US20220354835A1 - Compounds for degrading tau protein aggregates and uses thereof - Google Patents

Compounds for degrading tau protein aggregates and uses thereof Download PDF

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US20220354835A1
US20220354835A1 US17/320,882 US202117320882A US2022354835A1 US 20220354835 A1 US20220354835 A1 US 20220354835A1 US 202117320882 A US202117320882 A US 202117320882A US 2022354835 A1 US2022354835 A1 US 2022354835A1
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Ming-Kuei Jang
Paul Tempest
Yih-Shyan Lin
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Aprinoia Therapeutics Ltd
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    • C07D471/04—Ortho-condensed systems

Definitions

  • Tauopathies are a class of neurodegenerative diseases associated with pathological aggregation of Tau protein (microtubule-associated protein tau, MAPT) in the human brain, and include Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Parkinson's disease (PD), Pick's Disease (PiD), and Progressive Supranuclear Palsy (PSP).
  • AD Alzheimer's disease
  • ALS amyotrophic lateral sclerosis
  • HD Huntington's disease
  • PD Parkinson's disease
  • PiD Pick's Disease
  • PSP Progressive Supranuclear Palsy
  • tauopathy aggregation of Tau spreads through the brain in a prion-like manner, such as seen in AD brain (H.
  • Tau pathology manifests in a consistent spatiotemporal pattern.
  • Tau propagation seeds consisting mainly of short fibrils, have been found to be significantly enriched in the synaptic fractions of brain regions lacking extensive cellular Tau pathology, indicating that Tau seeds are able to spread through the human brain along synaptically-connected neuronal networks.
  • the present disclosure relates to novel bispecific conjugate compounds that bind to Tau aggregates, and recruit a ubiquitin E3 ligase to mark the aggregates for proteomic degradation and clearance. These compounds bind specifically to Tau aggregates, and discriminate between Tau aggregates and monomeric (normal) Tau. These results suggest the suitability of compounds for use in the clinic, where they have the potential for promoting the clearance of pathogenic Tau with minimal effects on normal/physiological Tau species in the brains of human tauopathy patients.
  • compositions and methods for the treatment of a group of disorders and abnormalities associated with Tau aggregates include the administration of a bispecific conjugate described herein or a pharmaceutical composition to a subject comprising a therapeutically effective amount of a compound of the invention effective to treat, alleviate or prevent a disorder or abnormality associated with Tau aggregates.
  • a therapeutically effective amount of a compound described herein is effective for halting, preventing, or reversing the progression of neurodegenerative diseases.
  • compositions of compounds for the treatment of Tau-associated neurodegenerative diseases comprise an effective amount of a compound as described herein, and a pharmaceutically acceptable excipient.
  • One aspect of the disclosure is a compound of Formula A,
  • EBM is a ubiquitin E3 ligase binding moiety
  • L is a linker covalently attached to EBM and TBM
  • TBM is a tau protein binding moiety of the formula:
  • Another aspect of the disclosure is a compound of any one of the Formula (I)-(VI):
  • composition comprising a compound of the disclosure, and a pharmaceutically acceptable excipient.
  • Another aspect of the disclosure is a method for aiding in the treatment of a tauopathy in a subject, the method comprising administering an effective amount of a compound of the disclosure, or the composition the disclosure, wherein the compound or the composition treats the subject or aids in the treatment of the subject.
  • Another aspect of the disclosure is the use of a compound of the disclosure in the treatment of a tauopathy or a tau-associated disease or disorder.
  • Another aspect of the disclosure is the use of a compound of the disclosure for the manufacture of a medicament for the treatment of a tauopathy or a tau-associated disease or disorder.
  • kits comprising a compound of the disclosure, or the composition of the disclosure, and printed instructions for the use thereof
  • Another aspect of the disclosure is a method for synthesizing the compounds of the disclosure.
  • the FIGURE shows the degradation of Tau aggregates measured by APNmAb005 ELISA assay.
  • Optical Density (O.D.) 450 value decreases 20% compared to vehicle, reflecting the reduction of Tau aggregates.
  • the present disclosure provides compounds that specifically bind to aggregated forms of Tau protein, and also bind to a ubiquitin E3 ligase.
  • E3 ligases are intracellular enzymes that transfer activated ubiquitin to a specific site of a targeted protein.
  • Ubiquitin is a highly conserved small protein (8 kDa, 76 amino acids), which is ubiquitously expressed intracellularly. After expression, ubiquitin is activated by a ubiquitin-activating enzyme (“E1”), then transferred to a ubiquitin-conjugating enzyme (“E2”). An E3 ligase transfers the ubiquitin from the E2 enzyme to a target substrate. There are estimated to be more than 600 different E3 ligases, which recognize a variety of different protein substrates. Once ubiquitinated, the substrate is transferred to a proteasome, which degrades the protein into oligopeptides, eventually degrading these to single amino acids. The ubiquitin-proteasome system serves to regulate the concentration of some proteins, and to degrade and recycle damaged or misfolded proteins.
  • compositions and methods for the treatment of a group of disorders and abnormalities associated with Tau aggregates include the administration of a compound described herein or a pharmaceutical composition to a subject comprising a therapeutically effective amount of a compound of the invention effective to treat, alleviate or prevent a disorder or abnormality associated with Tau aggregates.
  • a therapeutically effective amount of a compound described herein is effective for halting, preventing, or reversing the progression of neurodegenerative diseases.
  • One aspect of the disclosure is a compound of Formula A,
  • EBM is a ubiquitin E3 ligase binding moiety
  • L is a linker covalently attached to EBM and TBM
  • TBM is a tau protein binding moiety of the formula:
  • the substituted or unsubstituted bicyclic fused aromatic ring is a substituted or unsubstituted bicyclic 5-6 system.
  • Non-limiting examples include
  • TBM is of Formula B or Formula C
  • Z is C or N; U is O, S or CH; V is N or NH;
  • each occurrence of R′′′ is independently selected from the group consisting of H, OH, NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 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, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy; m is 0, 1, 2, 3 or 4;
  • each occurrence of R′′ is independently selected from the group consisting of H, halo, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkylamino, C 3-6 cycloalkylamino, C 3-6 cycloalkyl and C 3-6 heterocycloalkyl; n is 0, 1 or 2;
  • 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, NH 2 , C 1-6 alkyl and C 1-6 alkoxy, wherein NH 2 , C 1-6 alkyl or C 1-6 alkoxy is optionally substituted by 1 to 3 of C 1-3 alkyl, C 3-6 cycloalkyl and/or halo; and
  • V is N, where Z and U are not heteroatoms at the same time;
  • 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-N
  • R 3′ is H or C 1-6 alkyl
  • each occurrence of R 2′ is independently selected from the group consisting of H, OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and NH 2 ;
  • n 0, 1, 2, 3 or 4;
  • Y 1 is CH 2 or
  • the compound is of any one of the Formula (I)-(VI):
  • R 3′ is H or C 1-6 alkyl; Y 1 is CH 2 or
  • L 1 is a bond, —C( ⁇ O)—, —NR—, —O—, or —S—, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group
  • L 3 is a bond, —NR—, —O—, or —S—, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group
  • L 2 is a substituted or unsubstituted C 1-50 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, NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy and halogen; k is 0, 1,
  • each occurrence of R 2′ is independently selected from the group consisting of H, OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and NH 2 ; m6 is 0, 1, 2, 3 or 4; Y 1 is CH 2 or
  • L 1 is a bond, —C( ⁇ O)—, —NR—, —O—, or —S—, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L 2 is a substituted or unsubstituted C 1-50 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, NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 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, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy; m is 0, 1, 2, 3
  • L 1 is a bond, —C( ⁇ O)—, —NR—, —O—, or —S—, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L 2 is a substituted or unsubstituted C 1-50 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, NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 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, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy; m is 0,
  • R 3′ is H or C 1-6 alkyl; Y 1 is CH 2 or
  • L 1 is a bond, —C( ⁇ O)—, —NR—, —O—, or —S—, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group
  • L 3 is a bond, —NR—, —O—, or —S—, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group
  • L 2 is a substituted or unsubstituted C 1-50 hydrocarbon chain
  • Z is C or N; U is O, S or CH; V is N or NH; 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, NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy and
  • L 1 is a bond, —C( ⁇ O)—, —NR—, —O—, or —S—, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L 2 is a substituted or unsubstituted C 1-50 hydrocarbon chain; Z is C or N; U is O, S or CH; V is N or NH; 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, NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 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, C 1-6 alkyl, C 1-6 haloalkyl and C
  • one or more chain atoms of the substituted or unsubstituted C 1-50 hydrocarbon chain are independently replaced with —C( ⁇ O)—, —O—, —NR a1 —, —S— or a cyclic moiety, wherein R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl (e.g., substituted or unsubstituted methyl or ethyl), or 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)).
