EP4337259A1 - Verbindungen zum abbau von alpha-synucleinaggregaten und verwendungen davon - Google Patents

Verbindungen zum abbau von alpha-synucleinaggregaten und verwendungen davon

Info

Publication number
EP4337259A1
EP4337259A1 EP21726997.6A EP21726997A EP4337259A1 EP 4337259 A1 EP4337259 A1 EP 4337259A1 EP 21726997 A EP21726997 A EP 21726997A EP 4337259 A1 EP4337259 A1 EP 4337259A1
Authority
EP
European Patent Office
Prior art keywords
formula
alkyl
substituted
compound
unsubstituted
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.)
Pending
Application number
EP21726997.6A
Other languages
English (en)
French (fr)
Inventor
Ming-Kuei Jang
Paul Tempest
Yih-Shyan Lin
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.)
Aprinoia Therapeutics Ltd
Original Assignee
Aprinoia Therapeutics Ltd
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 Aprinoia Therapeutics Ltd filed Critical Aprinoia Therapeutics Ltd
Publication of EP4337259A1 publication Critical patent/EP4337259A1/de
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/545—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds

Definitions

  • Synucleinopathies are neurodegenerative diseases characterized by the abnormal accumulation of a-synuclein (a-Syn) aggregates in neurons and glial cells.
  • ⁇ -Synuclein is a 140 amino acid protein preferentially expressed in neurons at pre-synaptic terminals where it is thought to play a role in regulating synaptic transmission (Bendor et al., Neuron 2013; 79:1044-66).
  • a-Synuclein can form pathological aggregates in neurons known as Lewy bodies, which are characteristic of both Parkinson's Disease (PD) and dementia with Lewy bodies (DLB).
  • the pathological aggregates consist of aggregated, insoluble accumulations of misfolded a-synuclein proteins in neurons, nerve fibers or glial cells and are a characteristic feature of synucleinopathies.
  • Synucleinopathies include Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), the Lewy body variant of Alzheimer's disease (LBVAD), combined Parkinson's disease (PD) and Alzheimer's disease (AD), and neurodegeneration with brain iron accumulation type-1 (NBIA-1).
  • PD and DLB a-Syn aggregates are in the neuronal cytoplasm and axonal processes into Lewy bodies and Lewy neurites, respectively, whereas a-Syn inclusions in oligodendroglia are the recognized neuropathologic hallmarks of MSA.
  • the present disclosure stems from the recognition that a bispecific conjugate compound that includes an E3 ubiquitin ligase binding moiety that is based on an imide drug (e.g., lenalidomide, thalidomide, VHL ligand) and also includes a binder of a-synuclein may induce proteasome degradation of a-synuclein aggregates.
  • an imide drug e.g., lenalidomide, thalidomide, VHL ligand
  • the disclosure therefore provides compounds, compositions, and methods for the treatment of various neurodegenerative diseases associated with a-synuclein aggregates based on this discovery.
  • the bispecific conjugate compounds described herein degrade the a-synuclein aggregates by removing a-synuclein aggregates or reducing the degree of a-synuclein aggregation to low levels in a cellular model and/or animal model, thereby possessing therapeutic potential in the treatment of patients with synucleinopathies including but not limited to Parkinson’s disease (PD), dementia with Lewy bodies (DLB), or multiple system atrophy (MSA).
  • PD Parkinson’s disease
  • DLB dementia with Lewy bodies
  • MSA multiple system atrophy
  • the present disclosure also provides methods to remove a-synuclein aggregation or reduce Lewy bodies or a-synuclein aggregate in a patient having Lewy body disease or risk of Lewy body disease, and methods to reduce dementia with Lewy bodies (DLB) or multiple system atrophy (MSA) or other synucleinopathies.
  • DLB dementia with Lewy bodies
  • MSA multiple system atrophy
  • One aspect of the present disclosure is a compound of Formula A,
  • EBM is an E3 ubiquitin ligase binding moiety
  • L is a linker covalently attached to EBM and SBM; and SBM is an a-synuclein protein binding moiety of the formula: or a pharmaceutical acceptable salt, an enantiomer, a non-enantiomer, a tautomer, a racemate, a solvate, a metabolic precursor, a prodrug thereof, wherein covalently linked to L; and i .
  • s a substituted or unsubstituted bicyclic fused aromatic ring containing at least 1 ring heteroatom selected from O, S, and N; is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S, and N; and is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S, and N; or is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S, and N; is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S, and N; and is a substituted or unsubstituted bicyclic fused aromatic ring containing at least 1 ring heteroatom selected from O, S, and N.
  • Another aspect of the disclosure is a compound of any one of the Formula (I)-(VI): or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof, wherein Li, L2, L3, X,
  • composition comprising a compound of the disclosure, and a pharmaceutically acceptable excipient.
  • Another aspect of the present disclosure is a method of treating, lessening the severity of, delaying the progression of, reducing the risk of developing, and/or delaying the onset of a disease characterized by the presence of Lewy bodies or pathological aggregates of a-synuclein, the method comprising administering to a subject in need thereof an effective amount of a compound or a composition of the present disclosure.
  • Another aspect of the present disclosure is a method for synthesizing the compounds of the disclosure.
  • Figure 1 shows the high content-based quantifications of aggregated a-synuclein species in combination with determination of nuclei count (% remaining cells) in differentiated ReNcell VM cells. Results showed that 24 hour treatment with test compounds 166362, 170357, 162640 and 180948, respectively, induced a concentration-dependent inhibition of MJFR14 immunoreactivity, indicative of decreased a-synuclein aggregation.
  • Figures 2A-2D show the immunocytochemical images of cells treated with vehicle (0.1% DMSO) and test compounds 132168, 166362, and 170357, and immunostained with MJFR14, illustrating the reduction in a-synuclein expression following treatment with compounds 132168 and 166362.
  • Figure 2A DMSO (0.1%)
  • Figure 2B compound 132168 (3mM)
  • Figure 2C compound 166362 (3mM)
  • Figure 2D compound 170357 (10mM).
  • Figure 3 shows the result of an in vivo a-synuclein degradation study. Upon treatment of compound 132168, insoluble a-synuclein fraction decreases 30% compared to DMSO vehicle control, indicating the reduction of insoluble a-synuclein aggregates.
  • the present disclosure provides compounds, compositions, and methods useful for removing a-synuclein aggregates or reducing the degree of a-synuclein aggregation to low levels, thereby possessing therapeutic potential in the treatment of patients with synucleinopathies.
  • bispecific conjugate compounds that can simultaneously bind a target protein (i.e., aggregated a-synuclein) and an E3 ubiquitin ligase.
  • the bispecific conjugate compounds exhibit desirable functional properties including binding preferentially to a-synuclein aggregates, and allowing a-synuclein to be placed in proximity to the E3 ubiquitin ligase, thereby facilitating the selective ubiquitination and eventual proteasome-mediated degradation of a-synuclein aggregates.
  • Methods described herein include the administration of a compound or a composition of the present disclosure to a subject to treat, alleviate or prevent a neurodegenerative disease or disorder characterized by the presence of Lewy bodies or pathological aggregates of a-synuclein.
  • One aspect of the present disclosure is a compound of Formula A,
  • EBM is an E3 ubiquitin ligase binding moiety
  • L is a linker covalently attached to EBM and SBM
  • SBM is an a-synuclein protein binding moiety of the formula: or a pharmaceutical acceptable salt, an enantiomer, a non-enantiomer, a tautomer, a racemate, a solvate, a metabolic precursor, a prodrug thereof, wherein is covalently linked to L;
  • (i) is a substituted or unsubstituted bicyclic fused aromatic ring containing at least 1 ring heteroatom selected from O, S, and N; is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S, and N; and is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S, and N; or
  • (ii) is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S, and N; is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S, and N; and i .s a substi .tuted or unsubstituted bicyclic fused aromatic ring containing at least 1 ring heteroatom selected from O, S, and N.
  • the substituted or unsubstituted bicyclic fused aromatic ring is a substituted or unsubstituted bicyclic 5-6 system.
  • Non-limiting examples include
  • SBM is of Formula B or Formula C wherein
  • Z is C or N; U is O, S or CH; V is N or NH;
  • J is CR 6 or N;
  • X is CR 6 or N;
  • Y is CR 6 or N; where at least one of J, X and Y is N, but J and Y are not N at the same time, X and Y are not N at the same time;
  • R 6 is independently selected from the group consisting of H, NH2, Ci-6 alkyl and Ci-6 alkoxy, wherein NH2, Ci-6 alkyl or Ci-6 alkoxy is optionally substituted by 1 to 3 of C1-3 alkyl, C3-6 cycloalkyl and/or halo; and in Formula B, V is N, where Z and U are not heteroatoms at the same time; and in Formula C, V is N or NH; T is CH or N; where up to two of U, Z, V and T contain heteroatoms.
  • EBM is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 3 is H or Ci-6 alkyl; each occurrence of R 2 is independently selected from the group consisting of H,
  • the compound is of any one of the Formula (I)-(VI):
  • R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group
  • L3 is a bond, - R-, -0-, or -S-, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group
  • L2 is a substituted or unsubstituted Ci-50 hydrocarbon chain
  • Z is C or N
  • U is O, S or CH
  • V is N, where Z and U are not heteroatoms at the same time
  • K is CH or N
  • Q is CH or N; where K and Q are not N at the same time
  • each occurrence of R" is independently selected from the group consisting of H, OH, NH2, Ci-6 alkyl, Ci-6 alkylamino, Ci-6 alkoxy and halogen; k is 0, 1, 2 or 3;
  • each occurrence of R' is independently selected from the group consisting of H, halogen, OH, Ci-6 alkyl,
  • T is CH or N; where up to two of U, Z, V and T contain heteroatoms; K is CH or N; Q is CH or N; where K and Q are not N at the same time; each occurrence of R" is independently selected from the group consisting of H, OH, NH2, Ci-6 alkyl, Ci-6 alkylamino, Ci-6 alkoxy and halogen; k is 0, 1, 2 or 3; each occurrence of R 1 is independently selected from the group consisting of H, halogen, OH, Ci-6 alkyl, Ci-6 haloalkyl and Ci-6 alkoxy; m is 0, 1, 2, 3 or 4; each occurrence of R" is independently selected from the group consisting of H, halo, OH, NH2, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 alkylamino, C3-6 cycloalkyl, C3-6 cycloalkylamino and C3-6 heterocycloalkyl; n is 0, 1 or 2; J is
  • R al is independently hydrogen, substituted or unsubstituted Ci-6 alkyl (e.g., substituted or unsubstituted methyl or ethy
  • the compound is of the structure of Formula I.
  • the compound is of the structure of Formula II.
  • the compound is of the structure of Formula III.
  • the compound is of the structure of Formula IV.
  • the compound is of the structure of Formula V.
  • the compound is of the structure of Formula VI.
  • the moiety in Formula (I), (II) and (III) is [0030] In certain embodiments, the moiety in Formula (IV), (V) and (VI) is [0031] In certain embodiments, the moiety in Formulae (I)-(VI) is
  • LI is a bond
  • L3 is a bond
  • L3 is - H-, -0-, or -S-.
  • At least one chain atom of the hydrocarbon chain of L2 is independently replaced with -0-
  • the chain of L2 comprises up to 50 consecutive covalently bonded atoms in length, excluding hydrogen atoms and substituents.
  • L2 comprises up to, for example 46, 45, 40, 35, 32, 30, 25, 23, 20, 15, 14, 12, 11, 10, 9, 8, 7, 6, 5, 3 consecutive covalently bonded atoms in length, excluding hydrogen atoms and substituents.
  • any of the atoms in L2 can be substituted. In certain embodiments, none of the atoms in the linker L2 are substituted. In certain embodiments, none of the carbon atoms in the linker are substituted.
  • L2 is a linker that contains an asymmetric carbon/stereocenter, i.e., an sp3 hybridized carbon atom bearing 4 different groups attached thereto.
  • the compound comprising such an L2 group is enantiomerically enriched or substantially enantiomerically enriched.
  • the compound comprising such an L2 group is enantiomerically pure.
  • the compound comprising such an L2 group is racemic.
  • L2 comprises substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroaryl ene, or substituted or unsubstituted heteroalkylene, or combinations thereof.
  • L2 is substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroaryl ene, or substituted or unsubstituted heteroalkylene.
  • L2 is a linker selected from the group consisting of substituted and unsubstituted alkylene, substituted and unsubstituted alkenylene, substituted and unsubstituted alkynylene, substituted and unsubstituted heteroalkylene, substituted and unsubstituted heteroalkenylene, substituted and unsubstituted heteroalkynylene, substituted and unsubstituted heterocyclylene, substituted and unsubstituted carbocyclylene, substituted and unsubstituted arylene, substituted and unsubstituted heteroaryl ene, and combinations thereof.
  • L2 being a combination of at least two instances of the divalent moieties described herein refers to a linker consisting of at least one instance of a first divalent moiety and at least one instance of a second divalent moiety, wherein the first and second divalent moieties are the same or different and are within the scope of the divalent moieties described herein, and the instances of the first and second divalent moieties are consecutive covalently attached to each other.
  • L2 is a combination of alkylene and heteroalkylene linkers
  • -heteroalkylene-alkylene-heteroalkylene- are all within the scope of L2, wherein each instance of alkylene in any one of the linkers may be the same or different, and each instance of heteroalkylene in any one of the linkers may be the same or different.
