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EP3493814A1 - Composés amino 1,2-et 1,3-diol substitués par des lipides en tant que modulateurs de la dimérisation de tlr2 - Google Patents

Composés amino 1,2-et 1,3-diol substitués par des lipides en tant que modulateurs de la dimérisation de tlr2

Info

Publication number
EP3493814A1
EP3493814A1 EP17837574.7A EP17837574A EP3493814A1 EP 3493814 A1 EP3493814 A1 EP 3493814A1 EP 17837574 A EP17837574 A EP 17837574A EP 3493814 A1 EP3493814 A1 EP 3493814A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
bis
amino
propyl
tetradecyloxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP17837574.7A
Other languages
German (de)
English (en)
Other versions
EP3493814A4 (fr
Inventor
Wolfgang Wrasidlo
Srinivasa Reddy Natala
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Neuropore Therapies Inc
Original Assignee
Neuropore Therapies Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Neuropore Therapies Inc filed Critical Neuropore Therapies Inc
Publication of EP3493814A1 publication Critical patent/EP3493814A1/fr
Publication of EP3493814A4 publication Critical patent/EP3493814A4/fr
Withdrawn legal-status Critical Current

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    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • 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
    • 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 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.
  • TLRs 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.
  • TLR2 forms heterodimers with either TLR1 or TLR6 to initiate inflammatory responses with various microbial derived ligands.
  • LPS lipopolysaccharides
  • acylated lipopeptides lipoglycans
  • peptidoglycans porins
  • glycosylphosphatidyl-inosol anchors glycosylphosphatidyl-inosol anchors
  • LTA lipoteichoic acid
  • TLR2 microbial activation of TLR2
  • 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).
  • PD Parkinson's disease
  • MSA multiple system atrophy
  • AD Alzheimer's disease
  • 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).
  • Toll-like receptors 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:
  • 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.
  • lipid-substituted amino 1,2- and 1,3-diol compounds that serve as antagonists of TLR2 heterodimer binding with high potency and selectivity.
  • 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 e is H or Ci_ 4 alkyl and R f is H, Ci_ 4 alkyl, or -C0 2 Ci ⁇ alkyl;
  • 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 2 is H or Ci_ 4 alkyl
  • R 3a is H, -C 6 -i 4 alkyl, -CHR g -aryl, -CHR g -heteroaryl, -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 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 J is H or Ci_ 4 alkyl
  • R k is H or Ci_ 4 alkyl
  • each aryl, heteroaryl, and heterocycloalkyl is optionally substituted with -OH, Ci_ 4 alkyl, -C0 2 Ci- 4 alkyl, phenyl, or benzyloxy;
  • R 3b is H; or 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_ 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
  • n2 is 0 or 1 ;
  • 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 y is H or 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):
  • G is N or CH
  • 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 2 is a bond, -CH 2 -,-CH 2 NH-, or -CH 2 NHCH 2 -;
  • G 3 is -C(O)- or -CH 2 -;
  • R 51 is H, Ci_ 4 alkyl, -C0 2 Ci_ 4 alkyl, heterocycle, or -Ci_ 4 alkyl-NR 5a R 5b ; where R 5a is H or Ci_
  • R 5b is H, Ci_ 4 alkyl, or -C0 2 Ci_ 4 alkyl;
  • R 52 is H or Ci_ 4 alkyl
  • R 51 and R 52 together with the carbon to which they are attached, form a heterocycloalkyl optionally substituted with -C0 2 Ci_ 4 alkyl;
  • R 53 is H or Ci_ 4 alkyl
  • o 0 or 1 ;
  • 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 6a is H or Ci_i 5 alkyl
  • 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 62 is H or Ci_ 4 alkyl
  • 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 63 is H or Ci_ 4 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
  • R 65 is -Ci-i 8 alkyl, -Ci_i 8 alkenyl, -OCi_i 2 alkyl, or -OCi_i 2 alkenyl, each of which is optionally substituted with -OH or -OCi_ 4 alkyl; and
  • t is 0 or 1 ;
  • the compound of Formula (I), (II), (III), (IV), (V), or (VI) is a compound selected from those species described or exemplified herein.