  • R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl (e.g., substituted or unsubstituted
  • 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.
  • L1 is a bond
  • L1 is —C( ⁇ O)—, —NH—, —O—, or —S—.
  • L 3 is a bond
  • L 3 is —NH—, —O—, or —S—.
  • L2 is a substituted or unsubstituted C 1-30 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C( ⁇ O)—, —O—, —NR a1 , —S— or a cyclic moiety, wherein R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl or a nitrogen protecting group.
  • L 2 is an unsubstituted C 1-30 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C( ⁇ O)—, —O—, —NR a1 , —S— or a cyclic moiety, wherein R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl or a nitrogen protecting group.
  • L2 is a substituted or unsubstituted C 1-24 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C( ⁇ O)—, —O—, —NR a1 , —S— or a cyclic moiety, wherein R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl or a nitrogen protecting group.
  • L2 is an unsubstituted C 1-24 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C( ⁇ O)—, —O—, —NR a1 , —S— or a cyclic moiety, wherein R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl or a nitrogen protecting group.
  • L2 is a substituted or unsubstituted C 1-20 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C( ⁇ O)—, —O—, —NR a1 , —S— or a cyclic moiety, wherein R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl or a nitrogen protecting group.
  • L2 is an unsubstituted C 1-20 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with ——C( ⁇ O)—, —O—, —NR a1 , —S— or a cyclic moiety, wherein R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl or a nitrogen protecting group.
  • At least one chain atom of the hydrocarbon chain of L2 is independently replaced with —O—.
  • 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 heteroarylene, 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 heteroarylene, 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 heteroarylene, 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
  • -alkylene-heteroalkylene-, -alkylene-(heteroalkylene) 2 -, and -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 C 1-6 alkylene, substituted or unsubstituted C 1-2 alkylene, substituted or unsubstituted C 1-3 alkylene, substituted or unsubstituted C 3-4 alkylene, substituted or unsubstituted C 4-5 alkylene, substituted or unsubstituted C 5-6 alkylene, substituted or unsubstituted C 3-6 alkylene, or substituted or unsubstituted C 4-6 alkylene.
  • substituted or unsubstituted alkylene e.g., substituted or unsubstituted C 1-6 alkylene, substituted or unsubstituted C 1-2 alkylene, substituted or unsubstituted C 1-3 alkylene, substituted or unsubstituted C 3-4 alkylene, substituted or unsubstituted C 4-5 alky
  • Exemplary alkylene groups include unsubstituted alkylene groups such as methylene (—CH 2 —), ethylene (—(CH 2 ) 2 —), n-propylene (—(CH 2 ) 3 —), n-butylene (—(CH 2 ) 4 —), n-pentylene (—(CH 2 ) 5 —), and n-hexylene (—(CH 2 ) 6 —).
  • L2 comprises at least one instance of substituted or unsubstituted alkenylene, e.g., substituted or unsubstituted C 2-6 alkenylene, substituted or unsubstituted C 1-3 alkenylene, substituted or unsubstituted C 3-4 alkenylene, substituted or unsubstituted C 4-5 alkenylene or substituted or unsubstituted C 5-6 alkenylene.
  • substituted or unsubstituted alkenylene e.g., substituted or unsubstituted C 2-6 alkenylene, substituted or unsubstituted C 1-3 alkenylene, substituted or unsubstituted C 3-4 alkenylene, substituted or unsubstituted C 4-5 alkenylene or substituted or unsubstituted C 5-6 alkenylene.
  • L 2 comprises at least one instance of substituted or unsubstituted alkynylene, e.g., substituted or unsubstituted C 2-6 alkynylene, substituted or unsubstituted C 2-3 alkynylene, substituted or unsubstituted C 3-4 alkynylene, substituted or unsubstituted C 4-5 alkynylene or substituted or unsubstituted C 5-6 alkynylene.
  • substituted or unsubstituted alkynylene e.g., substituted or unsubstituted C 2-6 alkynylene, substituted or unsubstituted C 2-3 alkynylene, substituted or unsubstituted C 3-4 alkynylene, substituted or unsubstituted C 4-5 alkynylene or substituted or unsubstituted C 5-6 alkynylene.
  • L2 comprises at least one instance of substituted or unsubstituted heteroalkylene, e.g., substituted or unsubstituted heteroC 1-6 alkylene, substituted or unsubstituted heteroC 1-2 alkylene, substituted or unsubstituted heteroC 2-3 alkylene, substituted or unsubstituted heteroC 3-4 alkylene, substituted or unsubstituted heteroC 4-5 alkylene or substituted or unsubstituted heteroC 5-6 alkylene.
  • substituted or unsubstituted heteroalkylene e.g., substituted or unsubstituted heteroC 1-6 alkylene, substituted or unsubstituted heteroC 1-2 alkylene, substituted or unsubstituted heteroC 2-3 alkylene, substituted or unsubstituted heteroC 3-4 alkylene, substituted or unsubstituted heteroC 4-5 alkylene or substituted or unsubstituted heteroC 5-6 alkylene.
  • heteroalkylene groups include unsubstituted heteroalkylene groups, such as (—CH 2 ) 2 —O(CH 2 ) 2 —, OCH 2 —, —CH 2 O—, —O(CH 2 ) 2 —, —(CH 2 ) 2 O—, —O(CH 2 ) 3 —, —(CH 2 ) 3 O—, —O(CH 2 ) 4 —, —(CH 2 ) 4 O—, —O(CH 2 ) 5 —, —(CH 2 ) 5 O—, —O(CH 2 ) 6 —, and —O(CH 2 ) 6 O—, and amide groups (e.g., —NH—C( ⁇ O)— and —C( ⁇ O)NH—).
  • amide groups e.g., —NH—C( ⁇ O)— and —C( ⁇ O)NH—
  • L2 comprises at least one instance of substituted or unsubstituted heteroalkenylene, e.g., substituted or unsubstituted heteroC 2-6 alkenylene, substituted or unsubstituted heteroC 1-3 alkenylene, substituted or unsubstituted heteroC 3-4 alkenylene, substituted or unsubstituted heteroC 4-5 alkenylene, or substituted or unsubstituted heteroC 5-6 alkenylene.
  • substituted or unsubstituted heteroalkenylene e.g., substituted or unsubstituted heteroC 2-6 alkenylene, substituted or unsubstituted heteroC 1-3 alkenylene, substituted or unsubstituted heteroC 3-4 alkenylene, substituted or unsubstituted heteroC 4-5 alkenylene, or substituted or unsubstituted heteroC 5-6 alkenylene.