  • L2 comprises at least one instance of substituted or unsubstituted alkylene, e.g., substituted or unsubstituted Ci-6 alkylene, substituted or unsubstituted C1-2 alkylene, substituted or unsubstituted C1-3 alkylene, substituted or unsubstituted C3-4 alkylene, substituted or unsubstituted C4-5 alkylene, substituted or unsubstituted C5-6alkylene, substituted or unsubstituted C3-6alkylene, or substituted or unsubstituted C4-6alkylene.
  • substituted or unsubstituted alkylene e.g., substituted or unsubstituted Ci-6 alkylene, substituted or unsubstituted C1-2 alkylene, substituted or unsubstituted C1-3 alkylene, substituted or unsubstituted C3-4 alkylene, substituted or unsubstituted C4-5 alkylene, substituted or unsubstitute
  • alkylene groups include unsubstituted alkylene groups such as methylene (-CH2-), ethylene (-(CH2)2-), n-propylene (-(CH2)3-), n-butylene (- (CH2)4-), n-pentylene (-(Cl [2)5-), and n-hexylene (-(CH2)6-).
  • L2 comprises at least one instance of substituted or unsubstituted alkenylene, e g., substituted or unsubstituted C2-6 alkenyl ene, substituted or unsubstituted C1-3 alkenylene, substituted or unsubstituted C3-4 alkenylene, substituted or unsubstituted C4-5 alkenylene or substituted or unsubstituted C5-6 alkenylene.
  • substituted or unsubstituted alkenylene e g., substituted or unsubstituted C2-6 alkenyl ene, substituted or unsubstituted C1-3 alkenylene, substituted or unsubstituted C3-4 alkenylene, substituted or unsubstituted C4-5 alkenylene or substituted or unsubstituted C5-6 alkenylene.
  • L2 comprises at least one instance of substituted or unsubstituted alkynylene, e.g., substituted or unsubstituted C2-6 alkynylene, substituted or unsubstituted C2-3 alkynylene, substituted or unsubstituted C3-4 alkynylene, substituted or unsubstituted C4-5 alkynylene or substituted or unsubstituted C5-6 alkynylene.
  • substituted or unsubstituted alkynylene e.g., substituted or unsubstituted C2-6 alkynylene, substituted or unsubstituted C2-3 alkynylene, substituted or unsubstituted C3-4 alkynylene, substituted or unsubstituted C4-5 alkynylene or substituted or unsubstituted C5-6 alkynylene.
  • L2 comprises at least one instance of substituted or unsubstituted heteroalkylene, e.g., substituted or unsubstituted heteroCi- 6 alkylene, substituted or unsubstituted heteroCi-2alkylene, substituted or unsubstituted heteroC2- 3alkylene, substituted or unsubstituted heteroC3-4alkylene, substituted or unsubstituted heteroC4- salkylene or substituted or unsubstituted heteroCs ⁇ alkylene.
  • substituted or unsubstituted heteroalkylene e.g., substituted or unsubstituted heteroCi- 6 alkylene, substituted or unsubstituted heteroCi-2alkylene, substituted or unsubstituted heteroC2- 3alkylene, substituted or unsubstituted heteroC3-4alkylene, substituted or unsubstituted heteroC4- salkylene or substituted or unsubstituted heteroCs ⁇ alkylene
  • L2 comprises at least one instance of substituted or unsubstituted heteroalkenylene, e.g., substituted or unsubstituted heteroC2-6alkenylene, substituted or unsubstituted heteroCi-3alkenylene, substituted or unsubstituted heteroC3- 4alkenylene, substituted or unsubstituted heteroC4-salkenylene, or substituted or unsubstituted heteroC ealkenylene.
  • substituted or unsubstituted heteroalkenylene e.g., substituted or unsubstituted heteroC2-6alkenylene, substituted or unsubstituted heteroCi-3alkenylene, substituted or unsubstituted heteroC3- 4alkenylene, substituted or unsubstituted heteroC4-salkenylene, or substituted or unsubstituted heteroC ealkenylene.
  • L2 comprises at least one instance of substituted or unsubstituted heteroalkynylene, e.g., substituted or unsubstituted heteroC2-6alkynylene, substituted or unsubstituted heteroC2-3alkynylene, substituted or unsubstituted heteroCb-4 alkynylene, substituted or unsubstituted heteroCr-salkynylene, or substituted or unsubstituted heteroC5-6alkynylene.
  • substituted or unsubstituted heteroalkynylene e.g., substituted or unsubstituted heteroC2-6alkynylene, substituted or unsubstituted heteroC2-3alkynylene, substituted or unsubstituted heteroCb-4 alkynylene, substituted or unsubstituted heteroCr-salkynylene, or substituted or unsubstituted heteroC5-6alkynylene.
  • L2 comprises at least one instance of substituted or unsubstituted carbocyclylene, e.g., substituted or unsubstituted C3- 6 carbocyclylene, substituted or unsubstituted Cb-icarbocyclylene, substituted or unsubstituted C4- scarbocyclylene, or substituted or unsubstituted C5-6 carbocyclylene.
  • substituted or unsubstituted carbocyclylene e.g., substituted or unsubstituted C3- 6 carbocyclylene, substituted or unsubstituted Cb-icarbocyclylene, substituted or unsubstituted C4- scarbocyclylene, or substituted or unsubstituted C5-6 carbocyclylene.
  • L2 comprises at least one instance of substituted or unsubstituted heterocyclylene, e g., substituted or un substituted 3-6 membered heterocyclylene, substituted or unsubstituted 3-4 membered heterocyclylene, substituted or unsubstituted 4-5 membered heterocyclylene, or substituted or unsubstituted 5-6 membered heterocyclylene.
  • at least one chain atom of the hydrocarbon chain of L2 is independently replaced with a 5-8 membered heterocyclyl group with 1-4 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • At least one chain atom of the hydrocarbon chain of L2 is independently replaced with a 6-membered heterocyclyl group with 1-3 ring heteroatoms selected from the group consisting of nitrogen and oxygen. In certain embodiments, at least one chain atom of the hydrocarbon chain of L2 is independently replaced with piperidine, piperazine or morpholine.
  • L2 comprises at least one instance of substituted or unsubstituted arylene, e.g., substituted or unsubstituted phenylene.
  • at least one chain atom of the hydrocarbon chain of L2 is independently replaced with an optionally substituted phenyl group.
  • L2 comprises at least one instance of substituted or unsubstituted heteroaryl ene, e.g., substituted or unsubstituted 5- to 6-membered heteroaryl ene.
  • L2 is an unsubstituted hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with -NR al - and each instance ofR al is independently hydrogen, substituted or unsubstituted Ci-6 alkyl or a nitrogen protecting group, or optionally two instances of R al are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.
  • at least one instance of R al is hydrogen.
  • At least one instance of R al is substituted or unsubstituted Ci-6 alkyl (e.g., substituted or unsubstituted methyl or ethyl).
  • at least one instance of R al is a nitrogen protecting group (e g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl or p-toluenesulfonamide (Ts)).
  • L2 is an optionally substituted Ci-30 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced with -O- or -NR al - In certain embodiments, L2 is an unsubstituted Ci-30 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced with -O- or-NR al - In certain embodiments, L2 is an unsubstituted Ci-30 hydrocarbon chain, wherein at least one chain atom of the hydrocarbon chain is independently replaced with -0-.
  • L2 is a substituted or unsubstituted C5-40 hydrocarbon chain.
  • L2 is an unsubstituted Ci-26 hydrocarbon chain, wherein at least one chain atom of the hydrocarbon chain is independently replaced with - O — .
  • the cyclic moiety herein refers to a cycloalkylene or a heterocycloalkylene, such as
  • L2 is an all-carbon, substituted or unsubstituted Ci-45 hydrocarbon chain. In certain embodiments, L2 is an all-carbon, substituted or unsubstituted Ci-30 hydrocarbon chain. In certain embodiments, L2 is an all-carbon, substituted or unsubstituted Ci-26 hydrocarbon chain. In certain embodiments, L2 is an all-carbon, substituted or unsubstituted Ci-24 hydrocarbon chain. In certain embodiments, L2 is an all-carbon, substituted or unsubstituted Ci-20 hydrocarbon chain. In certain embodiments, L2 is an all-carbon, substituted or unsubstituted Ci-20 hydrocarbon chain.
  • L2 is wherein g is 1, 2, 3, 4, 5, or 6. In certain embodiments, g is 1. In certain embodiments, g is 2. In certain embodiments, g is
  • g is 4. In certain embodiments, g is 5. In certain embodiments, g is 6.
  • L2 includes the moiety -NH-.
  • L2 of the disclosure include, but are not limited to:
  • L2 is of the formula:
  • L2 is of the formula:
  • L2 is of the formula: wherein g is 1, 2, 3, 4 or 5; h is 0, 1, 2, 3, 4 or 5; and f is 1, 2, 3, 4, 5, 6,
  • L2 is of the formula:
  • L2 is of the formula: wherein g is 1, 2, 3, 4, 5, 6, 7 or 8.
  • L2 is of the formula:
  • L2 is of the formula: herein g is 1, 2, 3, 4, 5, 6, 7 or 8; and f is 1, 2, 3, 4, 5, 6, 7 or 8.
  • L2 is of the formula: , wherein g is 1, 2, 3, 4, 5, 6, 7 or 8.
  • R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group
  • L3 is a bond, -NR-, -0-, or -S-, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group
  • L2 is a substituted or unsubstituted Ci-50 hydrocarbon chain
  • Z is C orN
  • U is O, S or CH; where Z and U are not heteroatoms at the same time
  • Q is CH or N
  • K is CH or N; where Q and K are not N at the same time
  • each occurrence of R"' is independently selected from the group consisting of H, OH, NH2, Ci-6 alkyl, Ci-6 alkylamino, Ci-6 alkoxy and halogen; k is 0, 1, 2 or 3; each occurrence of R' is independently selected from the group consisting of H, halogen, OH, Ci-6 alkyl, Ci-6
  • the compound of Formula 1-1 is of the following:
  • R' is H, Ci-3 haloalkyl or C1-3 alkoxy, preferably H, CF3, CCb, methoxy or ethoxy, more preferably H, CF3 or methoxy.
  • An embodiment of the disclosure is the compound of Formula 1, wherein m is 0, 1, 2, 3 or 4, preferably 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 1, wherein R" is H, halo, OH, NH2, Ci-3 alkoxy, C1-3 alkylamino, C3-5 cycloalkyl, C3-5 cycloalkylamino and C3-5 heterocycloalkyl, preferably H, F, Cl, NH2, methoxy, ethoxy, methylamino, dimethylamino, ethylamino, diethylamino, cyclopropyl, cyclobutyl or cyclopentyl, more preferably H, F, dimethylamino or cyclopropyl.
  • An embodiment of the disclosure is the compound of Formula 1, wherein n is 0, 1 or 2, preferably 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 1, wherein R'" is H, OH or halogen, preferably H, OH, F or Cl, more preferably H.
  • An embodiment of the disclosure is the compound of Formula 1, wherein k is 0, 1, 2 or 3, preferably 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 1, wherein R 1 is O,
  • An embodiment of the disclosure is the compound of Formula 1, wherein A is O,
  • An embodiment of the disclosure is the compound of Formula 1, wherein m2 is 2, 3, 4 or 6, preferably 2 or 6.
  • An embodiment of the disclosure is the compound of Formula 1, wherein R 3 is H or Ci-3 alkyl, preferably H or methyl, more preferably H.
  • An embodiment of the disclosure is the compound of Formula 1 having the structure as shown in Formula 1-1, U is O, S or CH; Z is C or N; where U and Z are not heteroatoms at the same time; R 1 is H, Ci-3 haloalkyl or C1-3 alkoxy; R" is H, F, Cl, OH, NH2, C1-3 alkoxy, methylamino, dimethylamino, diethylamino or cyclopropylamino; n is 0, 1 or 2.
  • An embodiment of the disclosure is the compound of Formula 1-1, wherein m2 is 2, 3, 4 or 6, preferably 2 or 6.
  • An embodiment of the disclosure is the compound of Formula 1-1, wherein R 3 is H or methyl.
  • An embodiment of the disclosure is the compound of Formula 1-1, wherein A is O or
  • An embodiment of the disclosure is the compound of Formula 1-1, wherein R 1 is
  • An embodiment of the disclosure is the compound of Formula 1-1, wherein R 1 is O, NH,
  • An embodiment of the disclosure is the compound of Formula 1-1, wherein Z is N,
  • U is CH [0097]
  • An embodiment of the disclosure is the compound of Formula 1-1, wherein Z is C, U is S or O.
  • An embodiment of the disclosure is the compound of Formula 1-1, wherein R" is H, F, Cl, OF1, NH2, methoxy, methylamino, dimethylamino, diethylamino, cyclopropyl or cyclopropylamino, preferably H, F, methylamino, dimethylamino or cyclopropylamino.
  • R' is H, F, Cl, OF1, NH2, methoxy, methylamino, dimethylamino, diethylamino, cyclopropyl or cyclopropylamino, preferably H, F, methylamino, dimethylamino or cyclopropylamino.
  • R' is H, methoxy or CF3.
  • An embodiment of the disclosure is the compound of Formula 5, wherein R 3 is H or Ci-3 alkyl, preferably H or methyl.
  • An embodiment of the disclosure is the compound of Formula 5, wherein A is O, H
  • An embodiment of the disclosure is the compound of
  • An embodiment of the disclosure is the compound of Formula 5, wherein m4 is 0,
  • An embodiment of the disclosure is the compound of Formula 5, wherein m5 is 0,
  • An embodiment of the disclosure is the compound of Formula 5, wherein m3 is 1,
  • An embodiment of the disclosure is the compound of Formula 5, wherein R 1 is O,
  • An embodiment of the disclosure is the compound of Formula 5, wherein R 1 " is H, OH, Ci-3 alkyl, C1-3 alkoxy or halogen, preferably H, methyl, methoxy or F, more preferably H.
  • An embodiment of the disclosure is the compound of Formula 5, wherein k is 0, 1, 2 or 3, preferably 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 5, wherein Z is C, U is O or S.
  • An embodiment of the disclosure is the compound of Formula 5, wherein Z is N,
  • An embodiment of the disclosure is the compound of Formula 5, wherein R' is H, halogen, OH, C1-3 alkyl, C1-3 haloalkyl or C1-3 alkoxy, preferably H, F, CF3, CCh, methyl or methoxy, more preferably H or CF3.
  • An embodiment of the disclosure is the compound of Formula 5, wherein m is 0, 1, 2 or 3, preferably 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 5, wherein R" is H, halo, OH, NH2, Ci-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 alkylamino, C3-5 cycloalkyl, C3-5 cycloalkylamino or C3-5 heterocycloalkyl, preferably H, F, OH, NH2, methyl, methoxy, CF3, CCb, methylamino, cyclopropyl or dimethylamino, more preferably H, F, CF3, cyclopropyl, cyclopropylamino or dimethylamino.
  • An embodiment of the disclosure is the compound of Formula 5, wherein n is 0, 1 or 2, preferably 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 5 having the structure as shown in Formula 5-1, are not heteroatoms at the same time;
  • R'" is H, OH, C1-3 alkyl, C1-3 alkoxy or halogen;
  • R' is H, halogen, OH, C1-3 alkyl, Ci-3haloalkyl or C1-3 alkoxy;
  • R" is H, halo, OH, NH2, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 alkylamino, C3-5 cycloalkyl, C3-5 cycloalkylamino and C3-5 heterocycloalkyl;