  • 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 1 is -S0 2 -Ci_ 4 alkyl, -S0 2 -aryl, or -S0 2 -heteroaryl.
  • the R 1 aryl is phenyl.
  • the R 1 aryl is fluorenyl.
  • the R 1 heteroaryl is a bicyclic heteroaryl.
  • the R 1 heteroaryl is indolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, or benzothiazolyl.
  • the R 1 heteroaryl is indolyl.
  • the R 1 aryl or heteroaryl is unsubstituted.
  • the R 1 aryl or heteroaryl is substituted with one or more substituents
  • Ci_ 4 alkyl independently selected from the group consisting of halo, Ci_ 4 alkyl, Ci_ 4 fluoroalkyl, -OH, -OCi_ 4 alkyl, -OCi_ 4 fluoroalkyl, -CN, phenyl, and -OCi- 4 alkyl-aryl.
  • the R 1 aryl or heteroaryl is substituted with one or more substituents independently selected from the group consisting of halo, Ci_ 4 alkyl, Ci_ 4 fluoroalkyl, -OH, -OCi_ 4 alkyl, -OCi_ 4 fluoroalkyl, -CN, phenyl,- OCi_ 4 alkyl-aryl, and -C0 2 Ci_ 4 alkyl.
  • the R 1 aryl or heteroaryl is substituted with methyl, fluoro, phenyl, or benzyloxy.
  • the R 1 aryl or heteroaryl is substituted with methyl, fluoro, phenyl, benzyloxy, or tert-butyloxycarbonyl.
  • R 1 is -C0 2 -CH 2 -fluorenyl, acetyl, or carbobenzyloxy.
  • R 1 is tert-butyloxycarbonyl.
  • R 1 is substituted or unsubstituted benzyl.
  • R 1 is benzyl substituted with halo or phenyl.
  • R a is H. In other embodiments, R a is Ci-isalkyl. In other embodiments, R a is Cio-isalkyl.
  • R b is H. In some embodiments, R b is -Ci_5alkyl-NR e R f . In some embodiments, R e is H. In other embodiments, R e is Ci_ 4 alkyl. In some embodiments, R f is
  • R f is Ci ⁇ alkyl. In other embodiments, R f is -C0 2 Ci ⁇ alkyl.
  • R c is H. In some embodiments, R c is Ci_ 4 alkyl. In some embodiments, R d is H. In other embodiments, R d is Ci ⁇ alkyl. In other embodiments, R d is - C0 2 Ci_ 4 alkyl.
  • R 2 is H. In other embodiments, R 2 is Ci_ 4 alkyl.
  • R 1 and R 2 are both hydrogen.
  • R 3a is H. In other embodiments, R 3a is -C 6-14 alkyl. In other embodiments, R 3a is -CHR g -aryl, -CHR g -heteroaryl, or -CHR g -heterocycloalkyl. In some embodiments, the R 3a aryl is phenyl. In some embodiments, the R 3a heteroaryl is pyrrolyl, imidazolyl, indolyl, or benzimidazolyl. In other embodiments, the R 3a heteroaryl is pyrrolyl or indolyl. In other embodiments, the R 3a heterocycloalkyl is a monocyclic heterocycloalkyl. In some embodiments, the R 3a heterocycloalkyl is pyrrolidinyl or piperazinyl. In some
  • the R 3a aryl, heteroaryl, and heterocycloalkyl are unsubstituted. In other embodiments, the R 3a aryl, heteroaryl, and heterocycloalkyl are substituted with -OH, Ci_ 4 alkyl, or -C0 2 Ci_ 4 alkyl. In other embodiments, the R 3a aryl and heteroaryl are optionally substituted with phenyl or benzyloxy.
  • R 3a is In other embodiments, R 3a is -Ci_ 4 alkyl-C0 2 C M alkyl, -Ci_ 4 alkyl-C0 2 H, or -Ci_ 4 alkyl-CONR j R k .
  • R g is H. In other embodiments, R g is Ci_ 4 alkyl.