  • L2 comprises at least one instance of substituted or unsubstituted heteroalkynylene, e.g., substituted or unsubstituted heteroC 2-6 alkynylene, substituted or unsubstituted heteroC 2-3 alkynylene, substituted or unsubstituted heteroC 3-4 alkynylene, substituted or unsubstituted heteroC 4-5 alkynylene, or substituted or unsubstituted heteroC5-6alkynylene.
  • substituted or unsubstituted heteroalkynylene e.g., substituted or unsubstituted heteroC 2-6 alkynylene, substituted or unsubstituted heteroC 2-3 alkynylene, substituted or unsubstituted heteroC 3-4 alkynylene, substituted or unsubstituted heteroC 4-5 alkynylene, or substituted or unsubstituted heteroC5-6alkynylene.
  • L2 comprises at least one instance of substituted or unsubstituted carbocyclylene, e.g., substituted or unsubstituted C 3-6 carbocyclylene, substituted or unsubstituted C 3-4 carbocyclylene, substituted or unsubstituted C4-5carbocyclylene, or substituted or unsubstituted C 5-6 carbocyclylene.
  • substituted or unsubstituted carbocyclylene e.g., substituted or unsubstituted C 3-6 carbocyclylene, substituted or unsubstituted C 3-4 carbocyclylene, substituted or unsubstituted C4-5carbocyclylene, or substituted or unsubstituted C 5-6 carbocyclylene.
  • L2 comprises at least one instance of substituted or unsubstituted heterocyclylene, e.g., substituted or unsubstituted 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. In certain embodiments, 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 heteroarylene, e.g., substituted or unsubstituted 5- to 6-membered heteroarylene.
  • 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 a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl or a nitrogen protecting group, or optionally two instances of R a1 are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring. In certain embodiments, at least one instance of R a1 is hydrogen.
  • At least one instance of R a1 is substituted or unsubstituted C 1-6 alkyl (e.g., substituted or unsubstituted methyl or ethyl).
  • at least one instance of R a1 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 C 1-45 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C( ⁇ O)—, —O—, —NR a1 , —S— or a cyclic moiety, wherein R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl or a nitrogen protecting group.
  • L2 is an unsubstituted C 1-45 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C( ⁇ O)—, —O—, —NR a1 , —S— or a cyclic moiety, wherein R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl or a nitrogen protecting group.
  • L2 is an optionally substituted C 1-24 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C( ⁇ O)—, —O—, —NR a1 , —S— or a cyclic moiety, wherein R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl or a nitrogen protecting group.
  • L2 is an unsubstituted C 1-24 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C( ⁇ O)—, —O—, —NR a1 —, —S— or a cyclic moiety, wherein R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl or a nitrogen protecting group.
  • L2 is an optionally substituted C 1-20 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C( ⁇ O)—, —O—, —NR a1 , —S— or a cyclic moiety, wherein R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group.
  • L2 is an unsubstituted C 1-20 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C( ⁇ O)—, —O—, —NR a1 , —S— or a cyclic moiety, wherein R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl or a nitrogen protecting group.
  • L2 is an optionally substituted C 1-30 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —O— or —NR a1 —.
  • L2 is an unsubstituted C 1-30 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —O— or —NR a1 —. In certain embodiments, L2 is an unsubstituted C 1-30 hydrocarbon chain, wherein at least one chain atom of the hydrocarbon chain is independently replaced with —O—. In certain embodiments, L2 is an unsubstituted C 1-26 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C( ⁇ O)—, —O— or —NR a1 —.
  • L2 is an unsubstituted C 1-20 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —O—. In certain embodiments, L2 is an unsubstituted C 5-26 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C( ⁇ O)—, —O— or —NR a1 —. In certain embodiments, L2 is an unsubstituted C 5-26 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —O—.
  • L2 is an unsubstituted C 5-20 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C( ⁇ O)—, —O— or —NR a1 —In certain embodiments, L2 is an unsubstituted C 5-20 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —O—, or —NR a1 —. In certain embodiments, L2 is an unsubstituted C 5-15 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C( ⁇ O)—, —O— or —NR a1 —.
  • L2 is an unsubstituted C 15-20 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C( ⁇ O)—, —O— or —NR a1 —. In certain embodiments, L2 is an unsubstituted C 20-25 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C( ⁇ O)—, —O— or —NR a1 —. In certain embodiments, L2 is a substituted or unsubstituted C 1-45 hydrocarbon chain. In certain embodiments, L2 is a substituted or unsubstituted C 5-40 hydrocarbon chain.
  • one or more chain atoms of the hydrocarbon chain of L2 are independently replaced with —C( ⁇ O)—, —O—, —S—, —NR a1 —, —N ⁇ or ⁇ N—.
  • one or more chain atoms of the hydrocarbon chain of L2 are independently replaced with —C( ⁇ O)—, —O— or —NR a1 —, wherein R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl or a nitrogen protecting group.
  • L2 is an unsubstituted C 1-26 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 C 1-45 hydrocarbon chain. In certain embodiments, L2 is an all-carbon, substituted or unsubstituted C 1-30 hydrocarbon chain. In certain embodiments, L2 is an all-carbon, substituted or unsubstituted C 1-26 hydrocarbon chain. In certain embodiments, L2 is an all-carbon, substituted or unsubstituted C 1-24 hydrocarbon chain. In certain embodiments, L2 is an all-carbon, substituted or unsubstituted C 1-20 hydrocarbon chain. In certain embodiments, L2 is an all-carbon, substituted or unsubstituted C 1-20 hydrocarbon chain.
  • L2 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
  • 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 3. In certain embodiments, g is 4. In certain embodiments, g is 5. In certain embodiments, g is 6.
  • 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, —(CH 2 ) 2 —O(CH 2 ) 2 —, —OCH 2 —, —CH 2 O—, —O(CH 2 ) 2 —, —(CH 2 ) 2 O—, —O(CH 2 ) 3 —, —(CH 2 ) 3 O—, —O(CH 2 ) 4 —, —(CH 2 ) 4 O—, —O(CH 2 ) 5 —, —(CH 2 ) 5 O—, —O(CH 2 ) 6 —, —O(CH 2 ) 6 O—, —C( ⁇ O)O—, —O—C( ⁇ O)—, —NH—C( ⁇ O)— and —C( ⁇ O)
  • L 2 comprises at least one instance selected from the group consisting of substituted or unsubstituted methylene, ethylene, n-propylene, n-butylene, n-pentylene, n-hexylene, —(CH 2 ) 2 —O(CH 2 ) 2 —, —OCH 2 —, —CH 2 O—, —O(CH 2 ) 2 —, —(CH 2 ) 2 O—, —O(CH 2 ) 3 —, —(CH 2 ) 3 O—, —O(CH 2 ) 4 —, —(CH 2 ) 4 O—, —O(CH 2 ) 5 —, —(CH 2 ) 5 O—, —O(CH 2 ) 6 —, —O(CH 2 ) 6 O—, —NH—C( ⁇ O)— and —C( ⁇ O)NH—.
  • L2 includes the moiety —NHC( ⁇ O—.
  • 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:
  • L2 is of the formula:
  • 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:
  • g 1, 2, 3, 4, 5, 6, 7 or 8.
  • L2 is of the formula:
  • 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:
  • 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:
  • g 1, 2, 3, 4, 5, 6, 7 or 8.