  • n is 0, 1 or 2.
  • An embodiment of the disclosure is the compound of Formula 5-1, wherein A is O.
  • An embodiment of the disclosure is the compound of Formula 5-1, wherein m5 is 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 5-1, wherein m4 is 0 or 3.
  • An embodiment of the disclosure is the compound of Formula 5-1, wherein m3 is 3, 5.
  • An embodiment of the disclosure is the compound of Formula 5-1, wherein R 1 is
  • An embodiment of the disclosure is the compound of Formula 5-1, wherein Z is C, U is O or S.
  • An embodiment of the disclosure is the compound of Formula 5-1, wherein Z is N, U is CH.
  • An embodiment of the disclosure is the compound of Formula 5-1, wherein R' is H, halogen, C1-3 alkyl, C1-3 fluoroalkyl or C1-3 alkoxy, preferably H, methyl, CF3, methyl or methoxy, more preferably H or CF3.
  • An embodiment of the disclosure is the compound of Formula 5-1, wherein R" is H, halo, OH, NH2, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 alkylamino, C3-5 cycloalkyl, C3-5 cycloalkylamino or C3-5 heterocycloalkyl, preferably H, F, CF3, amino, methylamino, dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F, CF3, dimethylamino, cyclopropylamino or cyclopropyl.
  • R 3 is H or Ci-3 alkyl, preferably H or methyl.
  • An embodiment of the disclosure is the compound of Formula 6, wherein A is O, preferably O or NH.
  • An embodiment of the disclosure is the compound of Formula 6, wherein m2 is 1, 2, 3, 4, 5, 6 or 7, preferably 2 or 6.
  • An embodiment of the disclosure is the compound of Formula 6, wherein R 1 is O, , preferably O or NH.
  • An embodiment of the disclosure is the compound of Formula 6, wherein Z is C or N, and U is O, S or CH, where Z and U are not heteroatoms at the same time; preferably Z is C and U is S.
  • An embodiment of the disclosure is the compound of Formula 6, wherein R'" is H, OH, Ci-3 alkyl, C1-3 alkoxy or halogen, preferably H, methyl, methoxy or F, more preferably H.
  • An embodiment of the disclosure is the compound of Formula 6, wherein R is H, halogen, OH, C1-3 alkyl, C1-3 haloalkyl or C1-3 alkoxy, preferably H, F, CF3, CCb, methyl or methoxy, more preferably H or CF3.
  • An embodiment of the disclosure is the compound of Formula 6, wherein m is 0, 1, 2 or 3, preferably 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 6, wherein R" is H, halo, OH, NH2, Ci-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 alkylamino, C3-5 cycloalkyl, C3-5 cycloalkylamino or C3-5 heterocycloalkyl, preferably H, F, OH, NH2, methyl, methoxy, CF3, CCb, methylamino, cyclopropyl, cyclopropylamino or dimethylamino, more preferably H,
  • An embodiment of the disclosure is the compound of Formula 6, wherein n is 0 or
  • An embodiment of the disclosure is the compound of Formula 6 having the structure as shown in Formula 6-1, R" is H, OH, Ci-3 alkyl, C1-3 alkoxy or halogen; k is 0, 1, 2 or 3; Z is C or N; U is O, S or CH; where Z and U are not heteroatoms at the same time; R 1 is H, halogen, OH, C1-3 alkyl, Ci-3haloalkyl or C1-3 alkoxy; m is 0, 1, 2 or 3; R" is H, halo, OH, NH2, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 alkylamino, C3-5 cycloalkyl, C3-5 cycloalkylamino or C3-5 heterocycloalkyl; n is 0, 1 or 2.
  • R 3 is H or C1-3 alkyl; Yi is CH2 or ; R" is H, OH, C1-3 alkyl, C1-3 alkoxy or halogen; k is 0, 1, 2 or 3; Z is C or N; U is O, S or CH; where Z and U are not heteroatoms at the same time; R 1 is H, halogen, OH, C1-3 alkyl, C1-3 haloalkyl or C1-3 alkoxy; m is 0, 1, 2 or 3; R" is H, halo, OH, NH2, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 alkylamino, C3-5 cycloalkyl, C3-5 cycloalkylamino or C3-5 heterocycloalkyl; n is 0, 1 or 2. [0138] An embodiment of the disclosure is the compound of Formula 6-1, wherein R 3 is H or methyl.
  • An embodiment of the disclosure is the compound of Formula 6-1, wherein A is O or NI I.
  • An embodiment of the disclosure is the compound of Formula 6-1, wherein m2 is 2 or 6.
  • An embodiment of the disclosure is the compound of Formula 6-1, wherein R 1 is O, or NH.
  • An embodiment of the disclosure is the compound of Formula 6-1, wherein R is
  • An embodiment of the disclosure is the compound of Formula 6-1, wherein m is 0, 1, 2 or 3, preferably 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 6-1, wherein R" is H, halo, OH, NH2, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 alkylamino, C3-5 cycloalkyl, C3-5 cycloalkylamino or C3-5 heterocycloalkyl, preferably H, F, CF3, methoxy, methyl, dimethylamino, cyclopropyl, cyclopropylamino or methylamino, more preferably H, CF3, F, dimethylamino, cyclopropyl or cyclopropylamino, most preferably H, dimethylamino, cyclopropyl or cyclopropylamino.
  • An embodiment of the disclosure is the compound of Formula 6-1, wherein n is 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 6-1, wherein R" substitutes at the adjacent position to the N atom.
  • An embodiment of the disclosure is the compound of Formula 8, wherein R 3 is H or Ci-3 alkyl, preferably H or methyl.
  • An embodiment of the disclosure is the compound of Formula 8, wherein Yi is preferably CH2. [0149] An embodiment of the disclosure is the compound of Formula 8, wherein A is O,
  • An embodiment of the disclosure is the compound of Formula 8, wherein m2 is 1, 2, 3 or 4, preferably 2.
  • An embodiment of the disclosure is the compound of Formula 8, wherein R 1 is O, H, preferably O.
  • An embodiment of the disclosure is the compound of Formula 8, wherein R'" is H, OH, Ci-3 alkyl, C1-3 alkoxy or halogen, preferably H, methyl, methoxy or F, more preferably
  • An embodiment of the disclosure is the compound of Formula 8, wherein k is 0 or
  • An embodiment of the disclosure is the compound of Formula 8, wherein Z is C or N; U is O, S or CH; where Z and U are not heteroatoms at the same time; preferably Z is N and U is CH; preferably Z is C and U is S.
  • An embodiment of the disclosure is the compound of Formula 8, wherein R' is H, halogen, OH, C1-3 alkyl, C1-3 haloalkyl or C1-3 alkoxy, preferably H, F, CF3, CCb, methyl or methoxy, more preferably H or CF3.
  • An embodiment of the disclosure is the compound of Formula 8, wherein m is 0, 1 or 2.
  • An embodiment of the disclosure is the compound of Formula 8, wherein R" is H, halo, OH, NH2, Ci-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 alkylamino, C3-5 cycloalkyl, C3-5 cycloalkylamino or C3-5 heterocycloalkyl, preferably H, F, OH, NH2, methyl, methoxy, CF3, CCb, methylamino, dimethylamino, cyclopropyl or cyclopropylamino, more preferably H,
  • An embodiment of the disclosure is the compound of Formula 8, wherein n is 0, 1 or 2.
  • An embodiment of the disclosure is the compound of Formula 10, wherein R 3 is H or Ci-3 alkyl, preferably H or methyl.
  • An embodiment of the disclosure is the compound of Formula 10, wherein Yi is , preferably CH2.
  • An embodiment of the disclosure is the compound of Formula 10, wherein each A is independently ,
  • An embodiment of the disclosure is the compound of Formula 10, wherein A is preferably
  • An embodiment of the disclosure is the compound of Formula 10, wherein m5 is 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 10, wherein m4 is 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 10, wherein m3 is 1, 2, 3, 4 or 5, preferably 4.
  • An embodiment of the disclosure is the compound of Formula 10, wherein R 1 is
  • An embodiment of the disclosure is the compound of Formula 10, wherein R" is H, OH, C1-3 alkyl, C1-3 alkoxy or halogen, preferably H, methyl, methoxy or F, more preferably H.
  • An embodiment of the disclosure is the compound of Formula 10, wherein k is 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 10, wherein Z is C,
  • U is S or O.
  • An embodiment of the disclosure is the compound of Formula 10, wherein Z is N,
  • An embodiment of the disclosure is the compound of Formula 10, wherein R' is H, halogen, OH, C1-3 alkyl, C1-3 haloalkyl or C1-3 alkoxy, preferably H, F, CF3, CCb, methyl or methoxy, more preferably H or CF3.
  • An embodiment of the disclosure is the compound of Formula 10, wherein m is 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 10, wherein R" is H, halo, OH, NH2, Ci-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 alkylamino, C3-5 cycloalkyl, C3-5 cycloalkylamino or C3-5 heterocycloalkyl, preferably H, F, OH, NH2, methyl, methoxy, CF3, CCb, methylamino, cyclopropyl, cyclopropylamino or dimethylamino, more preferably H,
  • An embodiment of the disclosure is the compound of Formula 10, wherein n is 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 13, wherein R 3 is H or Ci-3 alkyl, preferably H or methyl.
  • An embodiment of the disclosure is the compound of Formula 13, wherein Yi is preferably CH2.
  • An embodiment of the disclosure is the compound of Formula 13, wherein A is O,
  • An embodiment of the disclosure is the compound of Formula 13, wherein m2 is 1, 2, 3 or 4, preferably 1.
  • An embodiment of the disclosure is the compound of Formula 13, wherein R 1 is
  • An embodiment of the disclosure is the compound of Formula 13, wherein R"' is
  • H OH, Ci-3 alkyl, C1-3 alkoxy or halogen, preferably H, methyl, methoxy or F, more preferably H.
  • An embodiment of the disclosure is the compound of Formula 13, wherein k is 0,
  • An embodiment of the disclosure is the compound of Formula 13, wherein Z is C, U is S or O.
  • An embodiment of the disclosure is the compound of Formula 13, wherein Z is N, U is CH
  • An embodiment of the disclosure is the compound of Formula 13, wherein R' is H, halogen, OH, C1-3 alkyl, C1-3 haloalkyl or C1-3 alkoxy, preferably H, F, CF3, CCb, methyl or methoxy, more preferably H or CF3.
  • An embodiment of the disclosure is the compound of Formula 13, wherein m is 0, 1, 2 or 3, preferably 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 13, wherein R" is H, halo, OH, NH2, Ci-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 alkylamino, C3-5 cycloalkyl, C3-5 cycloalkylamino or C3-5 heterocycloalkyl, preferably H, F, OH, NH2, methyl, methoxy, CF3, CCb, methylamino, cyclopropyl, cyclopropylamino or dimethylamino, more preferably H,
  • An embodiment of the disclosure is the compound of Formula 13, wherein n is 0,
  • An embodiment of the compound of Formula II-l is of the following Formula 3, wherein R 1 is O, NH,
  • An embodiment of the disclosure is the compound of Formula 3, wherein R 2 is H, OH, Ci-3 alkyl, C1-3 alkoxy, C1-3 alkylamino or NH2, preferably H, OH orML ⁇ .
  • An embodiment of the disclosure is the compound of Formula 3, wherein m6 is 0,
  • An embodiment of the disclosure is the compound of Formula 3, wherein R 1 is O or NH.
  • An embodiment of the disclosure is the compound of Formula 3, wherein R' is H, halogen, OH, C1-3 alkyl, C1-3 haloalkyl or C1-3 alkoxy, preferably H, halogen or C1-3 fluoroalkyl, more preferably H or F.
  • An embodiment of the disclosure is the compound of Formula 3, wherein m is 0, 1,
  • An embodiment of the disclosure is the compound of Formula 3, wherein R" is H, halo, OH, NH2, Ci-3 alkoxy, C3-5 cycloalkyl, C3-5 cycloalkylamino or C1-3 alkylamino, preferably H, halo, methylamino, dimethylamino, cyclopropylamino or cyclopropyl, more preferably H, F or dimethylamino.
  • An embodiment of the disclosure is the compound of Formula 3, wherein n is 0, 1, 2 or 3, preferably 0, 1 or 2.
  • An embodiment of the disclosure is the compound of Formula 3, wherein Z is C,
  • U is O or S.
  • An embodiment of the disclosure is the compound of Formula 3, wherein Z is N,
  • An embodiment of the disclosure is the compound of Formula 3, wherein R'" is H, OH, Ci-3 alkyl, C1-3 alkoxy or halogen, preferably H, F, methyl or methoxy, more preferably H.
  • An embodiment of the disclosure is the compound of Formula 3 having the structure as shown in Formula 3-1, wherein R 2 is H, OH, C1-3 alkyl, C1-3 alkoxy, C1-3 alkylamino or H2; m6 is 0, 1, 2 or 3; Yi
  • R" is H, halo, OH, NH2, C1-3 alkoxy, C1-3 haloalkyl, C3-5 cycloalkyl, C3-5 cycloalkylamino or C1-3 alkylamino; n is 0, 1 or 2.
  • An embodiment of the disclosure is the compound of Formula 3-1, wherein R 2 is H, NH2 or OH.
  • An embodiment of the disclosure is the compound of Formula 3-1, wherein m6 is 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 3-1, wherein when substituted at the following position in the phenyl:
  • An embodiment of the disclosure is the compound of Formula 3-1, wherein R 1 is O or NH.
  • An embodiment of the disclosure is the compound of Formula 3-1, wherein R" is F, dimethylamino, methylamino, cyclopropyl or cyclopropylamino.
  • An embodiment of the disclosure is the compound of Formula 3-1, wherein n is 0, 1, or 2.
  • An embodiment of the disclosure is the compound of Formula 15, wherein R 1 is , preferably O or NH.
  • An embodiment of the disclosure is the compound of Formula 15, wherein R" is H, OH, Ci-3 alkyl, C1-3 alkoxy or halogen, preferably H, F, methyl or methoxy, more preferably H.
  • An embodiment of the disclosure is the compound of Formula 15, wherein Z is C, U is O or S.
  • An embodiment of the disclosure is the compound of Formula 15, wherein Z is N,
  • An embodiment of the disclosure is the compound of Formula 15, wherein R' is H, halogen, OH, C1-3 alkyl, C1-3 haloalkyl or C1-3 alkoxy, preferably H, halogen or C1-3 fluoroalkyl, more preferably H, CF3 or F.
  • An embodiment of the disclosure is the compound of Formula 15, wherein m is 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 15, wherein R" is H, halo, OH, NH2, Ci-3 alkoxy, C3-5 cycloalkyl, C3-5 cycloalkylamino or C1-3 alkylamino, preferably H, halo, methylamino, dimethylamino, cyclopropylamino or cyclopropyl, more preferably H, F, methylamino, cyclopropylamino or dimethylamino, most preferably H or dimethylamino.
  • An embodiment of the disclosure is the compound of Formula 15, wherein n is 0,
  • An embodiment of the compound of Formula IV-1 is of the following Formula 2, 7, 9, 11, 12 or 14,
  • An embodiment of the disclosure is the compound of Formula 2, wherein R 3 is H or Ci-3 alkyl, preferably H or methyl.
  • An embodiment of the disclosure is the compound of Formula 2, wherein Yi is [0219]
  • An embodiment of the disclosure is the compound of Formula 2, wherein m2 is 2, 3, 4, 5 or 6, preferably 2 or 6.
  • An embodiment of the disclosure is the compound of Formula 2, wherein R 1 is O, preferably NH.
