solid (100% yield). 1H NMR (500 MHz, Chloroform-d) δ 7.75 (t, 7 = 6.3 Hz, 2H), 7.59 (t, 7 = 7.3 Hz, 2H), 7.39 (t, 7 = 7.1 Hz, 2H), 7.34 - 7.27 (m, 2H), 6.76 (s, 1H), 5.82 (d, 7 = 8.3 Hz, 1H), 4.47 - 4.24 (m, 3H), 4.20 (q, 7 = 7.1 Hz, 1H), 3.59 - 3.16 (m, 9H), 2.59 - 2.46 (m, 1H), 2.45 - 2.28 (m, 1H), 2.14 (s, 1H), 2.05 - 1.82 (m, 1H), 1.52 (h, 7 = 6.5 Hz, 4H), 1.24 (q, 7 = 6.7, 5.4 Hz, 44H), 0.88 (t, 7 = 6.9 Hz, 6H); ESI-MS m z [M+Na]+ calc'd for C51H82N2O7, 858; found, 858.
Example 31: Benzyl tert-butyl ((5R)-6-((2,3-bis(tetradecyloxy)propyl)amino)-6-oxohexane-l,5- diyPdicarbamate.
Figure imgf000083_0002
[0192] The title compound was prepared from 2,3 -bis(tetradecyloxy)propan-l -amine hydrochloride (260 mg, 0.5 mmol) and Na-Z-Ne-Boc-D-Lys-OSu (237 mg, 0.5 mmol) as described for Example 1 to give a white solid (280 mg, 66% yield). 1H NMR (499 MHz, Chloroform- ) δ 7.44 - 7.29 (m, 5H), 6.36 (d, 7 = 6.7 Hz, 1H), 5.43 (s, 1H), 5.10 (d, 7 = 3.5 Hz, 2H), 4.57 (s, 1H), 4.11 (d, 7 = 6.9 Hz, 1H), 3.65 - 3.18 (m, 9H), 3.09 (d, 7 = 7.0 Hz, 2H), 1.97 - 1.74 (m, 1H), 1.73 - 1.59 (m, 2H), 1.54 (q, 7 = 6.7 Hz, 4H), 1.50-1.31 (m, 3H), 1.42 (s, 9H), 1.25 (s, 44H), 0.88 (t, J = 6.9 Hz, 6H); ESI-MS m/z [M+Na]+ calc'd for C5oH91N307, 869;
found, 869.
Example 32: Benzyl ((2R)-6-amino-l-((2,3-bis(tetradecyloxy)propyl)amino)-l-oxohexan-2- vDcarbamate h drochloride.
Figure imgf000084_0001
[0193] The title compound was prepared from benzyl tert-butyl ((5R)-6-((2,3- bis(tetradecyloxy)propyl)amino)-6-oxohexane-l,5-diyl)dicarbamate (169 mg, 0.2 mmol) as described for Example 1 to give a white solid (100% yield). 1H NMR (500 MHz, Chloroform- ) δ 8.21 (s, 3H), 7.41 - 7.29 (m, 5H), 7.17 (s, IH), 6.09 (s, IH), 5.07 (s, 2H), 4.24 (s, IH), 3.59 - 3.20 (m, 9H), 2.93 (m, 2H), 2.15 (s, 3H), 1.74 (m, 3H), 1.53 (t, J = 6.8 Hz, 4H), 1.24 (d, J = 3.5 Hz, 44H), 0.88 (t, J = 6.9 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for C45H83N305, 747; found, 747.
Example 33: tert-Butyl ((2R)-3-(riJ,-biphenyll-4-yl)-l-((2,3-bis(tetradecyloxy)propyl)amino)-
1 -oxopropan-2-yl)carbamate
Figure imgf000084_0002
[0194] In a 30 mL sealed cap glass vial, a solution of Boc-4-Phe-D-Phenyl-Ala-OH (171 mg, 0.5 mmol) in DMF (5 mL) was treated with HATU (285 mg, 0.75 mmol) and diisopropyl ethylamine (174 μί, 1.0 mmol). After stirring for 5 min at rt, 2,3-bis(tetradecyloxy)propan-l- amine hydrochloride (260 mg, 0.5 mmol) was added to the reaction vial, the cap was closed, and stirring was continued at rt for 5 h. The mixture was diluted with water (10 mL) and brine (10 mL), and extracted with ethyl acetate (2 x 25 mL), and the combined organic layers were dried over sodium sulfate and concentrated. The residue was purified on a silica gel column (hexane- ethyl acetate (0-100%)) to give the title compound as white solid (172 mg, 43% yield). 1H NMR (500 MHz, Chloroform- ) δ 7.60 - 7.49 (m, 4H), 7.42 (t, = 7.5 Hz, 2H), 7.33 (t, = 7.4 Hz, 1H), 7.28 (dd, / = 8.7, 2.6 Hz, 2H), 6.15 (d, = 30.8 Hz, 1H), 5.04 (d, = 21.2 Hz, 1H), 4.34 (s, 1H), 3.80 (dt, / = 9.5, 6.5 Hz, 1H), 3.56 - 3.18 (m, 8H), 3.10 (dq, / = 8.1, 5.0, 4.2 Hz, 2H), 1.49 (dq, / = 14.5, 6.9 Hz, 4H), 1.41 (d, = 1.4 Hz, 9H), 1.35 - 1.09 (m, 44H), 0.88 (t, = 6.9 Hz, 6H); ESI-MS m/z [M+Na]+ calc'd for C5iH86N205, 830; found, 830.
Example 34: (2R)-3-(ri, l ,-Biphenyll-4-yl)-2-amino-N-(2,3- bis(tetradecyloxy)propyl)propanamide hydrochloride.
Figure imgf000085_0001
[0195] The title compound was prepared from tert-butyl ((2R)-3-([l,l '-biphenyl]-4-yl)-l- ((2,3-bis(tetradecyloxy)propyl)amino)- l-oxopropan-2-yl)carbamate (162 mg, 0.2 mmol) as described for Example 1 to give a solid (100% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.41 (dt, = 14.0, 5.8 Hz, 1H), 8.26 (s, 3H), 7.70 - 7.55 (m, 4H), 7.45 (t, = 7.6 Hz, 2H), 7.35 (dd, = 11.5, 7.7 Hz, 3H), 4.08 (d, = 34.4 Hz, 1H), 3.81 - 3.56 (m, 1H), 3.52 - 3.16 (m, 7H), 3.14 - 2.87 (m, 3H), 1.40 (ddd, = 28.0, 13.0, 6.6 Hz, 4H), 1.32 - 1.02 (m, 44H), 0.85 (t, = 6.8 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for C46H78N203, 708; found, 708. Example 35: tert-Butyl ((2S)-3-(rU,-biphenyll-4-yl)- l-((2,3-bis(tetradecyloxy)propyl)amino)- l-oxopropan- -yl)carbamate.
Figure imgf000086_0001
[0196] The title compound was prepared from Boc-4-Phe-L-Phenyl Ala-OH (171 mg, 0.5 mmol) and 2,3-bis(tetradecyloxy)propan-l-amine hydrochloride (260 mg, 0.5 mmol) as described in Example 33 to give a white solid (225 mg, 56% yield). 1H NMR (500 MHz, Chloroform-d) δ 7.54 (dd, 7 = 16.5, 7.8 Hz, 4H), 7.42 (t, 7 = 7.5 Hz, 2H), 7.33 (t, 7 = 7.4 Hz, 1H), 7.28 (dd, 7 = 8.7, 2.5 Hz, 2H), 6.15 (d, 7 = 30.9 Hz, 1H), 5.04 (d, 7 = 20.8 Hz, 1H), 4.34 (s, 1H), 3.57 - 3.17 (m, 9H), 3.17 - 2.95 (m, 2H), 1.49 (dd, 7 = 13.1, 7.5 Hz, 4H), 1.41 (s, 9H), 1.36 - 1.15 (m, 44H), 0.88 (t, 7 = 6.8 Hz, 6H); ESI-MS m/z [M+Na]+ calc'd for C5iH86N205, 830; found, 830.
Example 36: (2S)-3-(ri.l ,-Biphenyll-4-yl)-2-amino-N-(2.3- bis(tetradecyloxy)propyl)propanamide hydrochloride.
Figure imgf000086_0002
[0197] The title compound was prepared from tert-butyl ((2S)-3-([l,l '-biphenyl]-4-yl)- l- ((2,3-bis(tetradecyloxy)propyl)amino)- l-oxopropan-2-yl)carbamate (162 mg, 0.2 mmol) as described for Example 1 to give a white solid (100% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.41 (dd, 7 = 13.0, 6.5 Hz, 1H), 8.26 (s, 3H), 7.64 (t, 7 = 7.0 Hz, 4H), 7.45 (t, 7 = 7.6 Hz, 2H), 7.35 (dd, 7 = 11.2, 7.7 Hz, 3H), 4.05 (s, 1H), 3.67 (m, 1H), 3.58 - 3.15 (m, 7H), 3.15 - 2.84 (m, 3H), 1.56 - 1.32 (m, 4H), 1.21 (d, 7 = 8.9 Hz, 44H), 0.85 (t, 7 = 6.8 Hz, 6H); ESI-MS m/z
[M+H]+ calc'd for C46H78N203, 708; found, 708. Example 37: Di-tert-butyl ((5S)-6-((2S)-2-((2,3-bis(tetradecyloxy)propyl)carbamoyl)pyrrolidin- 1 -yl)-6-oxohexane- 1 5-diyl)dicarbamate.
[0198] The title compound was prepared from Boc-L-Lys-(Boc)-L-Pro-OH (222 mg, 0.5 mmol) and 2,3-bis(tetradecyloxy)propan-l-amine hydrochloride (260 mg, 0.5 mmol) as described in Example 33 to give a gummy solid (220 mg, 48% yield). 1H NMR (500 MHz, Chloroform- ) δ 6.74-6.64 (t, J = 5.6 Hz, 1H), 5.38 - 5.24 (m, 1H), 4.92 (s, 1H), 4.55 - 4.37 (m, 2H), 3.77 - 3.61 (m, 1H), 3.61 - 3.19 (m, 10H), 3.10 (d, J = 8.4 Hz, 2H), 2.34 - 2.17 (m, 1H), 2.12 (m, 1H), 2.00 - 1.87 (m, 2H), 1.80 - 1.64 (m, 1H), 1.55 (tdd, J = 12.7, 9.4, 5.5 Hz, 6H), 1.43 (d, / = 1.5 Hz, 18H), 1.25 (s, 48H), 0.88 (t, J = 6.9 Hz, 6H); ESI-MS m z [M+Na]+ calc'd for C52HiooN408, 932; found, 932.
Example 38: (2S)- l-(L-Lvsyl)-N-(2,3-bis(tetradecyloxy)propyl)pyrrolidine-2-carboxamide dihydrochloride.
Figure imgf000087_0002
[0199] The title compound was prepared from di-tert-butyl ((5S)-6-((2S)-2-((2,3- bis(tetradecyloxy)propyl)carbamoyl)pyrrolidin- l-yl)-6-oxohexane- l,5-diyl)dicarbamate (182 mg, 0.2 mmol) as described for Example 1 to give a white solid (100% yield). 1H NMR (500 MHz, Chloroform-d) δ 8.33 (s, 3H), 7.93 (s, 3H), 4.74 (s, 1H), 4.45 (s, 1H), 4.00 - 3.31 (m, 10H), 3.04 (d, J = 51.0 Hz, 2H), 2.47 (s, 2H), 1.93 (q, 7 = 51.8, 39.5 Hz, 4H), 1.61 - 1.45 (m, 4H), 1.25 (s, 48H), 0.88 (t, J = 6.8 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for C42H84N404, 710; found, 710.
Example 39: tert-Butyl (2-((2S)-2-((2,3-bis(tetradecyloxy)propyl)carbamoyl)pyrrolidin- l-yl)-2- oxoethvPcarbamate.
Figure imgf000088_0001
[0200] The title compound was prepared from Boc-Gly-L-Pro-OH (136 mg, 0.5 mmol) and 2,3 -bis(tetradecyloxy)propan- 1 -amine hydrochloride (260 mg, 0.5 mmol) as described in Example 33 to give a white solid (185 mg, 50% yield). 1H NMR (500 MHz, Chloroform- ) δ 6.87 (dt, = 16.5, 5.3 Hz, 1H), 5.40 (s, 1H), 4.51 (d, = 8.1 Hz, 1H), 4.08 - 3.80 (m, 2H), 3.79 - 3.12 (m, 11H), 2.34 (ddt, = 12.5, 5.8, 2.9 Hz, 1H), 2.18 - 2.06 (m, 1H), 2.00 (ddt, = 12.6, 6.8, 3.6 Hz, 1H), 1.90 (dddd, = 17.7, 12.9, 8.0, 2.3 Hz, 1H), 1.65 (s, 1H), 1.55 (td, = 7.2, 3.8 Hz, 4H), 1.45 (s, 9H), 1.25 (s, 44H), 0.88 (t, = 6.9 Hz, 6H); ESI-MS m/z [M+Na]+ calc'd for C43H83N306, 761; found, 761.
Example 40: (2S)-N-(2,3-Bis(tetradecyloxy)propyl)- l-glycylpyrrolidine-2-carboxamide hydrochloride.
Figure imgf000088_0002
[0201] The title compound was prepared from tert-butyl (2-((2S)-2-((2,3- bis(tetradecyloxy)propyl)carbamoyl)pyrrolidin-l-yl)-2-oxoethyl)carbamate (148 mg, 0.2 mmol) as described for Example 1 to give a white solid (100% yield). 1H NMR (500 MHz,
Chloroform- ) δ 8.01 (d, = 193.1 Hz, 3H), 4.57 (s, 1H), 4.01 (s, 1H), 3.83 - 3.04 (m, 11H), 2.52 (s, 1H), 2.35 - 1.76 (m, 3H), 1.53 (s, 4H), 1.25 (s, 44H), 0.88 (t, J
m/z [M+H]+ calc'd for C38H75N3O4, 639; found, 639.
Example 41: 3-(2-(5-(Benzyloxy)-lH-indol-3-yl)acetamido)-N-(2,3- bis(tetradecyloxy)propyl)propanamide.
Figure imgf000089_0001
[0202] The title compound was prepared from 2-(5-(benzyloxy)-lH-indol-3-yl)acetic acid (80 mg, 0.283 mmol) and 3-amino-N-(2,3-bis(tetradecyloxy)propyl)propanamide hydrochloride (167 mg, 0.283 mmol) as described in Example 33 to give a brown solid (192 mg, 83% yield). 1H NMR (499 MHz, Chloroform- ) δ 8.26 (d, = 2.3 Hz, 1H), 7.47 (d, = 7.1 Hz, 2H), 7.38 (t, = 7.6 Hz, 2H), 7.33 - 7.27 (m, 1H), 7.12 (d, = 2.3 Hz, 1H), 7.05 (d, = 2.4 Hz, 1H), 6.94 (dd, / = 8.8, 2.4 Hz, 1H), 6.53 (s, 1H), 6.24 (s, 1H), 6.11 (s, 1H), 5.09 (s, 2H), 3.77 - 3.61 (m, 2H), 3.48 - 3.31 (m, 9H), 3.16 (qd, = 7.4, 4.4 Hz, 3H), 2.33 (dd, / = 7.0, 5.1 Hz, 2H), 1.53 (q, = 7.3 Hz, 4H), 1.25 (s, 44H), 0.88 (t, = 6.9 Hz, 6H); ESI-MS m/z [M+Na]+ calc'd for CsiHssNsOs, 841; found, 841.
Example 42: (9H-Fluoren-9-yl)methyl ((2S)-l-((2,3-bis(tetradecyloxy)propyl)amino)-l-oxo-5-
(3-tosylguanidino entan-2-yl)carbamate.
Figure imgf000089_0002
[0203] The title compound was prepared from Na-Fmoc-L-Arg-Nw-Tos-OH (275 mg, 0.5 mmol) and 2,3-bis(tetradecyloxy)propan-l-amine hydrochloride (260 mg, 0.5 mmol) as described in Example 33 to give a gummy solid (182 mg, 36% yield). 1H NMR (500 MHz, Chloroform-d) δ 7.75 (dd, 7 = 7.8, 4.5 Hz, 4H), 7.57 (dd, 7 = 7.5, 3.4 Hz, 2H), 7.38 (t, 7 = 7.5 Hz, 2H), 7.26 (m, 2H), 7.20 (d, 7 = 8.1 Hz, 2H), 6.76 (s, 1H), 6.44 (s, 2H), 5.82 (s, 1H), 4.47 - 4.26 (m, 2H), 4.16 (dd, 7 = 15.3, 8.3 Hz, 1H), 3.73 - 3.15 (m, 7H), 3.00 (d, 7 = 9.6 Hz, 3H), 2.35 (s, 3H), 2.04 (m, 2H), 1.68 - 1.41 (m, 4H), 1.36 - 1.10 (m, 46H), 0.88 (td, 7 = 7.0, 1.6 Hz, 6H); ESI-MS m/z [M+Na]+ calc'd for C59H93N5O7S, 1039; found, 1039.
Example 43: (9H-Fluoren-9-yl)methyl ((2S)-l-((2,3-bis(tetradecyloxy)propyl)amino)-l-oxo-5- (l,3-bis-(tert-butyloxy)guanidino)pentan-2-yl)carbamate.
Figure imgf000090_0001
[0204] Prepared from Na-Fmoc-L-Arg-(Boc)2-OH (298 mg, 0.5 mmol) and 2,3- bis(tetradecyloxy)propan- 1 -amine hydrochloride (260 mg, 0.5 mmol) as described in Example 33 to give a gummy solid (105 mg, 20% yield). 1H NMR (500 MHz, Chloroform- ) δ 10.72 (s, 1H), 7.76 (dd, 7 = 7.6, 4.5 Hz, 2H), 7.70 - 7.54 (m, 2H), 7.46 - 7.36 (m, 2H), 7.31 (dd, 7 = 8.3, 6.6 Hz, 2H), 6.59 (s, 1H), 6.08 - 5.85 (m, 1H), 5.63 (s, 1H), 4.62 - 4.18 (m, 5H), 3.89 - 3.18 (m, 8H), 3.00 (s, 2H), 2.54 (s, 1H), 2.04 - 1.84 (m, 1H), 1.78 - 1.56 (m, 4H), 1.51 (d, 7 = 8.9 Hz, 18H), 1.35 - 1.07 (m, 44H), 0.88 (td, 7 = 7.0, 1.4 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for C62Hio3N509, 1063; found, 1063.
Example 44: (9H-Fluoren-9-yl)methyl ((2S)-l-((2.3-bis(tetradecyloxy)propyl)amino)-5- guanidino- l-oxopentan-2-yl)carbamate dihvdrochloride.
Figure imgf000091_0001
[0205] The title compound was prepared from Example 43 (53 mg, 0.05 mmol) as described in Example 1 to give a gummy solid (100% yield). 1H NMR (500 MHz, Chloroform-d) δ 7.83 - 7.67 (m, 2H), 7.61 (s, 2H), 7.44 - 7.32 (m, 2H), 7.29 (d, 7 = 7.3 Hz, 2H), 4.33 (d, 7 = 19.7 Hz, 3H), 4.21 (dt, 7 = 17.1, 8.5 Hz, 1H), 3.90 - 3.15 (m, 11H), 2.13 - 1.64 (m, 2H), 1.57 - 1.39 (m, 6H), 1.25 (s, 44H), 0.87 (t, 7 = 6.8 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for C52H87N5O5, 963; found, 963.
Example 45: tert-Butyl ((2S)-l-((2,3-bis(tetradecyloxy)propyl)amino)-l-oxo-5-(3- tosylguanidino entan-2-yl)carbamate.
Figure imgf000091_0002
[0206] The title compound was prepared from Na-Boc-L-Arg-(Nw-Tos)-OH (214 mg, 0.5 mmol) and 2,3-bis(tetradecyloxy)propan-l-amine hydrochloride (260 mg, 0.5 mmol) as described for Example 33 to give a gummy liquid (310 mg, 69% yield). 1H NMR (499 MHz, Chloroform- ) δ 7.75 (d, 7 = 8.0 Hz, 2H), 7.22 (d, 7 = 8.0 Hz, 2H), 6.76 (s, 1H), 6.40 (s, 2H), 5.32 (d, 7 = 30.0 Hz, 1H), 4.11 (q, 7 = 8.1, 7.6 Hz, 1H), 3.72 - 3.14 (m, 9H), 3.00 (d, 7 = 8.1 Hz, 2H), 2.38 (s, 3H), 1.98 (s, 2H), 1.54 (qd, 7 = 13.5, 7.6, 6.7 Hz, 6H), 1.41 (s, 9H), 1.24 (s, 44H), 0.87 (t, 7 = 6.8 Hz, 6H); ESI-MS m/z [M+Na]+ calc'd for C49H91N5O7S, 917; found, 917. Example 46: (2S)-2-Amino-N-(2,3-bis(tetradecyloxy)propyl)-5-(3-tosylguanidino)pentanamide hydrochloride.
Figure imgf000092_0001
[0207] The title compound was prepared from Example 45 (179 mg, 0.2 mmol) as described for Example 1 to give a light pink solid (100% yield). 1H NMR (500 MHz, Chloroform- ) δ 8.69 (s, 1H), 8.26 (d, J = 52.4 Hz, 3H), 8.03 (s, 1H), 7.88 (d, J = 7.8 Hz, 2H), 7.64 (s, 1H), 7.35 (d, J = 7.9 Hz, 2H), 4.29 (s, 1H), 3.86 - 3.19 (m, 11H), 2.42 (s, 3H), 2.06 (s, 2H), 1.88 (s, 2H), 1.51 (d, J = 8.6 Hz, 4H), 1.24 (dd, J = 7.9, 4.8 Hz, 44H), 0.88 (t, J = 6.9 Hz, 6H); ESI-MS m z [M+H]+ calc'd for C44H83N505S, 795; found, 795.
Example 47: tert-Butyl ((2S)-4-amino-l-((2,3-bis(tetradecyloxy)propyl)amino)-l,4-dioxobutan-
2-yl)carbamate.
Figure imgf000092_0002
[0208] The title compound was prepared from 2,3 -bis(tetradecyloxy)propan-l -amine hydrochloride (260 mg, 0.5 mmol) and Boc-L-Asp-OSu (165 mg, 0.5 mmol) as described for Example 1 to give a white solid (200 mg, 57% yield). 1H NMR (500 MHz, Chloroform-d) δ 3.61 (dt, J = 9.3, 6.6 Hz, 1H), 3.54 - 3.26 (m, 9H), 2.98 - 2.64 (m, 2H), 1.73 - 1.49 (m, 7H), 1.44 (s, 9H), 1.25 (s, 44H), 0.88 (t, J = 6.9 Hz, 6H). Example 48: Di-tert-butyl ((5S)-6-((2,3-bis(tetradecyloxy)propyl)amino)-6-oxohexane-l,5- diyPdicarbamate.
Figure imgf000093_0001
[0209] The title compound was prepared from 2,3 -bis(tetradecyloxy)propan-l -amine hydrochloride (260 mg, 0.5 mmol) and Boc-L-Lys(Boc)-OSu (222 mg, 0.5 mmol) as described for Example 1 to give a white solid (180 mg, 44% yield). 1H NMR (500 MHz, Chloroform-d) δ 6.38 (s, 1H), 5.08 (s, 1H), 4.58 (s, 1H), 4.03 (s, 1H), 3.68 - 3.19 (m, 9H), 3.10 (d, J = 7.4 Hz, 2H), 1.83 (dq, = 13.6, 7.3 Hz, 1H), 1.65 - 1.46 (m, 7H), 1.44 (s, 18H), 1.37 (q, = 7.7 Hz, 2H), 1.26 (s, 46H), 0.88 (t, = 6.9 Hz, 6H); ESI-MS m/z [M+Na]+ calc'd for C47H93N3O7, 835; found, 835.
Example 49: (2S)-2 6-Diamino-N-(2,3-bis(tetradecyloxy)propyl)hexanamide dihydrochloride.
Figure imgf000093_0002
[0210] The title compound was prepared from Example 48 (162 mg, 0.2 mmol) as described for Example 1 to give a white solid (100% yield). 1H NMR (500 MHz, Chloroform- ) δ 8.26 (s, 3H), 8.01 (s, 3H), 4.41 (s, 1H), 3.83 - 3.24 (m, 10H), 3.15 (s, 2H), 2.55 (s, 2H), 2.05 (s, 1H), 1.98 - 1.64 (m, 3H), 1.54 (s, 4H), 1.26 (s, 44H), 0.88 (t, = 6.8 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for C37H77N3O3, 613; found, 613.
Example 50: tert-Butyl ((5S)-5-acetamido-6-((2,3-bis(tetradecyloxy)propyl)amino)-6- oxohexyDcarbamate.
Figure imgf000094_0001
[0211] The title compound was prepared from Na-acetyl-Ne-Boc-L- Lysine (144 mg, 0.5 mmol) and 2,3-bis(tetradecyloxy)propan-l-amine hydrochloride (260 mg, 0.5 mmol) as described for Example 33 to give the title compound as an off-white solid (152 mg, 40% yield). 1H NMR (500 MHz, Chloroform- ) δ 6.34 (d, J = 16.1 Hz, 1H), 6.26 (s, 1H), 4.60 (s, 1H), 4.35 (dt, / = 8.2, 6.2 Hz, 1H), 3.65 - 3.19 (m, 9H), 3.09 (d, = 7.4 Hz, 2H), 2.01 (s, 3H), 1.90 - 1.71 (m, 1H), 1.63 (dt, / = 15.1, 7.5 Hz, 1H), 1.51 (m, 6H), 1.44 (s, 9H), 1.25 (s, 46H), 0.88 (t, = 6.9 Hz, 6H); ESI-MS m/z [M+Na]+ calc'd for C^H^NsOe, 777; found, 777.
Example 51 : (2S)-2-Acetamido-6-amino-N-(2,3-bis(tetradecyloxy)propyl)hexanamide hydrochloride.
Figure imgf000094_0002
[0212] The title compound was prepared from Example 50 (151 mg, 0.2 mmol) as described for Example 1 to give an off-white solid (100% yield). 1H NMR (500 MHz, Chloroform-d) δ 8.26 (s, 3H), 7.96 (s, 1H), 4.57 (s, 1H), 3.70 - 3.24 (m, 10H), 3.09 (d, = 11.8 Hz, 2H), 2.23 (d, 7 = 41.2 Hz, 3H), 1.97 - 1.71 (m, 5H), 1.54 (t, J = 7.1 Hz, 5H), 1.25 (s, 44H), 0.88 (t, J = 6.8 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for C39H79N3O4, 655; found, 655.
Example 52: tert-Butyl 4-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-((2.3- bis(tetradecyloxy)propyl)amino)-3-oxopropyl)piperidine- l-carboxylate.
Figure imgf000095_0001
[0213] The title compound was prepared from Na-Fmoc-P-(l-Boc-piperidin-4-yl)-DL- alanine (247 mg, 0.5 mmol) and 2,3-bis(tetradecyloxy)propan-l-amine hydrochloride (260 mg, 0.5 mmol) as described for Example 33 to give the title compound as a gummy solid (130 mg, 27% yield). 1H NMR (500 MHz, Chloroform- ) δ 7.77 (d, = 7.5 Hz, 2H), 7.57 (d, = 7.2 Hz, 2H), 7.40 (td, 7 = 7.5, 2.0 Hz, 2H), 7.31 (t, = 7.5 Hz, 2H), 6.31 (d, = 17.7 Hz, 1H), 5.24 (d, = 8.4 Hz, 1H), 4.56 - 4.30 (m, 2H), 4.26 - 3.95 (m, 4H), 3.71 - 3.15 (m, 9H), 2.66 (d, J = 12.3 Hz, 2H), 1.74 (s, 1H), 1.66 - 1.50 (m, 7H), 1.45 (s, 9H), 1.25 (d, = 4.6 Hz, 45H), 1.12 (dd, = 33.9, 12.7 Hz, 2H), 0.88 (t, = 6.8 Hz, 6H); ESI-MS m/z [M+Na]+ calc'd for C59H97N3O7, 983; found, 983.
Example 53: (9H-Fluoren-9-yl)methyl (l-((2,3-bis(tetradecyloxy)propyl)amino)-l-oxo-3-
(piperidin- -yl)propan-2-yl)carbamate hydrochloride.
Figure imgf000095_0002
[0214] The title compound was prepared from Example 52 (96 mg, 0.1 mmol) as described for Example 1 to give a brown solid (100% yield). 1H NMR (499 MHz, Chloroform- ) δ 9.43 (s, 1H), 9.13 (s, 1H), 7.75 (d, = 7.5 Hz, 2H), 7.58 (d, = 7.2 Hz, 2H), 7.40 (t, = 7.5 Hz, 2H), 7.34 - 7.28 (m, 2H), 6.80 (s, 1H), 5.64 (s, 1H), 4.55 - 4.29 (m, 2H), 4.20 (q, = 10.1, 6.8 Hz, 2H), 3.58 - 3.13 (m, 13H), 2.83 (s, 2H), 2.14 - 1.59 (m, 2H), 1.57 - 1.42 (m, 5H), 1.35 - 1.13 (m, 46H), 0.87 (t, J = 6.9 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for C54H89N305, 861; found, 861.
Example 54: tert-Butyl 4-(((benzyloxy)carbonyl)amino)-4-((2,3- bis(tetradecylox ropyl)carbamoyl)piperidine-l-carboxylate.
Figure imgf000096_0001
[0215] The title compound was prepared from Cbz-Pip(Boc)-OH (189 mg, 0.5 mmol) and 2,3 -bis(tetradecyloxy)propan- 1 -amine hydrochloride (260 mg, 0.5 mmol) as described for Example 33 to give the title compound as a gummy solid (160 mg, 38% yield). 1H NMR (500 MHz, Chloroform-d) δ 7.34 (q, = 7.3, 6.8 Hz, 5H), 6.88 (s, 1H), 5.08 (s, 2H), 4.88 (s, 1H), 3.83 (d, = 13.5 Hz, 2H), 3.61 - 3.20 (m, 9H), 3.06 (ddd, = 14.0, 10.6, 3.1 Hz, 2H), 2.17 - 1.83 (m, 4H), 1.64 - 1.45 (m, 4H), 1.45 (s, 9H), 1.35 - 1.13 (m, 44H), 0.88 (t, = 6.9 Hz, 6H); ESI-MS m/z [M+Na]+ calc'd for C5oH89N307, 867; found, 867.
Example 55: Benzyl (4-((2,3-bis(tetradecyloxy)propyl)carbamoyl)piperidin-4-yl)carbamate hydrochloride.
Figure imgf000096_0002
[0216] The title compound was prepared from Example 54 (85 mg, 0.1 mmol) as described for Example 1 to give a tan solid (100% yield). 1H NMR (499 MHz, Chloroform-d) δ 9.40 (s, 1H), 9.23 (d, = 59.5 Hz, 1H), 7.41 - 7.28 (m, 5H), 6.99 (d, = 17.6 Hz, 1H), 6.00 (s, 1H), 5.07 (d, = 2.1 Hz, 2H), 3.58 - 3.11 (m, 11H), 2.47 (d, = 13.5 Hz, 2H), 2.33 - 1.90 (m, 4H), 1.52 (m, 4H), 1.25 (d, = 4.7 Hz, 44H), 0.88 (t, = 6.8 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for C45H8iN305, 745; found, 745. Example 56: tert-Butyl ((5S)-5-((ri J'-biphenyll-4-ylmethyl)amino)-6-((2,3- bis(tetradec loxy)propyl)amino)-6-oxohexyl)carbamate.
Figure imgf000097_0001
[0217] Step 1: Methyl N2-(riJ'-biphenyll-4-ylmethyl)-N6-(tert-butoxycarbonyl)-L- lysinate. A mixture of [l,l'-biphenyl]-4-carbaldehyde (546 mg, 3.0 mmol) and methyl N6-(tert- butoxycarbonyl)-L-lysinate hydrochloride (890 mg, 3.0 mmol) in THF (50 mL) was treated with NaBH(OAc)3 (763 mg, 3.6 mmol) and the reaction mixture was stirred at rt overnight. The reaction mixture was treated with satd. aq. K2C03 (25 mL) and stirred for another 30 min. The resulting layers were separated and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, evaporated, and purified using silica gel column chromatography (hexane-EtOAc (0-100%)) to give the title compound as a colorless liquid (520 mg). 1H NMR (500 MHz, Chloroform- ) δ 7.70 - 7.48 (m, 4H), 7.48 - 7.30 (m, 5H), 4.51 (s, 1H), 3.85 (d, J = 13.0 Hz, 1H), 3.73 (s, 3H), 3.67 (d, J = 13.0 Hz, 1H), 3.29 (t, = 6.6 Hz, 1H), 3.10 (t, 7 = 6.5 Hz, 2H), 1.67 (m, 2H), 1.54 - 1.35 (m, 13H). ESI-MS m z [M+H]+ calc'd for C25H34N204, 427; found, 427.
[0218] Step 2: N2-(ri,r-Biphenyll-4-ylmethyl)-N6-(tert-butoxycarbonyl)-L-lysine. To a solution of methyl N2-([l,l'-biphenyl]-4-ylmethyl)-N6-(tert-butoxycarbonyl)-L-lysinate (427 mg, 1.0 mmol) in 1: 1 THF-MeOH (6 mL) was added a solution of LiOH (96 mg, 4.0 mmol) in water (3.0 mL). After stirring at rt for 4 h, the mixture was neutralized by the addition of satd. aq. KHS04 (10 mL). A precipitate formed, which was collected by vacuum filtration, dried, and used in next step without further purification. 1H NMR (500 MHz, DMSO- e) δ 7.62 (dd, = 25.5, 7.8 Hz, 4H), 7.52 - 7.28 (m, 5H), 6.73 (s, 1H), 3.80 (d, J = 13.6 Hz, 1H), 3.62 (d, J = 14.0 Hz, 1H), 2.87 (d, J = 6.6 Hz, 2H), 2.79 (s, 1H), 1.47 (m, 2H), 1.36 (s, 13H); ESI-MS m/z
[M+H]+ calc'd for C24H32N2O4, 413; found, 413.
[0219] Step 3. The title compound was prepared from N2-([l,l'-biphenyl]-4-ylmethyl)-N6- (tert-butoxycarbonyl)-L-lysine (206 mg, 0.5 mmol) and 2,3-bis(tetradecyloxy)propan-l -amine hydrochloride (260 mg, 0.5 mmol) as described for Example 33 to give the title compound as a gummy solid (285 mg, 65% yield). 1H NMR (500 MHz, Chloroform- ) δ 7.66 - 7.52 (m, 4H), 7.51 - 7.30 (m, 6H), 4.67 (s, 1H), 3.98 (s, 2H), 3.74 - 3.21 (m, 8H), 3.06 (ddt, J = 20.2, 13.2, 6.3 Hz, 2H), 1.83 (d, 7 = 52.7 Hz, 2H), 1.63 - 1.40 (m, 6H), 1.35 (s, 9H), 1.30 - 1.13 (m, 46H), 0.88 (t, J = 6.9 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for C55H95N3O5, 879; found, 879.
Example 57: (2S)-2-((ri,l,-Biphenyll-4-ylmethyl)amino)-6-amino-N-(2,3- bis(tetradec loxy)propyl)hexanamide dihydrochloride.
Figure imgf000098_0001
[0220] The title compound was prepared from Example 56 (176 mg, 0.2 mmol) as described for Example 1 to give a tan solid (100% yield). 1H NMR (500 MHz, Chloroform- ) δ 9.81 (s, 1H), 8.36 (s, 1H), 7.95 (s, 3H), 7.67 - 7.26 (m, 9H), 4.33 (s, 2H), 4.09 (m, 1H), 3.74 - 3.16 (m, 9H), 3.13 - 2.89 (m, 2H), 2.08 (s, 2H), 1.81 (s, 2H), 1.63 - 1.39 (m, 6H), 1.38 - 1.01 (m, 44H), 0.87 (t, J = 6.8 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for C50H87N3O3, 779; found, 779.
Example 58: tert-Butyl ((5S)-6-((2.3-bis(tetradecyloxy)propyl)amino)-5-((4- fluorobenzyl)amino)-6-oxohexyl)carbamate.
Figure imgf000099_0001
[0221] The title compound was prepared from N6-(tert-butoxycarbonyl)-N2-(4- fluorobenzyl)-L-lysine (176 mg, 0.5 mmol) (synthesized as described in Example 56) and 2,3- bis(tetradecyloxy)propan- 1 -amine hydrochloride (260 mg, 0.5 mmol) as described in Example 33 to give the title compound as a gummy solid (225 mg, 55% yield). 1H NMR (500 MHz, Chloroform- ) δ 7.40 (dd, = 8.2, 5.2 Hz, 2H), 7.21 (s, 1H), 7.05 (t, = 8.6 Hz, 2H), 4.69 (s, 1H), 4.03 - 3.81 (m, 2H), 3.75 - 3.20 (m, 10H), 3.06 (m, 2H), 1.84 (m, 2H), 1.62 - 1.48 (m, 4H), 1.48 - 1.41 (m, 2H), 1.37 (s, 9H), 1.25 (d, = 5.1 Hz, 46H), 0.88 (t, = 6.8 Hz, 6H); ESI- MS m/z [M+H]+ calc'd for C49H90FN3O5, 821; found, 821.
Example 59: (2S)-6-Amino-N-(2,3-bis(tetradecyloxy)propyl)-2-((4- fluorobenzyl)amino hexanamide dihydrochloride.
Figure imgf000099_0002
[0222] The title compound was prepared from Example 58 (164 mg, 0.2 mmol) as described for Example 1 to give a tan solid (100% yield). 1H NMR (499 MHz, Chloroform- ) δ 9.82 (s, 1H), 8.79 (s, 1H), 8.07 (s, 3H), 7.56 (s, 2H), 7.04 (t, = 8.4 Hz, 2H), 4.24 - 3.74 (m, 5H), 3.71 - 3.14 (m, 9H), 2.97 (s, 2H), 2.22 - 1.92 (m, 2H), 1.78 (s, 2H), 1.62 - 1.41 (m, 6H), 1.40 - 1.08 (m, 44H), 0.88 (t, = 6.9 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for
Figure imgf000099_0003
721; found, 721. Example 60: tert-Butyl ((5S)-5-(benzylamino)-6-((2,3-bis(tetradecyloxy)propyl)amino)-6- oxohexyPcarbamate.
Figure imgf000100_0001
[0223] The title compound was prepared from N2-benzyl-N6-(tert-butoxycarbonyl)-L-lysine (168 mg, 0.5 mmol) (synthesized by following the same procedure as in Example 56) and 2,3- bis(tetradecyloxy)propan- 1 -amine hydrochloride (260 mg, 0.5 mmol) as described in Example 33 to give the title compound as a gummy solid (168 mg, 42% yield). 1H NMR (500 MHz, Chloroform- ) δ 7.51 - 7.27 (m, 6H), 4.67 (s, 1H), 3.93 (s, 2H), 3.77 - 3.20 (m, 9H), 3.05 (qd, = 14.0, 6.6 Hz, 2H), 1.81 (m, 2H), 1.54 (dt, = 14.4, 7.4 Hz, 4H), 1.48 - 1.41 (m, 2H), 1.37 (s, 9H), 1.25 (br s, 46H), 0.88 (t, = 6.9 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for C49H91N3O5, 803; found, 803.
Example 61 : (2S)-6-Amino-2-(benzylamino)-N-(2,3-bis(tetradecyloxy)propyl)hexanamide dihydrochloride.
Figure imgf000100_0002
[0224] The title compound was prepared from Example 60 (160 mg, 0.2 mmol) as described for Example 1 to give a tan solid (100% yield). 1H NMR (500 MHz, Chloroform- ) δ 9.80 (s, 1H), 8.69 (s, 1H), 8.35 (s, 1H), 7.95 (s, 3H), 7.53 (d, = 5.7 Hz, 2H), 7.32 (d, = 6.8 Hz, 3H), 4.05 (s, 3H), 3.67 - 3.03 (m, 9H), 3.03 - 2.86 (m, 2H), 2.02 (d, = 36.0 Hz, 2H), 1.77 (s, 2H), 1.52 (p, = 7.0 Hz, 6H), 1.35 - 1.08 (m, 44H), 0.88 (t, = 6.8 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for C44H83N3O3, 703; found, 703. Example 62: tert-Butyl ((5R)-5-(benzylamino)-6-((2,3-bis(tetradecyloxy)propyl)amino)-6- oxohex carbamate.
[0225] The title compound was prepared from N2-benzyl-N6-(tert-butoxycarbonyl)-D-lysine (168 mg, 0.5 mmol) (synthesized as in Example 56) and 2,3-bis(tetradecyloxy)propan-l -amine hydrochloride (260 mg, 0.5 mmol) as described in Example 33 to give the title compound as a gummy solid (185 mg, 46% yield). 1H NMR (500 MHz, Chloroform- ) δ 7.58 - 7.30 (m, 5H), 7.21 (s, 1H), 4.71 (s, 1H), 4.09 - 3.86 (m, 2H), 3.79 - 3.23 (m, 10H), 3.16 - 2.97 (m, 2H), 2.04 - 1.67 (m, 2H), 1.54 (ddd, J = 14.0, 9.2, 5.2 Hz, 4H), 1.44 (t, J = 6.5 Hz, 2H), 1.35 (s, 9H), 1.25 (d, J = 5.3 Hz, 46H), 0.88 (t, J = 6.9 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for Q9H91N3O5, 803; found, 803.
Example 63 : ((2R)-6-Amino-2-(benzylamino)-N-(2,3-bis(tetradecyloxy)propyl)hexanamide
Figure imgf000101_0002
[0226] The title compound was prepared from Example 62 (160 mg, 0.2 mmol) as described for Example 1 to give an off-white solid \ (100% yield). 1H NMR (500 MHz, Chloroform- ) δ 9.75 (s, 1H), 8.61 (s, 1H), 7.96 (m, 3H), 7.50 (d, J = 34.3 Hz, 2H), 7.34 (s, 3H), 3.91 - 3.20 (m, 3H), 3.19 - 2.88 (m, 11H), 2.37 - 1.69 (m, 4H), 1.54 (s, 6H), 1.41 - 1.05 (m, 44H), 0.88 (t, J = 6.8 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for C44H83N303, 703; found, 703. Example 64: tert-Butyl ((c*s)-4-((2,3-bis(tetradecyloxy)propyl)
carbamoyl)cyclohexyl)carbamate.
Figure imgf000102_0001
[0227] The title compound was prepared from (czs)-4-((tert- butoxycarbonyl)amino)cyclohexane-l-carboxylic acid (122 mg, 0.5 mmol) and 2,3- bis(tetradecyloxy)propan- 1 -amine hydrochloride (260 mg, 0.5 mmol) as described in Example 33 to give a white solid (220 mg, 62% yield). 1H NMR (500 MHz, Chloroform- ) δ 6.00 (t, = 5.6 Hz, 1H), 4.70 (s, 1H), 3.71 (d, = 20.6 Hz, 1H), 3.63 - 3.36 (m, 8H), 3.29 (dt, / = 13.6, 5.2 Hz, 1H), 2.16 (dt, / = 9.0, 4.5 Hz, 1H), 1.80 - 1.49 (m, 12H), 1.44 (s, 9H), 1.25 (s, 44H), 0.88 (t, = 6.9 Hz, 6H); ESI-MS m/z [M+Na]+ calc'd for C43H84N205, 732; found, 732.
Example 65: (c¾' )-4-Amino-N-(2,3-bis(tetradecyloxy)propyl)cyclohexane- 1-carboxamide hydrochloride.
Figure imgf000102_0002
[0228] The title compound was prepared from tert-butyl ((czs)-4-((2,3- bis(tetradecyloxy)propyl) carbamoyl)cyclohexyl)carbamate (142 mg, 0.2 mmol) as described for Example 1 to give a white solid (100% yield). 1H NMR (499 MHz, Chloroform- ) δ 8.43 (s, 3H), 6.60 (s, 1H), 3.69 - 3.35 (m, 9H), 3.29 (s, 1H), 2.39 - 1.87 (m, 5H), 1.78 (d, = 21.5 Hz, 4H), 1.54 (q, = 6.9 Hz, 4H), 1.25 (s, 44H), 0.88 (t, = 6.9 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for C38H76N203, 610; found, 610.
Example 66: tert-Butyl ((trans)-4-((2,3- bis(tetradecyloxy)propyl)carbamoyl)cyclohexyl)carbamate.
Figure imgf000103_0001
[0229] The title compound was prepared from (irans)-4-((tert- butoxycarbonyl)amino)cyclohexane-l-carboxylic acid (122 mg, 0.5 mmol) and 2,3- bis(tetradecyloxy)propan- 1 -amine hydrochloride (260 mg, 0.5 mmol) as described in Example 33 to give a white solid (190 mg, 54% yield). 1H NMR (500 MHz, Chloroform- ) δ 5.95 (t, = 5.4 Hz, 1H), 4.35 (s, 1H), 3.65 - 3.33 (m, 9H), 3.28 (dt, J = 13.4, 5.2 Hz, 1H), 2.14 - 1.84 (m, 5H), 1.62 - 1.48 (m, 6H), 1.44 (s, 9H), 1.26 (s, 44H), 1.10 (qd, J = 12.8, 3.5 Hz, 2H), 0.88 (t, J = 6.9 Hz, 6H); ESI-MS m/z [M+Na]+ calc'd for C43H84N205, 732; found, 732.
Example 67: (?ran )-4-Amino-N-(2,3-bis(tetradecyloxy)propyl)cvclohexane-l-carboxamide hydrochloride.
Figure imgf000103_0002
[0230] The title compound was prepared from Example 66 (142 mg, 0.2 mmol) as described for Example 1 to give a white solid (100% yield). 1H NMR (500 MHz, Chloroform- ) δ 8.38 (s, 3H), 5.97 (s, 1H), 3.64 - 3.02 (m, 11H), 2.18 (d, = 85.5 Hz, 5H), 1.55 (s, 7H), 1.26 (s, 45H), 0.88 (t, = 6.8 Hz, 6H); ESI-MS m/z [M+H]+ calc'd for C38H76N203, 610; found, 610.
Example 68: Benzyl tert-butyl (6-(octadec-9-en-l-ylamino)-6-oxohexane-l,5-diyl)(R,Z)- dicarbamate.
Figure imgf000103_0003
[0231] The title compound was prepared from oleylamine (70%) (191 mg, 0.5 mmol) and Na-Z-Ne-Boc-D-Lys-OSu (237 mg, 0.5 mmol) as described for Example 1 to give a white solid (225 mg, 71% yield). 1H NMR (500 MHz, Chloroform- ) δ 7.45 - 7.29 (m, 5H), 6.05 (s, 1H), 5.43 (s, 1H), 5.40 - 5.28 (m, 2H), 5.10 (d, = 2.4 Hz, 2H), 4.57 (s, 1H), 4.07 (q, = 7.3 Hz, 1H), 3.22 (q, = 6.8 Hz, 2H), 3.09 (d, = 6.8 Hz, 2H), 2.10 - 1.89 (m, 4H), 1.85 (dtd, = 13.5, 7.9, 5.3 Hz, 1H), 1.64 (q, = 7.8 Hz, 2H), 1.57 - 1.47 (m, 4H), 1.42 (s, 9H), 1.34 - 1.10 (m, 26H), 0.88 (t, = 6.8 Hz, 3H); ESI-MS m/z [M+Na]+ calc'd for C37H63N3O5, 653; found, 653.
Example 69: Benzyl (R,Z)-(6-amino-l-(octadec-9-en-l-ylamino)-l-oxohexan-2-yl)carbamate hydrochlorid
Figure imgf000104_0001
[0232] The title compound was prepared from Example 68 (126 mg, 0.2 mmol) as described for Example 1 to give a white solid (100% yield). 1H NMR (500 MHz, Chloroform-d) δ 8.12 (s, 3H), 7.75 (s, 1H), 7.30 (m, 5H), 6.35 (s, 1H), 5.43 - 5.22 (m, 2H), 5.06 (s, 2H), 4.31 (s, 1H), 3.89 - 3.44 (m, 2H), 3.19 (s, 2H), 2.97 (s, 2H), 2.11 - 1.87 (m, 2H), 1.75 (d, = 44.9 Hz, 4H), 1.48 (s, 4H), 1.26 (q, = 9.6, 8.4 Hz, 24H), 0.88 (t, = 6.8 Hz, 3H); ESI-MS m/z [M+H]+ calc'd for C32H55N3O3, 531; found, 531.
Example 70: Benzyl tert-butyl (6-oxo-6-(tetradecylamino)hexane-l,5-diyl)(R)-dicarbamate.
Figure imgf000104_0002
[0233] The title compound was prepared from tetradecylamine (112 mg, 0.5 mmol) and Na- Z-Ne-Boc-D-Lys-OSu (237 mg, 0.5 mmol) as described for Example 1 to give a white solid (248 mg, 86% yield). 1H NMR (500 MHz, Chloroform-d) δ 7.45 - 7.29 (m, 5H), 6.04 (s, 1H), 5.43 (s, 1H), 5.10 (d, = 2.4 Hz, 2H), 4.57 (s, 1H), 4.10 (dd, = 23.2, 7.1 Hz, 1H), 3.22 (q, = 6.8 Hz, 2H), 3.09 (d, J = 6.8 Hz, 2H), 1.85 (dtd, J = 13.5, 7.9, 5.3 Hz, 1H), 1.71 - 1.55 (m, 1H), 1.54 - 1.45 (m, 2H), 1.42 (s, 9H), 1.37 (q, J = 7.6 Hz, 2H), 1.25 (s, 24H), 0.88 (t, J = 6.9 Hz, 3H); ESI-MS m/z [M+Na]+ calc'd for C33H57N3O5, 599; found, 599.
Example 71: Benzyl (R)-(6-amino-l-oxo-l-(tetradecylamino)hexan-2-yl)carbamate
hydrochloride.
Figure imgf000105_0001
[0234] The title compound was prepared from Example 70 (115 mg, 0.2 mmol) as described for Example 1 to give a white solid (100% yield). 1H NMR (500 MHz, Chloroform-d) δ 8.24 (s, 3H), 7.40 - 7.29 (m, 6H), 6.02 (d, J = 8.1 Hz, 1H), 5.05 (s, 2H), 4.28 (s, 1H), 3.19 (d, 7 = 11.6 Hz, 2H), 2.98 (s, 2H), 2.09 - 1.58 (m, 4H), 1.48 (s, 2H), 1.36 - 1.16 (m, 24H), 0.88 (t, J = 6.9 Hz, 3H); ESI-MS m/z [M+H]+ calc'd for C28H49N3O3, 477; found, 477.
Example 72: tert-butyl 3-((((10S)-2.2-dimethyl-4.11-dioxo-14-(tetradecyloxy)-3.16-dioxa-5.12- diazatriacontan-10- l)amino)methyl)-lH-indole-l-carboxylate
Figure imgf000105_0002
[0235] Step 1: tert-butyl (S)-3-(((6-((tert-butoxycarbonyl)amino)-l-methoxy-l-oxohexan-2- yl)amino)methyl)-lH-indole-l-carboxylate: A mixture of tert-butyl 3-formyl-lH-indole-l- carboxylate (736 mg, 3.0 mmol) and methyl N6-(tert-butoxycarbonyl)-L-lysinate hydrochloride (890 mg, 3.0 mmol) in THF (50 mL) was treated with NaBH(OAc)3 (763 mg, 3.6 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was treated with satd. aq. K2C03 (25 mL) and stirred for another 30 min. The resulting layers were separated and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layer washed with brine, dried over sodium sulfate, evaporated and purified using silica gel column chromatography (hexane-EtOAc (0-100%)) to give the title compound as a colorless liquid (1325 mg). ESI-MS m/z [M+H]+ calc'd for C26H39N306, 490; found, 490.
[0236] Step 2: N6-(tert-butoxycarbonyl)-N2-((l-(tert-butoxycarbonyl)-lH-indol-3- vPmethvP-L-lysine. To a solution of methyl N2-([l,l'-biphenyl]-4-ylmethyl)-N6-(tert- butoxycarbonyl)-L-lysinate (1225 mg, 2.5 mmol) in 1: 1 THF-MeOH (15 mL) was added a solution of LiOH (180 mg, 7.5 mmol) in water (8.0 mL). After stirring at room temperature for 4 h, the mixture was neutralized by the addition of saturated aq. KHS04 (20 mL). A precipitate formed, which was separated by vacuum filtration, and extracted the aqueous layer with EtOAc (2 x 50 mL) and evaporated. Then purified on a silica gel column using dichloromethane- methanol (0-10%) as eluent to get the desired product (680 mg). ESI-MS m/z [M+H]+ calc'd for C25H37N306, 476; found, 476.
[0237] Step 3. The title compound was prepared from N6-(tert-butoxycarbonyl)-N2-((l- (tert-butoxycarbonyl)-lH-indol-3-yl)methyl)-L-lysine (238 mg, 0.5 mmol) and 2,3- bis(tetradecyloxy)propan- 1 -amine hydrochloride (260 mg, 0.5 mmol) as described for Example 33 to give the title compound as a gummy solid (235 mg, 50% yield). 1H NMR (500 MHz, Chloroform- ) δ 8.18 (d, J = 8.3 Hz, 1H), 7.82 (s, 1H), 7.67 (t, J = 6.4 Hz, 1H), 7.32 (dt, J = 30.8, 7.6 Hz, 2H), 7.08 (d, J = 35.6 Hz, 1H), 5.92 (s, 1H), 4.72 (s, 1H), 4.25 (m, 2H), 3.79 - 3.20 (m, 12H), 3.17 - 2.90 (m, 2H), 1.92 - 1.80 (m, 1H), 1.53 (m, 6H), 1.47 - 1.36 (m, 2H), 1.33 - 1.04 (m, 66H), 0.87 (d, J = 7.0 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for C56HiooN407, 942; found, 942. Example 73 : (2S)-2-(((lH-indol-3-yl)methyl)amino)-6-amino-N-(2,3-bis(tetradecyloxy)propyl) hexanamide dihydrochloride
Figure imgf000107_0001
[0238] The title compound was prepared from Example 72 (188 mg, 0.2 mmol) as described for Example 1 to give an off-white solid (100% yield). 1H NMR (500 MHz, Chloroform- ) δ 9.40 (s, 1H), 8.46 (br s, 2H) 8.32 - 7.35 (m, 3H), 7.07 (d, J = 20.4 Hz, 1H), 5.99 (s, 1H), 5.05 - 3.95 (m, 2H), 3.95 - 3.14 (m, 6H), 2.86 (m, 2H), 1.77 - 1.33 (m, 6H), 1.40 - 1.02 (m, 48H), 0.88 (td, J = 6.8, 4.3 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for C46H84N403, 742; found, 742.
Example 74: tert-butyl 3-(2-(((10S)-2,2-dimethyl-4,l l-dioxo-14-(tetradecyloxy)-3,16-dioxa-
5 J2-diazatriacontan-10-yl)amino)-2-oxoethyl)-5-methoxy-lH-indole-l-carboxylate
Figure imgf000107_0002
[0239] Step 1. methyl N6-(tert-butoxycarbonyl)-N2-(2-(5-methoxy-lH-indol-3-yl)acetyl)-L- lysinate.
[0240] The title compound was prepared from 2-(5-methoxy-lH-indol-3-yl)acetic acid (616 mg, 3.0 mmol) and methyl N6-(tert-butoxycarbonyl)-L-lysinate hydrochloride (890 mg, 3.0 mmol) as described for Example 33 to give the title compound as a gummy solid (680 mg, 51% yield). ESI-MS m/z [M+H]+ calc'd for C23H33N306, 448; found, 448. [0241] Step 2. tert-butyl (S)-3-(2-((6-((tert-butoxycarbonyl)amino)-l-methoxy-l-oxohexan- 2-yl)amino)-2-oxoethyl)-5-methoxy- lH-indole- 1 -carboxylate: Methyl N6-(tert- butoxycarbonyl)-N -(2-(5-methoxy-lH-indol-3-yl)acetyl)-L-lysinate (1119 mg, 2.5 mmol) dissolved in dichloromethane (20 mL) and added di-tert-butyl dicarbonate (818 mg, 3.75 mmol), Ν,Ν-dimethylaminopyridine (DMAP) (55 mg, 0.25 mmol) to the mixture and continued the reaction at room temperature for two hours. After confirming the product formation by TLC, evaporated volatiles from the reaction mixture and purified on silica gel column chromatography using hexane through hexane-EtOAc (0-100%) as eluent. Pure product fractions combined and evaporated to give the desired product as a gummy liquid (1342 mg, 98% yield). ESI-MS m/z [M+H]+ calc'd for C28H4iN308, 548; found, 548.
[0242] Step 3. N6-(tert-butoxycarbonyl)-N2-(2-(l-(tert-butoxycarbonyl)-5-methoxy-lH- indol-3-yl)acetyl)-L-lysine: The title compound was prepared from above obtained tert-butyl (S)-3-(2-((6-((tert-butoxycarbonyl)amino)-l-methoxy-l-oxohexan-2-yl)amino)-2-oxoethyl)-5- methoxy-lH-indole-1 -carboxylate (1370 mg, 2.5 mmol) and LiOH (180 mg, 7.5 mmol) by following the procedure described in step 2 of Example 72 to give the title compound as a gummy solid (850 mg, 64% yield). ESI-MS m/z [M+H]+ calc'd for C27H39N308, 534; found, 534.
[0243] Step 4. The title compound was prepared from N6-(tert-butoxycarbonyl)-N2-(2-(l- (tert-butoxycarbonyl)-5-methoxy-lH-indol-3-yl)acetyl)-L-lysine (267 mg, 0.5 mmol) and 2,3- bis(tetradecyloxy)propan- 1 -amine hydrochloride (260 mg, 0.5 mmol) as described for Example 33 to give the title compound as a white solid (232 mg, 46% yield). 1H NMR (500 MHz, Chloroform- ) δ 8.02 (s, 1H), 7.64 - 7.46 (m, 1H), 7.05 - 6.85 (m, 2H), 6.27 (d, = 18.3 Hz, 1H), 5.93 (s, 1H), 4.57 (s, 1H), 4.36 (q, = 7.0 Hz, 1H), 3.83 (s, 3H), 3.71 - 3.34 (m, 10H), 3.29 (dt, = 12.5, 5.1 Hz, 2H), 2.97 (d, = 21.8 Hz, 2H), 1.66 (s, 9H), 1.55 (h, = 7.9, 7.4 Hz, 9H), 1.43 (s, 9H), 1.26 (br s, 44H), 0.88 (t, = 6.8 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for
C58Hio2N409, 1000; found, 1000.
Example 75: (2S)-6-amino-N-(2,3-bis(tetradecyloxy)propyl)-2-(2-(5-methoxy-lH-indol-3- yl)acetamido)hexanamide hydrochloride
Figure imgf000109_0001
[0244] The title compound was prepared from Example 74 (200 mg, 0.2 mmol) as described for Example 1 to give an off-white solid (100% yield). 1H NMR (500 MHz, Chloroform-d) δ 7.98 (s, 4H), 7.51 (m, 1H), 7.15 - 6.95 (m, 1H), 6.95 - 6.68 (m, 1H), 6.00 (s, 1H), 4.51 (s, 1H), 3.95 - 3.62 (m, 5H), 3.60 - 3.11 (m, 12H), 1.81 - 1.43 (m, 10H), 1.25 (br s, 44H), 0.88 (td, 7 = 6.9, 2.9 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for C48H86N405, 800; found, 800.
Example 76: tert-butyl 5-(benzyloxy)-3-(2-(((10S)-2,2-dimethyl-4,l l-dioxo-14-(tetradecyloxy)- 3 J6-dioxa-5 J2-diazatriacontan-10-yl)amino)-2-oxoethyl)-lH-indole-l-carboxylate
Figure imgf000109_0002
[0245] The title compound was prepared from N -(2-(5-(benzyloxy)-l-(tert- butoxycarbonyl)-lH-indol-3-yl)acetyl)-N6-(tert-butoxycarbonyl)-L-lysine (synthesized as in Example 74) (305 mg, 0.5 mmol) and 2,3-bis(tetradecyloxy)propan-l-amine hydrochloride (260 mg, 0.5 mmol) as described for Example 33 to give the title compound as a white solid (310 mg, 58% yield). 1H NMR (500 MHz, Chloroform- ) δ 8.03 (s, 1H), 7.53 (s, 1H), 7.46 (d, 7 = 7.6 Hz, 2H), 7.38 (dd, 7 = 8.5, 6.6 Hz, 2H), 7.31 (dd, 7 = 8.6, 6.1 Hz, 1H), 7.13 - 6.90 (m, 2H), 6.27 (d, 7 = 14.2 Hz, 2H), 5.09 (s, 2H), 4.51 (s, 1H), 4.35 (q, 7 = 7.0 Hz, 1H), 3.60 - 3.09 (m, 9H), 2.96 (s, 2H), 1.67 (s, 9H), 1.53 (tq, 7 = 13.8, 7.3 Hz, 6H), 1.42 (s, 9H), 1.26 (br s, 48H), 0.88 (t, 7 = 6.8 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for C64Hio6N409, 1076; found, 1076. Example 77: (2S)-6-amino-2-(2-(5-(benzyloxy)-lH-indol-3-yl)acetamido)-N-(2,3- bis(tetradecyloxy)propyl)hexanamide hydrochloride
Figure imgf000110_0001
[0246] The title compound was prepared from Example 76 (215 mg, 0.2 mmol) as described for Example 1 to give an off-white solid (100% yield). 1H NMR (500 MHz, Chloroform-d) δ 8.03 (m, 3H), 7.83 - 7.51 (m, 1H), 7.49 - 6.73 (m, 11H), 5.06 (d, = 15.3 Hz, 2H), 4.48 (s, 1H), 3.88 - 3.58 (m, 3H), 3.58 - 3.09 (m, 8H), 2.81 (m, 2H), 1.61 - 1.38 (m, 6H), 1.26 (br s, 48H), 0.88 (t, J = 6.6 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for C54H9oN405, 876; found, 876.
Example 78: tert-butyl ((5S)-6-((2,3-bis(tetradecyloxy)propyl)amino)-5-((naphthalen-2- ylmethyl)amino -6-oxohexyl)carbamate
Figure imgf000110_0002
[0247] The title compound was prepared from N6-(tert-butoxycarbonyl)-N2-(naphthalen-2- ylmethyl)-L-lysine (synthesized as in Example 56) (194 mg, 0.5 mmol) and 2,3- bis(tetradecyloxy)propan- 1 -amine hydrochloride (260 mg, 0.5 mmol) as described for Example 33 to give the title compound as off-white solid (315 mg, 74% yield). 1H NMR (500 MHz, Chloroform-d) δ 8.05 - 7.73 (m, 4H), 7.58 - 7.45 (m, 3H), 7.23 (s, 1H), 4.67 (s, 1H), 4.32 - 3.99 (m, 2H), 3.74 (m, 1H), 3.65 - 3.21 (m, 8H), 3.19 - 2.89 (m, 2H), 1.87 (br s, 2H), 1.53 (dq, = 11.8, 6.5, 6.0 Hz, 4H), 1.47 - 1.04 (m, 57H), 0.88 (t, = 6.9 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for C53H93N3O5, 853; found, 853. Example 79: (2S)-6-amino-N-(2,3-bis(tetradecyloxy)propyl)-2-((naphthalen-2-ylmethyl)amino) hexanamide dihydrochloride
Figure imgf000111_0001
[0248] The title compound was prepared from Example 78 (171 mg, 0.2 mmol) as described for Example 1 to give an off-white solid (100% yield). 1H NMR (499 MHz, Chloroform-d) δ 9.58 (s, 1H), 8.60 (s, 1H), 7.94 (s, 1H), 7.69 (m, 6H), 7.35 (s, 2H), 4.45 - 3.88 (m, 3H), 3.42 (s, 10H), 2.89 (s, 1H), 2.20 - 1.83 (m, 2H), 1.84 - 1.59 (m, 2H), 1.49 (s, 6H), 1.37 - 1.02 (br s, 44H), 0.88 (t, J = 6.9 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for C48H85N303, 753; found, 753.
Example 80: tert-butyl 4-(3-((2,3-bis(tetradecyloxy)propyl)carbamoyl)phenyl)piperazine-l- carboxylate
Figure imgf000111_0002
[0249] The title compound was prepared from 3-(4-(tert-butoxycarbonyl)piperazin-l- yl)benzoic acid (153 mg, 0.5 mmol) and 2,3-bis(tetradecyloxy)propan- l-amine hydrochloride (260 mg, 0.5 mmol) as described for Example 33 to give the title compound as white solid (285 mg, 74% yield). 1H NMR (500 MHz, Chloroform- ) δ 7.46 (d, = 2.6 Hz, 1H), 7.30 (t, = 7.9 Hz, 1H), 7.15 (d, = 7.6 Hz, 1H), 7.09 (d, = 8.2 Hz, 1H), 6.69 (t, J = 5.3 Hz, 1H), 3.74 (dt, = 13.5, 5.4 Hz, 1H), 3.67 - 3.34 (m, 12H), 3.21 (t, = 5.2 Hz, 4H), 1.57 (m, 4H), 1.49 (s, 9H), 1.41 - 1.11 (m, 44H), 0.88 (t, = 6.9 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for C47H85N305, 773; found, 773. Example 81: N-(2,3-bis(tetradecyloxy)propyl)-3-(piperazin-l-yl)benzamide hydrochloride
Figure imgf000112_0001
[0250] The title compound was prepared from Example 80 (155 mg, 0.2 mmol) as described for Example 1 to give an off-white solid (100% yield). 1H NMR (500 MHz, Chloroform-d) δ 10.09 (s, 2H), 8.15 (s, 1H), 8.03 - 7.38 (m, 2H), 3.92 - 3.00 (m, 16H), 1.56 (s, 4H), 1.25 (br s, 44H), 0.88 (t, J = 6.8 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for C42H77N3O3, 673; found, 673.
Example 82: tert-butyl 4-(3-((2,3-bis(tetradecyloxy)propyl)carbamoyl)phenyl)piperidine-l- carboxylate
Figure imgf000112_0002
[0251] The title compound was prepared from 3-(l-(tert-butoxycarbonyl)piperidin-4- yl)benzoic acid (153 mg, 0.5 mmol) and 2,3-bis(tetradecyloxy)propan-l-amine hydrochloride (260 mg, 0.5 mmol) as described for Example 33 to give the title compound as white solid (280 mg, 73% yield. 1H NMR (500 MHz, Chloroform- ) δ 7.67 (d, J = 1.9 Hz, 1H), 7.53 (dt, J = 7.2, 1.8 Hz, 1H), 7.41 - 7.29 (m, 2H), 6.69 (t, J = 5.4 Hz, 1H), 4.26 (d, / = 13.5 Hz, 2H), 3.75 (dt, = 13.7, 5.4 Hz, 1H), 3.66 - 3.26 (m, 8H), 2.92 - 2.59 (m, 3H), 1.83 (d, J = 12.7 Hz, 2H), 1.66 (td, J = 12.6, 4.3 Hz, 2H), 1.57 (m, 4H), 1.49 (s, 9H), 1.40 - 1.06 (m, 48H), 0.88 (t, J = 6.9 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for C48H86N205, 772; found, 772. Example 83: N-(2,3-bis(tetradecyloxy)propyl)-3-(piperidin-4-yl)benzamide hydrochloride
Figure imgf000113_0001
[0252] The title compound was prepared from Example 82 (154 mg, 0.2 mmol) as described for Example 1 to give an off-white solid (100% yield). 1H NMR (500 MHz, Chloroform-d) δ 9.73 (br d, Hz, 2H), 7.72 (s, 1H), 7.54 (d, 7 = 7.0 Hz, 1H), 7.39 (d, 7 = 8.3 Hz, 2H), 6.74 (s, 1H), 3.98 - 3.30 (m, 11H), 3.04 (s, 2H), 2.85 (s, 1H), 2.26 (s, 2H), 2.07 (d, 7 = 12.9 Hz, 2H), 1.76 (s, 4H), 1.57 (m, 4H), 1.26 (br s, 46H), 0.88 (t, 7 = 6.9 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for C43H78N2O3, 672; found, 672.
Example 84: tert-butyl 4-(2-((2,3-bis(tetradecyloxy)propyl)carbamoyl)phenyl)piperazine-l- carboxylate
Figure imgf000113_0002
[0253] The title compound was prepared from 2-(4-(tert-butoxycarbonyl)piperazin-l- yl)benzoic acid (153 mg, 0.5 mmol) and 2,3-bis(tetradecyloxy)propan- l-amine hydrochloride (260 mg, 0.5 mmol) as described for Example 33 to give the title compound as colorless liquid
(325 mg, 84% yield). 1H NMR (500 MHz, Chloroform- ) δ 9.58 (s, 1H), 8.15 (dd, 7 = 7.9, 1.7 Hz, 1H), 7.42 (td, 7 = 7.7, 1.8 Hz, 1H), 7.23 (t, 7 = 7.5 Hz, 1H), 7.16 (d, 7 = 8.0 Hz, 1H), 4.12 (q, 7 = 7.1 Hz, 1H), 3.88 - 3.31 (m, 12H), 2.94 (t, 7 = 5.2 Hz, 4H), 1.55 (m, 4H), 1.49 (s, 9H), 1.35 - 1.09 (m, 44H), 0.88 (t, 7 = 6.8 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for C47H85N3O5, 773; found, 773. Example 85: N-(2,3-bis(tetradecyloxy)propyl)-2-(piperazin-l-yl)benzamide hydrochloride
Figure imgf000114_0001
[0254] The title compound was prepared from Example 84 (155 mg, 0.2 mmol) as described for Example 1 to give an off-white solid (100% yield). 1H NMR (500 MHz, Chloroform-d) δ 10.41 (s, 2H), 7.96 (d, 7 = 7.7 Hz, 1H), 7.56 (dd, 7 = 19.1, 11.8 Hz, 2H), 7.38 (t, 7 = 7.4 Hz, 1H), 3.97 - 3.23 (m, 21H), 1.55 (m, 4H), 1.36 - 1.07 (m, 44H), 0.88 (t, 7 = 6.9 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for C42H77N3O3, 673; found, 673.
Example 86: tert-butyl 4-(2-((2,3-bis(tetradecyloxy)propyl)carbamoyl)phenyl)piperidine-l- carboxylate
Figure imgf000114_0002
[0255] The title compound was prepared from 2-(l-(tert-butoxycarbonyl)piperidin-4- yl)benzoic acid (153 mg, 0.5 mmol) and 2,3-bis(tetradecyloxy)propan-l-amine hydrochloride (260 mg, 0.5 mmol) as described for Example 33 to give the title compound as white solid (315 mg, 81% yield). 1H NMR (500 MHz, Chloroform- ) δ 7.38 (td, 7 = 7.6, 1.4 Hz, 1H), 7.34 - 7.28 (m, 2H), 7.21 (t, 7 = 7.3 Hz, 1H), 6.31 (t, 7 = 5.6 Hz, 1H), 4.39 - 4.13 (m, 2H), 3.77 (ddd, 7 = 13.7, 6.3, 4.6 Hz, 1H), 3.68 - 3.36 (m, 8H), 3.17 (tt, 7 = 12.1, 3.5 Hz, 1H), 2.80 (td, 7 = 13.0, 2.6 Hz, 2H), 1.83 (dd, 7 = 13.3, 3.3 Hz, 2H), 1.70 - 1.51 (m, 6H), 1.48 (s, 9H), 1.26 (br s, 44H), 0.88 (t, 7 = 6.9 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for C48H86N2O5, 772; found, 772.
Example 87: N-(2.3-bis(tetradecyloxy)propyl)-2-(piperidin-4-yl)benzamide hydrochloride
Figure imgf000115_0001
[0256] The title compound was prepared from Example 86 (154 mg, 0.2 mmol) as described for Example 1 to give an off-white solid (100% yield). 1H NMR (500 MHz, Chloroform-d) δ 9.63 (br d, 2H), 7.52 - 7.40 (m, 2H), 7.36 (d, = 7.5 Hz, 1H), 7.24 (d, = 7.5 Hz, 1H), 6.42 (t, = 5.5 Hz, 1H), 3.88 - 3.21 (m, 11H), 3.01 (m, 2H), 2.33 - 2.14 (m, 2H), 2.16 - 1.98 (m, 2H), 1.55 (m, 4H), 1.25 (br s, 44H), 0.88 (t, = 6.8 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for Q3H78N2O3, 672; found, 672.
Example 88: tert-butyl 4-(4-((2,3-bis(tetradecyloxy)propyl)carbamoyl)phenyl)piperazine-l- carboxylate
Figure imgf000115_0002
[0257] The title compound was prepared from 4-(4-(tert-butoxycarbonyl)piperazin-l- yl)benzoic acid (153 mg, 0.5 mmol) and 2,3-bis(tetradecyloxy)propan- l-amine hydrochloride (260 mg, 0.5 mmol) as described for Example 33 to give the title compound as light pink solid (310 mg, 80% yield). 1H NMR (500 MHz, Chloroform- ) δ 7.81 - 7.57 (m, 2H), 6.93 (d, = 8.5 Hz, 2H), 6.61 (t, = 5.5 Hz, 1H), 3.73 (dt, = 13.7, 5.4 Hz, 1H), 3.65 - 3.36 (m, 12H), 3.25 (t, = 5.2 Hz, 4H), 1.57 (m, 4H), 1.49 (s, 9H), 1.38 - 1.14 (m, 44H), 0.88 (t, = 6.9 Hz, 6H).; ESI- MS m/z [M+H]+ calc'd for C47H85N3O5, 773; found, 773.
Example 89: N-(2,3-bis(tetradecyloxy)propyl)-4-(piperazin-l-yl)benzamide hydrochloride
Figure imgf000116_0001
[0258] The title compound was prepared from Example 88 (155 mg, 0.2 mmol) as described for Example 1 to give a tan solid (100% yield). 1H NMR (500 MHz, Chloroform-d) δ 10.08 (s, 2H), 7.79 (s, 2H), 6.86 (s, 1H), 4.04 - 3.21 (m, 11H), 2.52 (s, 6H), 1.56 (q, = 6.9 Hz, 4H), 1.25 (br s, 44H), 0.88 (t, = 6.9 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for C42H77N3O3, 673; found, 673.
Example 90: tert-butyl 4-(4-((2,3-bis(tetradecyloxy)propyl)carbamoyl)phenyl)piperidine-l- carboxylate
Figure imgf000116_0002
[0259] T e title compound was prepared from 4-(l-(tert-butoxycarbonyl)piperidin-4- yl)benzoic acid (153 mg, 0.5 mmol) and 2,3-bis(tetradecyloxy)propan-l-amine hydrochloride (260 mg, 0.5 mmol) as described for Example 33 to give the title compound as white solid (325 mg, 84% yield). 1H NMR (500 MHz, Chloroform- ) δ 7.71 (d, = 8.1 Hz, 2H), 7.25 (d, = 8.0 Hz, 2H), 6.71 (t, = 5.5 Hz, 1H), 4.25 (d, = 13.1 Hz, 2H), 3.75 (dt, = 13.7, 5.4 Hz, 1H), 3.67 - 3.29 (m, 8H), 2.80 (t, = 12.9 Hz, 2H), 2.69 (t, = 12.1, 3.6 Hz, 1H), 1.90 - 1.74 (m, 2H), 1.70 - 1.52 (m, 6H), 1.48 (s, 9H), 1.41 - 1.16 (m, 44H), 0.88 (t, = 6.8 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for C48H86N205, 772; found, 772.
Example 91: N-(2,3-bis(tetradecyloxy)propyl)-4-(piperidin-4-yl)benzamide hydrochloride
Figure imgf000117_0001
[0260] The title compound was prepared from Example 90 (154 mg, 0.2 mmol) as described for Example 1 to give a white solid (100% yield). 1H NMR (500 MHz, Chloroform- ) δ 9.73 (br d, 2H), 7.73 (d, = 7.5 Hz, 2H), 7.30 (d, = 7.7 Hz, 2H), 6.72 (t, = 5.4 Hz, 1H), 3.97 - 3.29 (m, 11H), 3.03 (s, 2H), 2.83 (s, 1H), 2.25 (s, 2H), 2.06 (d, = 13.1 Hz, 2H), 1.70 (s, 4H), 1.56 (m, 4H), 1.37 - 1.10 (m, 44H), 0.87 (t, = 6.8 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for C43H78N2O3, 672; found, 672.
Example 92: 4-(3-((2,3-bis(tetradecyloxy)propyl)carbamoyl)phenyl)-lJ-dimethylpiperidin-l- ium iodide
Figure imgf000117_0002
[0261] Title compound prepared from Example 83 (336 mg, 0.5 mmol) that suspended in DMF (3.0 mL) and added K2C03 (207 mg, 1.5 mmol) and methyl iodide (62 uL, 1.0 mmol) to the mixture. Then heated at 60°C for 2 hours. After completion (monitored by TLC-5% MeOH- dichloromethane), evaporated volatiles and extracted using chloroform (2 x 25 mL) in water. Resulting organic layer dried over sodium sulfate and evaporated. Then dried completely on lyophilized to remove residual DMF to give the desired product as white solid (295 mg, 71% yield). 1H NMR (500 MHz, Chloroform- ) δ 7.87 (d, = 1.9 Hz, 1H), 7.57 (dt, = 7.6, 1.5 Hz, 1H), 7.45 - 7.33 (m, 2H), 7.08 (s, 1H), 4.15 - 3.91 (m, 2H), 3.83 (d, = 12.6 Hz, 2H), 3.71 - 3.51 (m, 9H), 3.48 - 3.33 (m, 5H), 3.22 (m, 1H), 2.24 (q, = 13.2 Hz, 2H), 2.13 (d, = 14.8 Hz, 2H), 1.98 (s, 3H), 1.56 (h, = 6.8, 6.0 Hz, 4H), 1.43 - 1.12 (m, 47H), 0.87 (t, = 6.9 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for C45H83N203, 701; found, 701. Example 93: N-(2,3-bis(heptyloxy)propyl)-3-(piperidin-4-yl)benzamide hydrochloride
Figure imgf000118_0001
[0262] Step 1 : tert-butyl (2,3-bis(heptyloxy)propyl)carbamate : Aqueous NaOH (50 %, 15 mL) and Bu4NI (2.76 g, 7.5 mmol) were added at room temperature to a stirred solution of t- Butyl (2,3-dihydroxypropyl) carbamate (3 g, 15 mmol) and 1-Bromoheptane (7.5 ml, 45 mmol) in toluene (30 mL). After vigorous stirring for 6 h at 50-60°C, the reaction mixture was allowed to obtain ambient temperature, ethyl acetate and water were added. The organic phase was washed with brine and dried (Na2S04). The residue was purified by column chromatography using 10-20% Ethyl acetate in Hexane to get the desired product (3.0 g, 52%). ESI-MS m/z [M+H]+ calc'd for C22H45N04, 388; found, 388.
[0263] Step 2: 2,3-bis(heptyloxy)propan-l -amine hydrochloride : Product obtained in above step 1 was dissolved in methanol (10 mL) and methanolic HCl (20 mL) was added and stirred at room temperature for 3 hours. Then solvent was evaporated to dryness to get the desired product (100% yield). ESI-MS m/z [M+H]+ calc'd for Ci7H37N02, 288; found, 288.
[0264] Step 3: tert-butyl 4-(3-((2,3-bis(heptyloxy)propyl)carbamoyl)phenyl)piperidine- l- carboxylate:
[0265] 3-(l-(t-butoxycarbonyl) piperidin-4-yl) benzoic acid (500 mg, 1.637 mmol) was dissolved in dichloromethane (5.0 mL). 2,3-bis(heptyloxy)propan- l-amine.HCl (478 mg, 1.637 mmol) and HBTU (620 mg, 1.637 mmol) were added and the reaction mixture was stirred for 10 min. DIPEA (0.84 ml, 6.548 mmol) was added and stirred for 3 hours at room temperature. The solvent was removed and purified by silica gel column chromatography using 15% ethyl acetate in hexane to obtain the desired product (550 mg, 58% yield). ESI-MS m/z [M+H]+ calc'd for
C34H58N205, 575; found, 575. [0266] Step 4: Compound obtained in step 3 (230 mg, 4.0 mmol) was dissolved in methanol (3.0 mL) and methanolic HCl (10 mL) was added and stirred at room temperature for 3 h and the solvent was evaporated to dryness under reduced pressure to get the desired product (100% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.3-9.2 (br s, 1H), 9.0 (br s,lH), 8.6-8.4 (s, 1H), 7.8-7.3 (m, 4H), 3.6-3.2 (m, 11H), 3.1-2.8 (m, 3H), 2.0-1.8 (m, 4H), 1.6-1.3 (m, 4H), 1.3-1.0 (m, 16 H), 0.87 (m, 6H). ESI-MS m/z [M+H]+ calc'd for C29H50N2O3, 475; found, 475.
Example 94 : N-(2,3-bis((5-methoxypentyl)oxy)propyl)-3-(piperidin-4-yl)benzamide
hydrochloride
Figure imgf000119_0001
[0267] Step 1: tert-butyl 4-(3-((2,3-bis((5- methoxypentyl)oxy)prop vDcarbamo vDphenvDpiperidine- 1 -carboxylate : 3-(l-(t- butoxycarbonyl) piperidin-4-yl) benzoic acid (500 mg, 1.637 mmol) was dissolved in
dichloromethane (5.0 mL). Then 2,3-bis (5-methoxypentyloxy) propan-l-amine.HCl (476 mg, 1.637 mmol) (prepared following the procedure in Example 93) and HBTU (620 mg, 1.637 mmol) were added and the reaction mixture was stirred for 10 min. DIPEA (0.84 ml, 6.548 mmol) was added and stirred for 3h at room temperature. The solvent was removed and purified by silica gel column chromatography using 25% ethyl acetate in hexane to obtain the desired product (500 mg, 53 % yield). ESI-MS m/z [M+H]+ calc'd for C32H54N207, 579; found, 579.
[0268] Step 2: Compound obtained in step 1 (232 mg, 4.0 mmol) was dissolved in methanol (3.0 mL) and methanolic HCl (10 mL) was added and stirred at room temperature for 3 h and the solvent was evaporated to dryness under reduced pressure to get the desired product (100% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.3 (br s, 1H), 9.2-9.0 (br s,lH), 8.6-8.4 (s, 1H), 7.8-7.3 (m, 4H), 3.6-3.3(m, 13H), 3.2 (m, 8H), 3.1-2.8 (m, 3H), 2.0-1.8 (m, 4H), 1.6-1.3 (m, 8H), 1.3-1.2 (m, 4H). ESI-MS m/z [M+H]+ calc'd for C27H46N205, 479; found, 479. Example 95 : N-(3-(benzyloxy)-2-(dodecyloxy)propyl)-3-(piperidin-4-yl)benzamide hydrochloride
Figure imgf000120_0001
[0269] Step 1: tert-butyl (3-(benzyloxy)-2-(dodecyloxy)propyl)carbamate : To a stirred mixture of ie/t-butyl-3(benzyloxy)2-hydroxypropylcarbamate (3.0 g, 16 mmol) and 1- bromododecane (7.98 g, 48 mmol) in toluene (15 mL) were added 50% aq. NaOH solution (9.0 mL) and Bu4NI (2.95 g, 8 mmol) and the resulting mixture was heated to 50-60 °C and maintained on vigorous stirring for 6 hours at the same temperature. After completion the mixture was cooled to ambient temperature and performed work up with ethyl acetate and water. The organic phase was concentrated and purified by silica gel column chromatography eluting with with 5-20% ethyl acetate in hexane to get desired as a brown liquid (3.0 g, 63% yield). ESI- MS m/z [M+H]+ calc'd for C27¾7N04, 450; found, 450.
[0270] Step 2: 3-(benzyloxy)-2-(dodecyloxy)propan-l-amine hydrochloride : To a stirred solution of compound obtained in step 1 (3 g) in methanol (5 mL) was added methanolic. HC1 (10 mL) and stirring was continued for lh at room temperature. After completion the mixture was concentrated to obtain the desired product as a colorless liquid (100% yield). ESI-MS m/z [M+H]+ calc'd for C22H39N02, 350; found, 350.
[0271] Step 3: tert-butyl 4-(3-((3-(benzyloxy)-2-
(dodecyloxy)propyl)carbamoyl)phenyl)piperidine-l-carboxylate : The title compound was prepared from 3-(l-(t-butoxycarbonyl) piperidin-4-yl) benzoic acid (1.76 g, 5.76 mmol) and 3- (benzyloxy)-2-(dodecyloxy)propan-l -amine hydrochloride (2.0 g, 5.76 mmol) as described for Example 93 to give the title compound as colorless liquid (2.1 g, 57% yield). ESI-MS m/z
[M+H]+ calc'd for C39H6oN205, 637; found, 637. [0272] Step 4: The title compound was prepared from above obtained step 3 product (64 mg, 0.1 mmol) as described for Example 1 to give an off-white solid (100% yield).; ESI-MS m/z [M+H]+ calc'd for C3 H52N2O3, 537; found, 537.
Example 96 : methyl 5-(2-(dodecyloxy)-3-(3-(piperidin-4-yl)benzamido)propoxy)pentanoate hydrochloride
Figure imgf000121_0001
[0273] Step 1: tert-butyl 4-(3-((2-(dodecyloxy)-3- hvdroxypropyDcarbamovDphenvDpiperidine- 1 -carboxylate : To a stirred solution of tert-butyl 4- (3-((3-(benzyloxy)-2-(dodecyloxy)propyl) carbamoyl)phenyl) piperidine-1 -carboxylate (2.0 g, 3.14 mmol) in methanol (20 mL) was added 10% Pd/C (200 mg) portion wise under nitrogen and then the reaction mixture was stirred under pressure of hydrogen (10-15 psi) for 18 hours. After completion the mixture was filtered through celite pad and concentrated to obtain crude product as a colorless liquid, which was used directly in the next step. ESI-MS m/z [M+H]+ calc'd for Csif^NiOs, 547; found, 547.
[0274] Step 2: tert-butyl 4-(3-((2-(dodecyloxy)-3-((5-methoxy-5- oxopentyl)oxy)prop vDcarbamo yl) phenvDpiperidine- 1 -carboxylate : To a stirred mixture of tert- butyl 4-(3-(2-(dodecyloxy)-3-hydroxypropylcarbamoyl)phenyl)piperidine-l-carboxylate (1.2 g, 2.19 mmol) and methyl 5-bromopentanoate (1.37 g, 6.59 mmol) in Toluene (10 mL) were added 50% aq. NaOH solution (4.0 mL) and Bu4NI (400 mg, 0.001 mol) and the resulting reaction mixture was heated to 50-60 0 C and maintained on vigorous stirring for one hour at same temperature. After completion the reaction mixture was cooled to ambient temperature and performed work up with ethyl acetate and water. The organic phase was concentrated and purified by silica gel column chromatography with 5-30% ethyl acetate in hexane to get desired product as a colorless liquid. ESI-MS m/z [M+H]+ calc'd for C38H64N2O7, 661; found, 661. [0275] Step 3: The title compound was prepared from above obtained step 2 product (264 mg, 0.4 mmol) as described for Example 1 to give a colorless gummy solid (100% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.62-8.41 (s, 1H), 7.74-7.65 (s, 2H), 7.45-7.31 (m, 2H), 3.66 (s, 3H), 3.63-3.31 (m, 10H), 2.96-2.71 (m, 4H), 2.31-2.19 (m, 2H), 2.03-1.83 (m, 5H), 1.58-1.32 (m, 7H), 1.31-1.24 (m, 18H), 0.85-0.83 (t, 7 =5.7 Hz, 3H).; ESI-MS m/z [M+H]+ calc'd for C33H56N2O5, 561; found, 561.
Example 97 : 5-(2-(dodecyloxy)-3-(3-(piperidin-4-yl)benzamido)propoxy)pentanoic acid hydrochloride
Figure imgf000122_0001
[0276] Step 1: 5-(3-(3-(l-(tert-butoxycarbonyl)piperidin-4-yl)benzamido)-2- (dodecyloxy)propoxy) pentanoic acid: To a stirred solution of tert-butyl 4-(3-((2-(dodecyloxy)- 3-((5-methoxy-5-oxopentyl)oxy)propyl)carbamoyl) phenyl)piperidine-l-carboxylate (1.15 g) in methanol (5 mL) was added 2M L1OH.H2O solution (10 mL) slowly at room temperature under inert atmosphere and stirring was continued for 18 hours. The reaction mixture was concentrated to dryness. The crude was diluted with water and washed with isopropyl ether. The resulting aqueous phase was acidified to P 2 using 2N HCl and extracted with ethyl acetate. The collected organic layer was concentrated and purified by silica gel column chromatography gradient elution with 5-10% Methanol in dichloromethane to provide desired product as a colorless liquid (900 mg, 82%). ESI-MS m/z [M+H]+ calc'd for C37H62N2O7, 647; found, 647.
[0277] Step 2: To a stirred solution of above obtained step 1 product (500 mg) in dichloromethane (4 mL) was added 4N HCl in 1,4-Dioxane (10 mL) slowly and continued to stir for 30 min at room temperature. The resultant reaction mixture was concentrated to furnish the desired product as an off white solid (100% yield). 1H NMR (300 MHz, DMSO -d6): δ 12.0 (s, 1H), 8.5 (br s, 1H), 8.62-8.51 (m, 2H), 7.71 (s, 2H), 7.43-7.36 (m, 2H), 3.58-3.45 (m, 11H), 3.16-2.91 (m, 3H), 2.31-2.19 (m, 2H), 1.91-1.82 (m, 4H), 1.51-1.62 (m, 6H), 1.22-1.03 (m, 18H), 0.85-0.83 (t, =5.7 Hz, 3H).; ESI-MS m/z [M+H]+ calc'd for C32H54N205, 547; found, 547.
Example 98 : N-(2-(dodecyloxy)-3-((5-(methylamino)-5-oxopentyl)oxy)propyl)-3-(piperidin-4- yPbenzamide hydrochloride
Figure imgf000123_0001
[0278] Step 1: tert-butyl 4-(3-(2-(dodecyloxy)-3-(5-(methylamino)-oxopentyloxy) prop ylcarbamo yl) phenvDpiperidine- 1 -carboxylate : To a stirred solution of 5-(3-(3-(l-(tert- butoxycarbonyl) piperidin-4-yl)benzamido)-2-(dodecyloxy)propoxy) pentanoic acid (250 mg, 0.38 mmol) in DMF (5 mL) were added DIPEA (0.656 mL, 3.8 mmol) and HBTU (230 mg, 0.608 mmol) and stirred for 30 min at room temperature. Then MeNH2.HCl (60 mg, 0.874 mmol) was added to the reaction mixture and stirring was continued for 18 hours at room temperature. Reaction mixture was diluted with ethyl acetate and washed with sat. NaHC03 solution, sat. NH4C1 solution, water and brine solution. The collected organic phase was dried, concentrated and purified by basic silica gel column chromatography gradient elution with 5% Methanol in dichloromethane to isolate desired pure product as a yellow liquid (220 mg, 88%).; ESI-MS m/z [M+H]+ calc'd for C38H65N306, 661; found, 661.
[0279] Step 2: To a stirred solution of above step 1 product (220 mg) in dichloromethane (2 mL) was added HC1 in 1,4-Dioxane (5 mL) and continued to stir for 30 min at room
temperature. The resultant reaction mixture was concentrated to furnish the desired product as viscous oil (100% yield). 1H NMR (300 MHz, DMSO-d6 ): δ 8.91 (br s, 1H), 8.67 ( br s, 1H), 8.54 (s, 1H), 7.67 (s, 2H), 7.37-7.35 (m, 2H), 3.58-3.41 (m, 11H), 3.16-2.91 (m, 3H), 2.92-2.71 (m, 3H), 2.31-2.19 (m, 2H), 1.91-1.82 (m, 4H) 1.61-1.32 (m, 6H), 1.22-1.03 (m, 18H), 0.85-0.83 (t, =5.7 Hz, 3H).; ESI-MS m/z [M+H]+ calc'd for C33H57N304, 561; found, 561. Example 99 : N-(3-((5-amino-5-oxopentyl)oxy)-2-(dodecyloxy)propyl)-3-(piperidin-4- yPbenzamide hydrochloride
Figure imgf000124_0001
[0280] Step 1: tert-butyl 4-(3-((3-((5-amino-5-oxopentyi)oxy)-2- (dodecyloxy)propyl)carbamoyl) phenyl )piperidine- 1-carboxylate: The title compound was prepared from 5-(3-(3-(l-(tert-butoxycarbonyl) piperidin-4-yl)benzamido)-2- (dodecyloxy)propoxy) pentanoic acid (250 mg, O.38mmol) and NH4C1 (46.75 mg, 0.874 mmo) as described for Example 98 to give the desired product as yellow liquid (220 mg, 88%). ESI- MS m/z [M+H]+ calc'd for C37H63N3O6, 647; found, 647.
[0281] Step 2: To a stirred solution of above step 1 product (220 mg) in dichloromethane (2 mL) was added HC1 in 1,4-Dioxane (5 mL) and continued to stir for 30 min at room
temperature. The resultant reaction mixture was concentrated to furnish the desired product as viscous oil (100% yield). 1H NMR (300 MHz, DMSO-d6 ): ): δ 8.91 (br s, IH), 8.67 ( br s, IH), 8.54 (s, IH), 7.67 (s, 2H), 7.37-7.35 (m, 2H), 7.13 (s, IH), 6.85 (s, IH), 3.75-3.41 (m, 11H), 3.16-2.91 (m, 3H), 2.31-2.19 (m, 2H), 1.91-1.82 (m, 4H), 1.62-1.45 (m, 6H), 1.22-1.03 (m, 19H), 0.85-0.83 (t, =5.8 Hz, 3H).; ESI-MS m/z [M+H]+ calc'd for C32H55N3O4, 547; found, 547.
Example 100 : N-(3-(octyloxy)propyl)-3-(piperidin-4-yl)benzamide hydrochloride
Figure imgf000124_0002
[0282] Step 1 : tert-butyl 4-(3 -((3 -(octyloxy)propyl)carbamoyl)phenyl)piperidine- 1 - carboxylate: The title compound was prepared from 3-(l-(tert-butoxycarbonyl)piperidin-4- yl)benzoic acid (153 mg, 0.5 mmol) and 3-(octyloxy)propan- l-amine (112 mg, 0.5 mmol) as described for Example 33 to give the title compound as colorless gummy liquid (226 mg, 95% yield). ESI-MS m/z [M+H]+ calc'd for C28H46N204, 475; found, 475.
[0283] Step 2: The title compound was prepared from above step 1 product (95 mg, 0.2 mmol) as described for Example 1 to give a white solid (100% yield). 1H NMR (500 MHz, Chloroform- ) δ 9.67 (br d, 2H), 7.55 (d, = 6.9 Hz, 1H), 7.45 - 7.32 (m, 3H), 7.14 (s, 1H), 3.83 - 3.50 (m, 6H), 3.44 (t, J = 6.6 Hz, 2H), 3.10 (d, J = 49.3 Hz, 2H), 2.85 (s, 1H), 2.26 (s, 2H), 2.13 - 1.97 (m, 2H), 1.85 (m, 4H), 1.57 (q, = 6.9 Hz, 2H), 1.34 - 1.15 (m, 8H), 0.95 - 0.70 (m, 3H).; ESI-MS m/z [M+H]+ calc'd for C23H38N202, 375; found, 375.
Example 101 : 3-(piperidin-4-yl)-N-tetradecylbenzamide hydrochloride
Figure imgf000125_0001
[0284] Stepl : tert-butyl 4-(3-(tetradecylcarbamoyl)phenyl)piperidine- l -carboxylate: The title compound was prepared from 3-(l-(tert-butoxycarbonyl)piperidin-4-yl)benzoic acid (153 mg, 0.5 mmol) and tetradecan- 1 -amine (107 mg, 0.5 mmol) as described for Example 33 to give the title compound as gummy white solid (210 mg, 84% yield). ESI-MS m/z [M+H]+ calc'd for C3iH52N203, 501 ; found, 501.
[0285] Step 2: The title compound was prepared from above step 1 product (100 mg, 0.2 mmol) as described for Example 1 to give a white solid (100% yield). 1H NMR (500 MHz,
Chloroform- ) δ 9.69 (br d, 2H), 7.67 (s, 1H), 7.61 (t, = 4.3 Hz, 1H), 7.39 (d, = 4.6 Hz, 2H), 6.24 (s, 1H), 3.65 (d, = 10.8 Hz, 2H), 3.43 (q, = 9.3, 8.2 Hz, 2H), 3.04 (s, 2H), 2.85 (s, 1H), 2.26 (d, = 12.8 Hz, 2H), 2.07 (d, = 13.2 Hz, 2H), 1.80 (s, 2H), 1.70 - 1.53 (m, 2H), 1.44 - 1.11 (m, 20H), 0.88 (t, J = 6.9 Hz, 3H).; ESI-MS m/z [M+H]+ calc'd for C26H44N2O, 401; found, 401.
Example 102 : N-(3-(2-methoxyethoxy)propyl)-3-(piperidin-4-yl)benzamide hydrochloride
Figure imgf000126_0001
[0286] Stepl: tert-butyl 4-(3-((3-(2-methoxyethoxy)propyl)carbamoyl)phenyl)piperidine-l- carboxylate: The title compound was prepared from 3-(l-(tert-butoxycarbonyl)piperidin-4- yl)benzoic acid (153 mg, 0.5 mmol) and 3-(2-methoxyethoxy)propan-l-amine (67 mg, 0.5 mmol) as described for Example 33 to give the title compound as colorless liquid (158 mg, 75% yield). ESI-MS m/z [M+H]+ calc'd for C23H36N2O5, 421; found, 421.
[0287] Step 2: The title compound was prepared from above step 1 product (84 mg, 0.2 mmol) as described for Example 1 to give a colorless liquid (100% yield). 1H NMR (500 MHz, Chloroform-d) δ 9.44 (s, 1H), 9.17 (s, 1H), 7.71 (m, 2H), 7.61 (d, = 6.9 Hz, 1H), 7.37 (d, = 7.7 Hz, 2H), 3.94 - 3.42 (m, 10H), 3.29 (s, 3H), 3.08 (d, = 16.1 Hz, 2H), 2.87 (s, 1H), 2.22 (t, = 8.5 Hz, 2H), 2.06 (q, = 13.8, 11.3 Hz, 2H), 1.92 (d, = 5.7 Hz, 2H).; ESI-MS m/z [M+H]+ calc'd for C18H28N2O3, 321; found, 321.
Example 103: N-(3-ethoxy-2-hvdroxypropyl)-3-(piperidin-4-yl)benzamide hydrochloride
Figure imgf000126_0002
[0288] Step 1 : tert-butyl 4-(3 -((3 -ethoxy-2-hvdroxypropyl)carbamoyl)phenyl)piperidine- 1 - carboxylate: The title compound was prepared from 3-(l-(tert-butoxycarbonyl)piperidin-4- yl)benzoic acid (153 mg, 0.5 mmol) and l-amino-3-ethoxypropan-2-ol (60 mg, 0.5 mmol) as described for Example 33 to give the title compound as colorless liquid (165 mg, 75% yield). ESI-MS m/z [M+H]+ calc'd for Ciif^NiOs, 407; found, 407.
[0289] Step 2: The title compound was prepared from above step 1 product (81 mg, 0.2 mmol) as described for Example 1 to give a colorless liquid (100% yield). 1H NMR (500 MHz, Chloroform- ) δ 9.69 (s, IH), 9.37 (s, IH), 7.77 (s, IH), 7.68 (d, = 6.5 Hz, IH), 7.39 (d, = 6.4 Hz, 2H), 7.07 (m, IH), 4.03 (s, IH), 3.42-3.80 (m, 10H), 2.69 (m, IH), 2.55 (s, 29H), 2.36 - 2.17 (m, 2H), 2.15 - 1.97 (m, 2H), 1.21 (t, J = 7.0 Hz, 3H).; ESI-MS m/z [M+H]+ calc'd for C17H26N2O3, 307; found, 307.
Example 104: tert-butyl 4-((2,3-bis(tetradecyloxy)propyl)carbamoyl)-4-phenylpiperidine-l- carboxylate
Figure imgf000127_0001
[0290] The title compound was prepared from l-(tert-butoxycarbonyl)-4-phenylpiperidine- 4-carboxylic acid (153 mg, 0.5 mmol) and 2,3-bis(tetradecyloxy)propan-l-amine hydrochloride (260 mg, 0.5 mmol) as described for Example 33 to give the title compound as colorless liquid (315 mg, 81% yield). 1H NMR (500 MHz, Chloroform- ) δ 7.35 (d, J = 4.3 Hz, 3H), 7.29 - 7.22 (m, 2H), 5.74 (t, = 5.5 Hz, IH), 3.60 (t, = 8.5 Hz, 2H), 3.55 - 3.02 (m, 1 IH), 2.47 - 2.25 (m, 2H), 2.02 (m, 2H), 1.48 (s, 2H), 1.45 (s, 9H), 1.42 - 1.35 (m, 2H), 1.27 (d, J = 4.3 Hz, 44H), 0.89 (t, J = 6.9 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for C48H86N205, 772; found, 772.
Example 105: N-(2,3-bis(tetradecyloxy)propyl)-4-phenylpiperidine-4-carboxamide
hydrochloride
Figure imgf000128_0001
[0291] The title compound was prepared from Example 103 (154 mg, 0.2 mmol) as described for Example 1 to give a white solid (100% yield). 1H NMR (500 MHz, Chloroform- ) δ 9.62 (s, 2H), 7.52 - 7.27 (m, 5H), 5.77 (d, J = 5.5 Hz, 1H), 3.87 - 3.60 (m, 1H), 3.51 (d, J = 13.0 Hz,2H), 3.42 (m, 7H), 2.55 (s, 2H), 2.39 (s, 2H), 1.66 (s, 4H), 1.55 - 1.08 (m, 44H), 0.88 (t, 7 = 6.8 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for C43H78N203, 672; found, 672.
Figure imgf000128_0002
[0292] Stepl : tert-butyl (3-((2,3-bis(tetradecyloxy)propyl)amino)-3-oxo-2- phenylpropyPcarbamate: The title compound was prepared from 3-((tert- butoxycarbonyl)amino)-2-phenylpropanoic acid (133 mg, 0.5 mmol) and 2,3- bis(tetradecyloxy)propan- 1 -amine hydrochloride (260 mg, 0.5 mmol) as described for Example 33 to give the title compound as colorless liquid (310 mg, 85% yield). 1H NMR (500 MHz, Chloroform- ) δ 7.27 (m, 5H), 5.83 (t, J = 5.8 Hz, 1H), 5.17 (s, 1H), 3.83 - 2.99 (m, 12H), 1.70 - 1.45 (m, 4H), 1.42 (s, 9H), 1.27 (br s, 44H), 0.89 (t, J = 6.8 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for
Figure imgf000128_0003
732; found, 732.
[0293] Step 2: The title compound was prepared from above step 1 product (146 mg, 0.2 mmol) as described for Example 1 to give a white solid (100% yield). 1H NMR (500 MHz, Chloroform- ) δ 8.71 (s, 3H), 7.35 (q, J = 10.5, 8.7 Hz, 3H), 7.26 (s, 2H), 5.96 (d, J = 26.3 Hz, 1H), 4.18 (s, 1H), 3.63 - 3.03 (m, 9H), 1.71 (s, 2H), 1.40 (dd, J = 14.3, 7.1 Hz, 4H), 1.26 (br s, 44H), 0.88 (t, J = 6.8 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for C40H74N2O3, 632; found, 632. Example 107: tert-butyl 3-benzyl-3-((2,3-bis(tetradecyloxy)propyl)carbamoyl)piperidine-l- carboxylate
Figure imgf000129_0001
[0294] The title compound was prepared 3-benzyl-l-(tert-butoxycarbonyl)piperidine-3- carboxylic acid (170 mg, 0.5 mmol) and 2,3-bis(tetradecyloxy)propan-l-amine hydrochloride (260 mg, 0.5 mmol) as described for Example 33 to give the title compound as colorless liquid (273 mg, 70% yield). 1H NMR (500 MHz, Chloroform-d) δ 7.25 - 7.16 (m, 3H), 7.14 - 7.06 (m, 2H), 4.03 (m, 1H), 3.65 - 3.21 (m, 6H), 3.19 - 2.73 (m, 4H), 2.62 (m, 2H), 1.73 - 1.47 (m, 4H), 1.43 (s, 9H), 1.26 (s, 44H), 0.88 (t, J = 6.9 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for
Q9H88N2O5, 786; found, 786.
Example 108: 3-benzyl-N-(2,3-bis(tetradecyloxy)propyl)piperidine-3-carboxamide
hydrochloride
Figure imgf000129_0002
[0295] The title compound was prepared from Example 107 (157 mg, 0.2 mmol) as described for Example 1 to give a white solid (100% yield). 1H NMR (500 MHz, Chloroform- ) δ 11.69 (s, 1H), 7.32 - 7.27 (m, 4H), 7.09 (t, J = 9.2 Hz, 2H), 6.65 (d, J = 19.4 Hz, 1H), 3.94 - 3.22 (m, 12H), 2.98 (t, J = 13.0 Hz, 1H), 2.77 (d, / = 13.9 Hz, 2H), 1.94 (m, 3H), 1.69 (m, 2H), 1.58 - 1.46 (m, 4H), 1.42 - 1.14 (m, 44H), 0.88 (t, J = 6.9 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for C44H80N2O3, 686; found, 686. Example 109: 2-(benzylamino)-N-(2,3-bis(tetradecyloxy)propyl)-2-(piperidin-4-yl)acetamide hydrochloride
Figure imgf000130_0001
[0296] Stepl : tert-butyl 4-(l-(benzylamino)-2-((2,3-bis(tetradecyloxy)propyl)amino)-2- oxoethyl) piperidine- 1-carboxylate: The title compound was prepared from 2-(benzylamino)-2- (l-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (174 mg, 0.5 mmol) and 2,3- bis(tetradecyloxy)propan- 1 -amine hydrochloride (260 mg, 0.5 mmol) as described for Example 33 to give the title compound as light yellow liquid (262 mg, 64% yield). ESI-MS m/z [M+H]+ calc'd for C50H91N3O5, 815; found, 815.
[0297] Step 2: The title compound was prepared from above step 1 product (163 mg, 0.2 mmol) as described for Example 1 to give a light yellow solid (100% yield). 1H NMR (500 MHz, Chloroform- ) δ 9.96 (d, = 72.6 Hz, 1H), 8.95 (d, = 94.9 Hz, 3H), 8.37 (s, 1H), 7.60 (s, 2H), 7.32 (s, 3H), 4.16 (s, 3H), 3.76 - 3.27 (m, 12H), 3.03 (d, = 75.6 Hz, 5H), 2.51 (s, 1H), 2.27 (s, 1H), 1.90 (s, 2H), 1.52 (s, 4H), 1.24 (t, = 10.2 Hz, 44H), 0.88 (t, = 6.9 Hz, 6H).; ESI- MS m/z [M+H]+ calc'd for C45H83N303, 715; found, 715.
Example 110: 4-((benzylamino)methyl)-N-(2,3-bis(tetradecyloxy)propyl)piperidine-4- carboxamide hydrochloride
Figure imgf000130_0002
[0298] Stepl : tert-butyl 4-((benzylamino)methyl)-4-((2,3- bis(tetradecyloxy)propyl)carbamoyl) piperidine- 1-carboxylate: The title compound was prepared from 4-((benzylamino)methyl)- l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (174 mg, 0.5 mmol) and 2,3-bis(tetradecyloxy)propan-l-amine hydrochloride (260 mg, 0.5 mmol) as described for Example 33 to give the title compound as yellow liquid (215 mg, 53% yield). ESI-MS m/z [M+H]+ calc'd for C50H91N3O5, 815; found, 815.
[0299] Step 2: The title compound was prepared from above step 1 product (163 mg, 0.2 mmol) as described for Example 1 to give a yellow solid (100% yield). 1H NMR (500 MHz, Chloroform- ) δ 9.82 - 8.66 (m, 4H), 7.62 (m, 2H), 7.36 (m, 3H), 6.03 (s, 1H), 4.32 (m, 2H), 3.98 - 2.77 (m, 14H), 2.57 - 2.04 (m, 4H), 1.54 (m, 4H), 1.25 (br s, 44H), 0.88 (td, J = 7.0, 2.0 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for C45H83N3O3, 715; found, 715.
Example 111: N-benzyl-2,3-bis(tetradecyloxy)propan-l-amine
Figure imgf000131_0001
[0300] In a 50 mL round bottom flask, 2,3-bis(tetradecyloxy)propan-l -amine hydrochloride (520 mg, 1.0 mmol) and benzaldehyde (127 mg, 1.2 mmol) were dissolved in THF (15 mL), then added NaBH(OAc)3 (414, 2.0 mmol) portion wise to the reaction mixture and continued stirring overnight at room temperature. Then neutralized with sat.NaHC03 solution and extracted into ethyl acetate (2 x 50 mL). Combined organic phase washed with brine and dried over sodium sulfate and evaporated. Then, purified on silica gel column chromatography using dichloromethane-MeOH (0-10%) as eluent. Pure product fractions combined evaporated to give the desired product as colorless liquid (225 mg, 39% yield). 1H NMR (500 MHz, Chloroform- ) δ 7.51 - 7.28 (m, 7H), 3.62 (ddd, J = 11.2, 8.1, 5.4 Hz, 2H), 3.54 - 3.32 (m, 6H), 2.77 (qd, J = 12.2, 5.7 Hz, 2H), 1.55 (m, 4H), 1.38 - 1.20 (m, 44H), 0.88 (t, J = 6.9 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for C38H71N02, 575; found, 575.
Example 112: N-benz l-N,N-dimethyl-2,3-bis(tetradecyloxy)propan-l-aminium iodide
Figure imgf000131_0002
[0301] The title compound was prepared from Example 110 (175 mg, 0.305 mmol) as described for Example 92 to give a light yellow solid (178 mg, 80%). 1H NMR (500 MHz, Chloroform- ) δ 7.68 (dd, J = 7.0, 1.8 Hz, 2H), 7.59 - 7.37 (m, 3H), 5.19 - 4.86 (m, 2H), 4.19 (dq, J = 10.0, 3.3, 2.8 Hz, 1H), 4.01 (dd, J = 13.8, 2.2 Hz, 1H), 3.80 - 3.45 (m, 5H), 3.43 - 3.26 (m, 8H), 1.74 - 1.47 (m, 4H), 1.25 (br s, 44H), 0.88 (t, J = 6.8 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for C40H76lNO2, 731; found, 731.
Example 113: tert-butyl 4-(3-((2,3-bis(((Z)-tetradec-8-en-l-yl)oxy)propyl)carbamoyl)phenyl) piperidine- 1 -carboxylate
Figure imgf000132_0001
[0302] To a stirred mixture of tert-butyl 4-(3-(2,3- dihydroxypropylcarbamoyl)phenyl)piperidine-l -carboxylate (500 mg, 1.322m mol) and olelyl bromide (2.2 g, 7.936 m mol) in toluene (15 mL) were added 50% aq. NaOH solution (4.0 mL) and Bu4NI (2.95 g, 0.661 m mol) and the resulting reaction mixture was heated to 50-60 °C and maintained on vigorous stirring for 6 hours at same temperature. The completion of reaction was monitored by TLC. The reaction mixture was work up with ethyl acetate (2X 20 ml) and water (10 ml) at room temperature. The combined organic phases were concentrated and purified by silica-gel column chromatography gradient elution with 5-20% ethyl acetate in hexane to obtain pure desired product as a colorless gel (450 mg, 54%). ESI-MS m/z [M+H]+ calc'd for
C48H82N205, 768; found, 768.
Example 114: N-(2,3-bis(((Z)-tetradec-8-en-l-yl)oxy)propyl)-3-(piperidin-4-yl)benzamide hydrochloride
Figure imgf000133_0001
[0303] To a stirred solution of Example 113 (550 mg) in methanol (5 ml) was added Methanolic HCl (10 mL) and stirring was continued for lh at room temperature. The completion of reaction monitored by TLC, the mixture was concentrated and the obtained crude product was purified by Preparative HPLC to furnish desired target product (N-(2,3-bis((Z)-tetradec-8- enyloxy)propyl)-3-(piperidin-4-yl)benzamide hydrochloride as colorless sticky solid (230 mg, 48%). 1H NMR (300 MHz, DMSO-d6): δ 7.70 (d, 7=5.7 Hz, 2H), 7.43-7.35 (m, 2H)), 5.36-5.26 (m, 4H), 3.56-3.26 (m, 16H), 3.01-2.89 (m, 3H), 1.97-1.93 (m, 12H), 1.44-1.41 (m, 5H), 1.41- 1.2 (m, 23H), 0.845 (t, 7= 6.0, 7.2 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for C43H74N203, 668; found, 668.
Example 115: tert-butyl 4-(3-((2.3-bis(((9Z.12Z)-octadeca-9.12-dien-l-yl)oxy)propyl) carbamoyl phenvDpiperidine- 1 -carboxylate
Figure imgf000133_0002
[0304] The title compound was prepared from 2-(l-(tert-butoxycarbonyl)piperidin-4- yl)benzoic acid (153 mg, 0.5 mmol) and 2,3-bis(((9Z,12Z)-octadeca-9,12-dien-l-yl)oxy)propan- 1 -amine hydrochloride (313 mg, 0.5 mmol) (prepared as in Example 1 using lenoleyl bromide) as described for Example 33 to give the title compound as colorless oil (325 mg, 74% yield). 1H NMR (499 MHz, Chloroform- ) δ 7.68 (d, 7 = 1.9 Hz, 1H), 7.53 (dt, 7 = 7.1, 1.8 Hz, 1H), 7.42 - 7.29 (m, 2H), 6.72 (t, J = 5.5 Hz, 1H), 5.63 - 5.05 (m, 8H), 4.25 (s, 2H), 3.83 - 3.33 (m, 10H), 2.88 - 2.56 (m, 7H), 2.20 - 1.93 (m, 9H), 1.92 - 1.73 (m, 2H), 1.72 - 1.51 (m, 6H), 1.48 (s, 9H), 1.40 - 1.17 (m, 26H), 0.89 (t, / = 6.8 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for CseH^NiOs, 876; found, 876.
Example 116: N-(2,3-bis(((9ZJ2Z)-octadeca-9 J2-dien-l-yl)oxy)propyl)-3-(piperidin-4- yPbenzamide hydrochloride
Figure imgf000134_0001
[0305] The title compound was prepared from Example 115 (175 mg, 0.2 mmol) as described for Example 1 to give an off-white solid (100% yield). 1H NMR (500 MHz,
Chloroform-d) δ 9.69 (br d, 2H), 7.73 (s, 1H), 7.54 (d, = 7.0 Hz, 1H), 7.39 (d, = 8.2 Hz, 2H), 6.77 (d, = 6.0 Hz, 1H), 5.55 - 5.13 (m, 8H), 3.90 - 3.30 (m, 9H), 3.04 (s, 2H), 2.77 (t, = 6.7 Hz, 6H), 2.26 (s, 2H), 2.15 - 1.92 (m, 10H), 1.77 (s, 4H), 1.56 (q, = 7.2 Hz, 4H), 1.44 - 1.12 (m, 28H), 0.88 (t, = 6.7 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for CsiHgeNiOs, 776; found, 776.
Example 117: tert-butyl ((5R)-5-(benzylamino)-6-((2,3-bis(((9Z,12Z)-octadeca-9,12-dien-l- yl)oxy)propyl)amino -6-oxohexyl)carbamate
Figure imgf000134_0002
[0306] The title compound was prepared from N2-benzyl-N6-(tert-butoxycarbonyl)-D- lysine (168 mg, 0.5 mmol) and 2,3-bis(((9Z,12Z)-octadeca-9,12-dien-l-yl)oxy)propan-l-amine hydrochloride (313 mg, 0.5 mmol) as described for Example 33 to give the title compound as colorless oil (410 mg, 90% yield). 1H NMR (500 MHz, Chloroform-d) δ 7.45 (d, J = 5.6 Hz, 2H), 7.43 - 7.32 (m, 3H), 7.13 - 6.92 (m, IH), 5.48 - 5.20 (m, 8H), 4.82 (s, IH), 4.24 (d, = 12.9 Hz, IH), 4.16 - 3.99 (m, 3H), 3.84 - 3.69 (m, IH), 3.69 - 3.27 (m, 7H), 3.18 - 2.94 (m, 3H), 2.79 (s, 6H), 2.13 - 1.80 (m, 8H), 1.66 - 1.41 (m, 5H), 1.40 - 1.16 (m, 44H), 0.89 (t, J = 6.8 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for C57H99N3O5, 907; found, 907.
Example 118: (2R)-6-amino-2-(benzylamino)-N-(2,3-bis(((9Z,12Z)-octadeca-9,12-dien-l- yl)oxy)propyl)hexanamide dihydrochloride
Figure imgf000135_0001
[0307] The title compound was prepared from Example 117 (181 mg, 0.2 mmol) as described for Example 1 to give an off-white solid (100% yield). 1H NMR (500 MHz,
Chloroform- ) δ 9.65 (s, IH), 8.51 (s, IH), 7.76 (s, 3H), 7.52 (s, 2H), 7.33 (s, 3H), 5.34 (m, 8H), 4.19 (m, 8H), 3.49 (m, 9H), 2.90 (m, 2H), 2.76 (dt, = 6.6, 4.3 Hz, 4H), 2.04 (q, = 8.0, 7.6 Hz, 8H), 1.77 (s, IH), 1.53 (s, 5H), 1.30 (br s, 32H), 0.88 (t, = 6.7 Hz, 6H).; ESI-MS m/z [M+H]+ calc'd for C52H91N3O3, 807; found, 807.
Figure imgf000135_0002
[0308] Step 1: tert-butyl (S)-(5-(benzylamino)-6-oxo-6-(tetradecylamino)hexyl)carbamate: The title compound was prepared from N2-benzyl-N6-(tert-butoxycarbonyl)-L-lysine (168 mg, 0.5 mmol) and tetradecan-1 -amine (107 mg, 0.5 mmol) as described for Example 33 to give the title compound as gummy solid (155 mg, 58% yield). ESI-MS m/z [M+H]+ calc'd for
C32H57N3O3, 532; found, 532.
[0309] Step 2: The title compound was prepared from above obtained step 1 product (106 mg, 0.2 mmol) as described for Example 1 to give an off-white solid (100% yield). 1H NMR (500 MHz, Chloroform- ) δ 9.19 (s, IH), 8.30 (s, IH), 7.78 (s, IH), 7.40 (m, 5H), 4.19 (s, IH), 4.00 (s, 2H), 3.36 - 3.10 (m, IH), 3.07 - 2.80 (m, 3H), 1.97 (s, 2H), 1.70 (m, 2H), 1.46 (s, 3H), 1.25 (d, J = 8.6 Hz, 26H), 0.88 (td, J = 6.9, 3.5 Hz, 3H).; ESI-MS m/z [M+H]+ calc'd for C27H49N30, 432; found, 432.
Example 120: (S)-6-amin -2-(benzylamino)-N-decylhexanamide dihydrochloride
Figure imgf000136_0001
[0310] Stepl: tert-butyl (S)-(5-(benzylamino)-6-(decylamino)-6-oxohexyl)carbamate: The title compound was prepared from N2-benzyl-N6-(tert-butoxycarbonyl)-L-lysine (168 mg, 0.5 mmol) and decyl-l-amine (79 mg, 0.5 mmol) as described for Example 33 to give the title compound as semi solid (158 mg, 66% yield). ESI-MS m/z [M+H]+ calc'd for CigH^C^, 476; found, 476.
[0311] Step 2: The title compound was prepared from above obtained step 1 product (97 mg, 0.2 mmol) as described for Example 1 to give an off-white solid (100% yield). 1H NMR (500 MHz, Chloroform- ) δ 9.30 (s, IH), 8.39 (s, IH), 7.42 (m, 7H), 4.10 (m, 3H), 3.52 - 2.63 (m, 4H), 1.88 (m, 5H), 1.47 (s, 4H), 1.26 (br s, 14H), 0.87 (t, J = 6.9 Hz, 3H).; ESI-MS m/z [M+H]+ calc'd for C23H4iN30, 376; found, 376.
Example 121: (S)-6-amino-2-(benzylamino)-N-(3-ethoxypropyl)hexanamide dihydrochloride
Figure imgf000137_0001
[0312] Step 1: tert-butyl (S)-(5-(benzylamino)-6-((3-ethoxypropyl)amino)-6- oxohexyPcarbamate: The title compound was prepared from N2-benzyl-N6-(tert- butoxycarbonyl)-L-lysine (168 mg, 0.5 mmol) and 3-ethoxypropan-l-amine (52 mg, 0.5 mmol) as described for Example 33 to give the title compound as semi solid (153 mg, 73% yield). ESI- MS m/z [M+H]+ calc'd for C23H39N3O4, 422; found, 422.
[0313] Step 2: The title compound was prepared from above obtained step 1 product (84 mg, 0.2 mmol) as described for Example 1 to give a gummy solid (100% yield). 1H NMR (500 MHz, Chloroform- ) δ 7.86 - 7.31 (m, 8H), 3.68 - 3.54 (m, 3H), 3.50 (m, 3H), 3.25 (s, 5H), 2.04 (m, 2H), 1.81 (m, 2H), 1.52-1.00 (m, 7H).; ESI-MS m/z [M+H]+ calc'd for C18H31N3O2, 322; found, 322.
Example 122: (S)-6-amino-2-(benzylamino)-N-(3-(octyloxy)propyl)hexanamide
dihydrochloride
Figure imgf000137_0002
[0314] Step 1: tert-butyl (S)-(5-(benzylamino)-6-((3-(octyloxy)propyl)amino)-6- oxohexyDcarbamate: The title compound was prepared from N2-benzyl-N6-(tert- butoxycarbonyl)-L-lysine (168 mg, 0.5 mmol) and 3 3-(octyloxy)propan-l -amine (112 mg, 0.5 mmol) as described for Example 33 to give the title compound as semi solid (172 mg, 68% yield). ESI-MS m/z [M+H]+ calc'd for C29H51N3O4, 506; found, 506. [0315] Step 2: The title compound was prepared from above obtained step 1 product (101 mg, 0.2 mmol) as described for Example 1 to give a gummy solid (100% yield). 1H NMR (500 MHz, Chloroform-d) δ 9.34 (s, IH), 8.42 (s, IH), 7.42 (m, 7H), 4.10 (m, 3H), 3.40 (s, 5H), 2.97 (m, 3H), 2.04 (m, 2H), 1.75 (s, 3H), 1.52 (s, 3H), 1.33 - 1.10 (m, 12H), 0.87 (t, J = 6.7 Hz, 3H).; ESI-MS m/z [M+H]+ calc'd for C24H43N302, 406; found, 406.
Example 123: (S)-6-amino-N-(2-cyclohexylethyl)-2-((naphthalen-2- ylmethyl)amino)hexanamide dihydrochloride
Figure imgf000138_0001
[0316] Step 1 : tert-butyl (S)-(6-((2-cyclohexylethyl)amino)-5-((naphthalen-2- ylmethyl)amino)-6-oxohexyl)carbamate: The title compound was prepared from N6-(tert- butoxycarbonyl)-N2-(naphthalen-2-ylmethyl)-L- lysine (193 mg, 0.5 mmol) and 2- cyclohexylethan- 1 -amine (82 mg, 0.5 mmol) as described for Example 33 to give the title compound as semi solid (182 mg, 73% yield). ESI-MS m/z [M+H]+ calc'd for C30H45N3O3, 496; found, 496.
[0317] Step 2: The title compound was prepared from above obtained step 1 product (100 mg, 0.2 mmol) as described for Example 1 to give an off-white solid (100% yield). 1H NMR (500 MHz, Chloroform- ) δ 9.53 (s, IH), 8.52 (s, IH), 7.62 (m, 10H), 4.09 (m, 5H), 2.93 (m, 2H), 2.21 - 0.51 (m, 19H).; ESI-MS m/z [M+H]+ calc'd for C25H37N30, 396; found, 396.
Example 124: (S)-6-amino-N-methyl-2-((naphthalen-2-ylmethyl)amino)hexanamide
dihydrochloride
Figure imgf000139_0001
[0318] Step 1: tert-butyl (S)-(6-((2-cyclohexylethyl)amino)-5-((naphthalen-2- ylmethyl)amino)-6-oxohexyl)carbamate: The title compound was prepared from N6-(tert- butoxycarbonyl)-N2-(naphthalen-2-ylmethyl)-L- lysine (193 mg, 0.5 mmol) and methylamine hydrochloride (34 mg, 0.5 mmol) as described for Example 33 to give the title compound as semi solid (156 mg, 78% yield). ESI-MS m/z [M+H]+ calc'd for C23H33N3O3, 400; found, 400.
[0319] Step 2: The title compound was prepared from above obtained step 1 product (80 mg, 0.2 mmol) as described for Example 1 to give an off-white gummy solid (100% yield). 1H NMR (500 MHz, DMSO- e) δ 9.85 (s, 1H), 9.35 (s, 1H), 8.63 (q, J = 4.7 Hz, 1H), 8.14 - 7.80 (m, 7H), 7.79 - 7.39 (m, 3H), 4.22 (q, J = 13.1 Hz, 2H), 3.88 - 3.36 (m, 1H), 2.79 - 2.70 (m, 2H), 2.50 (s, 3H), 2.10 - 1.06 (m, 6H).; ESI-MS m/z [M+H]+ calc'd for C18H25N3O, 300; found, 300.
Example 125: (2S)-6-amino-2-(benzylamino)-N-(2,3-bis(heptyloxy)propyl)hexanamide dihydrochloride
Figure imgf000139_0002
[0320] Step 1: tert-butyl ((5S)-5-(benzylamino)-6-((2,3-bis(heptyloxy)propyl)amino)-6- oxohexyl) carbamate: The title compound was prepared from N2-benzyl-N6-(tert- butoxycarbonyl)-L-lysine (400 mg, 1.19 mmol) and 2,3 -bis(heptyloxy)propan- 1 -amine (347 mg, 1.19 mmol) as described for Step 3 of Example 93 to give the title compound as semi solid (370 mg, 51% yield). ESI-MS m/z [M+H]+ calc'd for C35H63N3O5, 606; found, 606. [0321] Step 2: The above compound was dissolved in methanol (2 mL) and methanolic HC1 (10 mL) was added and stirred at room temperature for 3 hours and the solvent was concentrated to dryness under vacuum gave title compound (100% yield). 1H NMR (300 MHz, DMSO-d6) d ppm: 10.0 (br s, lH), 9.4-9.2 (br s,lH), 8.8-8.6 (s, IH), 8.0 (s, 3H), 7.6-7.3 (m, 5H), 4.0 (s, 2H), 3.8-3.6 (s, IH), 3.6-3.2 (m, 10H), 3.2 (m, IH), 2.8-2.6 (m, 2H), 2.0- 1.7 (m, 2H), 1.6-1.4 (m, 4H), 1.4- 1.0 (m, 18H), 0.8 (m, 6H).; ESI-MS m/z [M+H]+ calc'd for C30H55N3O3, 506; found, 506.
Example 126: (2S)-6-amino-2-(benzylamino)-N-(2,3-bis((5-methoxypentyl)oxy)propyl) hexanamide dihydrochloride
Figure imgf000140_0001
[0322] Step 1 : tert-butyl ((5S)-5-(benzylamino)-6-((2,3-bis((5- methoxypentyl)oxy)propyl)amino)-6-oxohexyl)carbamate: The title compound was prepared from N2-benzyl-N6-(tert-butoxycarbonyl)-L-lysine (400 mg, 1.19 mmol) and 2,3-bis (5- methoxypentyloxy) prop an- 1- amine. HC1 (476 mg, 1.637 mmol) as described for Step 3 of Example 93 to give the title compound as semi solid (400 mg, 55% yield). ESI-MS m/z [M+H]+ calc'd for C33H59N3O7, 610; found, 610.
[0323] Step 2: The above compound was dissolved in methanol (2 mL) and methanolic HC1 (10 mL) was added and stirred at room temperature for 3h and the solvent was concentrated to dryness under vacuum gave title compound (100% yield). 1H NMR (300 MHz, DMSO-d6) d ppm: 10.0-9.8 (br s, IH), 9.3 (br s, IH), 8.7 (s, IH), 8.0 (s, 3H), 7.6-7.3 (m, 5H), 4.0 (s, 2H), 3.8- 3.7 (s, IH), 3.6-3.3 (m, 11H), 3.0 (s, 6H), 2.8-2.6 (m, 2H), 2.0- 1.7 (m, 2H), 1.6- 1.3 (m, 18H).; ESI-MS m/z [M+H]+ calc'd for C28H51N3O5, 510; found, 510.
Example 127: tert-butyl (S)-(5-(benzylamino)-6-oxo-6-(tetradecylamino)hexyl)carbamate
Figure imgf000141_0001
Figure imgf000141_0002
[0324] The title compound was prepared from N2-benzyl-N6-(tert-butoxycarbonyl)-L-lysine (168 mg, 0.5 mmol) and tetradecan-1 -amine (107 mg, 0.5 mmol) as described for Example 33 to give the title compound as gummy solid (155 mg, 58% yield). ESI-MS m/z [M+H]+ calc'd for C32H57N3O3, 532; found, 532.
Example 128: tert-butyl (S)- -(benzylamino)-6-(decylamino)-6-oxohexyl)carbamate
Figure imgf000141_0003
[0325] The title compound was prepared from N2-benzyl-N6-(tert-butoxycarbonyl)-L-lysine (168 mg, 0.5 mmol) and decyl-l-amine (79 mg, 0.5 mmol) as described for Example 33 to give the title compound as semi solid (158 mg, 66% yield). ESI-MS m/z [M+H]+ calc'd for
C28H49N303, 476; found, 476.
Example 129: tert-butyl (S)-(5-(benzylamino)-6-((3-ethoxypropyl)amino)-6- oxohexyDcarbamate
Figure imgf000142_0001
[0326] The title compound was prepared from N2-benzyl-N6-(tert-butoxycarbonyl)-L-lysine (168 mg, 0.5 mmol) and 3-ethoxypropan-l-amine (52 mg, 0.5 mmol) as described for Example 33 to give the title compound as semi solid (153 mg, 73% yield). ESI-MS m/z [M+H]+ calc'd for C23H39N3C , 422; found, 422.
Example 130: tert-butyl (S)-(5-(benzylamino)-6-((3-(octyloxy)propyl)amino)-6-
Figure imgf000142_0002
[0327] The title compound was prepared from N2-benzyl-N6-(tert-butoxycarbonyl)-L-lysine (168 mg, 0.5 mmol) and 3 3-(octyloxy)propan-l-amine (112 mg, 0.5 mmol) as described for Example 33 to give the title compound as semi solid (172 mg, 68% yield). ESI-MS m/z [M+H]+ calc'd for C29H51N3O4, 506; found, 506.
Example 131: tert-butyl (S)-(6-((2-cvclohexylethyl)amino)-5-((naphthalen-2-ylmethyl)amino)- 6-oxohexyl)carbamate
Figure imgf000143_0001
[0328] The title compound was prepared from N6-(tert-butoxycarbonyl)-N2-(naphthalen-2- ylmethyl)-L-lysine (193 mg, 0.5 mmol) and 2-cyclohexylethan-l -amine (82 mg, 0.5 mmol) as described for Example 33 to give the title compound as semi solid (182 mg, 73% yield). ESI-MS m/z [M+H]+ calc'd for C30H45N3O3, 496; found> 496·
Example 132: tert-butyl (S)-(6-((2-cvclohexylethyl)amino)-5-((naphthalen-2-ylmethyl)amino)-
6-oxohexyl)carbamate
Figure imgf000143_0002
[0329] The title compound was prepared from N6-(tert-butoxycarbonyl)-N2-(naphthalen-2- ylmethyl)-L-lysine (193 mg, 0.5 mmol) and methylamine hydrochloride (34 mg, 0.5 mmol) as described for Example 33 to give the title compound as semi solid (156 mg, 78% yield). ESI-MS m/z [M+H]+ calc'd for C23H33N3O3, 400; found, 400.
Example 133: (2S)-6-amino-N-(3-ethoxy-2-hydroxypropyl)-2-((naphthalen-2-ylmethyl)amino) hexanamide dihydrochloride
Figure imgf000144_0001
[0330] Step 1: tert-butyl ((5S)-6-((3-ethoxy-2-hvdroxypropyl)amino)-5-((naphthalen-2- ylmethvPamino) -6-oxohexyl)carbamate: The title compound was prepared from N6-(tert- butoxycarbonyl)-N -(naphthalen-2-ylmethyl)-L-lysine (synthesized as in Example 56) (194 mg, 0.5 mmol) and l-amino-3-ethoxypropan-2-ol (60 mg, 0.5 mmol) as described for Example 33 to give the title compound as yellow liquid (173 mg, 71% yield). ESI-MS m/z [M+H]+ calc'd for C27H4iN305, 488; found, 488.
[0331] Step 2: The title compound was prepared from above obtained step 1 product (98 mg, 0.2 mmol) as described for step 2 of Example 1 to give a yellow solid (100% yield). 1H NMR (500 MHz, DMSO-i ) δ 9.76 (s, 1H), 9.34 (s, 1H), 8.63 (s, 1H), 8.12 - 7.78 (m, 8H), 7.76 - 7.38 (m, 3H), 4.21 (s, 2H), 4.05 - 3.62 (m, 3H), 3.53 - 3.22 (m, 6H), 3.09 (td, J = 13.8, 7.1 Hz, 1H), 2.04 - 1.68 (m, 2H), 1.56 (q, J = 7.7 Hz, 2H), 1.35 (s, 2H), 1.12 (dd, J = 7.4, 6.5 Hz, 3H).; ESI- MS m/z [M+H]+ calc'd for C22H33N303, 388; found, 388.
Example 134: (S)-6-amin -2-(benzylamino)-N-(2-(heptyloxy)ethyl)hexanamide dihvdrochloride
Figure imgf000144_0002
[0332] Step 1: tert-butyl (S)-(5-(benzylamino)-6-((2-(heptyloxy)ethyl)amino)-6- oxohexyDcarbamate: Title compound was prepared from (S)-2-(benzylamino)-6-(tert- butoxycarbonylamino)hexanoic acid (400 mg, 1.19 mmol) and 2-(heptyloxy) ethanamine (189 mg, 1.19 mmol) as described for Step 3 of Example 93 to give the title compound as semi solid (380 mg, 67% yield). ESI-MS m/z [M+H]+ calc'd for C27H47N304, 478; found, 478. [0333] Step 2: The above compound was dissolved in methanol (2 mL) and methanolic HC1 (10 mL) was added and stirred at room temperature for 3h and the solvent was evaporated to dryness gave title compound (100% yield). 1H NMR (300 MHz, DMSO-d6) δ 10.0 (br s,lH), 9.3 (br s, IH), 8.8 (s, IH), 8.1 (s, 2H), 7.6-7.3 (m, 5H), 4.0 (s, 2H), 3.7 (s, IH), 3.5-3.2 (m, 6H), 2.8- 2.6 (m, 2H), 1.9-1.4 (m, 8H), 1.4-1.0 ( m, 8H), 0.9-0.7 (m, 3H).; ESI-MS m/z [M+H]+ calc'd for C22H39N3O2, 378; found, 378.
Example 135: (2S)-6-amino-2-(benzylamino)-N-(2-(heptyloxy)-3-methoxypropyl)hexanamide dihydrochloride
Figure imgf000145_0001
[0334] Step 1: tert-butyl ((5S)-5-(benzylamino)-6-((2-(heptyloxy)-3-methoxypropyl)amino)- 6-oxohexyl)carbamate: Title compound was prepared from (S)-2-(benzylamino)-6-(tert- butoxycarbonylamino)hexanoic acid (400 mg, 1.19 mmol) and 2-(heptyloxy)3-methoxypropan- 1 -amine hydrochloride (241 mg, 1.19 mmol) as described for Step 3 of Example 93 to give the title compound as semi solid (350 mg, 56% yield). ESI-MS m/z [M+H]+ calc'd for C29H51N3O5, 522; found, 522.
[0335] Step 2: The above compound was dissolved in methanol (2 mL) and methanolic HC1 (10 mL) was added and stirred at room temperature for 3h and the solvent was evaporated to dryness gave title compound (100% yield). 1H NMR (300 MHz, DMSO-d6) δ 9.7 (br s,lH), 9.3 (br s,lH), 8.7 (s, IH), 8.0-7.8 (s, 2H), 7.6-7.3 ( m, 5H), 4.0 (s, 2H), 3.8-3.6 (s, IH), 3.5-3.2 (m, 8H), 2.8-2.6 (m, 3H), 2.9-2.7 (m, 2H), 1.6-1.4 (m, 4H), 1.4-1.1 ( m, 12H), 0.9-0.7 (m, 3H).; ESI- MS m/z [M+H]+ calc'd for C24H43N303, 422; found, 422.
[0336] The following compounds may be prepared using methods analogous to those described herein. Example 136: N-(l-((2,3-Bis(tetradecyloxy)propyl)amino)- l-oxotetradecan-2-yl)-5-fluoro- 1H- indole-3-carboxamide.
Figure imgf000146_0001
Example 137: N-(2,3-Bis(tetradecyloxy)propyl)-2-((l-(5-fluoro-lH-indol-3- yl)tetradecyl)amino)acetamide.
Figure imgf000146_0002
Example 138: 3-((l-(lH-Indol-3-yl)tetradecyl)amino)-N-(2,3-bis(tetradecyloxy)
Figure imgf000146_0003
Example 139: 2-Amino-N- l,3-bis(octadecyloxy)propan-2-yl)-3-guanidinopropanamide.
Figure imgf000146_0004
[0337] The title compound may be prepared from l,3-bis(octadecyloxy)propan-2-amine using methods analogous to those described herein.
Example 140: 2-Amino-N-(l,3-bis(octadecyloxy)propan-2-yl)-3-(lH-imidazol-5- vPpropanamide.
Figure imgf000147_0001
Example 141: 2-Amino-N- l,3-bis(octadecyloxy)propan-2-yl)-3-(lH-indol-2-yl)propanamide.
Figure imgf000147_0002
Example 142: 2 5-Diamino-N-(l,3-bis(octadecyloxy)propan-2-yl)pentanamide.
Figure imgf000147_0003
Example 143: 2 6-Diamino-N-(l,3-bis(octadecyloxy)propan-2-yl)hexanamide.
Figure imgf000147_0004
Biological Example 1: Preparation of liposomal formations.
[0338] Eight milligrams of Example 13 was dissolved in 1 mL of chloroform. The resulting colorless clear solution was evaporated using a Bueche rotovap apparatus under reduced pressure at 40 °C. [0339] To the resulting uniform nearly-clear coating on the glass walls was added 1 mL of IX PBS buffer at pH 7.3. The vial was vortexed for 3 min, resulting in a turbid suspension of the liposome. The vial was then immersed in a sonication bath for 3 min, followed by probe sonication at 5 second intervals repeatedly five times. The translucent solution was then extruded though a 100 nm membrane filter repeatedly 10 times, and the nearly clear solution was stored at 4 °C. Differential light scattering of this solution using a Wyatt (dynapro) apparatus showed the average particle size to be 120 nm with a dispersion factor of 0.15.
[0340] This procedure can be used to create liposomal formulations with mixtures of other nonactive lipids such as those sold commercially (Avantis polar lipids).
Biological Example 2: In vitro Assay
[0341] Synthetic diacylated lipoprotein (Pam2CSK4, TLR2/6 agonist) and synthetic triacylated lipoprotein (Pam3CSK4, TLR1/2 agonist) were obtained from InvivoGen and were dissolved in endotoxin-free water to a concentration 1 mg/mL, vortexed until complete solubilization, and stored in aliquots at -20 °C. TNFa was obtained from Thermo Fisher Scientific and was used as a counter- screen for specificity to TLR signaling. It was dissolved in endotoxin-free water to a concentration 0.2 mg/ml, and stored in aliquots at -20°C. Prior to addition to cells, an aliquot of the dissolved ligand was vortexed shortly and then was diluted in medium to 25 ng/mL Pam2CSK4, 1000 ng/mL Pam3CSK4 or TNFa. The final top
concentration used to determine the agonist EC50 for each assay run was 5 ng/mL (Pam2CSK4) or 200 ng/mL (Pam3CSK4 or TNFa).
[0342] Test compounds were solubilized fresh to 3 - 10 mM stocks in 50% DMSO/50% EtOH and sonicated for 5-10 minutes in a water bath sonicator. Serial dilutions were prepared in 50% DMSO/50% EtOH, and then diluted in medium. The final concentration of DMSO used in the assay was 0.5%, and the final concentration of EtOH was 0.5%.
[0343] HEK-Blue hTLR2 reporter cells (InvivoGen) are HEK-293 cells stably expressing both the human TLR2 gene and a secreted embryonic alkaline phosphatase (SEAP) reporter construct downstream of NFKB promotor sites. HEK-Blue hTLR2 reporters were cultured according to manufacturer's protocol using Dulbecco's Modified Eagle Medium (DMEM; Gibco) containing IX GlutaMax (Gibco), 10% heat-inactivated Fetal Bovine Serum (Gibco), Pen-Strep (50 U/mL penicillin, 50 μg/mL streptomycin, Gibco), 100 μg/mL Normocin
(InvivoGen), and the selective antibiotic, lx HEK-Blue Selection (InvivoGen). Quanti-Blue reagent (InvivoGen) for detection and quantification of secreted alkaline phosphatase was dissolved in 100 mL of endotoxin-free water, warmed to 37 °C for 30 minutes and then filtered using a 0.2 μιη membrane.
HEK-Blue hTLR2 antagonism assay
[0344] On day 1, 50 μΐ^ of each test compound dilution in duplicates or a vehicle control was added to each well of a 96-well plate followed by addition of 150 μΐ^ of HEK-Blue hTLR2 cell suspension (lxlO5 cells/well) and incubated at 37 °C/5% C02 for 2 h. Next, 50 μL· of an approximate EC50 concentration of each agonist (Pam2CSK4, Pam3CSK4, or TNFa) was added to the wells containing test compounds or the vehicle control. The plates were then incubated at 37 °C/5% C02 for 18 h. For each assay run, non-treated HEK-Blue hTLR2 cells were treated with serial dilutions of agonists to determine EC50 values for the respective run.
[0345] On day 2, secreted alkaline phosphatase (SEAP) activity was detected in cell culture supernatants. In brief, 20 μΐ^ was collected from each well and transferred to a 96-well plate. Next, 200 μΐ^ of Quanti-Blue detection reagent was added to each well. Plates were incubated at room temperature for 15 min and SEAP activity was assessed by spectrophotometer OD reading at 655 nm. Table 7 shows the activities of the compounds against Pam2CSK4, Pam3CSK4, and TNFa. The activities of the compounds against Pam2CSK4 and Pam3CSK4 are presented as IC50 values for the response from cells treated with agonists with the background signal subtracted. The compound of Example 93 displayed an IC50 of 10 μΜ against TNFa. The activities of all other compounds against TNFa are shown in Table 7 and are denoted as (+) for IC50 values < 30 μΜ and (-) for IC50 values > 30 μΜ.
Table 7:
Figure imgf000149_0001
4 >30 19.3 (-)
5 >30 >30 (-)
6 >30 9.2 (-)
7 >30 >30 (-)
8 >30 >30 (-)
9 >30 >30 (-)
10 >30 1.6 (-)
11 >30 >30 (-)
12 >30 >30 (-)
13 >30 >30 (-)
14 >30 >30 (-)
15 >30 >30 (-)
16 >30 >30 (-)
17 >30 14.3 (-)
18 >30 >30 (-)
19 >30 >30 (-)
20 >30 12.6 (-)
21 >30 >30 (-)
22 >30 6.2 (-)
23 >30 >30 (-)
24 >30 >30 (-)
25 >30 >30 (-)
26 >30 11.4 (-)
27 >30 >30 (-)
28 >30 26.3 (-)
29 >30 >30 (-)
30 13.3 15.3 (-)
31 >30 >30 (-)
32 >30 2.3 (-)
33 >30 >30 (-)
34 >30 >30 (-)
35 >30 >30 (-)
36 >30 >30 (-)
37 >30 >30 (-)
38 18 11.2 (-)
39 >30 >30 (-)
40 19.6 4.9 (-)
41 >30 >30 (-)
42 >30 >30 (-)
43 >30 >30 (-)
44 >30 18 (-)
45 >30 >30 (-)
46 >30 11 (+) 47 >30 12 (-)
48 >30 >30 (-)
49 >30 4.5 (-)
50 >30 >30 (-)
51 17 7.1 (-)
52 >30 >30 (-)
53 16.7 1.8 (-)
54 >30 >30 (-)
55 >30 2.6 (-)
56 >30 >30 (-)
57 27.9 2.8 (-)
58 >30 >30 (-)
59 >30 2.9 (-)
60 >30 >30 (-)
61 >30 0.2 (-)
62 >30 >30 (-)
63 >30 0.3 (-)
64 >30 >30 (-)
65 >30 3.4 (-)
66 >30 >30 (-)
67 >30 3.7 (-)
68 >30 >30 (-)
69 14.3 12.4 (+)
70 >30 >30 (-)
71 8.4 7.4 (+)
72 >30 >30 (-)
73 >30 0.9 (-)
74 >30 >30 (-)
75 >30 2.5 (-)
77 >30 2.1 (+)
78 >30 >30 (-)
79 >30 2.9 (-)
80 >30 >30 (-)
81 >30 6.6 (-)
82 >30 >30 (-)
83 >30 0.2 (-)
85 >30 3.6 (-)
86 >30 >30 (-)
87 >30 7.7 (-)
88 >30 >30 (-)
89 >30 12.5 (-)
90 >30 >30 (-)
91 >30 5.5 (-)
Figure imgf000152_0001

Claims

Claims
1. A compound of Formula (I):
Figure imgf000153_0001
wherein
R1 is H, -C02-Ci_8alkyl, -C02-CHRa-aryl, -C02-CHRa-heteroaryl, -C(0)-Ci_4alkyl, -C(0)aryl, - C(0)-heteroaryl, -C(0)-CHRb-NRcRd, -C(0)-CHRa-heteroaryl, -CHRa-aryl, -CHRa- heteroaryl, -S02-Ci_4alkyl, -S02-aryl, or -S02-heteroaryl;
wherein Ra is H or Ci-isalkyl;
Rb is H or -Ci_5alkyl-NReRf;
where Re is H or Ci_4alkyl and Rf is H, Ci_4alkyl, or -C02Ci^alkyl;
Rc is H or Ci^alkyl and Rd is H, Ci_4alkyl, or -C02Ci_4alkyl; and
each aryl or heteroaryl is optionally substituted with halo, Ci_4alkyl, Ci_4fluoroalkyl, -OH, - OCi_4alkyl, -OCi_4fluoroalkyl, -CN, phenyl,-OCi_4alkyl-aryl, or -C02Ci_4alkyl;
R2 is H or Ci_4alkyl;
R3a is H, -C6-i4alkyl, -CHRg-aryl, -CHRg-heteroaryl, -CHRg-heterocycloalkyl,
Figure imgf000153_0002
-Ci_4alkyl-C02Ci-4alkyl, -Ci_4alkyl-C02H, or -Ci_4alkyl-CONRjRk;
Rg is H or Ci_4alkyl;
Rh is H, Ci_4alkyl, or -C02Ci_4alkyl;
R[ is H, Ci_4alkyl, or -C(=NH)-NHRm;
wherein Rm is H, -S02aryl, or -C02Ci_4alkyl;
RJ is H or Ci_4alkyl; and
Rk is H or Ci_4alkyl;
and wherein each aryl, heteroaryl, and heterocycloalkyl is optionally substituted with -OH, Ci_4alkyl, -C02Ci_4alkyl, phenyl, or benzyloxy;
or R2 and R3a taken together with the atoms to which they are attached form C2_4alkylene;
R3b is H; or R3a and R3b taken together with the carbon to which they are attached form a 4- to 7- membered heterocycloalkyl, optionally substituted with Ci_4alkyl or -C02Ci_4alkyl; R4 is H or Ci_4alkyl;
R5 is C8-i6alkyl or C8_i6alkenyl;
R6 is C8-i6alkyl or C8_i6alkenyl;
m is 0 or 1 ;
n is 0 or 1 ; and
p is 0 or 1 ;
wherein at least one of n and p is 1 ;
or a pharmaceutically acceptable salt thereof;
provided that the compound is not a compound of Table lx, or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is H, -C02-Ci_8alkyl, -C02-CHRa-aryl, -C02-CHRa-heteroaryl, -C(0)-C alkyl, -C(0)aryl, -C(O)- heteroaryl, -C(0)-CHRb-NRcRd, -C(0)-CHRa-heteroaryl, -CHRa-aryl, -CHRa-heteroaryl, -S02- Ci-4alkyl, -S02-aryl, or -S02-heteroaryl; or is H; or is -C02-Ci_8alkyl; or is -C02-CHRa-aryl or - C02-CHRa-heteroaryl; or is -C(0)-Ci_4alkyl, -C(0)aryl, or -C(0)-heteroaryl; or is -C(0)-CHRb- NRcRd; or is -C(0)-CHRa-heteroaryl; or is -CHRa-aryl or -CHRa-heteroaryl; or is -S02-C^alkyl, -S02-aryl, or -S02-heteroaryl.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is H, -C02-CHRa-aryl, -C02-CHRa-heteroaryl, -C(0)-Ci_4alkyl, -C(0)aryl, -C(0)-heteroaryl, -C(O)- CHRa-heteroaryl, -CHRa-aryl, -CHRa-heteroaryl, -S02-Ci_4alkyl, -S02-aryl, or -S02-heteroaryl.
4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein the R1 aryl is phenyl; or the R1 aryl is fluorenyl; or the R1 heteroaryl is a bicyclic heteroaryl; or the R1 heteroaryl is indolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, or benzothiazolyl; or the R1 heteroaryl is indolyl.
5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein the R1 aryl or heteroaryl is unsubstituted; or the R1 aryl or heteroaryl is substituted with one or more substituents independently selected from the group consisting of halo, Ci_4alkyl, Ci_ 4fluoroalkyl, -OH, -OCi_4alkyl, -OCi_4fluoroalkyl, -CN, phenyl, and -OCi_4alkyl-aryl; or the R1 aryl or heteroaryl is substituted with methyl, fluoro, phenyl, benzyloxy, or tert- butyloxycarbonyl.
6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R1 is -C02-CH2-fluorenyl, acetyl, or carbobenzyloxy; or R1 is tert-butyloxycarbonyl; or R1 is substituted or unsubstituted benzyl; or R1 is benzyl substituted with halo or phenyl.
7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein Ra is H; or Ra is Ci-isalkyl; or Ra is Cio-isalkyl.
8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein Rb is H; or Rb is -Ci_5alkyl-NReRf.
9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein Re is H; or Re is Ci_4alkyl.
10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R f is H; or R f is Ci_4alkyl; or R f is -C02Ci_4alkyl.
11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein Rc is H; or Rc is Ci_4alkyl.
12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein Rd is H; or Rd is Ci_4alkyl; or Rd is -C02Ci_4alkyl.
13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein R 2 is H; or R 2 is Ci_4alkyl.
14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are both hydrogen.
15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R3a is H; or R3a is -C6-i4alkyl; or R3a is -CHRg-aryl, -CHRg-heteroaryl, or -CHRg- heterocycloalkyl; or R3a is
Figure imgf000156_0001
or R3a is -Ci_4alkyl-C02Ci-4alkyl, -Ci_4alkyl-C02H, or -Ci-4alkyl-CONRjRk. In some embodiments, R3a is substituted or unsubstituted -CH2-phenyl; or R3a is -CH2-phenyl substituted with benzyloxy, hydroxyl, or phenyl; or R3a is -CH2- imidazolyl, optionally substituted with tert-butoxycarbonyl; or R3a is -CH2- indolyl; or R3a is - CH2-piperidine, optionally substituted with tert-butoxycarbonyl; or R3a is butylamine, optionally substituted with tert-butoxycarbonyl; or R3a is propylamine, optionally substituted with guanidinyl, wherein the guanidinyl is optionally substituted; or R3a is carboxyethyl, optionally substituted with tert-butyl; or R3a is carboxymethyl, optionally substituted with tert-butyl.
16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein the R3a aryl is phenyl; or the R3a heteroaryl is pyrrolyl, imidazolyl, indolyl, or benzimidazolyl; or the R3a heteroaryl is pyrrolyl or indolyl; or the R3a heterocycloalkyl is a monocyclic heterocycloalkyl; or the R3a heterocycloalkyl is pyrrolidinyl or piperazinyl; or the R3a aryl, heteroaryl, and heterocycloalkyl are unsubstituted; or the R3a aryl, heteroaryl, and heterocycloalkyl are substituted with -OH, Ci_4alkyl, or -C02Ci_4alkyl; or the R3a aryl and heteroaryl are optionally substituted with phenyl or benzyloxy.
17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein Rg is H; or Rg is Ci_4alkyl.
18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein Rh is H; or Rh is Ci_4alkyl; or Rh is -C02Ci_4alkyl.
19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R[ is H; or R[ is Ci_4alkyl; or R[ is -C(=NH)-NHRm.
20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein Rm is H; or Rm is -S02phenyl; or Rm is -C02Ci_4alkyl.
21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein RJ is H; or RJ is Ci_4alkyl.
22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein Rk is H; or Rk is Ci_4alkyl.
23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R2 and R3a taken together form C2_4alkylene; or R2 and R3a taken together form C3alkylene.
24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein R3b is H; or R3a and R3b taken together with the carbon to which they are attached form a 4- to 7-membered heterocycloalkyl, optionally substituted with Ci_4alkyl or -C02Ci^alkyl.
25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein R3a and R3b are both hydrogen.
26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein R4 is H; or R4 is Ci_4alkyl.
27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R5 and R6 are each independently C8_i6alkyl or C8_i6alkenyl; or R5 and R6 are each independently C8_i6alkyl; or R5 and R6 are the same; or R5 and R6 are different; or R5 and R6 are unbranched hydrocarbons; or R5 and R6 are each Ci4alkyl.
28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein R5 and R6 are each independently Ci3_i6alkyl or Ci3_i6alkenyl.
29. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein R5 and R6 are each independently C8-11alkyl, Ci3_i6alkyl, Cg-nalkenyl, or Ci3_i6alkenyl.
30. The compound of claim 29, wherein R1 is H, -C02-Ci_8alkyl, -C02-CHRa-heteroaryl, - C(0)-Ci_4alkyl, -C(0)aryl, -C(0)-heteroaryl, -C(0)-CHRb-NRcRd, -C(0)-CHRa-heteroaryl, - CHRa-aryl, -CHRa-heteroaryl, -S02-Ci_4alkyl, -S02-aryl, or -S02-heteroaryl.
31. The compound of claim 29 or 30, wherein R3a is H, -C6-i4alkyl, -CHRg-aryl, -CHRg- heterocycloalkyl, -Ci_4alkyl-C02Ci_4alkyl, -Ci_4alkyl-C02H, or -Ci_4alkyl-CONRjRk;
32. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein R5 and R6 are each independently Ci4alkyl or Ci4alkenyl.
33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, wherein m is 0; or m is 1.
34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein n is 0; or n is 1.
35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein p is 0; or p is 1.
36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein n is 1 and p is 0; or n is 0 and p is 1.
37. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is - C02-Ci_8alkyl or -C(0)-CHRb-NRcRd, and R3a is -C6-i4alkyl, -CHRg-aryl, -CHRg-heteroaryl, - CHRg-heterocycloalkyl,
Figure imgf000159_0001
-Ci_4alkyl-C02Ci_4alkyl, -Ci_4alkyl-C02H, or -Ci_ 4alkyl-CONRjRk.
38. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is - C02-Ci_8alkyl and m is 1.
39. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is - C02-Ci_8alkyl and R2 is Ci_4alkyl.
40. A compound selected from the group consisting of:
tert-Butyl ((2S)-3-(4-(benzyloxy)phenyl)-l-((2,3-bis(tetradecyloxy)propyl)amino)-l- oxopropan-2-yl)carbamate;
(2S)-2-Amino-3-(4-(benzyloxy)phenyl)-N-(2,3-bis(tetradecyloxy)propyl)propanamide;
tert-Butyl ((2S)-l-((2,3-bis(tetradecyloxy)propyl)amino)-3-(lH-indol-3-yl)-l- oxopropan-2-yl)carbamate;
(2S)-2-Amino-N-(2,3-bis(tetradecyloxy)propyl)-3-(lH-indol-3-yl)propanamide;
tert-Butyl (2S)-2-((2,3-bis(tetradecyloxy)propyl)carbamoyl) pyrrolidine- 1-carboxylate;
(2S)-N-(2,3-Bis(tetradecyloxy)propyl)pyrrolidine-2-carboxamide;
tert-Butyl ((2S)- l-((2,3-bis(tetradecyloxy)propyl)amino)-3-(4-hydroxyphenyl)- 1- oxopropan-2-yl)carbamate;
(2S)-2-Amino-N-(2,3-bis(tetradecyloxy)propyl)-3-(4-hydroxyphenyl)propanamide;
(9H-Fluoren-9-yl)methyl tert-butyl ((5S)-6-((2,3-bis(tetradecyloxy)propyl)amino)-6- oxohexane- 1 ,5-diyl)dicarbamate;
(9H-Fluoren-9-yl)methyl ((2S)-6-amino-l-((2,3-bis(tetradecyloxy)propyl)amino)-l- oxohexan-2-yl)carbamate;
(9H-Fluoren-9-yl)methyl ((2S)-l-((2,3-bis(tetradecyloxy) propyl)amino)-3-(lH-indol-3- yl)- 1 -oxopropan-2-yl)carbamate;
tert-Butyl ((2R)-l-((2,3-bis(tetradecyloxy)propyl)amino)-3-(lH-indol-3-yl)-l- oxopropan-2-yl)carbamate;
(2R)-2-Amino-N-(2,3-bis(tetradecyloxy)propyl)-3-(lH-indol-3-yl)propan amide; tert-Butyl (4S)-5-((2,3-bis(tetradecyloxy)propyl)amino)-4-((tert- butoxyc arbonyl) amino) - 5 -oxopentanoate ;
(4S)-4-Amino-5-((2,3-bis(tetradecyloxy)propyl)amino)-5-oxopentanoic acid;
tert-Butyl (2R)-2-((2,3-bis(tetradecyloxy)propyl)carbamoyl)pyrrolidine-l-carboxylate;
(2R)-N-(2,3-Bis(tetradecyloxy)propyl)pyrrolidine-2-carboxamide;
N-(2,3-Bis(tetradecyloxy)propyl)-2-((4-methylphenyl)sulfonamido)acetamide;
tert-Butyl 4-((2S)-3-((2,3-bis(tetradecyloxy)propyl)amino)-2-((tert- butoxycarbonyl)amino)-3-oxopropyl)- lH-imidazole- 1-carboxylate;
(2S)-2-Amino-N-(2,3-bis(tetradecyloxy)propyl)-3-(lH-imidazol-4-yl)propanamide; tert-Butyl (3-((2,3-bis(tetradecyloxy)propyl)amino)-3-oxopropyl) carbamate;
3-Amino-N-(2,3-bis(tetradecyloxy)propyl)propanamide;
tert-Butyl (3S)-4-((2,3-bis(tetradecyloxy)propyl)amino)-3-((tert- butoxycarbonyl)amino)-4-oxobutanoate;
(3S)-3-Amino-4-((2,3-bis(tetradecyloxy)propyl)amino)-4-oxobutanoic acid;
tert-Butyl (2-((2,3-bis(tetradecyloxy)propyl)amino)-2-oxoethyl) (methyl)carbamate;
N-(2,3-bis(tetradecyloxy)propyl)-2-(methylamino)acetamide;
tert-Butyl (3S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-((2,3- bis(tetradecyloxy)propyl)amino)-4-oxobutanoate;
(3S)-3-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-4-((2,3- bis(tetradecyloxy)propyl)amino)-4-oxobutanoic acid;
tert-Butyl (4S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-((2,3- bis(tetradecyloxy)propyl)amino)-5-oxopentanoate;
(4S)-4-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-5-((2,3- bis(tetradecyloxy)propyl)amino)-5-oxopentanoic acid;
Benzyl tert-butyl ((5R)-6-((2,3-bis(tetradecyloxy)propyl)amino)-6-oxohexane-l,5- diyl)dicarbamate;
Benzyl ((2R)-6-amino- l-((2,3-bis(tetradecyloxy)propyl)amino)- l-oxohexan-2- yl)carbamate;
tert-Butyl ((2R)-3-([l,l'-biphenyl]-4-yl)-l-((2,3-bis(tetradecyloxy)propyl)amino)-l- oxopropan-2-yl)carbamate; (2R)-3-([l, -Biphenyl]-4-yl)-2-amino-N-(2,3-bis(tetradecyloxy)propyl)propanamide; tert-Butyl ((2S)-3-([ 1 , 1 ' -biphenyl] -4-yl)- 1 -((2,3-bis(tetradecyloxy)propyl)amino)- 1 - oxopropan-2-yl)carbamate;
(2S)-3-([l, -Biphenyl]-4-yl)-2-amino-N-(2,3-bis(tetradecyloxy)propyl)propanamide; Di-tert-butyl ((5S)-6-((2S)-2-((2,3-bis(tetradecyloxy)propyl)carbamoyl)pyrrolidin-l-yl)- 6-oxohexane- 1 ,5-diyl)dicarbamate;
(2S)-l-(L-Lysyl)-N-(2,3-bis(tetradecyloxy)propyl)pyrrolidine-2-carboxamide;
tert-Butyl (2-((2S)-2-((2,3-bis(tetradecyloxy)propyl)carbamoyl)pyrrolidin-l-yl)-2- oxoethyl)carbamate;
(2S)-N-(2,3-Bis(tetradecyloxy)propyl)-l-glycylpyrrolidine-2-carboxamide;
3-(2-(5-(Benzyloxy)-lH-indol-3-yl)acetamido)-N-(2,3- bis(tetradecyloxy)propyl)propanamide;
(9H-Fluoren-9-yl)methyl ((2S)-l-((2,3-bis(tetradecyloxy)propyl)amino)-l-oxo-5-(3- tosylguanidino)pentan-2-yl)carbamate;
(9H-Fluoren-9-yl)methyl ((2S)-l-((2,3-bis(tetradecyloxy)propyl)amino)-l-oxo-5-(l,3- bis-(tert-butyloxy)guanidino)pentan-2-yl)carbamate;
(9H-Fluoren-9-yl)methyl ((2S)-l-((2,3-bis(tetradecyloxy)propyl)amino)-5-guanidino-l- oxopentan-2-yl)carbamate;
tert-Butyl ((2S)-l-((2,3-bis(tetradecyloxy)propyl)amino)-l-oxo-5-(3- tosylguanidino)pentan-2-yl)carbamate;
(2S)-2-Amino-N-(2,3-bis(tetradecyloxy)propyl)-5-(3-tosylguanidino)pentan amide; tert-Butyl ((2S)-4-amino-l-((2,3-bis(tetradecyloxy)propyl)amino)-l,4-dioxobutan-2- yl)carbamate;
Di-tert-butyl ((5S)-6-((2,3-bis(tetradecyloxy)propyl)amino)-6-oxohexane-l,5- diyl)dicarbamate;
(2S)-2,6-Diamino-N-(2,3-bis(tetradecyloxy)propyl)hexanamide;
tert-Butyl ((5S)-5-acetamido-6-((2,3-bis(tetradecyloxy)propyl)amino)-6- oxohexyl)carbamate;
(2S)-2-Acetamido-6-amino-N-(2,3-bis(tetradecyloxy)propyl)hexanamide;
tert-Butyl 4-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-((2,3- bis(tetradecyloxy)propyl)amino)-3-oxopropyl)piperidine-l-carboxylate;
(9H-Fluoren-9-yl)methyl (l-((2,3-bis(tetradecyloxy)propyl)amino)-l-oxo-3-(piperidin-
4-yl)propan-2-yl)carbamate hydrochloride;
tert-Butyl 4-(((benzyloxy)carbonyl)amino)-4-((2,3- bis(tetradecyloxy)propyl)carbamoyl)piperidine- 1 -carboxylate;
Benzyl (4-((2,3-bis(tetradecyloxy)propyl)carbamoyl)piperidin-4-yl)carbamate;
tert-Butyl ((5S)-5-(([l,l'-biphenyl]-4-ylmethyl)amino)-6-((2,3- bis(tetradecyloxy)propyl)amino)-6-oxohexyl)carbamate;
(2S)-2-(([l,l'-Biphenyl]-4-ylmethyl)amino)-6-amino-N-(2,3- bis(tetradecyloxy)propyl)hexanamide;
tert-Butyl ((5S)-6-((2,3-bis(tetradecyloxy)propyl)amino)-5-((4-fluorobenzyl)amino)-6- oxohexyl)carbamate;
(2S)-6-Amino-N-(2,3-bis(tetradecyloxy)propyl)-2-((4-fluorobenzyl)amino)hexanamide; tert-Butyl ((5S)-5-(benzylamino)-6-((2,3-bis(tetradecyloxy)propyl)amino)-6- oxohexyl)carbamate;
(2S)-6-Amino-2-(benzylamino)-N-(2,3-bis(tetradecyloxy)propyl)hexanamide;
tert-Butyl ((5R)-5-(benzylamino)-6-((2,3-bis(tetradecyloxy)propyl)amino)-6- oxohexyl)carbamate;
((2R)-6-Amino-2-(benzylamino)-N-(2,3-bis(tetradecyloxy)propyl)hexanamide;
tert-butyl 3-((((10S)-2,2-dimethyl-4,l l-dioxo-14-(tetradecyloxy)-3,16-dioxa-5,12- diazatriacontan-10-yl)amino)methyl)-lH-indole-l-carboxylate;
(2S)-2-(((lH-indol-3-yl)methyl)amino)-6-amino-N-(2,3-bis(tetradecyloxy)propyl) hexanamide dihydrochloride;
tert-butyl 3-(2-(((10S)-2,2-dimethyl-4,l l-dioxo-14-(tetradecyloxy)-3,16-dioxa-5,12- diazatriacontan-10-yl)amino)-2-oxoethyl)-5-methoxy-lH-indole-l-carboxylate;
(2S)-6-amino-N-(2,3-bis(tetradecyloxy)propyl)-2-(2-(5-methoxy-lH-indol-3- yl)acetamido)hexanamide hydrochloride;
tert-butyl 5-(benzyloxy)-3-(2-(((10S)-2,2-dimethyl-4,l l-dioxo-14-(tetradecyloxy)-3,16- dioxa-5,12-diazatriacontan-10-yl)amino)-2-oxoethyl)-lH-indole-l-carboxylate;
(2S)-6-amino-2-(2-(5-(benzyloxy)-lH-indol-3-yl)acetamido)-N-(2,3- bis(tetradecyloxy)propyl)hexanamide hydrochloride;
tert-butyl ((5S)-6-((2,3-bis(tetradecyloxy)propyl)amino)-5-((naphthalen-2- ylmethyl)amino)-6-oxohexyl)carbamate;
(2S)-6-amino-N-(2,3-bis(tetradecyloxy)propyl)-2-((naphthalen-2-ylmethyl)amino)
hexanamide dihydrochloride;
N-(l-((2,3-Bis(tetradecyloxy)propyl)amino)-l-oxotetradecan-2-yl)-5-fluoro-lH-indole- 3-carboxamide;
N-(2,3-Bis(tetradecyloxy)propyl)-2-((l-(5-fluoro-lH-indol-3- yl)tetradecyl)amino)acetamide;
3-((l-(lH-Indol-3-yl)tetradecyl)amino)-N-(2,3-bis(tetradecyloxy) propyl)propanamide;
2-Amino-N-(l,3-bis(octadecyloxy)propan-2-yl)-3-guanidinopropanamide;
2-Amino-N-(l,3-bis(octadecyloxy)propan-2-yl)-3-(lH-imidazol-5-yl)propanamide;
2-Amino-N-(l,3-bis(octadecyloxy)propan-2-yl)-3-(lH-indol-2-yl)propanamide;
2.5- Diamino-N-(l,3-bis(octadecyloxy)propan-2-yl)pentanamide; and
2.6- Diamino-N-(l,3-bis(octadecyloxy)propan-2-yl)hexanamide, and pharmaceutically acceptable salts thereof. 41. A compound of Formula (IV) :
Figure imgf000163_0001
wherein
G is N or CH;
R41 is H, Ci_4alkyl, or -C02Ci_4alkyl;
R41 is absent, H, or Ci_4alkyl; wherein when R41 is H or Ci_4alkyl, the nitrogen attached to R 41' has a positive charge;
R4 is H or Ci_4alkyl; R is -OCi-igalkyl, -OCi_i8alkenyl, -Ci_i8alkyl, or -Ci_i8alkenyl, each optionally substituted with -OH, -OCi_4alkyl, -C(0)OH, -C(0)OCi_4alkyl, -C(0)NHR4b, or aryl; and
R44 is -OC4_i8alkyl or -OC4_i8alkenyl, each optionally substituted with -OH, -OCi_4alkyl -
C(0)OCi_4alkyl, -C(0)NHR4c, or aryl;
wherein R4b and R4c are each independently H or Ci_4alkyl;
or a pharmaceutically acceptable salt thereof.
42. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein G1 is N.
43. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein G1 is CH.
44. The compound of any one of claims 41-43, or a pharmaceutically acceptable salt thereof, wherein R41 is H, methyl, or tert-butyloxycarbonyl.
45. The compound of any one of claims 41-44, or a pharmaceutically acceptable salt thereof, wherein R41 is absent.
46. The compound of any one of claims 41-45, or a pharmaceutically acceptable salt thereof, wherein R 42 is H.
47. The compound of any one of claims 41-46, or a pharmaceutically acceptable salt thereof, wherein R43 is OCi_i8alkyl, -OCi_i8alkenyl, -Ci_i8alkyl, or -Ci_i8alkenyl, wherein the alkyl or alkenyl is optionally substituted with -OH or -OCi_4alkyl.
48. The compound of any one of claims 41-47, or a pharmaceutically acceptable salt thereof, wherein R44 is OC4_i8alkyl or -OC4_i8alkenyl, wherein the alkyl or alkenyl is optionally substituted with -OH, -OCi_4alkyl,-C(0)OCi_4alkyl, -C(0)NH2, -C(0)NHCi_4alkyl, or phenyl.
49. A compound selected from the group consisting of
tert-butyl 4-(3-((2,3-bis(tetradecyloxy)propyl)carbamoyl)phenyl)piperazine-l-carboxylate;
N-(2,3-bis(tetradecyloxy)propyl)-3-(piperazin-l-yl)benzamide hydrochloride;
tert-butyl 4-(3-((2,3-bis(tetradecyloxy)propyl)carbamoyl)phenyl)piperidine-l-carboxylate;
N-(2,3-bis(tetradecyloxy)propyl)-3-(piperidin-4-yl)benzamide hydrochloride;
tert-butyl 4-(2-((2,3-bis(tetradecyloxy)propyl)carbamoyl)phenyl)piperazine-l-carboxylate;
N-(2,3-bis(tetradecyloxy)propyl)-2-(piperazin-l-yl)benzamide hydrochloride;
tert-butyl 4-(2-((2,3-bis(tetradecyloxy)propyl)carbamoyl)phenyl)piperidine-l-carboxylate;
N-(2,3-bis(tetradecyloxy)propyl)-2-(piperidin-4-yl)benzamide hydrochloride;
tert-butyl 4-(4-((2,3-bis(tetradecyloxy)propyl)carbamoyl)phenyl)piperazine-l-carboxylate;
N-(2,3-bis(tetradecyloxy)propyl)-4-(piperazin-l-yl)benzamide hydrochloride;
tert-butyl 4-(4-((2,3-bis(tetradecyloxy)propyl)carbamoyl)phenyl)piperidine-l-carboxylate;
N-(2,3-bis(tetradecyloxy)propyl)-4-(piperidin-4-yl)benzamide hydrochloride;
4- (3-((2,3-bis(tetradecyloxy)propyl)carbamoyl)phenyl)-l,l-dimethylpiperidin-l-ium iodide; N-(2,3-bis(heptyloxy)propyl)-3-(piperidin-4-yl)benzamide hydrochloride;
N-(2,3-bis((5-methoxypentyl)oxy)propyl)-3-(piperidin-4-yl)benzamide hydrochloride;
N-(3-(benzyloxy)-2-(dodecyloxy)propyl)-3-(piperidin-4-yl)benzamide hydrochloride;
methyl 5-(2-(dodecyloxy)-3-(3-(piperidin-4-yl)benzamido)propoxy)pentanoate hydrochloride;
5- (2-(dodecyloxy)-3-(3-(piperidin-4-yl)benzamido)propoxy)pentanoic acid hydrochloride; N-(2-(dodecyloxy)-3-((5-(methylamino)-5-oxopentyl)oxy)propyl)-3-(piperidin-4-yl)benzamide hydrochloride;
N-(3-((5-amino-5-oxopentyl)oxy)-2-(dodecyloxy)propyl)-3-(piperidin-4-yl)benzamide hydrochloride;
N-(3-(octyloxy)propyl)-3-(piperidin-4-yl)benzamide hydrochloride;
3-(piperidin-4-yl)-N-tetradecylbenzamide hydrochloride;
N-(3-(2-methoxyethoxy)propyl)-3-(piperidin-4-yl)benzamide hydrochloride;
N-(3-ethoxy-2-hydroxypropyl)-3-(piperidin-4-yl)benzamide hydrochloride;
tert-butyl 4-(3-((2,3-bis(((Z)-tetradec-8-en- l-yl)oxy)propyl)carbamoyl)phenyl) piperidine- 1- carboxylate;
N-(2,3-bis(((Z)-tetradec-8-en-l-yl)oxy)propyl)-3-(piperidin-4-yl)benzamide hydrochloride; tert-butyl 4-(3-((2,3-bis(((9Z,12Z)-octadeca-9,12-dien-l-yl)oxy)propyl) carbamoyl
phenyl)piperidine- 1 -carboxylate; and
N-(2,3-bis(((9Z,12Z)-octadeca-9,12-dien-l-yl)oxy)propyl)-3-(piperidin-4-yl)benzamide hydrochloride,
or pharmaceutically acceptable salts thereof.
50. A compound of Formula (V):
Figure imgf000166_0001
wherein
G2 is a bond, -CH2-,-CH2NH-, or -CH2NHCH2-;
G3 is -C(O)- or -CH2-;
R51 is H, Ci_4alkyl, -C02Ci_4alkyl, heterocycle, or -Ci_4alkyl-NR5aR5b; where R5a is H or Ci_ 4alkyl and R5b is H, Ci_4alkyl, or -C02Ci_4alkyl; and
R52 is H or Ci_4alkyl;
or R 51 and R 52 , together with the carbon to which they are attached, form a heterocycloalkyl optionally substituted with -C02Ci_4alkyl;
R53 is H or Ci_4alkyl;
o is 0 or 1 ;
r is 0 or 1 ;
s is 0 or 1 ;
R54 is Cg-isalkyl or Cg-isalkenyl; and
R55 is Cg-igalkyl or Cg-igalkenyl;
or a pharmaceutically acceptable salt thereof.
51. The compound of claim 50, or a pharmaceutically acceptable salt thereof, wherein G2 is a bond.
52. The compound of claim 50, or a pharmaceutically acceptable salt thereof, wherein G2 is -CH2-.
53. The compound of claim 50, or a pharmaceutically acceptable salt thereof, wherein G2 is — CH2NH- or -CH2NHCH2-.
54. The compound of any one of claims 50-53, or a pharmaceutically acceptable salt thereof, wherein G3 is -C(O)-.
55. The compound of any one of claims 50-53, or a pharmaceutically acceptable salt thereof, wherein G3 is -CH2-.
56. The compound of any one of claims 50-55, or a pharmaceutically acceptable salt thereof, wherein R51 is H or -Ci_4alkyl-NR5aR5b; where R5a is H or Ci_4alkyl and R5b is H, Ci_4alkyl, or - C02Ci_4alkyl.
57. The compound of any one of claims 50-56, or a pharmaceutically acceptable salt thereof, wherein R 52 is H.
58. The compound of any one of claims 50-55, or a pharmaceutically acceptable salt thereof, wherein R 51 and R 52 , together with the carbon to which they are attached, form a
heterocycloalkyl; wherein the heterocycloalkyl is optionally substituted with tert- butyloxycarbonyl.
59. The compound of any one of claims 50-55, or a pharmaceutically acceptable salt thereof, wherein R 51 and R 52 , together with the carbon to which they are attached, form a piperidinyl, optionally substituted with -C02Ci_4alkyl.
60. A compound selected from the group consisting of
tert-butyl 4-((2,3-bis(tetradecyloxy)propyl)carbamoyl)-4-phenylpiperidine-l-carboxylate; N-(2,3-bis(tetradecyloxy)propyl)-4-phenylpiperidine-4-carboxamide hydrochloride; 3-amino-N-(2,3-bis(tetradecyloxy)propyl)-2-phenylpropanamide hydrochloride;
tert-butyl 3-benzyl-3-((2,3-bis(tetradecyloxy)propyl)carbamoyl)piperidine-l-carboxylate;
3- benzyl-N-(2,3-bis(tetradecyloxy)propyl)piperidine-3-carboxamide hydrochloride;
2-(benzylamino)-N-(2,3-bis(tetradecyloxy)propyl)-2-(piperidin-4-yl)acetamide hydrochloride;
4- ((benzylamino)methyl)-N-(2,3-bis(tetradecyloxy)propyl)piperidine-4-carboxamide
hydrochloride;
N-benzyl-2,3-bis(tetradecyloxy)propan- 1 -amine; and
N-benzyl-N,N-dimethyl-2,3-bis(tetradecyloxy)propan-l-aminium iodide,
or pharmaceutically acceptable salts thereof.
61. A compound of Formula VI) :
Figure imgf000168_0001
wherein
R61 is H, -C02-Ci_8alkyl, -C02-CHR6a-aryl, -C02-CHR6a-heteroaryl, -C(0)-Ci_4alkyl, -C(0)aryl,
-C(0)-heteroaryl, -C(0)-CHR6b-NR6cR6d, -C(0)-CHR6a-heteroaryl, -CHR6a-aryl, -CHR6a- heteroaryl, -S02-Ci_4alkyl, -S02-aryl, or -S02-heteroaryl;
where R6a is H or Ci_i5alkyl;
R6b is H or -Ci_5alkyl-NR6eR6f;
R6c is H or Ci_4alkyl;
R6d is H, Ci_4alkyl, or -C02C^alkyl;
R6e is H or Ci_4alkyl;
R6f is H, Ci_4alkyl, or -C02Ci_4alkyl; and
each aryl or heteroaryl is optionally substituted with halo, Ci_4alkyl, Ci_4fluoroalkyl, -OH, -OCi_
4alkyl, -OCi_4fluoroalkyl, -CN, phenyl, or -OCi_4alkyl-aryl;
R62 is H or Ci_4alkyl; R* is H, Ci_4alkyl, or -C02C^alkyl;
R67 is H, Ci_4alkyl, or -C(=NH)-NHR6m;
where R6m is H, -S02aryl, or -C02Ci_4alkyl;
R63 is H or Ci_4alkyl;
R64 is H or -OH,
or R64 is -Ci-igalkyl, -Ci_i8alkenyl, -OCi_i8alkyl, or -OCi_i8alkenyl, each of which is optionally substituted with -OH or -OCi_4alkyl;
R65 is H or -C4_8cycloalkyl,
or R65 is -Ci_i8alkyl, -Ci_i8alkenyl, -OCi_i2alkyl, or -OCi_i2alkenyl, each of which is optionally substituted with -OH or -OCi_4alkyl; and
t is 0 or 1 ;
or a pharmaceutically acceptable salt thereof.
62. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R61 is -CH2-phenyl or -CH2-napthyl.
63. The compound of claim 61 or claim 62, or a pharmaceutically acceptable salt thereof, wherein R62 is H.
64. The compound of any one of claims 61-63, or a pharmaceutically acceptable salt thereof, wherein R66 is H or -C02Ci_4alkyl
65. The compound of any one of claims 61-64, or a pharmaceutically acceptable salt thereof, wherein R66 and R67 are both H.
66. The compound of any one of claims 61-65, or a pharmaceutically acceptable salt thereof, wherein R63 is H or methyl.
67. The compound of any one of claims 61-66, or a pharmaceutically acceptable salt thereof, wherein R64 is H or -OH.
68. The compound of any one of claims 61-66, or a pharmaceutically acceptable salt thereof, wherein R64 is -Ci-igalkyl, -Ci-igalkenyl, -OCi-igalkyl, or -OCi-igalkenyl, each optionally substituted with -OH or -OCi_4alkyl;
69. The compound of any one of claims 61-68, or a pharmaceutically acceptable salt thereof, wherein R65 is H or -C4_8cycloalkyl.
70. The compound of any one of claims 61-68, or a pharmaceutically acceptable salt thereof, wherein R65 is -Ci-igalkyl, -Ci-igalkenyl, -OCi-igalkyl, or -OCi-igalkenyl, each optionally substituted with -OH or -OCi_4alkyl.
71. A compound selected from the group consisting of
tert-butyl ((5R)-5-(benzylamino)-6-((2,3-bis(((9Z,12Z)-octadeca-9,12-dien-l- yl)oxy)propyl)amino)-6-oxohexyl)carbamate;
(2R)-6-amino-2-(benzylamino)-N-(2,3-bis(((9Z,12Z)-octadeca-9,12-dien-l- yl)oxy)propyl)hexanamide dihydrochloride;
(S)-6-amino-2-(benzylamino)-N-tetradecylhexanamide dihydrochloride;
(S)-6-amino-2-(benzylamino)-N-decylhexanamide dihydrochloride;
(S)-6-amino-2-(benzylamino)-N-(3-ethoxypropyl)hexanamide dihydrochloride;
(S)-6-amino-2-(benzylamino)-N-(3-(octyloxy)propyl)hexanamide dihydrochloride;
(S)-6-amino-N-(2-cyclohexylethyl)-2-((naphthalen-2-ylmethyl)amino)hexanamide
dihydrochloride ;
(S)-6-amino-N-methyl-2-((naphthalen-2-ylmethyl)amino)hexanamide dihydrochloride;
(2S)-6-amino-2-(benzylamino)-N-(2,3-bis(heptyloxy)propyl)hexanamide dihydrochloride;
(2S)-6-amino-2-(benzylamino)-N-(2,3-bis((5-methoxypentyl)oxy)propyl) hexanamide dihydrochloride ;
tert-butyl (S)-(5-(benzylamino)-6-oxo-6-(tetradecylamino)hexyl)carbamate;
tert-butyl (S)-(5-(benzylamino)-6-(decylamino)-6-oxohexyl)carbamate;
tert-butyl (S)-(5-(benzylamino)-6-((3-ethoxypropyl)amino)-6-oxohexyl)carbamate; tert-butyl (S)-(5-(benzylamino)-6-((3-(octyloxy)propyl)amino)-6-oxohexyl)carbamate;
tert-butyl (S)-(6-((2-cyclohexylethyl)amino)-5-((naphthalen-2-ylmethyl)amino)-6- oxohexyl)carbamate;
tert-butyl (S)-(6-((2-cyclohexylethyl)amino)-5-((naphthalen-2-ylmethyl)amino)-6- oxohexyl)carbamate;
(2S)-6-amino-N-(3-ethoxy-2-hydroxypropyl)-2-((naphthalen-2-ylmethyl)amino) hexanamide dihydrochloride ;
(S)-6-amino-2-(benzylamino)-N-(2-(heptyloxy)ethyl)hexanamide dihydrochloride; and
(2S)-6-amino-2-(benzylamino)-N-(2-(heptyloxy)-3-methoxypropyl)hexanamide dihydrochloride, or pharmaceutically acceptable salts thereof.
A compound of Formula (II):
Figure imgf000171_0001
wherein
R21 is H, Ci_4alkyl, or -C02Cwalkyl;
R22 is H or Ci_4alkyl;
R24 is H or Ci_4alkyl;
R 25 is C8-i6alkyl or C8_i6alkenyl;
R26 is C8-i6alkyl or C8_i6alkenyl;
n2 is 0 or 1 ; and
p2 is 0 or 1 ;
wherein at least one of n2 and p2 is 1 ;
or a pharmaceutically acceptable salt thereof.
73. A compound selected from the group consisting of:
tert-Butyl ((czs)-4-((2,3-bis(tetradecyloxy)propyl) carbamoyl)cyclohexyl)carbamate;
(cz5)-4-Amino-N-(2,3-bis(tetradecyloxy)propyl)cyclohexane-l-carboxamide; tert-Butyl ((iran5)-4-((2,3-bis(tetradecyloxy)propyl)carbamoyl)cyclohexyl)carbamate; and
(iran5)-4-Amino-N-(2,3-bis(tetradecyloxy)propyl)cyclohexane-l-carboxamide; and pharmaceutically acceptable salts thereof.
74. A compound of Formula (III):
Figure imgf000172_0001
wherein
R 31 is phenyl or monocyclic heteroaryl;
R32 is H or Ci_4alkyl;
R33 is Ci_4alkyl-NRxRy;
where Rx is H, Ci_4alkyl, or -C02-Ci_4alkyl; and
Ry is H or Ci_4alkyl;
R34 is H or Ci_4alkyl; and
R 35 is Ci4_i8alkyl or Ci4_i8alkenyl;
or a pharmaceutically acceptable salt thereof.
75. A compound selected from the group consisting of:
Benzyl tert-butyl (6-(octadec-9-en-l-ylamino)-6-oxohexane-l,5-diyl)(R,Z)- dicarbamate;
Benzyl (R,Z)-(6-amino- l-(octadec-9-en- 1-ylamino)- l-oxohexan-2-yl)carbamate;
Benzyl tert-butyl (6-oxo-6-(tetradecylamino)hexane-l,5-diyl)(R)-dicarbamate; and Benzyl (R)-(6-amino- 1-oxo- l-(tetradecylamino)hexan-2-yl)carbamate; and pharmaceutically acceptable salts thereof.
76. A pharmaceutical composition comprising at least one compound according to any of claims 1-75, or a pharmaceutically acceptable salt thereof, optionally further comprising pharmaceutically acceptable excipient.
77. A method of treating a disease or condition associated with TLR2 heterodimerization, comprising administering to a subject in need of such treatment an effective amount of at least one compound according to any one of claims 1-75, or a pharmaceutically acceptable salt thereof.
78. The method of claim 77, wherein the disease or condition is selected from the group consisting of: Alzheimer's disease, Parkinson's disease, fronto-temporal dementia, dementia with Lewy bodies (Lewy body disease), Parkinson's disease with dementia, multiple system atrophy, amyotrophic lateral sclerosis, Huntington's disease, inflammatory diseases, asthma, chronic obstructive pulmonary disease (COPD), chronic peptic ulcers, tuberculosis, rheumatoid arthritis, chronic sinusitis, hepatitis, hepatitis B, hepatitis C, gout, lupus, pleurisy, eczema, gastritis, psoriasis, psoriatic arthritis, vasculitis, laryngitis, allergic reactions, multiple sclerosis, Crohn's disease, traumatic brain injury, CIDP (chronic inflammatory demyelinating
polyneuropathy), atopic dermatitis, acne vulgaris, rosacea, non-alcoholic fatty liver disease, non-alcoholic steatohepatisis, corneal wounds, corneal disorders, Stargardt disease (Juvenile macular degeneration), age-related macular degeneration, sepsis, diabetic wounds, herpes simplex virus, and anti-fungal, anti-bacterial, anitviral and antitumor diseases or conditions.
79. A method of interfering with the heterodimerization of TLR2 in a cell, or modulating, preventing, slowing, reversing, or inhibiting TLR2 heterodimerization in a cell, comprising contacting the cell with an effective amount of at least one compound according to any one of claims 1-75, or a salt thereof, and/or with at least one pharmaceutical composition according to claim 76, wherein the contacting is in vitro, ex vivo, or in vivo.
Ill
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