  • the compound of the disclosure is of any one of the structure as follows,
  • R 3′ is H or C 1-6 alkyl; Y 1 is CH 2 or
  • L 1 is a bond, —C( ⁇ O)—, —NR—, —O—, or —S—, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group
  • L 3 is a bond, —NR—, —O—, or —S—, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group
  • L 2 is a substituted or unsubstituted C 1-50 hydrocarbon chain
  • Z is C or N; 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, NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy and halogen; k is 0, 1, 2 or 3
  • L 1 is a bond, —C( ⁇ O)—, —NR—, —O—, or —S—, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group
  • L 3 is a bond, —NR—, —O—, or —S—, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group
  • L 2 is a substituted or unsubstituted C 1-50 hydrocarbon chain
  • Z is C or N; 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, NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy and halogen; k is 0, 1, 2 or 3
  • L 1 is a bond, —C( ⁇ O)—, —NR—, —O—, or —S—, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group
  • L 3 is a bond, —NR—, —O—, or —S—, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group
  • L 2 is a substituted or unsubstituted C 1-50 hydrocarbon chain
  • Z is C or N
  • 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, NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy and halogen; k is 0, 1, 2 or 3; each
  • R 3′ is H or C 1-6 alkyl; Y 1 is CH 2 or
  • L 1 is a bond, —C( ⁇ O)—, —NR—, —O—, or —S—, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group
  • L 3 is a bond, —NR—, —O—, or —S—, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group
  • L 2 is a substituted or unsubstituted C 1-50 hydrocarbon chain
  • Z is C or N
  • U is O, S or CH
  • T is CH or N; where only one of U, Z and T is heteroatom
  • 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, NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy and halogen; k is 0,
  • each occurrence of R 2′ is independently selected from the group consisting of H, OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and NH 2 ; m6 is 0, 1, 2, 3 or 4; Y 1 is CH 2 or
  • L 1 is a bond, —C( ⁇ O)—, —NR—, —O—, or —S—, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group
  • L 3 is a bond, —NR—, —O—, or —S—, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group
  • L 2 is a substituted or unsubstituted C 1-50 hydrocarbon chain
  • Z is C or N
  • U is O, S or CH
  • T is CH or N; where only one of U, Z and T is heteroatom
  • 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, NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy and halogen; k is 0,
  • L 1 is a bond, —C( ⁇ O)—, —NR—, —O—, or —S—, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group
  • L 3 is a bond, —NR—, —O—, or —S—, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group
  • L 2 is a substituted or unsubstituted C 1-50 hydrocarbon chain
  • Z is C or N
  • U is O, S or CH
  • T is CH or N; where only one of U, Z and T is heteroatom
  • 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, NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy and halogen; k is 0,
  • the compound of Formula I-1 is of the following Formula 1, 5, 6, 8, 10 or 13,
  • each A is independently O, NH,
  • n2 1, 2, 3, 4, 5, 6, or 7;
  • n3 is 1, 2, 3, 4, 5, or 6;
  • n4 0, 1, 2, or 3;
  • n5 0, 1, 2, or 3;
  • R′′ is O, NH,
  • An embodiment of the disclosure is the compound of Formula 1, wherein R′ is H, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, CF 3 , CCl 3 , methoxy or ethoxy, more preferably H, CF 3 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, NH 2 , C 1-3 alkoxy, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino and C 3-5 heterocycloalkyl, preferably H, F, Cl, NH 2 , 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, NH,
  • An embodiment of the disclosure is the compound of Formula 1, wherein R 1′ is O, NH,
  • An embodiment of the disclosure is the compound of Formula 1, wherein A is O, NH,
  • 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 C 1-3 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,
  • R 3′ is H or C 1-3 alkyl; Y 1 is CH 2 or
  • A is O, NH,
  • n 1 + 2 + 3 + 4 + 6 and 7
  • R 1′ is O, NH
  • U is O, S or CH; Z is C or N; where U and Z are not heteroatoms at the same time; R′ is H, C 1-3 haloalkyl or C 1-3 alkoxy; R′′ is H, F, Cl, OH, NH 2 , C 1-3 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 O, NH or
  • 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.
  • 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, OH, NH 2 , methoxy, methylamino, dimethylamino, diethylamino, cyclopropyl or cyclopropylamino, preferably H, F, methylamino, dimethylamino or cyclopropylamino.
  • An embodiment of the disclosure is the compound of Formula 1-1, wherein R′ is H, C 1-3 fluoroalkyl, methoxy or ethoxy, preferably R′ is H, methoxy or CF 3 .
  • An embodiment of the disclosure is the compound of Formula 5, wherein R 3′ is H or C 1-3 alkyl, preferably H or methyl.
  • An embodiment of the disclosure is the compound of Formula 5, wherein A is O, NH or
  • An embodiment of the disclosure is the compound of Formula 5, wherein each A is independently O, NH,
  • An embodiment of the disclosure is the compound of Formula 5, wherein m4 is 0, 1, 2, or 3, preferably 0 or 3.
  • An embodiment of the disclosure is the compound of Formula 5, wherein m5 is 0, 1, 2 or 3, preferably 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 5, wherein m3 is 1, 2, 3, 4, 5 or 6, preferably 3 or 5.
  • An embodiment of the disclosure is the compound of Formula 5, wherein R 1′ is O, NH or
  • An embodiment of the disclosure is the compound of Formula 5, wherein R′′′ is H, OH, C 1-3 alkyl, C 1-3 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, U is CH.
  • An embodiment of the disclosure is the compound of Formula 5, wherein R′ is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, F, CF 3 , CCl 3 , methyl or methoxy, more preferably H or CF 3 .
  • 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, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl, preferably H, F, OH, NH 2 , methyl, methoxy, CF 3 , CCl 3 , methylamino, cyclopropyl or dimethylamino, more preferably H, F, CF 3 , 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,
  • R 3′ is H or C 1-3 alkyl; Y 1 is CH 2 or
  • A is O, NH,
  • Z is C or N; U is O, S or CH; where Z and U are not heteroatoms at the same time; R′′′ is H, OH, C 1-3 alkyl, C 1-3 alkoxy or halogen; R′ is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy; R′′ is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino and C 3-5 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 O, NH or
  • 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, C 1-3 alkyl, C 1-3 fluoroalkyl or C 1-3 alkoxy, preferably H, methyl, CF 3 , methyl or methoxy, more preferably H or CF 3 .
  • An embodiment of the disclosure is the compound of Formula 5-1, wherein R′′ is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl, preferably H, F, CF 3 , amino, methylamino, dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F, CF 3 , dimethylamino, cyclopropylamino or cyclopropyl.
  • An embodiment of the disclosure is the compound of Formula 6, wherein R 3′ is H or C 1-3 alkyl, preferably H or methyl.
  • An embodiment of the disclosure is the compound of Formula 6, wherein A is O, NH or
  • 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, NH or
  • 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, C 1-3 alkyl, C 1-3 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, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, F, CF 3 , CCl 3 , methyl or methoxy, more preferably H or CF 3 .
  • 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, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl, preferably H, F, OH, NH 2 , methyl, methoxy, CF 3 , CCl 3 , methylamino, cyclopropyl, cyclopropylamino or dimethylamino, more preferably H, F, CF 3 , dimethylamino, cyclopropyl or cyclopropylamino.
  • An embodiment of the disclosure is the compound of Formula 6, wherein n is 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 6 having the structure as shown in Formula 6-1,
  • R 3′ is H or C 1-3 alkyl; Y 1 is CH 2 or
  • A is O, NH,
  • n 1 + 2 + 3 + 4 + 6 + 7
  • R 1′ is O, NH
  • R′′′ is H, OH, C 1-3 alkyl, C 1-3 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′ is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy; m is 0, 1, 2 or 3; R′′ is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl; n is 0, 1 or 2.
  • R 3′ is H or C 1-3 alkyl; Y 1 is CH 2 or
  • A is O, NH,
  • n 1 + 2 + 3 + 4 + 6 + 7
  • R 1′ is O, NH
  • R′′′ is H, OH, C 1-3 alkyl, C 1-3 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′ is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy; m is 0, 1, 2 or 3; R′′ is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C3-s cycloalkylamino or C 3-5 heterocycloalkyl; n is 0, 1 or 2.
  • 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 NH.
  • 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 H or CF 3 .
  • 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, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl, preferably H, F, CF 3 , methoxy, methyl, dimethylamino, cyclopropyl, cyclopropylamino or methylamino, more preferably H, CF 3 , 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 C 1-3 alkyl, preferably H or methyl.
  • An embodiment of the disclosure is the compound of Formula 8, wherein Y 1 is CH 2 or
  • An embodiment of the disclosure is the compound of Formula 8, wherein A is O, NH,
  • 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, NH,
  • An embodiment of the disclosure is the compound of Formula 8, wherein R′′′ is H, OH, C 1-3 alkyl, C 1-3 alkoxy or halogen, preferably H, methyl, methoxy or F, more preferably H.
  • An embodiment of the disclosure is the compound of Formula 8, wherein k is 0 or 1.
  • 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, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, F, CF 3 , CCl 3 , methyl or methoxy, more preferably H or CF 3 .
  • 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, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl, preferably H, F, OH, NH 2 , methyl, methoxy, CF 3 , CCl 3 , methylamino, dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F, CF 3 , cyclopropyl or cyclopropylamino.
  • 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 8 having the structure of
  • An embodiment of the disclosure is the compound of Formula 10, wherein R 3′ is H or C 1-3 alkyl, preferably H or methyl.
  • An embodiment of the disclosure is the compound of Formula 10, wherein Y 1 is CH 2 or
  • An embodiment of the disclosure is the compound of Formula 10, wherein each A is independently O, NH,
  • An embodiment of the disclosure is the compound of Formula 10, wherein A is O, NH,
  • 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′′ is O, NH,
  • R′′′ is H, OH, C 1-3 alkyl, C 1-3 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, U is CH.
  • An embodiment of the disclosure is the compound of Formula 10, wherein R′ is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, F, CF 3 , CCl 3 , methyl or methoxy, more preferably H or CF 3 .
  • 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, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl, preferably H, F, OH, NH 2 , methyl, methoxy, CF 3 , CCl 3 , methylamino, cyclopropyl, cyclopropylamino or dimethylamino, more preferably H, F or CF 3 .
  • 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 C 1-3 alkyl, preferably H or methyl.
  • An embodiment of the disclosure is the compound of Formula 13, wherein Y 1 is CH 2 or
  • An embodiment of the disclosure is the compound of Formula 13, wherein A is O, NH,
  • 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 O, NH,
  • An embodiment of the disclosure is the compound of Formula 13, wherein R′′′ is H, OH, C 1-3 alkyl, C 1-3 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, 1, 2 or 3, preferably 0 or 1.
  • 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, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, F, CF 3 , CCl 3 , methyl or methoxy, more preferably H or CF 3 .
  • 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, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl, preferably H, F, OH, NH 2 , methyl, methoxy, CF 3 , CCl 3 , methylamino, cyclopropyl, cyclopropylamino or dimethylamino, more preferably H, F, CF 3 , dimethylamino, cyclopropyl or cyclopropylamino, most preferably dimethylamino.
  • An embodiment of the disclosure is the compound of Formula 13, wherein n is 0, 1 or 2, preferably 0 or 1.
  • An embodiment of the compound of Formula II-1 is of the following Formula 3,
  • R 1′ is O, NH,
  • An embodiment of the disclosure is the compound of Formula 3, wherein R 2 ′ is H, OH, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino or NH 2 , preferably H, OH or NH 2 .
  • An embodiment of the disclosure is the compound of Formula 3, wherein m6 is 0, 1, 2 or 3, preferably 0 or 1.
  • 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, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, halogen or C 1-3 fluoroalkyl, more preferably H or F.
  • An embodiment of the disclosure is the compound of Formula 3, wherein m is 0, 1, 2, 3 or 4, preferably 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 3, wherein R′′ is H, halo, OH, NH 2 , C 1-3 alkoxy, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 1-3 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, U is CH.
  • An embodiment of the disclosure is the compound of Formula 3, wherein R′′′ is H, OH, C 1-3 alkyl, C 1-3 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,
  • R 2′ is H, OH, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino or NH 2 ; m6 is 0, 1, 2 or 3; Y 1 is CH 2 or
  • R 1′ is O, NH,
  • Z is C or N; U is O, S or CH; where Z and U are not heteroatoms at the same time; R′′ is H, halo, OH, NH 2 , C 1-3 alkoxy, C 1-3 haloalkyl, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 1-3 alkylamino; n is 0, 1 or 2.
  • An embodiment of the disclosure is the compound of Formula 3-1, wherein R 2′ is H, NH 2 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 m6 is 1, R 2′ is substituted at the following position in the phenyl:
  • An embodiment of the disclosure is the compound of Formula 3-1, wherein R′′ 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 compound of Formula III-1 is of the following Formula 15,
  • m2 is 1, 2, 3, 4, 5, 6, or 7; and R 1′ is O, NH,
  • An embodiment of the disclosure is the compound of Formula 15, wherein m2 is 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2, 3, 4, 5 or 6, more preferably 2 or 5.
  • An embodiment of the disclosure is the compound of Formula 15, wherein R 1′ is O, NH,
  • An embodiment of the disclosure is the compound of Formula 15, wherein R′′′ is H, OH, C 1-3 alkyl, C 1-3 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, U is CH.
  • An embodiment of the disclosure is the compound of Formula 15, wherein R′ is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, halogen or C 1-3 fluoroalkyl, more preferably H, CF 3 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, NH 2 , C 1-3 alkoxy, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 1-3 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, 1 or 2, preferably 0 or 1.
  • An embodiment of the compound of Formula IV-1 is of the following Formula 2, 7, 9, 11, 12 or 14,
  • each A is independently O, NH,
  • n2 is 2, 3, 4, 5, or 6;
  • n3 is 1, 2, 3, 4, 5, or 6;
  • n4 0, 1, 2, 3, or 4;
  • n5 0, 1, 2, or 3;
  • R 1′ is O, NH,
  • An embodiment of the disclosure is the compound of Formula 2, wherein R 3′ is H or C 1-3 alkyl, preferably H or methyl.
  • An embodiment of the disclosure is the compound of Formula 2, wherein Y 1 is CH 2 or
  • An embodiment of the disclosure is the compound of Formula 2, wherein A is O, NH,
  • 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, NH,
  • An embodiment of the disclosure is the compound of Formula 2, wherein R′′ is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl, preferably H, F, OH, NH 2 , methyl, methoxy, CF 3 , CCl 3 , methylamino, dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F, CF 3 , cyclopropyl or cyclopropylamino.
  • 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, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, F, CF 3 , CCl 3 , methyl or methoxy, more preferably H or CF 3.
  • 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, U is CH, W is CH.
  • 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, NH 2 , C 1-3 alkyl, C 1-3 alkylamino, C 1-3 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 C 1-3 alkyl, preferably H or methyl.
  • An embodiment of the disclosure is the compound of Formula 7, wherein Y 1 is CH 2 or
  • An embodiment of the disclosure is the compound of Formula 7, wherein A is O, NH,
  • 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,
  • An embodiment of the disclosure is the compound of Formula 7, wherein R′′ is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl, preferably H, F, OH, NH 2 , methyl, methoxy, CF 3 , CCl 3 , methylamino, dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F, CF 3 , cyclopropyl or cyclopropylamino.
  • 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, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, F, CF 3 , CCl 3 , methyl or methoxy, more preferably H or CF 3 .
  • 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, NH 2 , C 1-3 alkyl, C 1-3 alkylamino, C 1-3 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 C 1-3 alkyl, preferably H or methyl.
  • An embodiment of the disclosure is the compound of Formula 9, wherein Y 1 is CH 2 or
  • An embodiment of the disclosure is the compound of Formula 9, wherein A is O, NH,
  • 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, NH,
  • An embodiment of the disclosure is the compound of Formula 9, wherein R′′ is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl, preferably H, F, OH, NH 2 , methyl, methoxy, CF 3 , CCl 3 , methylamino, dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F, CF 3 , 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, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, F, CF 3 , CCl 3 , methyl or methoxy, more preferably H or CF 3 .
  • 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, U is CH, W is CH.
  • 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, NH 2 , C 1-3 alkyl, C 1-3 alkylamino, C 1-3 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 C 1-3 alkyl, preferably H or methyl.
  • An embodiment of the disclosure is the compound of Formula 11, wherein Y 1 is CH 2 or
  • An embodiment of the disclosure is the compound of Formula 11, wherein A is O, NH,
  • 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 O, NH,
  • An embodiment of the disclosure is the compound of Formula 11, wherein R′′ is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl, preferably H, F, OH, NH 2 , methyl, methoxy, CF 3 , CCl 3 , methylamino, dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F, CF 3 , cyclopropyl or cyclopropylamino.
  • An embodiment of the disclosure is the compound of Formula 11, wherein n is 0, 1 or 2, preferably 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 11, wherein R′ is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, F, CF 3 , CCl 3 , methyl or methoxy, more preferably H or CF 3 .
  • 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 H, OH, NH 2 , C 1-3 alkyl, C 1-3 alkylamino, C 1-3 alkoxy or halogen, preferably H, F, methoxy, methylamino or dimethylamino.
  • An embodiment of the disclosure is the compound of Formula 11, 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 12, wherein R 3′ is H or C 1-3 alkyl, preferably H or methyl.
  • An embodiment of the disclosure is the compound of Formula 12, wherein Y 1 is CH 2 or
  • 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,
  • 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 O, NH,
  • An embodiment of the disclosure is the compound of Formula 12, wherein R′′ is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl, preferably H, F, OH, NH 2 , methyl, methoxy, CF 3 , CCl 3 , methylamino, dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F, CF 3 , cyclopropyl or cyclopropylamino.
  • An embodiment of the disclosure is the compound of Formula 12, wherein n is 0, 1 or 2, preferably 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 12, wherein R′ is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, F, CF 3 , CCl 3 , methyl or methoxy, more preferably H or CF 3 .
  • 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 H, OH, NH 2 , C 1-3 alkyl, C 1-3 alkylamino, C 1-3 alkoxy or halogen, preferably H, F, methoxy, methylamino or dimethylamino.
  • An embodiment of the disclosure is the compound of Formula 12, 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 14, wherein R 3′ is H or C 1-3 alkyl, preferably H or methyl.
  • An embodiment of the disclosure is the compound of Formula 14, wherein Y 2 is CH 2 or
  • 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,
  • 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 O, NH,
  • An embodiment of the disclosure is the compound of Formula 14, wherein R′′ is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl, preferably H, F, OH, NH 2 , methyl, methoxy, CF 3 , CCl 3 , methylamino, dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F, CF 3 , cyclopropyl or cyclopropylamino.
  • An embodiment of the disclosure is the compound of Formula 14, wherein n is 0, 1, or 2, preferably 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 14, wherein R′ is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, F, CF 3 , CCl 3 , methyl or methoxy, more preferably H or CF 3 .
  • 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.
  • R′′′ is H, OH, NH 2 , C 1-3 alkyl, C 1-3 alkylamino, C 1-3 alkoxy or halogen, preferably H, F, methoxy, methylamino or dimethylamino.
  • An embodiment of the disclosure is the compound of Formula 14, wherein k is 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.
  • An embodiment of the compound of Formula V-1 is of the following Formula 4,
  • R′′ is O, NH
  • An embodiment of the disclosure is the compound of Formula 4, wherein R 2′ is H, OH, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino or NH 2 , preferably H, OH or NH 2 .
  • An embodiment of the disclosure is the compound of Formula 4, wherein m6 is 0, 1, 2 or 3, preferably 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 4, wherein R 1′ is O, NH,
  • An embodiment of the disclosure is the compound of Formula 4, wherein R′ is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, halogen or C 1-3 fluoroalkyl, more preferably H or F.
  • An embodiment of the disclosure is the compound of Formula 4, wherein m is 0, 1, 2, 3 or 4, preferably 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 4, wherein R′′ is H, halo, OH, NH 2 , C 1-3 alkoxy, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 1-3 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 0 or S, W is CH.
  • 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, NH 2 , C 1-3 alkyl, C 1-3 alkylamino, C 1-3 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,
  • R 2′ is H, OH, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino or NH 2 ;
  • Y 1 is CH 2 or
  • R 1′ is O, NH,
  • R′′ is H, halo, OH, NH 2 , C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino or C 3-5 heterocycloalkyl; n is 0, 1 or 2; R′ is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy; m is n is 0, 1 or 2; U is O or S; R′′′ is H, OH, NH 2 , C 1-3 alkyl, C 1-3 alkylamino, C 1-3 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 OH.
  • An embodiment of the disclosure is the compound of Formula 4-1, wherein R′′′ is H, OH, NH 2 , C 1-3 alkyl, C 1-3 alkylamino, C 1-3 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,
  • m2 is 1, 2, 3, 4, 5, 6, or 7; and R 1′ is O, NH,
  • An embodiment of the disclosure is the compound of Formula 16, wherein m2 is 1, 2, 3, 4, 5 or 6, preferably 2 or 5.
  • An embodiment of the disclosure is the compound of Formula 16, wherein R 1′ is O, NH,
  • An embodiment of the disclosure is the compound of Formula 16, wherein R′ is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, halogen or C 1-3 fluoroalkyl, more preferably H or F.
  • An embodiment of the disclosure is the compound of Formula 16, wherein m is 0, 1, 2, 3 or 4, preferably 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 16, wherein R′′ is H, halo, OH, NH 2 , C 1-3 alkoxy, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 1-3 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, 1, or 2, preferably 0 or 1.
  • 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 H, OH, NH 2 , C 1-3 alkyl, C 1-3 alkylamino, C 1-3 alkoxy or halogen, preferably H, F, methoxy, methylamino or dimethylamino.
  • An embodiment of the disclosure is the compound of Formula 16, 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 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′′ is O, NH,
  • An embodiment of the disclosure is the compound of Formula 17, wherein R′ is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, halogen or C 1-3 fluoroalkyl, more preferably H or F.
  • An embodiment of the disclosure is the compound of Formula 17, wherein m is 0, 1, 2, 3 or 4, preferably 0 or 1.
  • An embodiment of the disclosure is the compound of Formula 17, wherein R′′ is H, halo, OH, NH 2 , C 1-3 alkoxy, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 1-3 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, 1, or 2, preferably 0 or 1.
  • 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 H, OH, NH 2 , C 1-3 alkyl, C 1-3 alkylamino, C 1-3 alkoxy or halogen, preferably H, F, methoxy, methylamino or dimethylamino.
  • An embodiment of the disclosure is the compound of Formula 17, wherein k is 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.
  • Some embodiments of the disclosure are the compounds having a structure depicted in Table 1, or a pharmaceutical acceptable salt, an enantiomer, a non-enantiomer, a tautomer, a racemate, a solvate, a metabolic precursor, a prodrug thereof.
  • An embodiment is the compound wherein the compound is isotopically labeled or radiolabeled.
  • An embodiment is a solvate, hydrate, salt, or ester or the compound of the disclosure.
  • An aspect of the disclosure is a composition, comprising a compound of the disclosure and a pharmaceutically acceptable excipient.
  • An aspect of the disclosure is a method for aiding in the treatment of a tauopathy in a subject, the method comprising administering an effective amount of a compound of the disclosure, or the composition of the disclosure, wherein the compound or the composition treats the subject.
  • the tauopathy is a neurodegenerative tauopathy.
  • the tauopathy is selected from the group consisting of Alzheimer's Disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Parkinson's disease (PD), Creutzfeldt-Jacob disease, Dementia pugilistica, Down's Syndrome, Gerstmann-Straussler-Scheinker disease, British dementia, Danish dementia, inclusion-body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, Guam Parkinsonism-dementia complex, Non-Guamanian motor neuron disease with neurofibrillary tangles, argyrophilic grain dementia, corticobasal degeneration, diffuse neurofibrillary tangles with calcification, frontotemporal dementia, frontotemporal dementia with parkinsonism linked to chromosome 17, Hallevorden-Spatz disease, multiple system atrophy, Niemann-Pick disease type C
  • the method further comprises administering to the subject at least one additional therapy.
  • the at least one additional therapy is selected from neurological drugs, anti-Tau antibodies, Tau inhibitors, anti-amyloid beta antibodies, beta-amyloid aggregation inhibitors, anti-BACE1 antibodies, and BACE1 inhibitors.
  • the subject is diagnosed as having or being at risk of developing a Tau protein-associated disease.
  • the subject is diagnosed as having or being at risk of developing a tauopathy selected from the group consisting of Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick's disease (PiD).
  • AD Alzheimer's disease
  • PSP progressive supranuclear palsy
  • CBD corticobasal degeneration
  • MiD Pick's disease
  • a method of reducing pathological human Tau in a sample comprises a step of contacting the sample with a bispecific conjugate according to any of the embodiments described above.
  • the pathological human Tau is from a tauopathy selected from the group consisting of Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick's disease (PiD).
  • the pathological human Tau is Tau Type 1A, IB, 11A, or MB; misordered Tau; mis-disordered Tau; sarkosyl-insoluble Tau; an extracellular Tau deposit; a Tau aggregate; paired helical filaments; a neurofibrillary pathology; or a hyperphosphorylated form of truncated Tau or full-length Tau.
  • the pathological human Tau is hyperphosphorylated and sarkosyl-insoluble Tau.
  • the sample is a brain sample, a cerebrospinal fluid sample, or a blood sample.
  • the detecting comprising producing a readout comprising information about the presence of pathological human Tau in the sample.
  • the sample is from a subject and the method further comprises diagnosing whether the subject has a tauopathy or is likely to develop a tauopathy based on the readout.
  • a method of reducing the level of Tau protein in a subject having, or at risk of developing, a Tau protein-associated disease comprising administering to the subject a compound according to any of the embodiments described above, or a pharmaceutical composition according to any of the embodiments described above, wherein a) the level of non-phosphorylated Tau protein, phosphorylated Tau protein, and/or hyperphosphorylated Tau protein is reduced in the subject as compared to their levels in the subject prior to administration of the compound; and/or b) the level of a pathological Tau species is reduced in the subject as compared to its level in the subject prior to administration of the compound.
  • a method of retaining or increasing cognitive memory capacity or slowing memory loss in a subject having or at risk of developing a Tau protein-associated disease comprising administering to the subject a compound according to any of the embodiments described above or a pharmaceutical composition according to any of the embodiments described above.
  • provided herein is a method of inhibiting and/or reversing the propagation of Tau aggregation in a subject having or at risk of developing a Tau protein-associated disease, comprising administering to the subject a compound according to any of the embodiments described above or a pharmaceutical composition according to any of the embodiments described above.
  • provided herein is a method of inhibiting and/or reversing Tau seeding in a subject having or at risk of developing a Tau protein-associated disease, comprising administering to the subject a compound according to any of the embodiments described above or a pharmaceutical composition according to any of the embodiments described above.
  • C 1-6 is intended to encompass C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 .
  • 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 (“C 1-6 alkyl”).
  • an alkyl group has 1 to 5 carbon atoms (“C 1-5 alkyl”).
  • an alkyl group has 1 to 4 carbon atoms (“C 1-4 alkyl”).
  • an alkyl group has 1 to 3 carbon atoms (“C 1-3 alkyl”).
  • an alkyl group has 1 to 2 carbon atoms (“C 1-2 alkyl”).
  • an alkyl group has 1 carbon atom (“C 1 alkyl”).
  • an alkyl group has 2 to 6 carbon atoms (“C 2-6 alkyl”).
  • C 1-6 alkyl groups include methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), iso-propyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C 5 ), 3-pentyl (C 5 ), amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butyl (C 5 ), tertiary amyl (C 5 ), and n-hexyl (C 6 ).
  • Alkenyl refers to an alkyl group with one or more carbon-carbon double bonds at any position of the chain, which can be monosubstituted or polysubstituted, 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 monosubstituted or polysubstituted, and can be monovalent, divalent or multivalent. Examples of 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 monosubstituted 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.
  • the substituent is a keto (i.e., ⁇ O)
  • 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
  • a group is shown to be substituted by 0-2 of R, then 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.
  • this bonding group is a single bond.
  • Alkoxy refers to refers to said alkyl group with a specified number of carbon atoms attached through an oxygen bridge. Unless otherwise specified, C 1-6 alkoxy includes C 1 , C 2 , C 3 , C 4 , C 5 and C 6 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 monosubstituted 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(C 1-4 )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 (“C 2-6 heterocyclo”).
  • C 2-6 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.
  • Nonrogen 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 trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc.
  • 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.
  • Exemplary 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. Exemplary 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 C 6 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.
  • 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.
  • PBS phosphate buffered saline water
  • Effective amount means enough amount of medicine or agent which can achieve the desired affect without toxin.
  • effective amount of a kind of active substance in compositions means the amount needed to achieve the desired affect when combining with another active substance in compositions. The effective amount varies with each individual, and depends on ages of receptors and general situations, also specific active substances.
  • 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 invention.
  • 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.
  • the term “effective dose” refers to the amount of a compound or a composition which will have a targeted effect.
  • the effective dose may refer to the amount of a compound or a composition which will enable tau imaging.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease.
  • treatment is administered after one or more signs or symptoms of the disease have developed or have been observed.
  • treatment may be administered in the absence of signs or symptoms of the disease.
  • treatment may be administered to a susceptible subject prior to the onset of symptoms (for example, in light of a history of symptoms or a known genetic predisposition). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the embodiments listed below, combinations thereof with other chemical synthesis methods, and equivalent alternatives known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the invention.
  • Tauopathies include Alzheimer's Disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Parkinson's disease (PD), Creutzfeldt-Jacob disease, Dementia pugilistica, Down's Syndrome, Gerstmann-Straussler-Scheinker disease, British dementia, Danish dementia, inclusion-body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, Guam Parkinsonism-dementia complex, Non-Guamanian motor neuron disease with neurofibrillary tangles, argyrophilic grain dementia, corticobasal degeneration, diffuse neurofibrillary tangles with calcification, frontotetemporal dementia, frontotemporal dementia with parkinsonism linked to chromosome 17, Hall
  • compositions of this invention 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 subject 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.
  • At least one additional therapy is administered to the subject.
  • the additional therapy is a neurological drug, anti-Tau antibody, Tau inhibitor, anti-amyloid beta antibody, beta-amyloid aggregation inhibitor, anti-BACE1 antibody, or BACE1 inhibitor.
  • the subject is diagnosed as having or being at risk of developing a Tau protein-associated disease. In some embodiments, the subject is diagnosed as having or being at risk of developing a tauopathy selected from the group consisting of Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick's disease (PiD).
  • AD Alzheimer's disease
  • PSP progressive supranuclear palsy
  • CBD corticobasal degeneration
  • PiD Pick's disease
  • 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 (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof
  • kits described herein further includes instructions for using the kit.
  • a kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA).
  • the information included in the kits is prescribing information.
  • the kits and instructions provide for treating a disease (e.g., neurological disorder, neurodegenerative disease, or tauopathy) in a subject in need thereof.
  • the kits and instructions provide for preventing a disease (e.g., neurological disorder, neurodegenerative disease, or tauopathy) in a subject in need thereof.
  • kits and instructions provide for reducing the risk of developing a disease (e.g., neurological disorder, neurodegenerative disease, or tauopathy) in a subject in need thereof.
  • a disease e.g., neurological disorder, neurodegenerative disease, or tauopathy
  • the kits and instructions provide for promoting the degradation of tau protein in a subject or cell.
  • a kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.
  • 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 ⁇ m; Column Temperature: 50° C. Detectors: ADC ELSD, DAD (214 nm and 254 nm), ES-API.
  • Method B Mobile Phase: A: Water (10 mM NH 4 HCO 3 ) 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 ⁇ m; Column Temperature: 40° C. Detectors: ADC ELSD, DAD (214 nm and 254 nm), MSD (ES-API).
  • Method C Mobile Phase: A: Water (10 mM NH 4 HCO 3 ) 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 p.m; Column Temperature: 40° C. Detectors: ADC ELSD, DAD (214 nm and 254 nm), MSD (ES-API).
  • THF tetrahydrofuran
  • DMF N,N-dimethylformamide
  • EtOAc ethyl acetate
  • DCM diichloromethane
  • MeOH methanol
  • EtOH ethanol
  • TEA triethanolamine
  • TFA trifluoroacetic acid
  • RT room temperature.
  • Compound 162640 were synthesized according to methods similar to Example 6.
  • Compound 162842 were synthesized according to methods similar to Example 6.
  • Compound 162903 were synthesized according to methods similar to Example 6.
  • Compound 163123 were synthesized according to methods similar to Example 6.
  • Compound 163365 were synthesized according to methods similar to Example 6.
  • Compound 161409 could be synthesized by method similar to example 19.
  • Compound 160557 A mixture of 3-(6-oxidanyl-3-oxidanylidene-1H-isoindol-2-yl)piperidine-2,6-dione (169 mg, 0.65 mmol), Cs 2 CO 3 (317 mg, 0.97 mmol), tert-butyl N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-N-[2-(2-iodanylethoxy)ethyl]carbamate (209 mg, 0.32 mmol) in DMF (5 mL) was heated at 50° C. for 1 h.
  • Compound 160210 A mixture of 3-(6-oxidanyl-3-oxidanylidene-1H-isoindol-2-yl)piperidine-2,6-dione (95 mg, 0.37 mmol), K 2 CO 3 (101 mg, 0.73 mmol) and tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-[2-[2-[2-[2-[2-(2-iodanylethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (200 mg, 0.24 mmol) in DMF (5 mL) was heated at 50° C.
  • Compound 160508 A mixture of 2-[2-[[2-[4-[6-(dimethylamino)-2-fluoranyl-pyridin-3-yl]phenyl]-3,8a-dihydroimidazo[1,2-a]pyridin-6-yl]oxy]ethoxy]ethyl 4-methylbenzenesulfonate (232 mg, 0.39 mmol) and NaI (70 mg, 0.47 mmol) in ACN (2 mL) was heated at 80° C. for 14 h. The mixture was added water and extracted with DCM.
  • Compound 160570 A mixture of 2-[2,6-bis(oxidanylidene)piperidin-3-yl]-5-oxidanyl-isoindole-1,3-dione (101 mg, 0.37 mmol), Cs 2 CO 3 (180 mg, 0.55 mmol) and 6-fluoranyl-5-[4-[6-[2-(2-iodanylethoxy)ethoxy]-3,8a-dihydroimidazo[1,2-a]pyridin-2-yl]phenyl]-N,N-dimethyl-pyridin-2-amine (101 mg, 0.18 mmol) in DMF (3 mL) was heated at 50° C. for 4 h and then stirred at room temperature for 3 days.
  • Compound 160686 A mixture of 2-[2,6-bis(oxidanylidene)piperidin-3-yl]-5-oxidanyl-isoindole-1,3-dione (68 mg, 0.25 mmol), Cs 2 CO 3 (121 mg, 0.37 mmol) and tert-butyl N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-N-[2-(2-iodanylethoxy) ethyl]carbamate (80 mg, 0.12 mmol) in DMF (5 mL) was heated at 50° C. for 3 h.
  • Compound 161230 A mixture of 4-[2-[2-[[5-[4-[1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolo[2,3-c]pyridin-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]phthalic acid (201 mg, 0.31 mmol) and 3-azanylpiperidine-2,6-dione hydrochloride (78 mg, 0.47 mmol) in pyridine (3 mL) was heated at 120° C. for 19 h. The solvent was removed by vacuum and the resulting residue was triturated with water.
  • Compound 164581 A mixture of tert-butyl 3-[2-(2-iodanylethoxy)ethoxy]propanoate (500 mg, 1.45 mmol), K 2 CO 3 (602 mg, 4.36 mmol) and methyl 5-azanyl-5-oxidanylidene-4-(6-oxidanyl-3-oxidanylidene-1H-isoindol-2-yl)pentanoate (467 mg, 1.60 mmol) in DMF (15 mL) was heated at 80° C. for 7 h.
  • Compound 164625 A mixture of 3-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethoxy]propanoic acid (346 mg, 0.82 mmol), TBTU (352 mg, 1.10 mmol) and 2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-amine (190 mg, 0.55 mmol) in pyridine (3 mL) was stirred at room temperature for 17 h.
  • Compound 164350 A mixture of tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]-N-[2-(2-iodanylethoxy)ethyl]carbamate (110 mg, 0.15 mmol), K 2 CO 3 (64 mg, 0.46 mmol), and methyl 5-azanyl-5-oxidanylidene-4-(6-oxidanyl-3-oxidanylidene-1H-i soindol-2-yl)pentanoate (50 mg, 0.17 mmol) in DMF (2.5 mL) was heated at 80° C.
  • Compound 162568 A mixture of 2-[2-[[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl 4-methylbenzenesulfonate (924 mg, 1.40 mmol) and NaI (421 mg, 2.81 mmol) in CH 3 CN (20 mL) was heated at 80° C. for 17 h.

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JP7605504B2 (ja) 2024-12-24
WO2021097243A1 (en) 2021-05-20
TW202128657A (zh) 2021-08-01
AU2020383593A1 (en) 2022-06-09
US12377152B2 (en) 2025-08-05
US11291732B1 (en) 2022-04-05
KR20220100921A (ko) 2022-07-18
CA3161455A1 (en) 2021-05-20
US11642413B2 (en) 2023-05-09
US20230346955A1 (en) 2023-11-02
TWI759962B (zh) 2022-04-01
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CN114728071A (zh) 2022-07-08
JP2023502605A (ja) 2023-01-25

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