  • An embodiment of the disclosure is the compound of Formula 2, wherein R" is H, halo, OH, NH2, Ci-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 alkylamino, C3-5 cycloalkyl, C3-5 cycloalkylamino or C3-5 heterocycloalkyl, preferably H, F, OH, H2, methyl, methoxy, CF3, CCb, methylamino, dimethylamino, cyclopropyl or cyclopropylamino, more preferably H,
  • An embodiment of the disclosure is the compound of Formula 2, wherein n is 0, 1 or 2, preferably 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 2, wherein R' is H, halogen, OH, C1-3 alkyl, C1-3 haloalkyl or C1-3 alkoxy, preferably H, F, CF3, CCb, methyl or methoxy, more preferably H or CF3.
  • An embodiment of the disclosure is the compound of Formula 2, wherein m is 0, 1, 2 or 3, preferably 0, 1 or 2.
  • An embodiment of the disclosure is the compound of Formula 2, wherein Z is C,
  • U is O or S
  • W is CH
  • An embodiment of the disclosure is the compound of Formula 2, wherein Z is N,
  • An embodiment of the disclosure is the compound of Formula 2, wherein Z is C, W is N, U is CH.
  • An embodiment of the disclosure is the compound of Formula 2, wherein R'" is H, OH, NH2, Ci-3 alkyl, C1-3 alkylamino, C1-3 alkoxy or halogen, preferably H, F, methoxy, methylamino or dimethylamino.
  • An embodiment of the disclosure is the compound of Formula 2, wherein k is 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 7, wherein R 3 is H or Ci-3 alkyl, preferably H or methyl.
  • An embodiment of the disclosure is the compound of Formula 7, wherein Yi is
  • An embodiment of the disclosure is the compound of Formula 7, wherein A is O,
  • An embodiment of the disclosure is the compound of Formula 7, wherein m2 is 2, 3, 4, 5 or 6, preferably 2 or 3.
  • An embodiment of the disclosure is the compound of Formula 7, wherein R 1 is O,
  • NH preferably NH.
  • An embodiment of the disclosure is the compound of Formula 7, wherein R" is H, halo, OH, NH2, Ci-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 alkylamino, C3-5 cycloalkyl, C3-5 cycloalkylamino or C3-5 heterocycloalkyl, preferably H, F, OH, NH2, methyl, methoxy, CF3, CCb, methylamino, dimethylamino, cyclopropyl or cyclopropylamino, more preferably H,
  • An embodiment of the disclosure is the compound of Formula 7, wherein n is 0, 1, or 2, preferably 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 7, wherein R' is H, halogen, OH, C1-3 alkyl, C1-3 haloalkyl or C1-3 alkoxy, preferably H, F, CF3, CCb, methyl or methoxy, more preferably H or CF3.
  • An embodiment of the disclosure is the compound of Formula 7, wherein m is 0, 1, 2 or 3, preferably 0, 1 or 2.
  • An embodiment of the disclosure is the compound of Formula 7, wherein Z is C,
  • U is O or S, W is CH.
  • An embodiment of the disclosure is the compound of Formula 7, wherein Z is N, U is CH, W is CH.
  • An embodiment of the disclosure is the compound of Formula 7, wherein Z is C, W is N, U is CH.
  • An embodiment of the disclosure is the compound of Formula 7, wherein R'" is H, OH, NH2, Ci-3 alkyl, C1-3 alkylamino, C1-3 alkoxy or halogen, preferably H, F, methoxy, methylamino or dimethylamino.
  • An embodiment of the disclosure is the compound of Formula 7, wherein k is 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 9, wherein R 3 is H or Ci-3 alkyl, preferably H or methyl.
  • An embodiment of the disclosure is the compound of Formula 9, wherein Yi is
  • An embodiment of the disclosure is the compound of Formula 9, wherein A is O,
  • An embodiment of the disclosure is the compound of Formula 9, wherein m2 is 2, 3, 4, 5 or 6, preferably 2 or 3.
  • An embodiment of the disclosure is the compound of Formula 9, wherein R 1 is O, , preferably NH.
  • An embodiment of the disclosure is the compound of Formula 9, wherein R" is H, halo, OH, NH2, Ci-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 alkylamino, C3-5 cycloalkyl, C3-5 cycloalkylamino or C3-5 heterocycloalkyl, preferably H, F, OH, NH2, methyl, methoxy, CF3, CCb, methylamino, dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F, CF3, cyclopropyl or cyclopropylamino.
  • An embodiment of the disclosure is the compound of Formula 9, wherein n is 0, 1, or 2, preferably 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 9, wherein R' is H, halogen, OH, C1-3 alkyl, C1-3 haloalkyl or C1-3 alkoxy, preferably H, F, CF3, CCb, methyl or methoxy, more preferably H or CF3.
  • An embodiment of the disclosure is the compound of Formula 9, wherein m is 0, 1, 2 or 3, preferably 0, 1 or 2.
  • An embodiment of the disclosure is the compound of Formula 9, wherein Z is C,
  • U is O or S
  • W is CH
  • An embodiment of the disclosure is the compound of Formula 9, wherein Z is N,
  • An embodiment of the disclosure is the compound of Formula 9, wherein Z is C, W is N, U is CH.
  • An embodiment of the disclosure is the compound of Formula 9, wherein R'" is H, OH, NH2, Ci-3 alkyl, C1-3 alkylamino, C1-3 alkoxy or halogen, preferably H, F, methoxy, methylamino or dimethylamino.
  • An embodiment of the disclosure is the compound of Formula 9, wherein k is 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 11, wherein R 3 is H or Ci-3 alkyl, preferably H or methyl.
  • An embodiment of the disclosure is the compound of Formula 11, wherein Yi is
  • An embodiment of the disclosure is the compound of Formula 11, wherein A is O,
  • An embodiment of the disclosure is the compound of Formula 11, wherein m2 is 2, 3, 4, 5 or 6, preferably 2 or 3.
  • An embodiment of the disclosure is the compound of Formula 11, wherein R 1 is
  • An embodiment of the disclosure is the compound of Formula 11, wherein R" is H, halo, OH, NH2, Ci-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 alkylamino, C3-5 cycloalkyl, C3-5 cycloalkylamino or C3-5 heterocycloalkyl, preferably H, F, OH, NH2, methyl, methoxy, CF3, CCb, methylamino, dimethylamino, cyclopropyl or cyclopropylamino, more preferably H,
  • An embodiment of the disclosure is the compound of Formula 11, wherein n is 0,
  • An embodiment of the disclosure is the compound of Formula 11, wherein R' is H, halogen, OH, C1-3 alkyl, C1-3 haloalkyl or C1-3 alkoxy, preferably H, F, CF3, CCb, methyl or methoxy, more preferably H or CF3.
  • An embodiment of the disclosure is the compound of Formula 11, wherein m is 0, 1, 2 or 3, preferably 0, 1 or 2.
  • An embodiment of the disclosure is the compound of Formula 11, wherein Z is C, U is O or S, W is CH.
  • An embodiment of the disclosure is the compound of Formula 11, wherein Z is N, U is CH, W is CH
  • An embodiment of the disclosure is the compound of Formula 11, wherein Z is C, W is N, U is CH.
  • An embodiment of the disclosure is the compound of Formula 11, wherein R" is
  • An embodiment of the disclosure is the compound of Formula 11, wherein k is 0,
  • An embodiment of the disclosure is the compound of Formula 12, wherein R 3 is H or Ci-3 alkyl, preferably H or methyl. [0273] An embodiment of the disclosure is the compound of Formula 12, wherein Yi is , preferably CH2.
  • An embodiment of the disclosure is the compound of Formula 12, wherein each A is independently O, NH, An embodiment of the disclosure is the compound of Formula 12, wherein A is O, NH, , preferably O.
  • An embodiment of the disclosure is the compound of Formula 12, wherein m3 is 1, 2, 3, 4, 5 or 6, preferably 2 or 3.
  • An embodiment of the disclosure is the compound of Formula 12, wherein m4 is 0 or 1, 2 or 3, preferably 0 or 3.
  • An embodiment of the disclosure is the compound of Formula 12, wherein m5 is 0 or 1, 2 or 3, preferably 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 12, wherein R 1 is
  • An embodiment of the disclosure is the compound of Formula 12, wherein R" is H, halo, OH, NH2, Ci-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 alkylamino, C3-5 cycloalkyl, C3-5 cycloalkylamino or C3-5 heterocycloalkyl, preferably H, F, OH, NH2, methyl, methoxy, CF3, CCb, methylamino, dimethylamino, cyclopropyl or cyclopropylamino, more preferably H,
  • An embodiment of the disclosure is the compound of Formula 12, wherein n is 0,
  • An embodiment of the disclosure is the compound of Formula 12, wherein R' is H, halogen, OH, C1-3 alkyl, C1-3 haloalkyl or C1-3 alkoxy, preferably H, F, CF3, CCb, methyl or methoxy, more preferably H or CF3.
  • R' is H, halogen, OH, C1-3 alkyl, C1-3 haloalkyl or C1-3 alkoxy, preferably H, F, CF3, CCb, methyl or methoxy, more preferably H or CF3.
  • An embodiment of the disclosure is the compound of Formula 12, wherein m is 0, 1, 2 or 3, preferably 0, 1 or 2.
  • An embodiment of the disclosure is the compound of Formula 12, wherein Z is C, U is O or S, W is CH.
  • An embodiment of the disclosure is the compound of Formula 12, wherein Z is N, U is CH, W is CH
  • An embodiment of the disclosure is the compound of Formula 12, wherein Z is C, W is N, U is CH.
  • An embodiment of the disclosure is the compound of Formula 12, wherein R"' is
  • An embodiment of the disclosure is the compound of Formula 12, wherein k is 0,
  • An embodiment of the disclosure is the compound of Formula 14, wherein R 3 is H or C1-3 alkyl, preferably H or methyl.
  • An embodiment of the disclosure is the compound of Formula 14, wherein Yi is , preferably CH2.
  • An embodiment of the disclosure is the compound of Formula 14, wherein each A is independently O, NH, An embodiment of the disclosure is the compound of Formula 14, wherein A is O, NH , preferably O.
  • An embodiment of the disclosure is the compound of Formula 14, wherein m3 is 1, 2, 3, 4, 5 or 6, preferably 2, 3 or 4.
  • An embodiment of the disclosure is the compound of Formula 14, wherein m4 is 0 , 1, 2, 3 or 4, preferably 0 or 3.
  • An embodiment of the disclosure is the compound of Formula 14, wherein m5 is 0 or 1, 2 or 3, preferably 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 14, wherein R 1 is
  • An embodiment of the disclosure is the compound of Formula 14, wherein R" is H, halo, OH, NH2, Ci-3 alkyl, C1-3 alkoxy, C1.3 haloalkyl, C1.3 alkylamino, C3-5 cycloalkyl, C3-5 cycloalkylamino or C3-5 heterocycloalkyl, preferably H, F, OH, H2, methyl, methoxy, CF3, CCb, methylamino, dimethylamino, cyclopropyl or cyclopropylamino, more preferably H,
  • An embodiment of the disclosure is the compound of Formula 14, wherein n is 0,
  • An embodiment of the disclosure is the compound of Formula 14, wherein R' is H, halogen, OH, C1-3 alkyl, C1-3 haloalkyl or C1-3 alkoxy, preferably H, F, CF3, CCb, methyl or methoxy, more preferably H or CF3.
  • An embodiment of the disclosure is the compound of Formula 14, wherein m is 0, 1, 2 or 3, preferably 0, 1 or 2.
  • An embodiment of the disclosure is the compound of Formula 14, wherein Z is C, U is O or S, W is CH.
  • An embodiment of the disclosure is the compound of Formula 14, wherein Z is N, U is CH, W is CH
  • An embodiment of the disclosure is the compound of Formula 14, wherein Z is C, W is N, U is CH.
  • An embodiment of the disclosure is the compound of Formula 14, wherein R" is
  • An embodiment of the disclosure is the compound of Formula 14, wherein k is 0,
  • An embodiment of the disclosure is the compound of Formula 4, wherein R 2 is H, OH, Ci-3 alkyl, C1-3 alkoxy, C1-3 alkylamino or NH2, preferably H, OH orML ⁇ .
  • An embodiment of the disclosure is the compound of Formula 4, wherein m6 is 0,
  • An embodiment of the disclosure is the compound of Formula 4, wherein R 1 is O,
  • NH preferably O or NH.
  • An embodiment of the disclosure is the compound of Formula 4, wherein R' is H, halogen, OH, C1-3 alkyl, C1-3 haloalkyl or C1-3 alkoxy, preferably H, halogen or C1-3 fluoroalkyl, more preferably H or F.
  • An embodiment of the disclosure is the compound of Formula 4, wherein m is 0, 1,
  • An embodiment of the disclosure is the compound of Formula 4, wherein R" is H, halo, OH, NH2, Ci-3 alkoxy, C3-5 cycloalkyl, C3-5 cycloalkylamino or C1-3 alkylamino, preferably H, halo, methylamino, dimethylamino, cyclopropylamino or cyclopropyl, more preferably H, F or dimethylamino.
  • An embodiment of the disclosure is the compound of Formula 4, wherein n is 0, 1, or 2, preferably 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 4, wherein Z is C,
  • U is O or S, W is CH [0313]
  • An embodiment of the disclosure is the compound of Formula 4, wherein Z is N, U is CH, W is CH
  • An embodiment of the disclosure is the compound of Formula 4, wherein Z is C, U is CH, W is N.
  • An embodiment of the disclosure is the compound of Formula 4, wherein R'" is H, OH, NH2, Ci-3 alkyl, C1-3 alkylamino, C1-3 alkoxy or halogen, preferably H, F, methoxy, methylamino or dimethylamino.
  • An embodiment of the disclosure is the compound of Formula 4, wherein k is 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 4 having the structure as shown in Formula 4-1, alkoxy, C1-3 haloalkyl, C1-3 alkylamino or C3-5 heterocycloalkyl; n is 0, 1 or 2; R is H, halogen, OH, C1-3 alkyl, C1-3 haloalkyl or C1-3 alkoxy; m is n is 0, 1 or 2; U is O or S; R 1 " is H, OH, NH2, Ci-3 alkyl, C1-3 alkylamino, C1-3 alkoxy or halogen; k is 0, 1, 2, 3 or 4.
  • An embodiment of the disclosure is the compound of Formula 4-1, wherein R 1 is NH.
  • An embodiment of the disclosure is the compound of Formula 4-1, wherein R" is H.
  • An embodiment of the disclosure is the compound of Formula 4-1, wherein R' is H.
  • An embodiment of the disclosure is the compound of Formula 4-1, wherein R 2 is
  • An embodiment of the disclosure is the compound of Formula 4-1, wherein R'" is H, OH, NH2, Ci-3 alkyl, C1-3 alkylamino, C1-3 alkoxy or halogen, preferably H, F, methoxy, methylamino or dimethylamino.
  • An embodiment of the disclosure is the compound of Formula 4, wherein k is 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 4, wherein U is S.
  • An embodiment of the compound of Formula VI-1 is of the following Formula 16 or 17,
  • An embodiment of the disclosure is the compound of Formula 16, wherein m2 is 1,
  • An embodiment of the disclosure is the compound of Formula 16, wherein R 1 is [0329]
  • An embodiment of the disclosure is the compound of Formula 16, wherein R' is H, halogen, OH, C1-3 alkyl, C1-3 haloalkyl or C1-3 alkoxy, preferably H, halogen or C1-3 fluoroalkyl, more preferably H or F.
  • An embodiment of the disclosure is the compound of Formula 16, wherein m is 0,
  • An embodiment of the disclosure is the compound of Formula 16, wherein R" is H, halo, OH, NH2, Ci-3 alkoxy, C3-5 cycloalkyl, C3-5 cycloalkylamino or C1-3 alkylamino, preferably H, halo, methylamino, dimethylamino, cyclopropylamino or cyclopropyl, more preferably H, F or dimethylamino.