  • R m is H. In some embodiments, R m is -S0 2 phenyl. In other embodiments, R m is -C0 2 Ci_ 4 alkyl.
  • R J is H. In some embodiments, R J is Ci_ 4 alkyl. In some embodiments, R k is H. In some embodiments, R k is Ci ⁇ alkyl.
  • 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_
  • 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.
  • R 25 and R 26 are each independently C 8 _i6alkyl or C 8 _i6alkenyl. In some embodiments, R 25 and R 26 are each independently C 8 _i6alkyl. In some embodiments,
  • R 25 and R 26 o 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 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 or monocyclic heteroaryl.
  • 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 is H. In some embodiments, R J 3 i 4 ⁇ i ⁇ s Ci_ 4 alkyl.
  • 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 4J is -OCi_i 8 alkyl or -OCi_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.
  • R 43 is -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.
  • 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.
  • R 43 is -OCi_i 2 alkyl and R 44 is -OC 4 _i 2 alkyl. In some embodiments, R 43 is -OCi_i 2 alkenyl and R 44 is -OC 4 _i 2 alkenyl, wherein R 43 and R 44 are each optionally substituted with -OH, -OCi_ 4 alkyl,-C(0)OCi_ 4 alkyl, - C(0)NH 2 , -C(0)NHCi_ 4 alkyl, or aryl. In some embodiments, R 43 and R 44 are each -OC 7 alkyl. In some embodiments, R 43 and R 44 are each -OCi 4 alkyl or -OCi 4 alkenyl. In some embodiments, R 43 and R 44 are each -OCi 6 alkyl or -OCi 6 alkenyl. In some embodiments, R 43 and R 44 are each - OCisalkyl or -OCi 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 -.
  • G 3 is -C(O)-. In other embodiments, G 3 is -CH 2 -.
  • R 51 is H. In some embodiments, R 51 is Ci_ 4 alkyl. In some embodiments, R 51 is -C0 2 Ci_ 4 alkyl. In some embodiments, R 51 is a heterocycle, such as pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl. In other embodiments, R 51 is -Ci_ 4 alkyl-NR 5a R 5b ; where R 5a is H or Ci_ 4 alkyl and R 5b is H, Ci_ 4 alkyl, or -C0 2 Ci_ 4 alkyl.
  • R 52 is H. In other embodiments, R 52 is Ci_ 4 alkyl;
  • R 51 and R 52 together with the carbon to which they are attached, form a heterocycloalkyl; wherein the heterocycloalkyl is optionally substituted with -
  • 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.
  • R 51 and R 52 together with the carbon to which they are attached, form a piperidinyl, optionally substituted with -C0 2 Ci_ 4 alkyl, such as tert- butyloxycarbonyl.
  • R 53 is H. In other embodiments, R 53 is Ci_ 4 alkyl.
  • 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.
  • 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 G 2 is a bond, r is 1, and s is 0. In some embodiments G 2 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 -C0 2 Ci_ 4 alkyl. In some embodiments G 2 is -CH 2 -, r is 1, and s is 0. In some embodiments
  • G 2 is -CH 2 -, 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 -C0 2 Ci_ 4 alkyl.
  • G 2 is -CH 2 NH-, r is 1, and s is 0.
  • G 2 is -
  • G 2 is -CH 2 NHCH 2 -, r is 1, and s is 0. In some embodiments G 2 is -
  • G 2 is -CH 2 NHCH 2 -, r is 1, and s is 0.
  • G 2 is -CH 2 - or -CH 2 NH-, r is 1, s is 0, and R 51 is a heterocycle.
  • R 51 is a heterocycle and R 52 is H.
  • 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 54 and R 55 are each Ci 4 alkyl. In some embodiments, R 54 and R 55 are each Ci 4 alkenyl. In some embodiments, R 54 and R 55 are each Ci 6 alkyl or Ci 6 alkenyl. In some embodiments, R 54 and R 55 are each Cigalkyl or Cigalkenyl.