  • An embodiment of the disclosure is the compound of Formula 16, wherein n is 0,
  • An embodiment of the disclosure is the compound of Formula 16, wherein Z is C, U is O or S, W is CH.
  • An embodiment of the disclosure is the compound of Formula 16, wherein Z is N, U is CH, W is CH
  • An embodiment of the disclosure is the compound of Formula 16, wherein Z is C, U is CH, W is N.
  • An embodiment of the disclosure is the compound of Formula 16, wherein R" is
  • An embodiment of the disclosure is the compound of Formula 16, wherein k is 0,
  • An embodiment of the disclosure is the compound of Formula 17, wherein m2 is 1, 2, 3, 4, 5 or 6, preferably 2 or 5.
  • An embodiment of the disclosure is the compound of Formula 17, wherein R 1 is preferably NH.
  • An embodiment of the disclosure is the compound of Formula 17, wherein R' is H, halogen, OH, C1-3 alkyl, C1-3 haloalkyl or C1-3 alkoxy, preferably H, halogen or C1-3 fluoroalkyl, more preferably H or F.
  • An embodiment of the disclosure is the compound of Formula 17, wherein m is 0,
  • An embodiment of the disclosure is the compound of Formula 17, wherein R" is H, halo, OH, NH2, Ci-3 alkoxy, C3-5 cycloalkyl, C3-5 cycloalkylamino or C1-3 alkylamino, preferably H, halo, methylamino, dimethylamino, cyclopropylamino or cyclopropyl, more preferably H, F or dimethylamino.
  • An embodiment of the disclosure is the compound of Formula 17, wherein n is 0,
  • An embodiment of the disclosure is the compound of Formula 17, wherein Z is C, U is O or S, W is CH.
  • An embodiment of the disclosure is the compound of Formula 17, wherein Z is N, U is CH, W is CH
  • An embodiment of the disclosure is the compound of Formula 17, wherein Z is C, U is CH, W is N.
  • An embodiment of the disclosure is the compound of Formula 17, wherein R" is
  • An embodiment of the disclosure is the compound of Formula 17, wherein k is 0,
  • Some embodiments of the disclosure are the compounds having a structure depicted in Table 2, or a pharmaceutical acceptable salt, an enantiomer, a non-enantiomer, a tautomer, a racemate, a solvate, a metabolic precursor, a prodrug thereof.
  • solvate, hydrate, salt, or ester of a compound of the present disclosure is provided herein.
  • An aspect of the disclosure is a composition, comprising a compound disclosed herein and at least one pharmaceutically acceptable excipient.
  • Ci-6 is intended to encompass Ci, C2, C3, C4, Cs, Ce, Ci-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6.
  • Alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having indicated number of carbon atoms.
  • an alkyl group has 1 to 6 carbon atoms (“Ci-6 alkyl”).
  • an alkyl group has 1 to 5 carbon atoms (“Ci-5 alkyl”).
  • an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”).
  • an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”).
  • an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”).
  • an alkyl group has 1 carbon atom (“Ci alkyl”).
  • an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”).
  • Ci-6 alkyl groups include methyl (Ci), ethyl (C2), «-propyl (C3), Ao-propyl (C3), «-butyl (C4), tert- butyl (C4), sec-butyl (C4), /.so-butyl (C4), «-pentyl (Cs), 3-pentyl (Cs), amyl (C5), neopentyl (Cs), 3 -methy 1-2-butyl (C5), tertiary amyl (C5), and «-hexyl (C6).
  • alkenyl refers to an alkyl group with one or more carbon-carbon double bonds at any position of the chain, which can be monosub stituted or poly substituted, and can be monovalent, divalent or multivalent.
  • alkenyl group include a vinyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a butadienyl group, a pentadienyl group, a hexadienyl group, etc.
  • Alkynyl refers to an alkyl group with one or more carbon-carbon triple bonds at any position of the chain, which can be monosub stituted or poly sub stituted, and can be monovalent, divalent or multivalent.
  • alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, etc.
  • Cycloalkyl includes any stable cyclic or polycyclic hydrocarbon group and any carbon atom which is saturated, which can be monosub stituted or polysubstituted, and can be monovalent, divalent or multivalent.
  • Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclononane, etc.
  • Substituted means that any one or more hydrogen atoms on a particular atom are replaced with substituents, including deuterium and hydrogen variants, as long as the valence of a particular atom is normal and the substituted compound is stable.
  • substituents including deuterium and hydrogen variants, as long as the valence of a particular atom is normal and the substituted compound is stable.
  • Ketone substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of being chemically achievable.
  • any variable e.g., R
  • its definition at each occurrence is independent of its definition at every other occurrence.
  • R e.g., R
  • said group may optionally be substituted by up to two R groups and R at each occurrence is selected independently from the definition of R.
  • substituents and/or variables are permissible only if such combinations result in stable compounds.
  • Alkoxy refers to refers to said alkyl group with a specified number of carbon atoms attached through an oxygen bridge. Unless otherwise specified, Ci-6 alkoxy includes Ci, Ci, Ci, C4, Cs and Ce alkoxy group. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- pentyloxy.
  • Aryl refers to a polyunsaturated, aromatic hydrocarbon substituent which can be monosub stituted or polysubstituted, and can be monovalent, divalent or polyvalent, and can be monocyclic or polycyclic (e.g., 1 to 3 rings; at least one of which is aromatic). They are fused together or covalently linked.
  • Halo or "halogen” by itself or as part of another substituent refers to a fluorine, chlorine, bromine or iodine atom.
  • Haloalkyl includes both monohaloalkyl and polyhaloalkyl.
  • halo(Ci-4)alkyl includes, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc.
  • examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • Heterocyclo refers to a radical of a 3 - to 10-membered non-aromatic ring or aromatic ring system having indicated ring carbon atoms (such as 2 to 6 ring carbon atoms) and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“C2-6 heterocyclo”).
  • C2-6 heterocyclo nitrogen, oxygen and sulfur
  • a heterocyclo group can either be monocyclic (“monocyclic heterocyclo”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclo”), and can be saturated or partially unsaturated.
  • Heterocyclo bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • “Heterocyclo” also includes ring systems wherein the heterocyclic ring, as defined above, is fused with one or more carbocyclic groups wherein the point of attachment is either on the carbocyclic or heterocyclic ring, or ring systems wherein the heterocyclic ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclic ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclic ring system.
  • Nitrogen protecting group refers to a protecting group for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc); Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethyl silyl (TMS) and tert-butyldimethylsilyl (TBS), etc..
  • acyl such as alkanoyl (e.g., acetyl,
  • a heterocyclo group is a 5-10 membered non-aromatic ring system or aromatic ring system having indicated ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur.
  • a heterocyclo group is a 5-6 membered non-aromatic ring system or aromatic ring system having indicated ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclo”).
  • the 5-6 membered heterocyclo has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclo has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclo has one ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3-membered heterocyclo groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, and thiorenyl.
  • Exemplary 4-membered heterocyclo groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl.
  • Exemplary 5-membered heterocyclo groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione.
  • 5-membered heterocyclo groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.
  • Exemplary 5-membered heterocyclo groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclo groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6-membered heterocyclo groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl.
  • 6-membered heterocyclo groups containing two heteroatoms include, without limitation, triazinanyl.
  • Exemplary 7-membered heterocyclo groups containing one heteroatom include, without limitation, azepanyl, oxepanyl, and thiepanyl.
  • Exemplary 8-membered heterocyclo groups containing one heteroatom include, without limitation, azocanyl, oxecanyl, and thiocanyl.
  • Exemplary 5-membered heterocyclo groups fused to a Cr, aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
  • Exemplary 6-membered heterocyclo groups fused to an aryl ring include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
  • pharmaceutically acceptable salt means a salt that is not harmful to mammals, especially humans.
  • Pharmaceutically acceptable salts can be formed using non-toxic acids or bases, including mineral acids or inorganic bases, or organic acids or organic bases.
  • examples of pharmaceutically acceptable salts include metal salts formed with aluminum, calcium, lithium, magnesium, potassium, sodium, zinc and so on, and organic salts formed with lysine, N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine and so on.
  • pharmaceutically acceptable salts contain acid-addition salts and base-addition salts.
  • solvate means a solvent-containing compound that is formed by association of one or a plurality of solvent molecules to the compounds of the present disclosure.
  • Solvates include, for example, monosolvates, disolvates, trisolvates, and tetrasolvates.
  • solvates include hydrates.
  • hydrate means a compound further containing a stoichiometric or a non-stoichiometric amount of water constrained by non-covalent bonding intermolecular force, or a salt thereof. Hydrates include monohydrates, dihydrates, trihydrates, tetrahydrates, and the like.
  • a “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) and/or other non-human animals, for example, mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs) and birds (e.g., commercially relevant birds such as chickens, ducks, geese, and/or turkeys).
  • the animal is a mammal.
  • the animal may be a male or female and at any stage of development.
  • a non-human animal may be a transgenic animal.
  • administer refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing an inventive compound, or a pharmaceutical composition thereof.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a “pathological condition” (e.g., a disease, disorder, or condition, or one or more signs or symptoms thereof) described herein.
  • pathological condition e.g., a disease, disorder, or condition, or one or more signs or symptoms thereof
  • treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease or condition.
  • treatment may be administered to a susceptible subj ect prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
  • an “effective amount” of a compound or a composition refers to an amount sufficient to elicit the desired biological response, i.e., treating the condition.
  • the effective amount of a compound or a composition may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject.
  • An effective amount encompasses therapeutic and prophylactic treatment.
  • a “therapeutically effective amount” of a compound or a composition is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition.
  • a therapeutically effective amount of a compound or a composition means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition.
  • the term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces, or avoids symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent.
  • alpha-synuclein refers to a 140 amino acid polypeptide with the following amino acid sequence (wild-type human a-synuclein).
  • binder refers to a compound that binds to a protein.
  • the binder binds to a protein with a Kd of less than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM.
  • proteasome refers to a protease complex for carrying out degradation of proteins.
  • the proteasome is a multisubunit enzyme complex, which can also play a key role regulating proteins that control cell-cycle progression and apoptosis.
  • the proteasome conducts proteolysis of selected proteins.
  • pharmaceutically acceptable excipient means pharmaceutically acceptable materials, compositions, or vehicles such as physiological saline solutions, liquid or solid fillers, diluents, solvents, or encapsulants.
  • pharmaceutically acceptable excipients include water, saline water, physiological saline water or phosphate buffered saline water (PBS), sodium chloride injection solution, Ringer’s injection solution, isotonic dextrose injection solution, sterile water injection solution, dextrose, and lactated Ringer’s injection solution.
  • Another aspect of the present disclosure is a method for aiding in the treatment of a synucleinopathy in a subject, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of a compound as disclosed herein, or a composition as disclosed herein.
  • Another aspect of the present disclosure is a method of treating a subject (e.g., a human) suffering from a disease characterized by the presence of Lewy bodies or pathological aggregates of a-synuclein, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of a compound as disclosed herein or a composition as disclosed herein.
  • a subject e.g., a human
  • Another aspect of the present disclosure is a method for prophylaxis of a disease characterized by the presence of Lewy bodies or pathological aggregates of a-synuclein in a subject, the method comprising, consisting essentially of, or consisting of administering to the subject an effective amount of a compound or a composition as disclosed herein.
  • kits for treating a disease characterized by the presence of Lewy bodies or pathological aggregates of a-synuclein in a subject comprising, consisting essentially of, or consisting of administering to the subject an effective amount of a compound or a pharmaceutical composition described herein.
  • kits for lessening the severity of a disease characterized by the presence of Lewy bodies or pathological aggregates of a-synuclein in a subject comprising, consisting essentially of, or consisting of administering to the subject an effective amount of a compound or a pharmaceutical composition described herein.
  • kits for delaying the progression of a disease characterized by the presence of Lewy bodies or pathological aggregates of a-synuclein in a subject comprising, consisting essentially of, or consisting of administering to the subject an effective amount of a compound or a pharmaceutical composition described herein.
  • kits for reducing the risk of developing a disease characterized by the presence of Lewy bodies or pathological aggregates of a-synuclein in a subject comprising, consisting essentially of, or consisting of administering to the subject at risk of developing the disease an effective amount of a compound or a pharmaceutical composition described herein.
  • kits for delaying the onset of a disease characterized by the presence of Lewy bodies or pathological aggregates of a-synuclein in a subject at risk of developing the disease comprising, consisting essentially of, or consisting of administering to the subject an effective amount of a compound or a pharmaceutical composition described herein.
  • the subject to be treated exhibits one or more symptoms (signs) of synucleinopathies, such as neuropsychiatric manifestations (depression, dementia, hallucinations, anxiety, apathy, anhedonia), autonomic changes (orthostatic hypotension, bladder disturbances, constipation, fecal incontinence, sialorrhea, dysphagia, sexual dysfunction, changes in cerebral blood flow), sensory changes (olfactory, pain, color discrimination abnormal sensations), sleep disorders (REM sleep behavior disorder (RBD), restless legs syndrome/periodic extremity movements, hypersomnia, insomnia), or other signs and symptoms (fatigue, diplopia, blurred vision, seborrhea, weight loss/gain).
  • neuropsychiatric manifestations depression, dementia, hallucinations, anxiety, apathy, anhedonia
  • autonomic changes orthostatic hypotension, bladder disturbances, constipation, fecal incontinence, sialorrhea, dysphagia, sexual dysfunction, changes in
  • the subject to be treated does not exhibit one or more symptoms of a synucleinopathy, but is known to have a genetic risk for developing a disease characterized by the presence of Lewy bodies or pathological aggregates of a-synuclein in the brain.
  • a genetic risk for developing a disease characterized by the presence of Lewy bodies or pathological aggregates of a-synuclein in the brain.
  • such an individual may have one or more relatives with the disease, or their risk is determined by analysis of genetic or biochemical markers.
  • mutations in SNCA PARK1, encoding a-synuclein
  • A30P, E46K, H50Q, G51D, and A53T mutations in SNCA (PARK1, encoding a-synuclein), including A30P, E46K, H50Q, G51D, and A53T, as well as duplications and triplications of the entire SNCA gene cause autosomal dominant forms of PD.
  • PINK1 PARK6, PTEN-induced kinase 1
  • DJ-1 PARK7
  • Parkin PARK2
  • ATP13A2 PARK9, ATPase type 13A2
  • FBX07 PARK 15, F-box only protein 7
  • PLA2 GB PARK14, phospholipase A2, group VI
  • 28 different genetic risk loci associated with PD and related synucleinopathies have been identified including SNCA, LRRK2, GBA/SYT11, MAPT, HLA-DRB5, GAK, GCH1, NUCKS1/RAB7L1, SLC41A1, BST1, SIPA1L2,
  • ACM SD/TMEM 163, STK39, MCCC1, TMEM 175/GAK/DGKQ, FAM47E/SCARB2, GPNMB, FGF20, INPP5F, MIR4697, CCDC62, GCH1, VPS13C, BCKDK/STX1B, SREBF/RAIl, RIT2 and DDRGK1 (Nails et al. (2014) Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nature Genetics 46(9): 989-993).
  • the antibodies described herein, or pharmaceutical compositions comprising the same are administered to a patient susceptible to, or otherwise at risk of the disease in a regime (dose, frequency and route of administration) effective to reduce the risk, lessen the severity, or delay the onset of at least one sign or symptom of the disease.
  • a regime dose, frequency and route of administration
  • the regime is effective to inhibit or delay accumulation of a-synuclein in the brain, and/or inhibit or delay its toxic effects and/or inhibit or delay development of behavioral deficits in the patient.
  • the methods described above generate a beneficial therapeutic response in a patient (e.g., reduction of a-synuclein aggregates in the brain, improved cognitive function, and/or reversing, treating or preventing cognitive decline) in the subject.
  • the compounds or the pharmaceutical compositions described herein are administered to a patient suspected of, or already suffering from a disease characterized by the presence of Lewy bodies or pathological aggregates of a-synuclein in a regime (dose, frequency and route of administration) effective to ameliorate or at least inhibit further deterioration of at least one sign or symptom of the disease.
  • the regime is effective to reduce or at least inhibit further increase of levels of a-synuclein, associated toxicities, and/or behavioral deficits.
  • the treatments can result in, e.g., a reduction of a-synuclein aggregates in the brain by 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more, relative to before initiating treatment or as compared to a population of untreated control patients.
  • the disease characterized by the presence of Lewy bodies or pathological aggregates of a-synuclein in the brain is Parkinson's disease (including idiopathic Parkinson's disease), DLB, DLBD, LBVAD, pure autonomic failure, Lewy body dysphagia, incidental LBD, inherited LBD (e.g., mutations of SNCA (PARKl), LRRK2 (PARK8), VP S35 (PARK 17), PINK1 (PARK6), DJ-1 (PARK7), Parkin (PARK2), ATP13A2 (PARK9), FBX07 (PARK 15) and PLA2 GB (PARK 14)), or multiple system atrophy (MSA; e.g., olivopontocerebellar atrophy, striatonigral degeneration and Shy-Drageri syndrome).
  • MSA multiple system atrophy
  • compositions of the present disclosure can be administered to humans and other animals orally, parenterally, intracisternally, intraperitoneally, intrathecally, intraventricularly, topically, bucally, or the like, depending on the disease or condition being treated.
  • a pharmaceutical composition comprising a compound of the disclosure is administered orally or parenterally, at dosage levels sufficient to deliver from about 0.001 mg/kg to about 200 mg/kg in one or more doses for one or several days.
  • the effective amount per dose varies from about 0.001 mg/kg to about 200 mg/kg, about 0.001 mg/kg to about 100 mg/kg, about 0.01 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, from about 0.1 mg/kg to about 40 mg/kg, from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic and/or prophylactic effect.
  • the compounds described herein are at dosages sufficient to deliver from about 0.001 mg/kg to about 200 mg/kg, from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, from about 0.1 mg/kg to about 40 mg/kg, from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, or from about 1 mg/kg to about 25 mg/kg, of subj ect body weight per day, one or more times a day, to obtain the desired therapeutic and/or prophylactic effect.
  • the desired dosage may be delivered three times a day, twice a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks.
  • the dosage is delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).
  • the composition described herein is administered at a dose that is below the dose at which the agent causes non-specific effects.
  • compositions described herein can be prepared by methods generally known in the art of pharmacology. In general, such methods include the steps of combining the compound of the disclosure with a carrier and/or one or more other accessory ingredients, and then shaping and/or packaging the product into a desired single- or multi-dose unit.
  • compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
  • a “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as, for example, one-half or one-third of such a dosage.
  • compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, stabilizers, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
  • Suitable diluents include calcium carbonate, sodium carbonate, calcium phosphate, calcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.
  • Suitable granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate
  • LCMS measurement was run on an Agilent 1200 HPLC/6100 SQ System using the following conditions: Method A: Mobile Phase: A: Water (0.01% TFA) B: CAN (0.01% TFA); Gradient Phase: 5%B increasing to 95%B within 1.4 min, 95%B with 1.6 min (total runtime: 3 min); Flow Rate: 2.3 mL/min; Column: SunFire C18, 4.6*50 mm, 3.5 pm; Column Temperature: 50°C. Detectors: ADC ELSD, DAD (214 nm and 254 nm), ES-API.
  • Method B Mobile Phase: A: Water (10 mMNFEHCCri) B: Acetonitrile; Gradient Phase: 5% to 95%B within 1.5 min, 95%B with 1.5 min (total runtime: 3 min); Flow Rate: 2.0 mL/min; Column: XBridge C18, 4.6*50 mm, 3.5 pm; Column Temperature: 40°C. Detectors: ADC ELSD, DAD (214 nm and 254 nm), MSD (ES-API).
  • Method C Mobile Phase: A: Water (10 mM H4HC03)B: Acetonitrile; Gradient Phase: 5% to 95%B within 1.5 min, 95%B with 1.5 min (total runtime: 3 min); Flow Rate: 2.0 mL/min; Column: XBridge C18, 4.6*50mm, 3.5 pm; Column Temperature: 40°C. Detectors: ADC ELSD, DAD (214 nm and 254 nm), MSD (ES-API).
  • N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-l,3-benzothiazol-6-yl]carbamate 500 mg, 1.12 mmol
  • DMF 10 mL
  • NaFI 107.49 mg, 4.48 mmol
  • Compound 161409 could be synthesized by method similar to example 19.
  • Compound 164263 A mixture of tert-butyl N-(2-bromanyl-l,3-benzothiazol-6-yl)carbamate (1100 mg, 3.34 mmol), N,N-dimethyl-5-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl )phenyl]pyridin-2-amine (1704 mg, 4.34 mmol), Pd(dppf)Ch (247 mg, 0.33 mmol) and 2M Na2CC>3(aq) solution (5 mL, 10.02 mmol) in dioxane (35 mL) was heated at 80°C for 16 h under argon.
  • N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-l,3-benzothiazol-6-yl] carbamate (1056 mg, 2.05 mmol) in DMF (20 mL) was added NaH (148 mg, 6.16 mmol) at 0°C and stirred at 25°C for 1 h.
  • 2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate (2.55 g, 6.16 mmol) in DMF (20 mL) was added to the reaction mixture and stirred at room temperature for 14 h.
  • N-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate (1.52 g, 4.75 mmol)
  • 2-(4-bromophenyl)-6-methoxy-imidazo[l,2-a]pyridine 1.2 g, 3.96 mmol
  • triphenylphosphine (34.6 mg, 0.13 mmol) in EtOH (4 mL) and toluene (2.8 mL) was purged with argon and then added with K2CO3 solution (1.75M, 7.92 mL, 13.85 mmol) dropwise.
  • N-[2-[2-(2-iodanylethoxy)ethoxy]ethyl]-N-[4-[4-(6-methoxyimidazo[l,2-a]pyri din-2 -yl)phe nyl]pyridin-2-yl]carbamate 100 mg, 0.15 mmol
  • K2CO3 63 mg, 0.46 mmol
  • methyl 5-azanyl-5-oxidanylidene-4-(6-oxidanyl-3-oxidanylidene-lH-isoindol-2-yl)pentanoate 49 mg, 0.17 mmol
  • DMF 5 mL
  • N-methyl-N-[5-[4-[6-[(2-methylpropan-2-yl)oxycarbonylamino]-l,3-benzothiazol-2-yl]-3-(t rifluoromethyl)phenyl]pyridin-2-yl]carbamate 200 mg, 0.33 mmol
  • dry DMF 5 mL
  • NaH 40 mg, 1.00 mmol
  • N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-l,3-benzothiazol-6-yl] carbamate (447 mg, 0.87 mmol) in DMF (8 mL) was added NaH (63 mg, 2.61 mmol) at 0°C, stirred at room temperature for 1 h and then added 5-(4-methylphenyl)sulfonyloxypentyl
  • N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-l,3-benzothiazol-6-yl] carbamate 300 mg, 0.58 mmol) in DMF (5 mL) was cooled to 0°C and added NaH (56 mg, 2.33 mmol). The mixture was stirred at room temperature for 1 h, added 2-azidoethyl 4-methylbenzenesulfonate (281 mg, 1.17 mmol) in DMF (5 mL) and heated at 50°C for 20 h. The mixture was cooled to 0°C and added water (5 mL).
  • N-(2-azidoethyl)-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-l,3-b enzothiazol-6-yl]carbamate (341 mg, 0.58 mmol) in THF (5mL)/EtOH (5mL) was added Pd(OH)2 (1701 mg, 1.61 mmol) and stirred under 1 atmosphere of Lb for 4 h. The mixture was filtered through a Celite pad and the filtrate was concentrated to dryness.
  • the supernatant was then boiled at 95 °C for 15 min with manual agitation by every 5 minutes, followed by centrifugation (6000 g, 30 min, 4 °C).
  • Supernatant was dialyzed with (10 mM Tris, 1 mM EGTA, 50 mMNaCl, pH 7.5) buffer and concentrated with concentrator.
  • the collected sample was loaded onto a Superdex200 column, the flow-through fraction was then loaded onto a Q-HP column. Collected fractions with a-synuclein eluates were pooled, concentrated and stored at -80 °C.
  • ReNcell VM a-synuclein aggregation assay was conducted at Charles River Laboratories (CRL).
  • ReNcell VM is an immortalized human neural progenitor cell line derived from the ventral mesencephalon region of the brain.
  • ReNcell VM cells were selected as in vitro cellular model for the a-synuclein aggregation assay, based on their growth features, differentiation potential into terminally differentiated neurons and amenability to adenoviral transduction. Aggregated human wild type a-synuclein was overexpressed through adenoviral delivery.
  • Aggregated a-synuclein was detected with the aggregate-selective anti-a-synuclein antibody MJFR14 using immunocytochemistry; total a-synuclein levels were detected with Syn205 (a/b-synuclein-specific antibody).
  • the ReNcell VM a-synuclein aggregation assay was applied for compound screening to identify compounds capable of degrading a-synuclein aggregates. Specifically, adenovirally transduced ReNcell VM cells were treated with test compounds (serially diluted) for 24 hours, followed by fixation, and then processed for ReNcell immunocytochemistry by staining with Syn205 and MJFR14.
  • Immunoreactivity toward aggregated (MJFR14) and total a-synuclein (Syn205) was quantified using high content-based segmentation of immunoactive areas in immunocytochemical images (performed with the IN Cell 2200 (GE Healthcare)), followed by quantification of immunofluorescent intensity (performed by CRL’s developed algorithm using IN Cell Developer Toolbox software).
  • FIG. 1 shows the high content-based quantifications of aggregated a-synuclein species in combination with determination of nuclei count (% remaining cells) in differentiated ReNcell VM cells. Results showed that 24 hour treatment with test compounds 166362, 170357, 162640 and 180948, respectively, induced a concentration-dependent inhibition of MJFR14 immunoreactivity, indicative of decreased a-synuclein aggregation. Each panel of graph displays normalized data for percentage effect (PE) and remaining cells (%).