  • the compound of Formula (V) is selected from the group consisting of compounds of Table 5:
  • R 61 is H. In some embodiments, R 61 is -C0 2 - Ci-galkyl. In some embodiments, R 61 is -C0 2 -CHR 6a -aryl or -C0 2 -CHR 6a -heteroaryl, where R 6a is H or Ci-i 5 alkyl and the 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 -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 H. In some embodiments, R 64 is -OH. In some embodiments, R 64 is -Ci_i 8 alkyl or -Ci_i 8 alkenyl, each optionally substituted with -OH or -OCi_ 4 alkyl. In some embodiments, R 64 is -OCi_i 8 alkyl or -OCi_i 8 alkenyl, each optionally substituted with -OH or -OCi_ 4 alkyl. In some embodiments, R 65 is H. In some embodiments, R 65 is -C 4 _ 8 cycloalkyl.
  • R 65 is -Ci_i 8 alkyl or -Ci_i 8 alkenyl, each of which is optionally substituted with -OH or -OCi_ 4 alkyl. In some embodiments, 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 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:
  • 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.
  • the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for N-oxide, -S(O)-, or -S0 2 - 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.
  • substituted means that the specified group or moiety bears one or more substituents.
  • unsubstituted means that the specified group bears no substituents.
  • 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.
  • 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.
  • 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.
  • Ci_ 3 refers independently to embodiments that have one carbon member (CO, embodiments that have two carbon members (C 2 ), and embodiments that have three carbon members (C 3 ).
  • any disubstituent referred to herein is meant to encompass the various attachment possibilities when more than one of such possibilities are allowed.
  • 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.
  • 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.
  • 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.
  • 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,
  • propylsulfonates besylates, xylenesulfonates, naphthalene- 1- sulfonates, naphthalene-2- sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, ⁇ - hydroxybutyrates, glycolates, tartrates, and mandelates.
  • Lists of other suitable pharmaceutically acceptable salts are found in Remington's Pharmaceutical Sciences, 17th Edition, Mack
  • 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 glucur
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid,
  • 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.
  • 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.
  • 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.
  • 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.
  • a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease or condition.
  • a method that "delays" development of Parkinson's disease 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.
  • 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.
  • 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 ⁇ g 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).
  • 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.
  • 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.
  • 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.
  • 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
  • compositions and formulations of the invention 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.
  • 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.
  • 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
  • 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
  • compositions herein may be used to treat or prevent a disease or condition in an individual.
  • methods of treating a disease or condition associated with TLR2 heterodimerization comprising
  • 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.
  • 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.
  • 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.
  • 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.
  • compounds of the Formula (I) may be synthesized according to Scheme 1.
  • PG is a protecting group
  • X is a halogen
  • compounds of the Formula (II) may be synthesized according to Scheme 2.
  • 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.
  • compounds of the Formula (III) may be synthesized according to Scheme 3.
  • R , R , R , and R are as defined for Formula (III), or any variation thereof detailed herein.
  • compounds of the Formula (IV) may be synthesized according to Scheme 4.
  • R 41 , R 41 ,R 42 , R 43 , R 44 , and Gi are as defined for Formula (IV), or any variation thereof detailed herein.
  • compounds of the Formula (V) may be synthesized according to Scheme 5.
  • 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.
  • compounds of the Formula (VI) may be synthesized according to Scheme 6.
  • R , R ,R , R , R , R , and t are as defined for Formula (VI), or any variation thereof detailed herein.
  • Example 1 tert-Butyl ((2S)-3-(4-(benzyloxy)phenyl)- l-((2,3-bis(tetradecyloxy)propyl)amino)- l-oxopropan-2-yl)carbamate.
  • Step 1 tert-Butyl (2,3-bis(tetradecyloxy)propyl)carbamate.
  • 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.
  • 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).
  • 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 3 tert-Butyl ((2S)-l-((2,3-bis(tetradecyloxy)propyl)amino)-3-(lH-indol-3-yl)-l- oxopropan-2-yl)carbamate.
  • Example 5 tert-Butyl (2S)-2-((2,3-bis(tetradecyloxy)propyl)carbamoyl) pyrrolidine- 1- carboxylate.
  • 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.
  • Example 10 (9H-Fluoren-9-yl)methyl ((2S)-6-amino-l-((2,3-bis(tetradecyloxy)propyl)amino)- l-oxohexan-2- l)carbamate hydrochloride.
  • 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).
  • Example 12 tert-Butyl ((2R)-l-((2,3-bis(tetradecyloxy)propyl)amino)-3-(lH-indol-3-yl)-l- oxopropan-2-yl)carbamate.
  • Example 14 tert-Butyl (4S)-5-((2,3-bis(tetradecyloxy)propyl)amino)-4-((tert- butoxyc arbonyl) amino - 5 -oxopentanoate .
  • 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 16 tert-Butyl (2R)-2-((2,3-bis(tetradecyloxy)propyl)carbamoyl)pyrrolidine-l- carboxylate.
  • Example 17 (2R)- -(2,3-Bis(tetradecyloxy)propyl)pyrrolidine-2-carboxamide hydrochloride.
  • 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).
  • Example 18 -(2,3-Bis(tetradecyloxy)propyl)-2-((4-methylphenyl)sulfonamido)acetamide.
  • Example 19 tert-Butyl 4-((2S)-3-((2,3-bis(tetradecyloxy)propyl)amino)-2-((tert- butoxycarbon l)amino)-3-oxopropyl)- lH-imidazole- 1-carboxylate.
  • Example 20 (2S)-2-Amino-N-(23-bis(tetradecyloxy)propyl)-3-( lH-imidazol-4- vPpropanamide dihydrochloride.
  • Example 22 3-Amino-N-(2,3-bis(tetradecyloxy)propyl)propanamide hydrochloride.
  • Example 23 tert-Butyl (3S)-4-((2,3-bis(tetradecyloxy)propyl)amino)-3-((tert- butox carbonyl)amino)-4-oxobutanoate.
  • Example 24 (3S)-3-Amino-4-((2,3-bis(tetradecyloxy)propyl)amino)-4-oxobutanoic acid hydrochloride.
  • Example 25 tert-Butyl (2-((2,3-bis(tetradecyloxy)propyl)amino)-2-oxoethyl) (methyl)carbamate.
  • Example 26 N-(2, -bis(tetradecyloxy)propyl)-2-(methylamino)acetamide hydrochloride.
  • Example 28 (3S)-3-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-4-((2,3- bis(tetradecyloxy)propyl)amino)-4-oxobutanoic acid.
  • Example 29 tert-Butyl (4S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-((2,3- bis(tetradecylox ropyl)amino)-5-oxopentanoate.
  • Example 30 (4S)-4-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-5-((2,3- bis(tetradecyloxy)propyl)amino)-5-oxopentanoic acid.
  • Example 31 Benzyl tert-butyl ((5R)-6-((2,3-bis(tetradecyloxy)propyl)amino)-6-oxohexane-l,5- diyPdicarbamate.
  • Example 32 Benzyl ((2R)-6-amino-l-((2,3-bis(tetradecyloxy)propyl)amino)-l-oxohexan-2- vDcarbamate h drochloride.
  • Example 34 (2R)-3-(ri, l , -Biphenyll-4-yl)-2-amino-N-(2,3- bis(tetradecyloxy)propyl)propanamide hydrochloride.
  • Example 35 tert-Butyl ((2S)-3-(rU , -biphenyll-4-yl)- l-((2,3-bis(tetradecyloxy)propyl)amino)- l-oxopropan- -yl)carbamate.
  • Example 36 (2S)-3-(ri.l , -Biphenyll-4-yl)-2-amino-N-(2.3- bis(tetradecyloxy)propyl)propanamide hydrochloride.
  • Example 38 (2S)- l-(L-Lvsyl)-N-(2,3-bis(tetradecyloxy)propyl)pyrrolidine-2-carboxamide dihydrochloride.
  • Example 39 tert-Butyl (2-((2S)-2-((2,3-bis(tetradecyloxy)propyl)carbamoyl)pyrrolidin- l-yl)-2- oxoethvPcarbamate.
  • Example 40 (2S)-N-(2,3-Bis(tetradecyloxy)propyl)- l-glycylpyrrolidine-2-carboxamide hydrochloride.
  • Example 41 3-(2-(5-(Benzyloxy)-lH-indol-3-yl)acetamido)-N-(2,3- bis(tetradecyloxy)propyl)propanamide.
  • 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.
  • Example 44 (9H-Fluoren-9-yl)methyl ((2S)-l-((2.3-bis(tetradecyloxy)propyl)amino)-5- guanidino- l-oxopentan-2-yl)carbamate dihvdrochloride.
  • Example 45 tert-Butyl ((2S)-l-((2,3-bis(tetradecyloxy)propyl)amino)-l-oxo-5-(3- tosylguanidino entan-2-yl)carbamate.
  • 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.
  • 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.
  • 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.
  • Example 84 tert-butyl 4-(2-((2,3-bis(tetradecyloxy)propyl)carbamoyl)phenyl)piperazine-l- carboxylate
  • Example 86 tert-butyl 4-(2-((2,3-bis(tetradecyloxy)propyl)carbamoyl)phenyl)piperidine-l- carboxylate
  • 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).
  • Example 88 tert-butyl 4-(4-((2,3-bis(tetradecyloxy)propyl)carbamoyl)phenyl)piperazine-l- carboxylate
  • 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).
  • Example 90 tert-butyl 4-(4-((2,3-bis(tetradecyloxy)propyl)carbamoyl)phenyl)piperidine-l- carboxylate
  • 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).
  • Example 92 4-(3-((2,3-bis(tetradecyloxy)propyl)carbamoyl)phenyl)-lJ-dimethylpiperidin-l- ium iodide
  • Step 1 tert-butyl (2,3-bis(heptyloxy)propyl)carbamate : Aqueous NaOH (50 %, 15 mL) and Bu 4 NI (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.
  • 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).
  • Step 3 tert-butyl 4-(3-((2,3-bis(heptyloxy)propyl)carbamoyl)phenyl)piperidine- l- carboxylate:
  • 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).
  • 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
  • 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 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 Bu 4 NI (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.
  • 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-
  • 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
  • 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.
  • 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.
  • 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).
  • 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.H 2 O solution (10 mL) slowly at room temperature under inert atmosphere and stirring was continued for 18 hours.
  • 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-(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.
  • DIPEA 0.656 mL, 3.8 mmol
  • HBTU 230 mg, 0.608 mmol
  • 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-((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).
  • 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).
  • 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).
  • 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).
  • Example 104 tert-butyl 4-((2,3-bis(tetradecyloxy)propyl)carbamoyl)-4-phenylpiperidine-l- carboxylate
  • 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).
  • 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
  • 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 C 50 H9 1 N 3 O 5 , 815; found, 815.
  • 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).
  • Example 110 4-((benzylamino)methyl)-N-(2,3-bis(tetradecyloxy)propyl)piperidine-4- carboxamide hydrochloride
  • 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 128 tert-butyl (S)- -(benzylamino)-6-(decylamino)-6-oxohexyl)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.
  • This procedure can be used to create liposomal formulations with mixtures of other nonactive lipids such as those sold commercially (Avantis polar lipids).
  • 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 ⁇ .

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Abstract

La présente invention concerne des composés amino 1,2-et 1,3-diol substitués par des lipides, des compositions pharmaceutiques comprenant de tels composés, et l'utilisation de tels composés dans des procédés de traitement ou dans des médicaments pour le traitement de maladies inflammatoires et de certains troubles neurologiques qui sont associés à des processus de signalisation inflammatoires, comprenant, mais sans s'y limiter, des protéines mal repliées.
EP17837574.7A 2016-08-03 2017-08-01 Composés amino 1,2-et 1,3-diol substitués par des lipides en tant que modulateurs de la dimérisation de tlr2 Withdrawn EP3493814A4 (fr)

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US20190119236A1 (en) 2016-02-23 2019-04-25 Portola Pharmaceuticals, Inc. Compounds for binding proprotein convertase subtilisin/kexin type 9 (pcsk9)
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