  • Percentage effect (PE) Inhibition in comparison to BLANK (0.1% DMSO).
  • PE 100 - (signal of compound/average signal BLANK) x 100 [0561] Compound-induced cytotoxicity (% remaining cells)
  • % remaining cells (nuclei count of compound/average nuclei count of BLANK) x 100
  • FIGS 2A-2D show the representative immunocytochemical images of cells treated with vehicle (0.1% DMSO) and test compounds 132168, 166362, and 170357, and immunostained with MJFR14, illustrating the reduction in a-synuclein expression following treatment with compounds 132168 and 166362.
  • DC50 indicates the concentration at which 50% of a-synuclein aggregates has been degraded.
  • Example 40 In Vivo Assay For Degrading a-Synuclein Ag2regates
  • mice Male transgenic Line61 mice at age of three-month-old were used for the study. Mice were treated once via intravenous injection with the compound 132168 (25 mpk). Plasma and brain samples were collected at 0.25, 0.5, 1, 2, 4, 8 and 24 h post treatment. Blood samples were collected via cardiac puncture into MiniCollect® 0.5 mL K2EDTA (Potassium ethylenediaminetetraacetic acid) tubes. The blood samples were centrifuged at 3000 x g for 10 minutes at room temperature (22°C). Plasma was transferred to a pre-labeled 1.5 ml LoBind Eppendorf tube (2 aliquot, each ⁇ 75 m ⁇ ), frozen on dry ice and stored at -80°C until analysis.
  • K2EDTA Paratassium ethylenediaminetetraacetic acid
  • example compound 132168 was administered to mice in a pharmacokinetic study (10 and 25 mg/kg, intravenous).
  • Animal Husbandry Mice were housed at animal room environment with ventilation 15 times/hour, lighting 12 hours/day, temperature 20 °C to 24 °C and humidity 40 % to 70 %. The study rooms were disinfected and cleaned prior to the start of the study and the operation area was cleaned after each dosing or sampling during the study conduct. All animals had free access to food and water during the study. The animals had access to Certified Rodent Diet and water ad libitum. The nutritional composition and levels of contaminants of the diet and impurities and contaminants of the water were monitored by third organization. The health status of the animals was evaluated in accordance with accepted animal husbandry procedures and deemed suitable for experimental use.
  • Sample Collection & Processing Approximately 110 pL of whole blood were collected from all animals via facial or cardiac puncture under anesthesia with Isoflurane into test tubes containing potassium ethylenediaminetetraacetate (K2EDTA) at 0.25, 0.5, 1, 2, 4, 8 and 24 hr post dose. Brian samples were collected at 0.25, 0.5, 1, 2, 4, 8 and 24 hours post dose. A perfusion with pre-cold saline will be conducted via cardiac puncture before brain collection. Blood samples were centrifuged at 2000g at 4°C for 5 minutes to obtain plasma samples by transferring the supernatants into new tubes. All plasma and brain samples were stored at approximately -70 °C until analysis.
  • K2EDTA potassium ethylenediaminetetraacetate
  • Bioanalytical Method Development The concentrations of compound in plasma and brain samples were determined using a liquid chromatography with tandem mass spectrometry (LC-MS/MS) based method.
  • Embodiment 1 A method to treat synucleinopathy in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula A,
  • EBM is an E3 ubiquitin ligase binding moiety
  • L is a linker covalently attached to EBM and TBM; and SBM is an a-synuclein protein binding moiety of the formula: or a pharmaceutical acceptable salt, an enantiomer, a non-enantiomer, a tautomer, a racemate, a solvate, a metabolic precursor, a prodrug thereof, wherein is covalently linked to L; and is a substituted or unsubstituted bicyclic fused aromatic ring containing at least 1 ring heteroatom selected from O, S, and N; is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S, and N; and is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S, and N; or is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S,
  • Embodiment 2 A method to reduce a-synuclein aggregation in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula A,
  • EBM is an E3 ubiquitin ligase binding moiety
  • L is a linker covalently attached to EBM and TBM; and SBM is an a-synuclein protein binding moiety of the formula: or a pharmaceutical acceptable salt, an enantiomer, a non-enantiomer, a tautomer, a racemate, a solvate, a metabolic precursor, a prodrug thereof, wherein is covalently linked to L; and is a substituted or unsubstituted bicyclic fused aromatic ring containing at least 1 ring heteroatom selected from O, S, and N; is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S, and N; and is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S, and N; or is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S,
  • Embodiment 3 A method to reduce Lewy bodies in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula A,
  • EBM is an E3 ubiquitin ligase binding moiety
  • L is a linker covalently attached to EBM and TBM; and SBM is an a-synuclein protein binding moiety of the formula: or a pharmaceutical acceptable salt, an enantiomer, a non-enantiomer, a tautomer, a racemate, a solvate, a metabolic precursor, a prodrug thereof, wherein is covalently linked to L; and is a substituted or unsubstituted bicyclic fused aromatic ring containing at least 1 ring heteroatom selected from O, S, and N; is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S, and N; and is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S, and N; or is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S,
  • Embodiment 4 Use of a compound of Formula A:
  • EBM-L-SBM (Formula A) or a pharmaceutical acceptable salt, a enantiomer, a non-enantiomer, a tautomer, a racemate, a solvate, a metabolic precursor, or a prodrug thereof, in the manufacture of a medicament for treating synucleinopathy, wherein
  • EBM is an E3 ubiquitin ligase binding moiety
  • L is a linker covalently attached to EBM and TBM; and SBM is an a-synuclein protein binding moiety of the formula: wherein covalently linked to L, and is a substituted or unsubstituted bicyclic fused aromatic ring containing at least 1 ring heteroatom selected from O, S, and N; is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S, and N; and is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S, and N; or is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S, and N; is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S, and N; is a substituted or unsubstituted mono
  • Embodiment 5 Use of a compound of Formula A:
  • EBM-L-SBM (Formula A) or a pharmaceutical acceptable salt, a enantiomer, a non-enantiomer, a tautomer, a racemate, a solvate, a metabolic precursor, or a prodrug thereof, in the manufacture of a medicament for reducing a-synuclein aggregation, wherein
  • EBM is an E3 ubiquitin ligase binding moiety
  • L is a linker covalently attached to EBM and TBM; and SBM is an a-synuclein protein binding moiety of the formula: wherein is covalently linked to L; and is a substituted or unsubstituted bicyclic fused aromatic ring containing at least 1 ring heteroatom selected from O, S, and N; is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S, and N; and is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S, and N; or is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S, and N; is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S, and N; is a substituted or unsubstituted
  • Embodiment 6 Use of a compound of Formula A:
  • EBM-L-SBM (Formula A) or a pharmaceutical acceptable salt, a enantiomer, a non-enantiomer, a tautomer, a racemate, a solvate, a metabolic precursor, or a prodrug thereof, in the manufacture of a medicament for reducing Lewy bodies, wherein
  • EBM is an E3 ubiquitin ligase binding moiety
  • L is a linker covalently attached to EBM and TBM; and SBM is an a-synuclein protein binding moiety of the formula: wherein is covalently linked to L; and is a substituted or unsubstituted bicyclic fused aromatic ring containing at least 1 ring heteroatom selected from O, S, and N; is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S, and N; and is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S, and N; or is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S, and N; is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S, and N; is a substituted or unsubstituted
  • Embodiment 7 The method of Embodiment 1 or the use of Embodiment 4, wherein the synucleinopathy is Parkinson’s Disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), or a combination of two or more thereof
  • Embodiment 8 The method or use of any one of Embodiments 1-7, wherein the substituted or unsubstituted bicyclic fused aromatic ring is a substituted or unsubstituted bicyclic 5-6 system.
  • Embodiment 9 The method or use of any one of Embodiments 1-8, wherein SBM is of Formula B or Formula C wherein
  • Z is C or N; U is O, S or CH; V is N or Mi;
  • Embodiment 10 The method or use of any one of Embodiments 1-9, wherein EBM is wherein
  • R 3 is H or Ci-6 alkyl; each occurrence of R 2 is independently selected from the group consisting of H, OH, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 alkylamino andMB; m6 is 0, 1, 2, 3 or 4; and
  • Embodiment 11 The method or use of any one of Embodiments 1-10, wherein the compound is of any one of Formula I to Formula YI,
  • Z is C or N; U is O, S or CH;
  • J is CR 6 or N;
  • X is CR 6 or N;
  • Y is CR 6 or N; where at least one of J, X and Y is N, but J and Y are not N at the same time, X and Y are not N at the same time;
  • R 6 is independently selected from the group consisting of H, NH2, Ci-6 alkyl and Ci-6 alkoxy, wherein NH2, Ci-6 alkyl or Ci-6 alkoxy is optionally substituted by 1 to 3 of C1-3 alkyl, C3-6 cycloalkyl and/or halo; in Formula I, L3 is a bond, -NR-, -0-, or -S-, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; R 3 is H or Ci- 6 alkyl; Yi is CH2 or V is N, where Z and U are not heteroatoms at the same time; in Formula II, each occurrence of R 2 is independently selected from the group consisting of H, OH, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 alkylamino and NH2; m6 is 0, 1, 2, 3 or 4;
  • Yi is CH2 or V is N, where Z and U are not heteroatoms at the same time; in Formula III, V is N, where Z and U are not heteroatoms at the same time; in Formula IV, L3 is a bond, -NR-, -0-, or -S-, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; R 3 is H or Ci-6 alkyl; two of U, Z, V and T contain heteroatoms; in Formula V, each occurrence of R 2 is independently selected from the group consisting of H, OH, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 alkylamino and NH2; m6 is 0, 1, 2, 3 or 4; two of U, Z, V and T contain heteroatoms; in Formula VI, V is N; T is CH or N; where up to two of U, Z, V and T contain heteroatoms.
  • Embodiment 14 The method or use of Embodiment 11, wherein L2 is selected from the group consisting of substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroaryl ene, or substituted or unsubstituted heteroalkylene, and combinations thereof; preferably, L2 is selected from the group consisting of substituted and unsubstituted alkylene, substituted and unsubstituted alkenylene, substituted and unsubstituted alkynylene, substituted and unsubstituted heteroalkylene, substituted and unsubstituted heteroalkenylene, substituted and unsubstituted heteroalkynylene, substituted and unsubstituted heterocyclylene, substituted and unsubstituted carbocyclylene, substituted and unsubstituted arylene, substituted and unsubstitute
  • Embodiment 16 The method or use of Embodiment 14, wherein L2 comprises at least one instance selected from the group consisting of substituted or unsubstituted Ci-6 alkylene, substituted or unsubstituted C2-6 alkenylene, substituted or unsubstituted C2-6 alkynylene, substituted or unsubstituted heteroCi-6alkylene, substituted or unsubstituted heteroC2-6alkenylene, substituted or unsubstituted heteroC2-6alkynylene, substituted or unsubstituted C3-6carbocyclylene, substituted or unsubstituted 3-6 membered heterocyclylene, substituted or unsubstituted phenylene, and substituted or unsubstituted 5- to 6-membered heteroarylene.
  • L2 comprises at least one instance selected from the group consisting of substituted or unsubstituted Ci-6 alkylene, substituted or unsubstituted C2-6 alkenylene,
  • Embodiment 17 The method or use of Embodiment 14, wherein L2 comprises at least one instance selected from the group consisting of substituted or unsubstituted methylene, ethylene, n-propylene, n-butylene, n-pentylene, n-hexylene, -
  • Embodiment 18 The method or use of Embodiment 14, wherein at least one chain atom of the hydrocarbon chain of L2 is independently replaced with a 6-membered heterocyclyl group with 1-3 ring heteroatoms selected from the group consisting of nitrogen and oxygen; preferably, at least one chain atom of the hydrocarbon chain of L2 is independently replaced with piperidine, piperazine or morpholine; preferably, at least one chain atom of the hydrocarbon chain of L2 is independently replaced with an optionally substituted phenyl group.
  • Embodiment 19 Embodiment 19.
  • Embodiment 14 wherein L2 is an unsubstituted hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with -NR a1 -, and each instance of R al is independently hydrogen, substituted or unsubstituted Ci-e alkyl or a nitrogen protecting group, or optionally two instances of R al are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.
  • Embodiment 20 The method or use of Embodiment 19, wherein at least one instance of R al is hydrogen, substituted or unsubstituted Ci-6 alkyl (e.g., substituted or unsubstituted methyl or ethyl), or a nitrogen protecting group (e.g., benzyl, t-butyl carbonate, benzyl carbamate, 9-fluorenylmethyl carbonate, trifluoroacetyl, triphenylmethyl, acetyl or p-toluenesulfonamide).
  • a nitrogen protecting group e.g., benzyl, t-butyl carbonate, benzyl carbamate, 9-fluorenylmethyl carbonate, trifluoroacetyl, triphenylmethyl, acetyl or p-toluenesulfonamide.
  • Embodiment 21 The method or use of Embodiment 11, wherein Li i iss wherein g is 1, 2, 3, 4, 5, or 6.
  • Embodiment 22 The method or use of Embodiment 11, wherein L2 includes the moiety
  • Embodiment 23 The method or use of Embodiment 11, wherein L2 is selected from the group consisting of

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Treating Waste Gases (AREA)
EP21726997.6A 2021-05-14 2021-05-14 Verbindungen zum abbau von alpha-synucleinaggregaten und verwendungen davon Pending EP4337259A1 (de)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IB2021/054167 WO2022238737A1 (en) 2021-05-14 2021-05-14 Compounds for degrading alpha-synuclein aggregates and uses thereof

Publications (1)

Publication Number Publication Date
EP4337259A1 true EP4337259A1 (de) 2024-03-20

Family

ID=76034924

Family Applications (1)

Application Number Title Priority Date Filing Date
EP21726997.6A Pending EP4337259A1 (de) 2021-05-14 2021-05-14 Verbindungen zum abbau von alpha-synucleinaggregaten und verwendungen davon

Country Status (8)

Country Link
EP (1) EP4337259A1 (de)
JP (1) JP2024517340A (de)
KR (1) KR20240008335A (de)
CN (1) CN117377496A (de)
AU (1) AU2021444937A1 (de)
CA (1) CA3218573A1 (de)
TW (1) TW202304516A (de)
WO (1) WO2022238737A1 (de)

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10300155B2 (en) * 2015-12-31 2019-05-28 Washington University Alpha-synuclein ligands
WO2018102067A2 (en) 2016-11-01 2018-06-07 Arvinas, Inc. Tau-protein targeting protacs and associated methods of use
ES2965049T3 (es) 2017-07-12 2024-04-10 Dana Farber Cancer Inst Inc Compuestos para la degradación de la proteína tau
AU2019265346B2 (en) 2018-05-09 2022-06-16 Aprinoia Therapeutics Limited Heteroaryl compounds and uses thereof
WO2020041331A1 (en) * 2018-08-20 2020-02-27 Arvinas Operations, Inc. Proteolysis targeting chimeric (protac) compound with e3 ubiquitin ligase binding activity and targeting alpha-synuclein protein for treating neurodegenerative diseases

Also Published As

Publication number Publication date
AU2021444937A1 (en) 2023-11-30
JP2024517340A (ja) 2024-04-19
TW202304516A (zh) 2023-02-01
WO2022238737A1 (en) 2022-11-17
KR20240008335A (ko) 2024-01-18
CN117377496A (zh) 2024-01-09
CA3218573A1 (en) 2022-11-17

Similar Documents

Publication Publication Date Title
US11065231B2 (en) Compounds and methods for the targeted degradation of interleukin-1 receptor- associated kinase 4 polypeptides
AU2017222958B2 (en) Glycosidase inhibitors
AU2017222964B2 (en) Glycosidase inhibitors
JP6851367B2 (ja) Ｉｒａｋ４阻害剤、及びその応用
US20080188502A1 (en) New Compounds I
WO2018102751A1 (en) Ire1 small molecule inhibitors
TW202000674A (zh) 稠合噻吩化合物
KR20170083135A (ko) 시르투인 조정제로서의 치환된 가교된 우레아 유사체
US20220280650A1 (en) Compounds for degrading alpha-synuclein aggregates and uses thereof
CA3167339A1 (en) Substituted pyrazolo-pyrimidines and uses thereof
EP4337259A1 (de) Verbindungen zum abbau von alpha-synucleinaggregaten und verwendungen davon
TW201113290A (en) Novel fused thiazolo and oxazolo pyrimidinones
AU2021262281A1 (en) 1,5-dihydro-2,4-benzodiazepine-3-one derivative and application thereof

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: UNKNOWN

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20231213

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR