Compounds

Abstract

To provide compounds for the treatment of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, other dementia and neurodegenerative diseases, spinal cord injury, sensorineural hearing loss, and the like.SOLUTION: The present invention provides compounds that demonstrate increased stability in simulated intestinal fluid and simulated gastric fluid, but that can be hydrolyzed in plasma to produce compounds that retain base structure's beneficial properties. In one embodiment, the compound is represented by formula (I), possesses a di-amino acid core structure, and is substituted with one or more organic functional groups at the C-terminus, N-terminus, and / or the side-chain of the core.SELECTED DRAWING: None

Description

[Technical field]

[0001] 1. Cross-reference to related applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 344,305, filed June 1, 2016, which is incorporated by reference in its entirety. [Background technology]

[0002] 2.Background The small molecule peptide compound, N-hexanoic acid-L-tyrosine-L-isoleucine-(6)-aminohexanoic acid amide ("Basic Structure"), has been demonstrated or predicted to have potential as a neuroprotectant / neuroregenerator, to protect against or reverse neurodegenerative diseases, to prevent or reverse symptoms of dementia, to promote repair of traumatic damage to the nervous system, and to enhance cognitive function. Summary of the Invention [Problem to be solved by the invention]

[0003] Given the therapeutic potential of the platform for treating Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, other dementias and neurodegenerative diseases, spinal cord injury, traumatic brain injury, and sensorineural hearing loss and vision loss, there is a need in the art for compounds that retain the therapeutic activity of the platform while possessing optimized pharmacokinetic and pharmacodynamic properties. [Means for solving the problem]

[0004] 3. Overview Compounds have been synthesized that, upon hydrolysis in plasma, yield compounds of the base structure or similar base structure that have increased stability in simulated intestinal and gastric fluids and retain the beneficial properties of the base structure. Thus, in a first aspect there is provided a compound.

[0005] In an exemplary embodiment, the compounds have a di-amino acid core structure, with the C-terminus, N-terminus, and / or side chains of the core substituted with one or more organic functional groups.

[0006] In some embodiments, the compound has formula I: [ka] [In the formula, n is 1, 2, 3, 4, 5, 6, 7, 8, or 9; m is 0, 1, 2, 3 or 4; R 1 is amino, substituted amino, alkoxy, substituted alkoxy, C1-C 12 Alkyl, C1-C 12 Substituted Alkyl, C1-C 12 Alkenyl, C1-C 12 Substituted alkenyl, C1-C 12 Alkynyl, C1-C 12 selected from the group consisting of substituted alkynyl, C1-C6 alkylaryl, C1-C6 substituted alkylaryl, C1-C6 alkenylaryl, C1-C6 substituted alkenylaryl, C1-C6 alkynylaryl, C1-C6 substituted alkynylaryl, norleucine, tyrosine, phenylalanine, aspartic acid, arginine, isoleucine, serine, threonine, histidine, glycine, cysteine, methionine, tryptophan, lysine, norvaline, norleucine, ornithine, S-benzylcysteine, O-benzylserine, O-benzylthreonine, cyclohexylalanine, 4-tetrahydropyranyl-glycine, and azaleucine; R 2 is hydrogen, -CH(R a )OPO(OH)2, -CO-Y, [ka] -C(=O)-Y, -CO-U, -C(=O)-(CH2) r is selected from the group consisting of -U, -CH2-V, Where: R ais hydrogen or CH3, Y is -Z-(CH2) q WR b and q is 0 to 4; Z and W are CH2, O, S, NR c and R b are independently selected from the group consisting of R c is selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl; R b is hydrogen, C1-C 12 Alkyl, C1-C 12 Substituted Alkyl, C1-C 12 Alkenyl, C1-C 12 Substituted alkenyl, C1-C 12 Alkynyl, C1-C 12 Substituted alkynyl, C3-C8 cycloalkyl, C3-C8 substituted cycloalkyl, C6-C 10 Aryl, C6-C 10 Substituted aryl, C3-C8 heterocycloalkyl, C3-C8 substituted heterocycloalkyl, C4-C 10 Heteroaryl, and C4-C 10 substituted heteroaryl; r is 0 to 5; U is selected from aryl, heteroaryl, or heterocycloalkyl; V is -OC(=O)-Q-(CH2) r -R d and Where: Q is a bond, O, and N(R c ) selected from the group consisting of R d is C6-C 10 Aryl, C4-C 10heteroaryl, C3-C8 heterocycloalkyl, hexose, pentose and -(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl), or -C(=)O)-Y forms an amide bond through a nitrogen atom on Y, where Y is selected from the group consisting of glycine, sarcosine, N,N-dimethylglycine, alanine, valine, leucine, isoleucine, lysine, ornithine, arginine, serine and threonine; R 3 and R 4 is hydrogen, C1-C 12 Alkyl, C1-C 12 Substituted Alkyl, C1-C 12 Alkenyl, C1-C 12 Substituted alkenyl, C1-C 12 Alkynyl, C1-C 12 Substituted alkynyl, C3-C8 cycloalkyl, C3-C8 substituted cycloalkyl, C6-C 10 Aryl, C6-C 10 Substituted aryl, C3-C8 heterocycloalkyl, C3-C8 substituted heterocycloalkyl, C4-C 10 Heteroaryl, C4-C 10 substituted heteroaryl, [ka] or optionally R 3 and R 4 are linked to form a fused bicyclic or spirocyclic ring system; R 5 is hydrogen, [ka] selected from the group consisting of; R 6 are hydrogen, deuterium, CH3, F, 19 F and 18 F; Optionally, Z and W together represent C3-C8 heterocycloalkyl or C4-C 10Heteroaryl or one of the rings is C4-C 10 forming a bicyclic ring system which is a heteroaryl; R 1 If present, the amino acid [ka] is covalently bonded to the carbon atom of C(=O) through the nitrogen atom at the N-terminus of the amino acid, or [ka] Together [ka] Just as the C(=O) in represents the amino acid that is the carboxy terminal of the amino acid, 1 The carbon atom of the amino acid is bonded to C(=O); Any and all heterocycles and heteroaryl rings contain up to four heteroatoms selected from the group consisting of O, N and S; however, If both Z and W are heteroatoms, the value of q is not 1; R 2 and R 5 are hydrogen and n is 5, then R 3 or R 4 At least one of them is not hydrogen. or a tautomer thereof and / or a pharma- ceutically acceptable salt thereof.

[0007] In various embodiments, the compound is selected from the specific compounds disclosed herein.

[0008] In another aspect, a composition comprising at least one of the compounds described herein is provided.

[0009] In a further aspect, a pharmaceutical composition comprising at least one of the compounds described herein is provided.

[0010] In a further aspect, a method of treatment is provided.

[0011] The method comprises administering to the subject at least one compound described herein in an amount effective to treat, protect against, or reverse neurodegenerative disease, prevent or reverse dementia symptoms, promote repair of traumatic damage to the nervous system, or enhance cognitive function. In various embodiments, the subject has a disease selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, other dementias and neurodegenerative diseases, spinal cord injury, traumatic brain injury, and / or sensorineural hearing loss. In an exemplary embodiment, the method comprises administering a pharmaceutical composition comprising at least one compound described herein, as described herein.

[0012] In various embodiments, the compound is administered as the sole medical treatment. In various embodiments, the compound is administered in combination with other medical and / or surgical interventions in accordance with the general standard of care.

[0013] These and other embodiments are described in further detail herein. [Brief description of the drawings]

[0014] 4. Brief description of the drawings These and other features, aspects, and advantages of the present invention will become better understood with regard to the following description and accompanying drawings.

[0015] [Figure 1] Figure 1 is a graph containing experimental data testing the stability of various compounds synthesized as potential prodrugs of the basic structure in the presence of simulated intestinal fluid (SIP) (pH 6.8, + / - pancreatin) or simulated gastric fluid (SGF) (pH 1.2, + / - pepsin). The results show increased stability for some of the prodrugs, even in the presence of enzymes specific to intestinal or gastric fluids (for 240 minutes).

[0016] [Diagram 2]FIG. 2 is a graph showing data measuring the formation of parent structures from various prodrugs in human and rat plasma over a 240 minute period, measured as the percent remaining prodrug compound (left y-axis). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] 5. Detailed Description 5.1.Definition Various terms used in the specification and claims are defined as set forth below, unless expressly defined otherwise in this disclosure. All technical and scientific terms not defined herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

[0018] "Alkyl" refers to a monovalent saturated aliphatic hydrocarbyl group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. This term includes linear and branched hydrocarbyl groups, such as, for example, methyl (CH-), ethyl (CHCH-), n-propyl (CHCHCH-), isopropyl ((CH)CH-), t-propyl (CHCHCHCH-), isobutyl ((CH)CHCH-), sec-butyl ((CH)(CHCH)CH-), t-butyl ((CHC-), n-pentyl (CHCHCHCHCHCH-), neopentyl ((CH)CCH-), etc. Cx alkyl refers to an alkyl group having x carbon atoms.

[0019] "Alkenyl" refers to straight or branched chain hydrocarbyl groups having 1 to 6 carbon atoms, preferably 2 to 4 carbon atoms, and at least one, preferably one to two sites of unsaturation (>C=C<). Such groups include, for example, vinyl, allyl, and butan-3-en-1-yl. The term includes cis and trans isomers or mixtures of such isomers. Cx alkenyl refers to an alkenyl group having x carbon atoms.

[0020] "Alkynyl" refers to a straight or branched chain monovalent hydrocarbyl group having from 2 to 6 carbon atoms, preferably from 2 to 3 carbon atoms, and having at least one, preferably from 1 to 2, sites of acetylenic (-C≡C-) unsaturation. Examples of such alkynyl groups include acetylenyl (-C≡CH) and propargyl (-CH2C≡CH). Cxalkynyl refers to an alkynyl group having x carbon atoms.

[0021] "Substituted alkyl" includes alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cyano, cycloalkyl, cycloalkyloxy ... means an alkyl group having 1 to 5, preferably 1 to 3, and more preferably 1 to 2 substituents selected from the group consisting of cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylylthio, nitro, SOH, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein.

[0022] In some embodiments, substituted alkyl groups include halogenated alkyl groups, particularly halogenated methyl groups such as trifluoromethyl, difluoromethyl, fluoromethyl, and the like.

[0023] "Alkylaryl" refers to an alkyl group having a length of 1-8 carbon atoms, preferably 1-5 carbon atoms, more preferably 1-3 carbon atoms, where any one of the carbons along the chain is specifically substituted with an aryl group. "Alkenylaryl" refers to an alkenyl or alkene group having a length of 1-8 carbon atoms, preferably 1-5 carbon atoms, more preferably 1-3 carbon atoms, where any one of the carbons along the chain is specifically substituted with an aryl group. The aryl group may or may not contain heteroatoms. "Alkynylaryl" refers to an alkynyl or alkyne group having a length of 1-8 carbon atoms, preferably 1-5 carbon atoms, more preferably 1-3 carbon atoms, where any one of the carbons along the chain is specifically substituted with an aryl group. The aryl group may or may not contain heteroatoms.

[0024] "Cycloalkyl" or "cyclylalkyl" means a saturated or partially saturated, non-aromatic group having from 3 to 10 ring carbon atoms and no heteroatoms. Cycloalkyl includes monocyclic ring systems.

[0025] "Substituted alkenyl" includes alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkyl. means an alkenyl group having 1-3 substituents, preferably 1-2 substituents, selected from the group consisting of thio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SOH, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein, with the proviso that the hydroxy or thiol substituents are not attached to a vinyl (unsaturated) carbon atom.

[0026] "Substituted alkynyl" includes alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloa means an alkynyl group having 1 to 3 substituents, preferably 1 to 2 substituents, selected from the group consisting of alkynylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SOH, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein, with the proviso that the hydroxyl or thiol substituents are not attached to an acetylenic carbon atom.

[0027] "Ar" and / or "aryl" refer to any group that is aromatic, that is cyclic, and that does not contain heteroatoms.

[0028] "Alkoxy" means an -O-alkyl group where alkyl is defined herein. Alkoxy includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.

[0029] "Substituted alkoxy" refers to the group -O-(substituted alkyl), where substituted alkyl is defined herein. Preferred substituted alkyl groups in -O-(substituted alkyl) include halogenated alkyl groups, particularly halogenated methyl groups such as trifluoromethyl, difluoromethyl, fluoromethyl, and the like.

[0030] "Acyl" refers to the group HC(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocycle-C(O)-, and substituted heterocycle-C(O)-, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein. Acyl includes the "acetyl" group CHC(O)-.

[0031] "Acylamino" means -NR 30 C(O)alkyl, -NR 30 C(O) substituted alkyl, -NR 30 C(O)cycloalkyl, -NR 30 C(O)-substituted cycloalkyl, -NR 30 C(O)alkenyl, -NR 30 C(O) Substituted alkenyl, alkoxy, substituted alkoxy-NR 30 C(O)alkynyl, -NR 30 C(O) substituted alkynyl, -NR 30 C(O)aryl, -NR 30 C(O) substituted aryl, -NR 30 C(O)heteroaryl, -NR 30 C(O)-substituted heteroaryl, -NR 30 C(O) heterocycles, and -NR 30C(O) Substituted Heterocycle [wherein R 30 is hydrogen or alkyl, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0032] "Aminoacyl" means the group HC(N)-, alkyl-C(N)-, substituted alkyl-C(N)-, alkenyl-C(N)-, substituted alkenyl-C(N)-, alkynyl-C(N)-, substituted alkynyl-C(N)-, cycloalkyl-C(N)-, substituted cycloalkyl-C(N)-, aryl-C(N)-, substituted aryl-C(N)-, heteroaryl-C(N)-, substituted heteroaryl-C(N)-, heterocycle-C(N)-, and substituted heterocycle-C(N)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0033] "Acyloxy" means the group alkyl-C(O)O-, substituted alkyl-C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O-, alkynyl-C(O)O-, substituted alkynyl-C(O)O-, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, heteroaryl-C(O)O-, substituted heteroaryl-C(O)O-, heterocycle-C(O)O-, and substituted heterocycle-C(O)O-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

[0034] "Amino" refers to a group represented by -NH2.

[0035] "Substituted amino" refers to -NR 31 R 32 [Where, R 31 and R 32 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, and substituted sulfonyl; R 31 and R 32 may optionally form, together with the nitrogen to which they are attached, a heterocyclic or substituted heterocyclic group, with the proviso that R 31 and R 32 are not both hydrogen, and R refers to a group represented by the formula: alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein. 31 is hydrogen and R 32 When R is alkyl, the substituted amino group is sometimes referred to herein as alkylamino. 31 and R 32 When R is alkyl, the substituted amino group is sometimes referred to herein as dialkylamino. When referring to a monosubstituted amino, R 31 or R 32 is hydrogen, but not both. When referring to disubstituted amino, R 31 and R 32 This means that none of the groups is hydrogen.

[0036] "Aminocarbonyl" means -C(O)NR 33 R 34 [Where, R 33 and R 34is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle; and optionally R 33 and R 34 optionally taken together with the nitrogen to which they are attached form a heterocyclic or substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0037] "Aminoacylcarbonyloxy" means -C(NR 33 ) OR 34 [Where, R 33 and R 34 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle; R 33 and R 34 may optionally together with the nitrogen to which they are attached form a heterocyclic or substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0038] "Aminothiocarbonyl" means -C(S)NR 33 R 34 [Where, R 33 and R 34is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle; R 33 and R 34 may together with the nitrogen to which they are attached form a heterocyclic or substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0039] "Aminocarbonylamino" refers to the group -NR 30 C(O)NR 33 R 34 [Where, R 30 is hydrogen or alkyl, and R 33 and R 34 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle; R 33 and R 34 may optionally together with the nitrogen to which they are attached form a heterocyclic or substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0040] "Aminothiocarbonylamino" refers to the group -NR 30 C(S)NR 33 R 34[Where, R 30 is hydrogen or alkyl, and R 33 and R 34 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle; R 33 and R 34 may optionally together with the nitrogen to which they are attached form a heterocyclic or substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0041] "Aminocarbonyloxy" is -OC(O)NR 33 R 34 means a group, where R 33 and R 34 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle; R 33 and R 34 may optionally together with the nitrogen to which they are attached form a heterocyclic or substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0042] "Aminosulfonyl" means -SO2NR 33 R34 [Here R 33 and R 34 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle; R 33 and R 34 may optionally together with the nitrogen to which they are attached form a heterocyclic or substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0043] "Aminosulfonyloxy" means -O-SONR 33 R 34 [Here R 33 and R 34 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle; R 33 and R 34 may optionally together with the nitrogen to which they are attached form a heterocyclic or substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0044] "Aminosulfonylamino" refers to the group -NR 30 -SO2NR 33 R34 [Where, R 30 is hydrogen or alkyl, and R 33 and R 34 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle; R 33 and R 34 may optionally together with the nitrogen to which they are attached form a heterocyclic or substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0045] "Amidino" means -C(=NR 35 )NR 33 R 34 [Where, R 33 , R 34 and R 35 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle; R 33 and R 34 may optionally together with the nitrogen to which they are attached form a heterocyclic or substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0046] "Substituted aryl" includes alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, ...

[0046] In the present invention, the aryl group is substituted by 1 to 5, preferably 1 to 3, and more preferably 1 to 2 substituents selected from the group consisting of alkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SOH, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, a monosaccharide which may be covalently bonded to an aryl group via any oxygen atom on the monosaccharide, and a substituted alkylthio, wherein said substituents are as defined herein.

[0047] "Aryloxy" means an --O-aryl group, where aryl is as defined herein, that includes, by way of example, phenoxy and naphthoxy.

[0048] "Substituted aryloxy" refers to the group -O-(substituted aryl), where substituted aryl is as defined herein.

[0049] "Arylthio" refers to the group --S-aryl, where aryl is as defined herein.

[0050] "Substituted arylthio" refers to the group -S-(substituted aryl), where substituted aryl is as defined herein.

[0051] "Carbonyl" means the divalent group -C(O)- which is equivalent to -C(=O)-.

[0052] "Carboxy" or "carboxyl" refers to --COOH or salts thereof.

[0053] By "carboxyl ester" or "carboxy esters" is meant the groups -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-alkenyl, -C(O)O-substituted alkenyl, -C(O)O-alkynyl, -C(O)O-substituted alkynyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)O-cycloalkyl, -C(O)O-substituted cycloalkyl, -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heterocycle and -C(O)O-substituted heterocycle, where alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0054] "(Carboxyl ester) amino" means -NR 30 -C(O)O-alkyl, -NR 30 -C(O)O-substituted alkyl, -NR 30 -C(O)O-alkenyl, -NR 30 -C(O)O-substituted alkenyl, -NR 30 -C(O)O-alkynyl, -NR 30 -C(O)O-substituted alkynyl, -NR 30 -C(O)O-aryl, -NR 30 -C(O)O-substituted aryl, -NR 30 -C(O)O-cycloalkyl, -NR 30-C(O)O-substituted cycloalkyl, -NR 30 -C(O)O-heteroaryl, -NR 30 -C(O)O-substituted heteroaryl, -NR 30 -C(O)O-heterocycle, and -NR 30 -C(O)O-substituted heterocycle, where R 30 is alkyl or hydrogen, and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

[0055] "(Carboxyl ester)oxy" refers to the groups -OC(O)O-alkyl, -OC(O)O-substituted alkyl, -OC(O)O-alkenyl, -OC(O)O-substituted alkenyl, -OC(O)O-alkynyl, -OC(O)O-substituted alkynyl, -OC(O)O-aryl, -OC(O)O-substituted aryl, -OC(O)O-cycloalkyl, -OC(O))O-substituted cycloalkyl, -OC(O)O-heteroaryl, -OC(O)O-substituted heteroaryl, -OC(O)O-heterocycle and -OC(O)O-substituted heterocycle, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

[0056] "Cyano" refers to the radical -C≡N.

[0057] "Cycloalkyl" refers to saturated or unsaturated, non-aromatic cyclic alkyl groups of 3 to 10 carbon atoms having single or multiple rings, including fused, bridged, and spiro ring systems. Cx cycloalkyl refers to a cycloalkyl group having x ring carbon atoms. Suitable examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. One or more of the rings may be aryl, heteroaryl, or heterocyclic, but the point of attachment is through a non-aromatic, non-heterocyclic saturated carbocyclic ring. "Substituted cycloalkyl" includes oxo, thione, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cyano, cycloalkyl ... means a cycloalkyl group having 1 to 5, preferably 1 to 3, substituents selected from the group consisting of cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein.

[0058] "Cycloalkyloxy" means -O-cycloalkyl.

[0059] "Substituted cycloalkyloxy" means --O-(substituted cycloalkyl).

[0060] "Cycloalkylthio" refers to -S-cycloalkyl.

[0061] "Substituted cycloalkylthio" means --S-(substituted cycloalkyl).

[0062] "Ethylene glycol" refers to the group -O-CH2CH2-OE, where E is H or CH3.

[0063] "Guanidino" means -NHC(=NH)NH2.

[0064] "Substituted guanidino" is -NR 36 C(=NR 36 )N(R 36 )2[where, R 36 are each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle, and are connected to a common guanidino nitrogen atom by two R 36 may optionally form a heterocycle or substituted heterocycle together with the nitrogen atom to which they are attached, provided that at least one R 36 is not hydrogen, and said substituents are as defined herein.

[0065] "Halo" or "halogen" means fluoro, chloro, bromo and iodo, preferably fluoro or chloro.

[0066] "Hydroxy" or "hydroxyl" refers to the group --OH.

[0067] "Heteroaryl" refers to an aromatic group having 4-10 carbon atoms and 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. Such heteroaryl groups can have a single ring (e.g., pyridinyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl), which may or may not be aromatic and / or may contain heteroatoms, provided that the point of attachment is through an atom of the aromatic heteroaryl group. In one embodiment, the nitrogen and / or sulfur ring atoms of the heteroaryl group are optionally oxidized to N-oxide (N→O), sulfinyl, or sulfonyl moieties. Preferred heteroaryls include 5- or 6-membered heteroaryls such as pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl.

[0068] "Substituted heteroaryl" refers to a heteroaryl group substituted with 1 to 5, preferably 1 to 3, and more preferably 1 to 2, substituents selected from the same group of substituents defined for substituted aryl.

[0069] "Heteroaryloxy" means -O-heteroaryl.

[0070] "Substituted heteroaryloxy" means -O-(substituted heteroaryl).

[0071] "Heteroarylthio" refers to -S-heteroaryl.

[0072] "Substituted heteroarylthio" refers to -S-(substituted heteroaryl).

[0073] "Heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially saturated, non-aromatic group having 2-10 ring carbon atoms and 1-4 ring heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen. Cx cycloalkyl or heterocycloalkyl refers to a group having x ring carbon atoms, excluding the ring heteroatoms. Heterocycle encompasses single or multiple fused rings, including fused, bridged, and spiro ring systems. In fused ring systems, one or more of the rings may be cycloalkyl, aryl, or heteroaryl, provided that the point of attachment is through the non-aromatic ring. In one embodiment, the nitrogen and / or sulfur atoms of the heterocyclic group may be optionally oxidized to N-oxide, sulfinyl, or sulfonyl moieties.

[0074] "Substituted heterocycle" or "substituted heterocycloalkyl" or "substituted heterocyclyl" means a heterocyclyl group substituted with one to five, preferably one to three, substituents that are the same as those defined for substituted cycloalkyl.

[0075] "Heterocyclyloxy" means -O-heterocyclyl.

[0076] "Substituted heterocyclyloxy" means --O-(substituted heterocyclyl).

[0077] "Heterocyclylthio" means -S-heterocyclyl.

[0078] "Substituted heterocyclylthio" means --S-(substituted heterocyclyl).

[0079] Examples of heterocycles and heteroaryls include azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, dexahydroindole, dihydropyridine, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, iso Examples of suitable amines include, but are not limited to, xazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, imidazolinone, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also called thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine, and tetrahydrofuranyl.

[0080] "Nitro" means -NO2.

[0081] "Oxo" refers to the atom (=O) or (-O - )

[0082] "Phthalimide" is [ka] The formula (I) is used herein to refer to a group represented by the following formula: Phthalimide functional groups are well known in the art and can be generated by covalently linking the nitrogen atom to a C6H4(CO)2 group.

[0083] "Polyethylene glycol" is -O-(CH2CH2-O) n -E, where E is H or CH3, and n is between 2 and 20,000.

[0084] "Spirocyclic ring system" refers to a bicyclic ring system in which both rings share a single ring carbon atom. As used herein, the term bicyclic may incorporate up to four heteroatoms in either ring.

[0085] "Bicycle" or "bicyclic ring system" means a bicyclic ring system in which the two rings share two ring carbon atoms which can be located at any position along either ring. As used herein, the term bicyclic ring system may incorporate up to four heteroatoms in either ring.

[0086] "Sulfinyl" means the divalent group -SO-.

[0087] "Sulfonyl" refers to the divalent group -S(O)2-.

[0088] "Substituted sulfonyl" refers to -SO2-alkyl, -SO2-substituted alkyl, -SO2-OH, -SO2-alkenyl, -SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl, -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl, -SO2-heterocycle, -SO2-substituted heterocycle, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein. Substituted sulfonyl includes groups such as methyl-SO2-, phenyl-SO2-, and 4-methylphenyl-SO2-. Preferred substituted alkyl groups on the substituted alkyl-SO2- include halogenated alkyl groups, particularly halogenated methyl groups such as trifluoromethyl, difluoromethyl, and fluoromethyl.

[0089] "Substituted sulfinyl" refers to a group represented by -SO-alkyl, -SO-substituted alkyl, -SO-alkenyl, -SO-substituted alkenyl, -SO-cycloalkyl, -SO-substituted cycloalkyl, -SO-aryl, -SO-substituted aryl, -SO-heteroaryl, -SO-substituted heteroaryl, -SO-heterocycle, -SO-substituted heterocycle, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein. Substituted sulfinyl includes groups such as methyl-SO-, phenyl-SO- and 4-methylphenyl-SO-. Preferred substituted alkyl groups on the substituted alkyl-SO- include halogenated alkyl groups, particularly halogenated methyl groups such as trifluoromethyl, difluoromethyl and fluoromethyl.

[0090] "Sulfonyloxy" or "substituted sulfonyloxy" means a group represented by -OSO2-alkyl, -OSO2-substituted alkyl, -OSO2-OH, -OSO2-alkenyl, -OSO2-substituted alkenyl, -OSO2-cycloalkyl, -OSO2-substituted cycloalkyl, -OSO2-aryl, -OSO2-substituted aryl, -OSO2-heteroaryl, -OSO2-substituted heteroaryl, -OSO2-heterocycle, -OSO2-substituted heterocycle, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0091] "Substituted" or "substituted" generally refers to a group that is covalently bonded to an atom, replacing a hydrogen atom. The atom in this general context can be a carbon atom or a heteroatom (e.g., a nitrogen atom).

[0092] "Thioacyl" means the group HC(S)-, alkyl-C(S)-, substituted alkyl-C(S)-, alkenyl-C(S)-, substituted alkenyl-C(S)-, alkynyl-C(S)-, substituted alkynyl-C(S)-, cycloalkyl-C(S)-, substituted cycloalkyl-C(S)-, aryl-C(S)-, substituted aryl-C(S)-, heteroaryl-C(S)-, substituted heteroaryl-C(S)-, heterocycle-C(S)-, and substituted heterocycle-C(S)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0093] "Mercapto" or "thiol" refers to the group --SH.

[0094] "Formyl" refers to the radical -C(O)H.

[0095] "Tautomer" means another form of a compound that differs in the location of a proton (e.g., enol-keto and imine-enamine tautomers), or a tautomeric form of a heteroaryl group that contains ring atoms that are bonded to both the NH portion of the ring and the =N portion of the ring (e.g., pyrazole, imidazole, benzimidazole, triazole, and tetrazole).

[0096] "Thiocarbonyl" means the divalent group -C(S)- which is equivalent to -C(=S)-.

[0097] "Thione" means the atom (=S).

[0098] "Alkylthio" refers to the group --S-alkyl, where alkyl is defined herein.

[0099] "Substituted alkylthio" refers to the group -S-(substituted alkyl), where substituted alkyl is as defined herein. Preferred substituted alkyl groups on -S-(substituted alkyl) include halogenated alkyl groups, particularly halogenated methyl groups such as trifluoromethyl, difluoromethyl, fluoromethyl, and the like.

[0100] The term "ameliorating" refers to any beneficial therapeutic outcome in treating a disease state, e.g., an inflammatory disease state, including reduction in severity or progression, remission, or cure. In some embodiments, "ameliorating" includes prevention of a disease state.

[0101] As used herein, the term "mammal" includes both humans and non-humans, including, but not limited to, humans, non-human primates, canines, felines, murines, bovines, equines, and porcines.

[0102] The term "sufficient amount" means an amount sufficient to produce a desired effect (eg, an amount sufficient to modulate protein aggregation in a cell).

[0103] The term "therapeutically effective amount" is an amount effective for ameliorating symptoms of a disease. In some embodiments, prevention can be considered treatment, such that a therapeutically effective amount can be a "prophylactically effective amount."

[0104] "Subject" means a mammal that is treated with a compound of the invention. A "subject" may be a human or non-human mammal.

[0105] "Treating" or "treatment" of a disease or disorder in a subject means 1) preventing the onset of the disease or disorder in a subject who is predisposed to or who is not yet symptomatic of the disease or disorder; 2) arresting or preventing the development of the disease or disorder; or 3) ameliorating or alleviating factors that contribute to the regression of the disease or disorder.

[0106] As used herein, a substance is said to be "specific" if it reacts or associates with a particular target more frequently, more rapidly, for a longer period of time, and / or with higher affinity than other substances, particularly compared to substances structurally related to the target (e.g., isoforms of the target). In some embodiments, an agent is said to be "specific" for a target if the concentration of the agent that produces a maximal effect in an in vitro or in vivo target assay (e.g., a binding assay or an enzyme activity assay) produces no measurable effect in a similar assay performed with other substances, particularly one or more substances structurally related to the target.

[0107] As used herein, the term "contacting" includes both direct contacting of a cell, e.g., in vivo, in vitro, or ex vivo, or indirect contacting of a cell (e.g., by administering an agent to a subject). Additionally, "contacting" a cell with an agent includes administering or applying a prodrug of the agent.

[0108] As used herein, the terms "prevent," "preventing," "prevention," "prophylactic treatment," and the like refer to reducing the likelihood of onset of a disease, disorder, or condition in a subject who has not developed the disease, disorder, or condition but is at risk of developing the disease, disorder, or condition. Thus, in some embodiments, an agent can be administered prophylactically to prevent the onset of a disease, disorder, or condition or to prevent the recurrence of a disease, disorder, or condition.

[0109] 5.2. Further rules of interpretation In general, a reference or description of a particular element, such as hydrogen or H, is meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium. Thus, tritium, 14 C. 32 P and 35Within the scope of the present technology are compounds comprising radioisotopes such as S. Procedures for incorporating such labels into the compounds of the present technology will be readily apparent to those of skill in the art based on the disclosure herein.

[0110] Unless a specific stereochemistry is specified, all chiral, diastereomeric, and racemic forms of the compound are intended.That is, the compounds described herein include enriched or resolved optical isomers for any or all asymmetric atoms as is clear from the drawing.Racemic mixtures, and d- or 1-enriched stereomeric mixtures, as well as individual optical isomers, can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric counterparts, and all of these stereoisomers are within the scope of the present technology.

[0111] The compounds described herein may exist as solvates, particularly hydrates, and all such solvates and hydrates are intended unless otherwise stated.Hydrates may form during the preparation of the compounds or compositions containing the compounds, or hydrates may form over time due to the hygroscopic nature of the compounds.The compounds of the present technology may also exist as organic solvates, including DMF, ether and alcohol solvates, among others.The identification and preparation of specific solvates are within the skill of those skilled in the art of synthetic organic chemistry or medicinal chemistry.

[0112] In the present specification, any functional substituent is substituted at 1 to 3 different positions, and each of the 1 to 3 substituents may be independently substituted at 1 to 3 positions, and each of the substituents is selected from the group consisting of halogen, hydroxyl, C1-C8 alkyl, substituted C1-C8 alkyl, C1-C8 alkenyl, substituted C1-C8 alkenyl, C1-C8 alkynyl, substituted C1-C8 alkynyl, acyl, acylamino, aminocarbonylamino, aminoacyl, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminoacyl, and aminoacyl. arylcarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, C1-C8 alkoxy, substituted C1-C8 alkoxy, C3-C7 aryl, substituted C3-C7 aryl, C3-C7 aryloxy, substituted C3-C7 aryloxy, C3-C7 arylthio, substituted C3-C7 arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, C3-C 10 Cycloalkyl, substituted C3-C 10 and independently selected from the group consisting of cycloalkyl, C3-C7 heterocycloalkyl, guanidino, substituted guanidino, C3-C7 heteroaryloxy, C3-C7 substituted heteroaryloxy, C3-C7 heteroarylthio, C3-C7 substituted heteroarylthio, sulfonyl, substituted sulfonyl, sulfinyl, substituted sulfinyl, sulfonyloxy, substituted sulfonyloxy, thioacyl, alkylthio, substituted alkylthio, C3-C7 heteroaryl, and substituted C3-C7 heteroaryl.

[0113] As used herein, any and all heteroaryl and heterocycloalkyl substituents may contain up to four heteroatoms selected from the group consisting of O, N, and S, but do not include heteroatom-heteroatom bonds such as OO, OS, NS, NO, and SS. In all of the above defined substituents, it is understood that polymers resulting from defining a substituent with further substituents on itself (such as substituted aryl having a substituted aryl group as a substituent that is itself substituted with a substituted aryl group) are not intended to be included herein. In such cases, the maximum number of such substituents is three. That is, each of the above definitions is constrained by the limitations that each functional group is substituted (in 1-3 positions), and that any and all of these substituents may be substituted once more (in 1-3 positions).

[0114] It is understood that the definitions provided herein are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups), such impermissible substitution patterns being well known to those of ordinary skill in the art.

[0115] Throughout this application, the text refers to various embodiments of the compounds, compositions, and methods.The various embodiments described are meant to provide examples for various descriptions, and should not be interpreted as further species descriptions.Rather, it should be noted that the descriptions of the various embodiments provided herein may be of overlapping scope.The embodiments described herein are merely illustrative and are not meant to limit the scope of the technology.

[0116] For the purposes of this specification and the appended claims, unless otherwise indicated, all numbers expressing amounts, sizes, dimensions, proportions, shapes, formulations, parameters, percentages, parameters, quantities, characteristics, and other numerical values ​​used in this specification and the appended claims are to be understood in all instances as being modified by the term "about," even if the term "about" does not explicitly appear with that value, amount, or range. Thus, unless otherwise indicated, the numerical parameters set forth in the following specification and the appended claims are not and need not be precise, but may be approximately as desired and / or more or less than desired, reflecting tolerances, conversion factors, rounding, measurement errors, and the like, as well as other factors known to those of ordinary skill in the art, depending on the desired properties believed to be obtained by the subject matter disclosed herein. For example, the term "about" when referring to a value can mean that in some embodiments it encompasses a variation of ±100%, in some embodiments ±50%, in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1% of the specified amount, as appropriate for practicing the disclosed methods or using the disclosed compositions.

[0117] As used herein and in the appended claims, in the context of describing elements (particularly in the context of the claims below), singular articles such as "a," "an," and "the" are to be construed as including both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The recitation of ranges of values ​​herein is intended to serve as a shorthand method of individually referring to each separate value falling within the range, including the upper and lower limits of the range, unless otherwise indicated herein, and each separate value is incorporated as if it were individually recited herein. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "etc.") described herein is intended merely to make the embodiments more clear, and does not limit the scope of the claims unless otherwise specified. No language in this specification should be construed as indicating any non-claimed element as a required element.

[0118] Unless otherwise stated, the nomenclature of substituents not explicitly defined herein is derived by naming the terminal portion of the functional group followed by the adjacent functional group toward the point of attachment. For example, the substituent "alkoxycarbonylalkyl" refers to the group (alkoxy)-C(O)-(alkyl)-.

[0119] 5.3. Compounds In a first aspect, compounds are provided that exhibit improved drug properties and increased solubility properties, improved DMPK properties, as demonstrated by enhanced stability in simulated intestinal and simulated gastric fluids, and that upon hydrolysis in plasma yield compounds of the base structure or compounds similar to the base structure that retain the therapeutic activity of the base structure.

[0120] In an exemplary embodiment, the compounds have a di-amino acid core structure, substituted with one or more organic functional groups at the C-terminus, N-terminus, and / or side chains of the core.

[0121] In some embodiments, the compound has formula II: [ka] [In the formula, n is 1, 2, 3, 4, 5, 6, 7, 8 or 9; m is 0, 1, 2, 3 or 4; R 1 is C1-C 12 Alkyl, C1-C 12 Substituted Alkyl, C1-C 12 Alkenyl, C1-C 12 Substituted alkenyl, C1-C 12 Alkynyl and C1-C 12 substituted alkynyl; R 2 is hydrogen, [ka] -C(=O)-Y and -CO-U; Where: Y is -Z-(CH2) q WR b and q is 0 to 4; Z and W are CH2, O, S, NR c and R b are independently selected from the group consisting of R c is selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl; R b is hydrogen, C1-C 12 Alkyl, C1-C 12or -C(=)O)-Y forms an amide bond through a nitrogen atom on Y, where Y is selected from the group consisting of glycine, sarcosine, N,N-dimethylglycine, alanine, valine, leucine, isoleucine, lysine, ornithine, arginine, serine and threonine; U is selected from the group consisting of pyridine, 1,4-dihydropyridine, N-alkyl-1,4-dihydropyridine and C-imidazole, or U is selected from aryl, heteroaryl or heterocycloalkyl; R 3 and R 4 is hydrogen, C1-C 12 Alkyl, C1-C 12 Substituted Alkyl, C1-C 12 Alkenyl, C1-C 12 Substituted alkenyl, C1-C 12 Alkynyl and C1-C 12 substituted alkynyl, or optionally R 3 and R 4 are linked to form a fused bicyclic or spirocyclic ring system; R 6 are hydrogen, deuterium, CH3, F, 19 F and 18 F; Optionally, Z and W together represent C3-C8 heterocycloalkyl or C4-C 10 Heteroaryl or one of the rings is C4-C 10 forming a bicyclic ring system which is a heteroaryl; Any and all heterocycles and heteroaryl rings contain up to four heteroatoms selected from the group consisting of O, N and S; however, If both Z and W are heteroatoms, the value of q is not 1; R 2 If is hydrogen, R 3 or R 4At least one of them is not hydrogen. or a tautomer thereof and / or a pharma- ceutically acceptable salt thereof.

[0122] In some embodiments, the compound has formula III: [ka] [In the formula, R 1 is C1-C 12 Alkyl or C1-C 12 is a substituted alkyl; R 2 is hydrogen, [ka] and -C(=O)-Y; Where: Y is -Z-(CH2) q WR b and q is 0 to 4; Z and W are CH2, O, S, NR c and R b are independently selected from the group consisting of R c is selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl; R b is hydrogen, C1-C 12 Alkyl, C1-C 12 selected from the group consisting of substituted alkyl, C3-C8 cycloalkyl, C3-C8 substituted cycloalkyl, C3-C8 heterocycloalkyl, and C3-C8 substituted heterocycloalkyl; R 3 and R 4 is hydrogen, C1-C 12 Alkyl, C1-C 12 Substituted Alkyl, C1-C 12 Alkenyl, C1-C 12 Substituted alkenyl, C1-C 12 Alkynyl and C1-C 12substituted alkynyl, or optionally R 3 and R 4 are linked to form a fused bicyclic or spirocyclic ring system, wherein the fused rings are C3-C8 heterocycloalkyl or C6-C 10 Aryl or C4-C 10 is heteroaryl; Optionally, Z and W together represent C3-C8 heterocycloalkyl or C4-C 10 Heteroaryl or one of the rings is C4-C 10 forming a bicyclic ring system which is a heteroaryl; Any and all heterocycles and heteroaryl rings contain up to four heteroatoms selected from the group consisting of O, N and S; however, If both Z and W are heteroatoms, the value of q is not 1; R 2 If is hydrogen, R 3 or R 4 At least one of them is not hydrogen. or a tautomer thereof and / or a pharma- ceutically acceptable salt thereof.

[0123] In some embodiments, the compound has formula IV: [ka] [In the formula, n is 1, 2, 3, 4, 5, 6, 7, 8, or 9; m is 0, 1, 2, 3 or 4; R 2 is hydrogen, -CH(R a )OPO(OH)2, -CO-Y, [ka] -C(=O)-Y, -CO-U, -C(=O)-(CH2) r is selected from the group consisting of -U, -CH2-V, Where: R ais hydrogen or CH3, Y is -Z-(CH2) q WR b and q is 0 to 4; Z and W are CH2, O, S, NR c and R b are independently selected from the group consisting of R c is selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl; R b is hydrogen, C1-C 12 Alkyl, C1-C 12 Substituted Alkyl, C1-C 12 Alkenyl, C1-C 12 Substituted alkenyl, C1-C 12 Alkynyl, C1-C 12 Substituted alkynyl, C3-C8 cycloalkyl, C3-C8 substituted cycloalkyl, C6-C 10 Aryl, C6-C 10 Substituted aryl, C3-C8 heterocycloalkyl, C3-C8 substituted heterocycloalkyl, C4-C 10 Heteroaryl, and C4-C 10 substituted heteroaryl; r is 0 to 5; U is selected from aryl, heteroaryl, or heterocycloalkyl; V is -OC(=O)-Q-(CH2) r -R d and Where: Q is a bond, O, and N(R c ) selected from the group consisting of R d is C6-C 10 Aryl, C4-C 10heteroaryl, C3-C8 heterocycloalkyl, hexose, pentose and -(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl), or -C(=)O)-Y forms an amide bond through a nitrogen atom on Y, where Y is selected from the group consisting of glycine, sarcosine, N,N-dimethylglycine, alanine, valine, leucine, isoleucine, lysine, ornithine, arginine, serine and threonine; R 3 and R 4 is hydrogen, C1-C 12 Alkyl, C1-C 12 Substituted Alkyl, C1-C 12 Alkenyl, C1-C 12 Substituted alkenyl, C1-C 12 Alkynyl and C1-C 12 substituted alkynyl, or optionally R 3 and R 4 are linked to form a fused bicyclic or spirocyclic ring system; R 6 are hydrogen, deuterium, CH3, F, 19 F and 18 F; Optionally, Z and W together represent C3-C8 heterocycloalkyl or C4-C 10 Heteroaryl or one of the rings is C4-C 10 forming a bicyclic ring system which is a heteroaryl; Any and all heterocycles and heteroaryl rings contain up to four heteroatoms selected from the group consisting of O, N and S; however, If both Z and W are heteroatoms, the value of q is not 1; R 2 If is hydrogen, R 3 or R 4 At least one of them is not hydrogen. or a tautomer thereof and / or a pharma- ceutically acceptable salt thereof.

[0124] In some embodiments, the compound has formula V: [ka] [In the formula, m is 0, 1, 2, 3 or 4; R 2 is hydrogen, [ka] and -C(=O)-Y; Where: Y is -Z-(CH2) q WR b and q is 0 to 4; Z and W are CH2, O, S, NR c and R b are independently selected from the group consisting of R c is selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl; R b is hydrogen, C1-C 12 Alkyl, C1-C 12 or -C(=)O)-Y forms an amide bond through a nitrogen atom on Y, where Y is selected from the group consisting of glycine, sarcosine, N,N-dimethylglycine, alanine, valine, leucine, isoleucine, lysine, ornithine, arginine, serine, and threonine; R 3 and R 4 is hydrogen, C1-C 12 Alkyl, C1-C 12 Substituted Alkyl, C1-C 12 Alkenyl, C1-C 12 Substituted alkenyl, C1-C 12 Alkynyl and C1-C 12 substituted alkynyl, or optionally R 3 and R4 are linked to form a fused bicyclic or spirocyclic system, the fused rings being C3-C8 heterocycloalkyl or C6-C 10 Aryl or C4-C 10 is heteroaryl; R 6 are hydrogen, deuterium, CH3, F, 19 F and 18 F; Optionally, Z and W together represent C3-C8 heterocycloalkyl or C4-C 10 Heteroaryl or one of the rings is C4-C 10 forming a bicyclic ring system which is a heteroaryl; Any and all heterocycles and heteroaryl rings contain up to four heteroatoms selected from the group consisting of O, N and S; however, If both Z and W are heteroatoms, the value of q is not 1; R 2 If is hydrogen, R 3 or R 4 At least one of them is not hydrogen. or a tautomer thereof and / or a pharma- ceutically acceptable salt thereof.

[0125] In some embodiments, the compound has formula VI: [ka] [In the formula, R 2 is hydrogen, [ka] and -C(=O)-Y; Where: Y is -Z-(CH2) q WR b and q is 0 to 4; Z and W are CH2, O, S, NR c and R bare independently selected from the group consisting of R c is selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl; R b is hydrogen, C1-C 12 Alkyl, C1-C 12 selected from the group consisting of substituted alkyl, C3-C8 cycloalkyl, C3-C8 substituted cycloalkyl, C3-C8 heterocycloalkyl, and C3-C8 substituted heterocycloalkyl; Optionally, Z and W together represent C3-C8 heterocycloalkyl or C4-C 10 Heteroaryl or one of the rings is C4-C 10 forming a bicyclic ring system which is a heteroaryl; Any and all heterocycles and heteroaryl rings contain up to four heteroatoms selected from the group consisting of O, N and S; However, when both Z and W are heteroatoms, the value of q is not 1. or a tautomer thereof and / or a pharma- ceutically acceptable salt thereof.

[0126] In some embodiments, the compound has the formula R 1 is a compound of formula I, wherein

[0127] In some embodiments, the compound has the formula: 2 is -C(=O)-Y, Z is N, and Z and W together form a C5 heterocycle.

[0128] In some embodiments, the compound has the formula: 2 but [ka] is a compound of formula I,

[0129] In some embodiments, the compound has the formula: 5 but [ka] is a compound of formula I,

[0130] In some embodiments, the compound has the formula: 1 C1-C 12 is alkyl, R 3 and R 4 are both hydrogen and R 5 is a compound of formula I where

[0131] In some embodiments, the compound has the formula: 1 C1-C 12 The compound of formula II is alkynyl.

[0132] In some embodiments, the compound has the formula: 2 is -C(=O)-Y, Z is CH2, q is 0, W is N, and R 3 and R 4 taken together form a spiro ring system, one ring being a C4 heterocycle and the other ring being a C5 cycloalkyl.

[0133] In some embodiments, the compound has the formula: 1 C1-C 12 is alkyl, R 3 and R 4 taken together form a spiro ring system.

[0134] In some embodiments, the compound has the formula: 1 C1-C 12 is alkyl, R 3 and R 4 together form a spiro ring system, and R 6 are hydrogen, deuterium, F, 19 F and 18 F.

[0135] In some embodiments, the compound has the formula: 1 is a C5 alkyl compound of formula III.

[0136] In some embodiments, the compound has the formula: 3 and R 4 are both hydrogen and R 2 but [ka] is a compound of formula III,

[0137] In some embodiments, the compound has the formula: 1 C1-C 12 is alkyl, R 2 is -C(=O)-Y, and R 3 and R 4 are both hydrogen.

[0138] In some embodiments, the compound has the formula: 1 C1-C 12 is alkyl, R 2 but [ka] and R 3 and R 4 are both hydrogen.

[0139] In some embodiments, the compound has the formula: 6 are hydrogen, deuterium, F, 19 F and 18 F.

[0140] In some embodiments, the compound has the formula: 5 is a C5 alkyl.

[0141] In some embodiments, the compound has the formula: 3 and R 4 are both hydrogen and R 6 are hydrogen, deuterium, F, 19 F and 18 F.

[0142] In some embodiments, the compound has the formula: 3 and R 4 are both hydrogen.

[0143] In some embodiments, the compound has the formula: 2 is -C(=O)-Y and Y is -Z-(CH2) q WR b q is 2, Z is NH, W is N(CH3), and R b is CH3.

[0144] In some embodiments, the compound has the formula: 3 and R 4 taken together to form a spiro ring system.

[0145] In some embodiments, the compound has the formula: 2 is -C(=O)-Y, and R 6 But hydrogen, deuterium, F, 19 F, and 18 F.

[0146] In some embodiments, the compound has the formula: 2 but [ka] and R 6 But hydrogen, deuterium, F, 19 F, and 18F.

[0147] In some embodiments, the compound has the formula: 2 but [ka] is a compound of formula VI,

[0148] In some embodiments, the compound has the formula: 2 is a compound of formula VI where

[0149] In some embodiments, the compound has the formula: 2 is -C(=O)-Y, and Z and W together form a C3-C8 heterocycloalkyl.

[0150] In some embodiments, the compound has the formula: 2 but [ka] is a compound of formula VI,

[0151] In some embodiments, the compound is a compound selected from the following structures: [ka] [ka] [ka] [ka] [ka]

[0152] In some embodiments, the compound is a compound selected from the following structures: [ka]

[0153] synthesis 5.3.1. General synthesis method The compounds described herein can be prepared from readily available starting materials using the following general methods and procedures. It will be understood that, unless otherwise stated, typical or preferred manufacturing conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) may also be used. Optimal reaction conditions vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through routine optimization procedures.

[0154] In addition, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.Proper protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting certain functional groups, are well known in the art.For example, numerous protecting groups are described in TW Greene and PGM Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.

[0155] When the compounds described herein contain one or more chiral centers, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or d(1) stereoisomers, or as stereoisomer-enriched mixtures. Unless otherwise indicated, all such stereoisomers (and enriched mixtures) are within the scope of the present technology. Pure stereoisomers (or enriched mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, chiral resolving agents, and the like.

[0156] The starting materials for the following reactions are either commonly known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials can be purchased from Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrentino, CA), or other chemical companies. aThese are commercially available from commercial sources such as Chemistry of Carbon Compounds, Volumes 1-5, and Supplemental (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or can be prepared by procedures described in such standard textbooks as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplemental (Elsevier Science Publishers, 1989), or obvious modifications thereof.

[0157] 5.3.2. Synthetic routes to the compounds listed The following specific, non-limiting examples are intended to illustrate the present invention.

[0158] In one general embodiment, the method involves reacting a suitably N-protected compound with a nucleophilic coupling partner and HATU to obtain the desired amide. It is understood that other suitable coupling conditions and reagents, such as HOBt and / or DMAP, may be used to form the required amide. Those skilled in the art will recognize that there are many synthetic conditions or methods that can form an amide functionality (e.g., reacting a starting carboxylate to synthesize a reactive derivative, such as the corresponding acid chloride, and then reacting that intermediate directly with an amine nucleophile to form the desired amide). Nucleophile to generate the desired amide. These synthetic methods are well within the scope of the disclosed technology.

[0159] On the other hand, it is commonly known that the N-terminus of a dipeptide derivative can be prepared by first protecting or blocking the C-terminus (i.e., placing the desired amide group at the C-terminus if the functional group is compatible, i.e., "orthogonal," so as not to interfere with later steps in the overall synthesis of the compound) and reacting the free dipeptide amine with an activated electrophile such as an acid anhydride, an acid chloride, phosphorus oxychloride or a phosphonyl chloride.

[0160] Of course, it is recognized that esterification reactions can be used to generate non-trivial groups on the tyrosine moiety. Such reactions can be facilitated by using an anhydride or other acid catalyst when reacting a free alcohol with a reactive carboxy compound. Suitable functional groups for active carboxy compounds include, but are not limited to, anhydrides, acid chlorides, Mitsunobu or Steglich-type conditions, or anhydrous acid conditions using carboxylic acids.

[0161] In one general embodiment, the synthesis may include functionalizing the amide nitrogen atom on the dipeptide derivative. Such a reaction is generally accomplished by generating an anion at one or both of the nitrogens by adding a strong base such as sodium amide, LDA, Grignard reagent, or LiN(i-Pr)2, while protecting other reactive functional groups on the molecule. Of course, these bases listed are not exhaustive. The next step is to add a suitable electrophile. If one wishes to create a spirocyclic ring system with two nitrogen atoms of the dipeptide derivative, a bifunctional electrophile such as 1,1-dibromocyclopentane can be added, or a carbonyl compound may be used that is required under strongly Lewis acidic conditions.

[0162] As used herein, amino, keto, thio, hydroxyl, and any other necessary protecting groups and methods for their deprotection are known in the art and are described, for example, in TW Greene and PGM Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999.

[0163] Alternatively, one skilled in the art will recognize that there are additional synthetic functional group modifications that can be used to prepare spirocyclic and other bicyclic or tricyclic compounds from dipeptide derivative intermediates.

[0164] 5.4. Composition In another aspect, a composition comprising at least one compound described herein is provided.

[0165] In various embodiments, the composition comprises one compound as described herein. In other embodiments, the composition comprises multiple compounds as described herein. In some of these latter embodiments, the composition comprises two, three, four or five or more compounds as described herein. In typical embodiments that comprise multiple compounds, the compounds are selected to have different pharmacokinetic properties from each other.

[0166] In certain embodiments, the composition comprises at least one compound and the basic structure described herein.In various embodiments, the composition comprises 1, 2, 3, 4 or 5 compounds and the basic structure described herein.In typical embodiments, the compound is selected to have different pharmacokinetic properties from the basic structure.In certain embodiments that include multiple compounds described herein, the compounds are selected to have different pharmacokinetic properties from each other.

[0167] In various embodiments, the compositions comprise at least one compound of formula I, or a tautomer, stereoisomer, salt, solvate, or hydrate thereof.

[0168] In various embodiments, the compositions include at least one compound of formula II, or a tautomer, stereoisomer, salt, solvate, or hydrate thereof.

[0169] In certain embodiments, the composition comprises at least one compound selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, and Compound 10, or a tautomer, stereoisomer, salt, solvate, or hydrate thereof, as described herein above.

[0170] In certain embodiments, the composition comprises at least one compound selected from the group consisting of compounds 1-10, A2-A17, A17a-7m, A18-A34f, and B1-B5, or a tautomer, stereoisomer, salt, solvate, or hydrate thereof, as described hereinabove.

[0171] In various embodiments, the composition is a solid.

[0172] In various embodiments, the composition is a liquid.

[0173] In various embodiments of the fluid, at least one of the at least one compound in the composition is present at a concentration of at least 10 ng / mL, 50 ng / mL, 100 ng / mL, 500 ng / mL, 1 μg / mL, 10 μg / mL, 50 μg / mL, 75 μg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, or even at least 0.5 mg / mL. In some embodiments of the fluid, at least one of the at least one compound in the composition is present at a concentration of at least 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, or 5 mg / mL. In some embodiments of the fluid, at least one of the at least one compound in the composition is present at a concentration of at least 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, or 50 mg / mL. In some fluid embodiments, at least one compound in the composition is present at a concentration of at least 100 mg / mL, 125 mg / mL, 150 mg / mL, 175 mg / mL, or 200 mg / mL. In some fluid embodiments, at least one of the at least one compound in the composition is present at a concentration of at least 250 mg / mL.

[0174] In certain embodiments of the fluid, each of the at least one compound in the composition is present at a concentration of at least 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, or even at least 0.5 mg / mL. In some fluid embodiments, each of the at least one compound in the composition is present at a concentration of at least 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, or 5 mg / mL. In some fluid embodiments, each of the at least one compound in the composition is present at a concentration of at least 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, or 50 mg / mL. In some fluid embodiments, each of the at least one compound in the composition is present at a concentration of at least 100 mg / mL, 125 mg / mL, 150 mg / mL, 175 mg / mL, or 200 mg / mL. In some fluid embodiments, each of the at least one compound in the composition is present at a concentration of at least 250 mg / mL.

[0175] Pharmaceutical Compositions In a further aspect, there is provided a pharmaceutical composition comprising at least one of the compounds described herein and a pharma- ceutically acceptable carrier or excipient.

[0176] In various embodiments, the pharmaceutical composition comprises one compound as described herein. In other embodiments, the pharmaceutical composition comprises multiple compounds as described herein. In certain of these latter embodiments, the pharmaceutical composition comprises two, three, four or five or more compounds as described herein. In typical embodiments that comprise multiple compounds, the compounds are selected to have different pharmacokinetic properties from each other.

[0177] In certain embodiments, the pharmaceutical composition comprises at least one compound and the basic structure described herein.In various embodiments, the pharmaceutical composition comprises 1, 2, 3, 4 or 5 compounds and the basic structure described herein.In typical embodiments, the compound is selected to have different pharmacokinetic properties from the basic structure.In certain embodiments, which include multiple compounds described herein, the compounds are selected to have different pharmacokinetic properties from each other.

[0178] In various embodiments, the pharmaceutical compositions comprise at least one compound of Formula I, or a tautomer, stereoisomer, salt, solvate or hydrate thereof.

[0179] In various embodiments, the pharmaceutical compositions comprise at least one compound of formula II, or a tautomer, stereoisomer, salt, solvate or hydrate thereof.

[0180] In certain embodiments, the pharmaceutical composition comprises at least one compound selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, and Compound 10, or a tautomer, stereoisomer, salt, solvate, or hydrate thereof, as described herein above.

[0181] In certain embodiments, the pharmaceutical composition comprises at least one compound selected from the group consisting of compounds 1-10, A2-A17, A17a-7m, A18-A34f, and B1-B5, or a tautomer, stereoisomer, salt, solvate, or hydrate thereof, as described hereinabove.

[0182] In various embodiments, the pharmaceutical composition is formulated for the enteral route of administration.

[0183] Pharmaceutical compositions for enteral administration route may be in tablet, capsule, powder or liquid form. Tablets may contain solid carriers such as gelatin or adjuvants. Liquid pharmaceutical compositions generally contain liquid carriers such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline, dextrose or other sugar solution, or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included. Pharmaceutical compositions may contain cyclodextrin. Pharmaceutical compositions may contain poloxamer and / or vitamin E TPGS.

[0184] In embodiments in which the pharmaceutical composition is formulated in a solid dosage form for enteral administration route, the composition may contain, on a weight percent (wt%) basis, from about 0.01 to 99.99 wt% of the compound of the present technology of the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of from about 1 to 80 wt%.

[0185] In other embodiments, the pharmaceutical compositions are formulated for inhalation suspended in a solution or mixture of additives (e.g., preservatives, viscosity modifiers, emulsifiers, buffers) in a non-pressurized or pressurized dispenser that delivers a spray containing a metered dose of at least one compound described herein. In certain embodiments of inhalation, the pharmaceutical compositions are formulated for nasal or oral administration.

[0186] In other embodiments, the pharmaceutical composition is formulated for topical administration. In certain topical embodiments, the pharmaceutical composition is formulated for transdermal administration, epidermal administration, instillation, or application / wiping.

[0187] In other embodiments, the pharmaceutical composition is formulated for parenteral administration. In certain parenteral embodiments, the pharmaceutical composition is formulated for intravenous, subcutaneous or intradermal administration. In other embodiments, the pharmaceutical composition is formulated for intrathecal or intraventricular administration.

[0188] In typical parenteral embodiments, the composition is in the form of a pyrogen-free parenterally acceptable aqueous solution with suitable pH, isotonicity and stability.Those skilled in the art can fully prepare suitable solutions using isotonic vehicles such as sodium chloride injection, Ringer's injection, lactated Ringer's injection, etc.If necessary, preservatives, stabilizers, buffers, antioxidants and / or other additives can be included.

[0189] In various embodiments of the fluid, at least one of the compounds in the pharmaceutical composition is present at a concentration of at least 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, or even at least 0.5 mg / mL. In some embodiments of the fluid, at least one of the compounds in the pharmaceutical composition is present at a concentration of at least 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, or 5 mg / mL. In some embodiments of the fluid, at least one of the compounds in the pharmaceutical composition is present at a concentration of at least 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, or 50 mg / mL. In some embodiments of the fluid, at least one of the compounds in the pharmaceutical composition is present at a concentration of at least 100 mg / mL, 125 mg / mL, 150 mg / mL, 175 mg / mL, or 200 mg / mL. In some embodiments of the fluid, at least one of the compounds in the pharmaceutical composition is present at a concentration of at least 250 mg / mL.

[0190] In certain embodiments of the fluid, each of the at least one compound in the pharmaceutical composition is present in a concentration of at least 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, or even at least 0.5 mg / mL.

[0191] In some fluid embodiments, at least one compound in the pharmaceutical composition is present at a concentration of at least 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, or 5 mg / mL. In some fluid embodiments, at least one compound in the pharmaceutical composition is present at a concentration of at least 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, or 50 mg / mL. In some fluid embodiments, at least one compound in the pharmaceutical composition is present at a concentration of at least 100 mg / mL, 125 mg / mL, 150 mg / mL, 175 mg / mL, or 200 mg / mL. In some fluid embodiments, at least one compound in the pharmaceutical composition is present at a concentration of at least 250 mg / mL.

[0192] 5.6. Method of Use In another aspect, a method of treatment is provided.

[0193] The method comprises administering at least one compound as described herein in an amount effective to treat, protect against, or reverse neurodegenerative disease, prevent or reverse dementia symptoms, promote repair of traumatic damage to the nervous system, or enhance cognitive function.In various embodiments, the subject has a disease selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, other dementias and neurodegenerative diseases, spinal cord injury, traumatic brain injury, and / or sensorineural hearing loss and vision loss.In typical embodiments, the method comprises administering a pharmaceutical composition comprising at least one compound as described herein, as described above.

[0194] In some embodiments, methods are provided for treating a disease condition comprising administering to a subject in need thereof an effective amount of one or more compounds of the formulas disclosed herein or a pharmaceutical composition described herein.

[0195] In some aspects, a method of treating a disease condition is provided, wherein the disease is a neurodegenerative disease.

[0196] In some aspects, methods are provided for treating a disease state, wherein the disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, other dementias and neurodegenerative diseases, spinal cord injury, traumatic brain injury, sensorineural hearing loss, and vision loss.

[0197] In some aspects, methods are provided for treating a disease condition, wherein the disease is Alzheimer's disease.

[0198] In some aspects, methods are provided for treating a disease state, wherein the disease is Parkinson's disease.

[0199] In some aspects, methods are provided for treating a disease condition, wherein the route of administration is selected from the group consisting of enteral, parenteral, inhalation, topical, including but not limited to oral, intravenous, subcutaneous, intrathecal and intraventricular administration.

[0200] In some aspects, methods are provided for treating a disease condition, wherein the administration is intravenous administration.

[0201] In some aspects, methods for treating a disease condition are provided that are performed in vitro. In some aspects, methods for treating a disease condition are provided that are performed in vivo.

[0202] In some aspects, methods are provided for treating a disease condition, wherein the subject is a mammal. In some aspects, methods are provided for treating a disease condition, wherein the subject is a human.

[0203] In some embodiments, there is provided the use of one or more compounds described herein in the manufacture of a medicament for treating a disease condition described herein.

[0204] In various embodiments, the compound is administered as the sole medical treatment. In various embodiments, the compound is administered in combination with other medical and / or surgical interventions in accordance with the general standard of care.

[0205] In various embodiments, the dosage is determined regardless of the patient's weight.In certain embodiments, the dosage is between 0.1mg and about 1000mg, between 1mg and about 500mg, between 1mg and about 300mg, or between 1mg and about 100mg per day.Such dosage can be administered once or more times per day, for example, 2, 3, 4, 5 or 6 times per day, preferably once or twice per day.Furthermore, dosage can be administered daily or several times per week, in which case subsequent dosages are administered after an interval of 1, 2 or 3 days.

[0206] In some embodiments, the dosage is determined based on the patient's body weight. In certain embodiments, the dosage is between 0.001 mg / kg and about 15 mg / kg, or between 0.01 mg / kg and about 1.5 mg / kg, of the patient's body weight.

[0207] The amount of compound administered will vary depending on the disease being treated, the route of administration, and the dosage regimen.

[0208] It will be understood, however, that the specific dosage level for a particular subject will depend on a variety of factors, including the specific compound used; the age, weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs previously administered; and the severity of the particular disease being treated, as is well understood by those of skill in the art.

[0209] Treatment may last for days, weeks or months, and in some cases, years.

[0210] The compositions may be administered alone or in combination with other treatments, either simultaneously or sequentially, depending on the condition being treated.

[0211] Dosage and administration schedule can be adjusted individually to produce a plasma level of the active moiety that is sufficient to achieve the desired effect, i.e., the minimum effective concentration (MEC). The MEC varies for each compound, but can be estimated, for example, from in vitro data and animal studies. The dosage required to achieve the MEC will depend on individual characteristics and the route of administration. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to the plasma concentration.

[0212] The amount of agent or composition administered will depend on a variety of factors, including the sex, age, and weight of the subject being treated, the severity of the illness, the manner of administration, and the judgment of the prescribing physician.

[0213] 6. Working Example The following synthetic and biological examples are offered to illustrate the present technology and are not to be construed in any way as limiting the scope of the present technology. All temperatures are given in degrees Celsius unless otherwise specified.

[0214] The examples are given for illustrative purposes only and are not intended to limit the scope of the invention in any way. Efforts have been made to be as precise as possible with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should, of course, be allowed for.

[0215] The practice of the present invention will employ, unless otherwise indicated, conventional methods of protein chemistry, biochemistry, recombinant DNA technology and pharmacology, within the skill of the art, such techniques being fully explained in the literature. For example, TE Creighton, Proteins: Structures and Molecular Properties (WH Freeman and Company, 1993); AL Lehninger, Biochemistry (Worth Publishers, Inc., current addition); Sambrook, et al., Molecular Cloning: A Laboratory Manual (2nd Edition, 1989); Methods In Enzymology (S. Colowick and N. Kaplan eds., Academic Press, Inc.); Remington's Pharmaceutical See Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990); Carey and Sundberg Advanced Organic Chemistry 3rd Ed. (Plenum Press) Vols A and B (1992), and Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991).

[0216] The present technology will be further understood by reference to the following examples, which are intended as purely illustrative of the present technology. The present technology is not limited in scope by the illustrated embodiments, which are intended as merely illustrative of a single aspect of the present technology. Any method that is functionally equivalent is within the scope of the present technology. In addition to those described herein, various modifications of the present technology will become apparent to those skilled in the art from the foregoing description and the accompanying drawings. Such modifications are within the scope of the appended claims.

[0217] In the examples below, the following abbreviations have the following meanings: If an abbreviation is not defined, it has its generally accepted meaning. aq. = aqueous LC-MS = Liquid Chromatography-Mass Spectrometry MS=mass spectrometry THF = tetrahydrofuran NaHCO3 = Sodium bicarbonate DIEA = diisopropylethylamine MS=mass spectrometry NaH = sodium hydride o / n=overnight HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-trizolo[4,5-b]pyridinium 3-oxide hexafluorophosphate. rt=room temperature LAH=Lithium Aluminum Hydride DCM = dichloromethane DMF = Dimethylformamide DMSO = dimethyl sulfoxide equiv.=equivalent EtOAc = ethyl acetate EtOH = ethanol g = grams h=time HCl = Hydrochloric Acid HPLC = High Performance Liquid Chromatography HOAc = acetic acid M = molar concentration MeOH = methanol mg = milligrams mL = milliliters mmol = millimolar mp = melting point m / z=mass-to-charge ratio NaCl = Sodium chloride Na2CO3 = Sodium Carbonate NMR=nuclear magnetic resonance NaOH = Sodium hydroxide Na2SO4 = Sodium sulfate TLC = Thin Layer Chromatography UV=ultraviolet light wt% = weight percent μM = micromolar

[0218] 6.1. Example 1: Synthesis General experiment details: The final compound was confirmed by FIPLC / MS analysis and determined to be >90%. 1 H and 13 C NMR spectra were recorded in CDCW (residual internal standard CHCW-δ 7.26), DMSO-d6 (residual internal standard CDSOCD2H = δ 2.50), or methanol-d4 (residual internal standard CD2HOD = δ 3.20), or acetone-d6 (residual internal standard CD3COCD2H = δ 2.05). Reported chemical shifts (δ) are in parts per million (ppm) and coupling constants (J) are in hertz (Hz). Spin multiplicities are expressed as s = singlet, bs = broad singlet, bm = broad multiplet, d = doublet, t = triplet, q = quartet, p = quintet, dd = doublet of doublets, ddd = doublet of doublets, dt = triplet of doublets, td = triplet of doublets, tt = triplet of triplets, and m = multiplet.

[0219] HPLC-MS analysis was performed with gradient elution. Medium pressure liquid chromatography (MPLC) was performed with both normal and reverse phase on a silica gel column.

[0220] In general, the compounds of the present invention can be prepared using readily available starting materials, reagents, and conventional synthetic procedures as shown in the general reaction scheme below, or by modification thereof, or can be inferred by those skilled in the art. In general, compounds of formula I can be prepared from commercially available materials by standard solution or solid phase synthesis, by procedures well established in the art. For example, acylation of the amino terminus will give common intermediate A2. The tyrosyl hydroxyl group of A2 can be acylated with a carboxylic acid derivative (A3), which can be an N-BOC protected amino acid (e.g., α, β, γ, or ω amino acid, or a diamino acid derivative such as Lys or Orn), followed by removal of the amine protecting group under acidic conditions to give A4 (Scheme 1 below). [ka]

[0221] Alternatively, carboxylic acid A3 may represent an N-mono or N,N-dialkylated amino acid derivative, several analogs of which are commercially available, and the final product can be converted to the corresponding amine salt A4 shown in Scheme I.

[0222] Alternatively, the tyrosyl hydroxyl of A2 can be derivatized to give mixed carbonate derivatives A6, which can then be reacted with alcohol or amine derivatives A7 to give the corresponding carbonate or carbamate derivatives (e.g., A8 and A10), respectively (Scheme II). The various starting materials, alcohol or amine derivatives represented by A7, are either commercially available or can be prepared by short synthetic procedures reported in the literature. Carbamate derivatives A10 can also be prepared directly from A2 via reaction with carbamoyl chloride A9. Some carbamoyl chlorides are commercially available, others can be prepared immediately before use from the corresponding secondary amines and diphosgene. [ka]

[0223] As shown in Scheme III, the tyrosyl hydroxyl can be converted to the phosphate derivatives A12, A13, A15. Reaction of two equivalents of the appropriate alcohol with POCl3 or 4-nitrophenyl phosphorodichloride gives intermediate A14, which is then used to derivatize the phenolic hydroxyl of A2 to give the desired product A15. [ka]

[0224] The prodrug moiety represents an alkoxy-carbonyl-based derivative R 2 Other derivatives can be prepared by the routes and chemistry shown in Scheme IV. To alkylate A2, alkoxy-carbonyl reagents A16, in which the amine is protected with an acid-labile BOC group, can be prepared using the chemistry outlined in Scheme V or via commercially available reagents. Table 1 below lists the R 2 Some non-limiting examples of these derivatives as substituents are presented below, where A17g represents an example of a non-amine-based polyhydroxyl solubility enhancing moiety. [ka] [Table 1] [Table 2]

[0225] R 3 -R 4The chemical reactions for incorporating the bicyclic derivatives are shown in the following scheme. If a symmetric acyclic or cyclic ketone is used for ring formation, no new chiral centers will be generated. However, cyclization from unsymmetric ketones or aldehydes will generate new chiral centers. The cyclization is expected to proceed via Schiff base mediation, and since chirally pure peptide derivatives are used, a thermodynamically stable cyclic aminal (imidazolidinone) product is expected to be obtained. Lydie, H. et.al. Tett. Letters (2015) 6240-6243 discloses an example of a cyclization reaction using 2-pyridinecarboxaldehyde with a dipeptide (to give two diastereomers in 46% and 11% yields). R 3 -R 4 The bridged monocyclic and / or spirocyclic aminals can be prepared under acidic or base catalyzed conditions similar to or modified from those reported in the literature, such as Gomes, P. et.al. Tetrahedron, 2004, 5551-62, DeMong. D. et.al. J. Med. Chem. 2014, 57, 2601-10, which are incorporated herein by reference. Subsequent N-acylation of A23A followed by hydrogenation and, if appropriate, removal of the acid labile protecting group, provides the desired imidazolidinone derivative A24A of Scheme VI. [ka]

[0226] Alternatively, reaction of the dipeptide (A25A) with a carbonyl compound can be used to prepare the cyclic aminal A26A (Scheme VII). Subsequent N-acylation followed by a coupling reaction gives the desired key intermediate (A23A), which is further detailed as shown in Scheme VI. [ka]

[0227] An alkoxy-carbonyl bearing an amino group can also be introduced into the C-terminal amide, which again gives A2 after esterase-mediated bioconversion. The chemistry for preparing the reagent [A16] is similar to that described in Scheme V, except that the prodrug-generating reagent [A16] contains a CBZ-protected amine. Some examples of the reagents used are shown in the box (insert) of Scheme VIII. Following synthesis of the penultimate protected intermediate, a final hydrogenation step in the presence of acid gives the desired prodrug derivative A33A. [ka]

[0228] One is Tyr and the other is the C-terminal amide, i.e., R 3 / R 4 Crosslinking and R 2 , or some combination of the above chemistries can also be prepared. As an example, a double prodrug analog by one of these approaches, and the corresponding proposed synthetic route, is shown below in Scheme IX. [ka]

[0229] Furthermore, F, 2 R such as H and CH3 6 Tyrosine analogs having variants are reported in the published literature and / or in the patents and references cited therein. [(R 6 )m 2 H: 2,6-dideuterotyrosine, B. et. al., J. Labeled Compounds and Radiopharmaceuticals, 1994, 34(9), 831-37;2,3,4,6-tetradeuterotyrosine: Walker, TE etal.al J. Org Chem. 1986, 51(8), 1775-79; (R 6)m is CH3: 2-methyltyrosine, Schmidt, EW Tett. Letters, 2004, 3921-24; for 2,3-dimethyltyrosine or 2,5-dimethyltyrosine, Santagada, VJ Med. Chem. 2006, 49(6), 1882-90, for 2,6-dimethyltyrosine, EP1481965A1 (2004) and EP2959918A1 (2015); and (R 6 ) m is F: 2,6- or 2,3- or 2,4-difluoro and / or 2,3,5- or 2,3,6-trifluorotyrosine, Seyedsayamdost, H. et.al. J. Am. Chem. Soc 2006, 49(6), 1882-90; and 2,3,5,6-tetrafluorotyrosine are commercially available.] Furthermore, R 6 Derivatives of A2 in which R is 2-fluoro, such derivatives are accessible via regiospecific electrophilic fluorination of tyrosine-containing peptides or peptidomimetics using in situ generated CH3COOF as described in Hebel, D., Tett. Letters, 1990, 31(5), 619-622. Other such R 6 Derivatives are available from the extension of these chemistries.

[0230] The following specific, non-limiting examples are illustrative of the present invention. Example 1A [ka]

[0231] To a mixture of 4-nitrophenyl phosphorodichloride (504 mg, 1.98 mmol) in THF (30 mL) at 0 °C, 2-(dimethylamino)ethanol (397 μL, 3.97 mmol) was added and stirred at room temperature for 2 h. After evaporation of THF and dissolving the crude in DMF (20 mL), the base structure (500 mg, 0.992 mmol) and LiOH·HO (208 mg, 4.96 mmol) were added and the mixture was stirred at room temperature overnight. After quenching with 4 M HCl, concentrating, washing (DCM / CH3CN) and purification by preparative HPLC using isocratic 40% MeOH vs. 60% aqueous formic acid (0.1%), the pure fractions were combined (HCl salt was formed by adding 4 M HCl) and lyophilized to give the title compound as a white solid. [(obs) MH + =727.5]

[0232] Example 1B [ka] Step-1: A mixture of basic structure (500 mg, 0.992 mmol), tetrabenzyl diphosphate (587 mg, 1.09 mmol) and L1OH·HO (46 mg, 1.09 mmol) in DMF was stirred at room temperature overnight, concentrated, washed (DCM) and used in the next step without further purification.

[0233] Step-2: 4-((S)-3-((2S,3S)-1-(6-amino-6-oxohexylamino)-3-methyl-1-oxopentan-2-ylamino)-2-hexanamido-3-oxopropyl)phenyl dibenzyl phosphate was dissolved in acetic acid (15 mL) and 0.5 equivalents (w / w) of 10% Pd / C was added and stirred under hydrogen atmosphere for 2 hours. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated, washed (DCM) and purified by preparative HPLC (isocratic 70% MeOH vs. 30% ammonium acetate buffer (pH 8)) to give the desired compound as a white solid after lyophilization (H4 + salt). [(obs)MH+ = 684.5]

[0234] Example 1C [ka] The base structure (564.9 mg, 1.119 mmol) was dissolved in dry DMF (12 mL) followed by the addition of LiOH·HO (46.9 mg, 1.119 mmol) and bis(4-nitrophenyl)carbonate (374.6 mg, 1.213 mmol). The solution was stirred at room temperature under nitrogen for 17 h. N-Methylpiperazine hydrochloride (198.8 mg, 1.455 mmol) was added and the mixture was stirred for an additional 6 h before being quenched with HCl and concentrated to dryness. The solid was washed (DCM, EtOAc) and then purified by Biotage C-18 reverse phase flash chromatography (30% to 100% MeOH in 0.1% formic acid in water) and treated with HCl to give the title compound base structure-C-PIPM (227.6 mg, 30%) after lyophilization. [(obs)MH + =631.4 and M + Na + =653.4]

[0235] Example 1D [ka] The base structure (508.1 mg, 1.007 mmol) was dissolved in dry DMF (8 mL) followed by the addition of LiOH·HO (42.2 mg, 1.007 mmol) and bis(4-nitrophenyl)carbonate (336.9 mg, 1.107 mmol). The solution was stirred overnight at room temperature under nitrogen. N,N-Dimethylethane-1,2-diamine hydrochloride (163.1 mg, 1.309 mmol) was added and the mixture was stirred for an additional 4 h before being quenched with HCl and concentrated to dryness. The solid was washed (DCM, EtOAc) and then purified by preparative HPLC (50%-70% MeOH in 0.1% formic acid in water) to give the title compound (154.8 mg, 12%) after treatment with HCl and lyophilization. [(obs) MH + = 619.5 and M + Na + = 641.6]

[0236] Example 1E [ka] To a solution of the basic structure (200 mg; 0.39 mmol) and 2-(4-methylpiperazin-1-yl)acetic acid (175.6 mg; 1.1 mmol) in anhydrous DMF (15 mL) was added EDC HCl (247.3 mg; 1.3 mmol) and HOBt (61 mg; 039 mmol) at 0 °C. The mixture was warmed to room temperature and stirred overnight. The reaction was quenched with 4 M HCl in 1,4-dioxane (0.5 mL). The solvent was removed in vacuo and the solid was dissolved in methanol (2 mL). The product was precipitated by addition of diethyl ether to the solution and isolated by filtration. The crude was purified by reversed-phase HPLC using methanol (B): 0.1% formic acid in water (D) [gradient elution from 10 to 100% B vs. D in 20 min]. The combined fractions were acidified with HCl and lyophilized to give the compound (206 mg, 82%) as a white solid. + =645.4]

[0237] Example 1F [ka] Step-1: A mixture of 2-morpholinoacetic acid (975 mg, 6.73 mmol), 4-nitrophenol (850 mg, 6.12 mmol), DCC (1386 mg, 6.73 mmol) and DMAP (40 mg, 0.306 mmol) in DCM (50 mL) was stirred at room temperature overnight. The reaction mixture was filtered, concentrated and washed with DCM to give 4-nitrophenyl 2-morpholinoacetate as a white solid, which was used in the next step without further purification.

[0238] Step-2: A mixture of 4-nitrophenyl 2-morpholinoacetate (288 mg, 0.95 mmol), basic structure (400 mg, 0.79 mmol), and LiOH·HO (74 mg, 1.75 mmol) in DMF (10 mL) was stirred at room temperature overnight. Quenched with 4M HCl, concentrated, and washed (DCM / THF / CH3CN) to give the desired compound as a white solid (HCl salt). [(obs)MH + =632.5, M + Li + =638.5]

[0239] Example 1G [ka] Step-1: A mixture of 2-(pyrrolidin-1-yl)acetic acid hydrochloride (1000 mg, 6.06 mmol), 4-nitrophenol (842 mg, 6.06 mmol), DCC (1500 mg, 7.27 mmol) and DMAP (39 mg, 0.30 mmol) in CH3CN (50 mL) was stirred at room temperature overnight. The reaction mixture was filtered, concentrated and washed with DCM to give 4-nitrophenyl 2-(pyrrolidin-1-yl)acetate hydrochloride as a yellow viscous oil, which was used in the next step without further purification.

[0240] Step-2: A mixture of 4-nitrophenyl 2-(pyrrolidin-1-yl)acetate hydrochloride (187 mg, 0.66 mmol), basic structure (300 mg, 0.59 mmol), and LiOH·HO (55 mg, 1.31 mmol) in DMF (10 mL) was stirred at room temperature overnight. Quenched with 4M HCl, concentrated, washed (DCM / CH3CN), purified by preparative HPLC using isocratic 40% MeOH and 60% 0.1% formic acid in water, and 4M HCl was added to make the hydrochloride salt of the final product, which after lyophilization gave the desired compound as a white solid. [(obs)MH + =616.5 and M + Na + =638.4]

[0241] Example 1H [ka] To a solution of the basic structure (200 mg; 0.39 mmol) and 2-(dimethylamino)acetic acid (124.4 mg; 1.1 mmol) in anhydrous DMF (15 mL) was added EDC HCl (191.7 mg; 1 mmol) and HOBt (61.2 mg, 0.39 mmol) at 0 °C. The mixture was warmed to room temperature and stirred overnight. The reaction was quenched with 4 M HCl in 1,4-dioxane (0.5 mL). The solvent was removed in vacuo and the solid was dissolved in methanol (2 mL). Diethyl ether was added to this solution to precipitate the product, which was isolated by filtration. The crude was purified by reverse-phase HPLC using methanol (B): 0.1% formic acid in water (D) [gradient elution of 40 to 100% B vs. D in 20 min]. The combined fractions were acidified with HCl and lyophilized to give a white solid (94 mg, 40%). Additionally, 63 mg of the basic structure was recovered from this reaction. [(obs)MH + =590.4 and M + Na + =612.4]

[0242] Example 1I [ka] Step-1: A mixture of Boc-(S)-Lys(Boc)-OH (741 mg, 2.14 mmol), 4-nitrophenol (282.7 mg, 2.03 mmol), DCC (441.3 mg, 2.14 mmol) and DMAP (26.1 mg, 0.214 mmol) in dry acetonitrile (20 mL) was stirred overnight at room temperature under nitrogen atmosphere. The reaction mixture was filtered, concentrated and the crude was purified by flash chromatography (silica gel, hexane / EtOAc) to give (S)-4-nitrophenyl 2,6-bis(tert-butoxycarbonylamino)hexanoate (548.7 mg, 55%).

[0243] Step-2: (S)-4-Nitrophenyl 2,6-bis(tert-butoxycarbonylamino)hexanoate (512.0 mg, 1.095 mmol) in solution in dry DMF (5 mL) was added to a solution of the basic structure (460.6 mg, 0.9127 mmol) and LiOH·HO (40.2 mg, 0.958 mmol). The mixture was stirred overnight at room temperature under nitrogen atmosphere. Concentration and washing (DCM, acetonitrile) gave bis(Boc protected)-(578.2 mg, 76%).

[0244] Step-3: Bis(Boc-protected) (307.1 mg, 0.369 mmol) was stirred in DMF (1.5 mL) / 4N HCl in dioxane (8 mL) mixture at room temperature for 3.5 h, then concentrated, washed (DCM), purified by preparative HPLC (40%-100% MeOH vs. 0.1% formic acid in water), treated with HCl and after lyophilization gave the title compound (204.1 mg, 68%). [(obs)MH + =633.5 and M + Na + =655.6]

[0245] Example 1J [ka] Step-1: To a solution of 4-nitrophenol (1 g, 7.2 mmol) and (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (1.8 g, 8.6 mmol) in anhydrous acetonitrile (25 mL) was added DCC (1.8 g, 8.6 mmol) and DMAP (44 mg, 0.36 mmol). The mixture was stirred overnight under nitrogen atmosphere. The solvent was removed in vacuum and the crude mixture was purified by normal phase column chromatography using DCM (100%) as eluent to obtain (S)-4-nitrophenyl-2-(tert-butoxycarbonylamino)-3-methylbutanoate (0.7 g, 29%).

[0246] (S)-4-Nitrophenyl-2-(tert-butoxycarbonylamino)-3-methylbutanoate and the basic structure (300 mg; 0.59 mmol) were dissolved in anhydrous DMF (25 mL). LiOH·HO (24.9 mg, 0.59 mmol) was added to the solution. The mixture was stirred overnight at room temperature under nitrogen atmosphere. The solvent was removed in vacuo and the solid was washed with DCM (100%) and then acetonitrile (100%) to give the pure BOC-protected product (300 mg), which was dissolved in a mixture of DMF (3 mL) and 1,4-dioxane (1 mL). To this solution was added 4 M HCl in 1,4-dioxane (10 mL). The mixture was stirred at room temperature for 4 h. The solvent was removed in vacuo and the crude product was purified by reverse-phase HPLC using methanol (B):0.1% formic acid in water (D) [gradient elution from 40 to 100% B vs. D in 20 min]. The combined fractions were acidified with HCl and lyophilized to give the compound (180 mg, 50%) as a white solid. + =604.4, M + Na + =626.5]

[0247] 6.2 Example 2: Stability and permeability in simulated intestinal fluid, simulated gastric fluid, and plasma Experiments were performed to assess the metabolic stability of test compounds in simulated intestinal fluid (SIF), simulated gastric fluid (SGF), and plasma.

[0248] Plasma stability test Assay conditions Compound concentration = 1μΜ Time = 0, 60, 120, and 240 minutes Temperature=37℃ Experimental protocol Human and rat plasma (K2 EDTA) were obtained from Bioreclamation. Compounds were dissolved as 0.3 mM DMSO stocks. Compounds were added (1 μM) to plasma on 96-well deep-well plates. After mixing, samples were transferred (25 μl / well) to several 96-well plates and incubated at 37° C. The extent of metabolism was calculated as the disappearance of test compound compared to the control reaction incubation (0 min). Propantheline was included as a positive control to verify assay performance. At each time point, 150 μl of quenching solution (50% acetonitrile, 50% methanol with 0.05% formic acid) was added to each well along with an internal standard (bucetin for positive ESI mode, warfarin for negative ESI mode). The plate was sealed and centrifuged at 4000 rpm for 15 min at 4° C. The supernatant was transferred to a fresh plate for LC / MS / MS analysis. All samples were analyzed for LC / MS / MS using an AB Sciex API 4000 instrument coupled with a Shimadzu LC-20AD LC pump system. Analytical samples were separated using a Waters Atlantis T3 dC18 reversed-phase HPLC column (20 mm x 2.1 mm) at a flow rate of 0.5 mL / min. The mobile phases were 0.1% formic acid in water (solvent A) and 0.1% formic acid in 100% acetonitrile (solvent B). The detailed elution conditions are given in the table below. [Table 3] The initial rate of elimination of the test compound was calculated using linear regression of a semi-log plot of % compound remaining versus time. The elimination rate constant (equal to the negative slope) of the linear regression was then used to determine the t value.

[0249] Metabolic stability in SIF and SGF (simulated intestinal fluid and simulated gastric fluid) Assay conditions Drug concentration = 5 μM Buffer 1 = SGF (without enzyme) Buffer 2 = SGF (with 0.32% pepsin) Buffer 3 = SIF (without enzyme) Buffer 4 = SIF (with 1% pancreatin) Time = 0, 60, 120, and 240 minutes Temperature=37℃ Experimental protocol SIF was freshly prepared with 8.7 mM NaOH, 28.65 mM NaH2PO4, 105.85 mM NaCl to a final pH of 6.8. SGF was freshly prepared with 34.2 mM NaCl to a final pH of 1.2. Enzymes (pepsin or pancreatin) were added to some buffers. Human and rat plasma (K2 EDTA) were purchased from Bioreclamation VT. Compounds were dissolved as 1.5 mM DMSO stocks. Compounds were added (5 μM) to SIF, SGF, or plasma on 96-well deep-well plates. After mixing, samples were transferred to several 96-well plates (25 μL / well) and incubated at 37° C. The extent of metabolism was calculated as disappearance of test compound compared to a 0 min control reaction incubation. To validate assay performance, candesartan cilexetil and omeprazole were included as positive controls for SIF and SGF, respectively. At each time point, 150 μL of quench solution (100% acetonitrile with 0.1% formic acid) was added to each well along with an internal standard (bucetin for positive ESI mode, warfarin for negative ESI mode). The plate was sealed and centrifuged at 4000 rpm for 15 min at 4° C. The supernatant was transferred to a fresh plate for LC / MS / MS analysis. All samples were analyzed for LC / MS / MS using an AB Sciex API 4000 instrument coupled with a Shimadzu LC-20AD LC pump system. Analytical samples were separated using a Waters Atlantis T3 dC18 reversed-phase HPLC column (20 mm x 2.1 mm) at a flow rate of 0.5 mL / min. The mobile phase was 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrile (solvent B). The detailed elution conditions are given in the table below. [Table 4] The initial rate of elimination of the test compound was calculated using linear regression of a semi-log plot of % compound remaining versus time. The elimination rate constant (equal to the negative slope) of the linear regression was then used to determine the t value.

[0250] Permeability Test Caco Experimental Method Assay conditions Compound concentration = 10μΜ GF120918 concentration=0~10μΜ Buffer solution = HBSS (adjusted to pH 7.4 with 5 mM HEPES) Time = 1 hour Control = digoxin Experimental protocol Caco-2 cell plates were commercially obtained and maintained at 37°C with 5% CO2 for 21 days. Cells were washed with Hank's balanced salt solution (HBSS) 30 min before the start of the experiment. Solutions of test compounds were prepared by diluting from DMSO stock solutions in HBSS buffer in the presence or absence of 10 μM of the P-gp inhibitor GF 120918. The final DMSO concentration is 0.2%. Before each experiment, the integrity of the cell monolayer was verified by transendothelial electrical resistance (TEER). Transport experiments were initiated by adding test compounds to the top (75 μl) side. Apparent transmittance (P app ) values ​​were calculated using the following formula: P app =(dQ / dt) / A / C0 where dQ / dt is the initial rate of the amount of test compound transported through the cell monolayer, A is the surface area of ​​the filter membrane, and C0 is the initial concentration of the test compound. C0 is calculated for each condition using a four-point calibration curve. P app To calculate , each prodrug and MM-201 were monitored simultaneously and the concentrations were summed to determine the final compound concentration in the system. The absorbance index between the two assay conditions was calculated by the following formula: Absorption quotient (AQ) = (Papp(with AB inhibitor)-Papp(without AB inhibitor) / Papp(with AB inhibitor) where Papp (with AB inhibitor) and Papp (without AB inhibitor) represent the apparent permeability of the test compound from the top side of the cell monolayer to the measurement side in the presence and absence of 10 μM P-gp inhibitor GF120918, respectively. All samples were analyzed by LC / MS / MS using an AB Sciex API 4000 instrument coupled with a Shimadzu LC-20AD LC pump system. Analytical samples were separated using a Waters Atlantis T3 dC18 reversed-phase HPLC column (20 mm x 2.1 mm) at a flow rate of 0.5 mL / min. The mobile phases were 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrile (solvent B). [Table 5]

[0251] 6.3 Example 3: In Vivo Pharmacokinetics Methods and Materials: 1.8 male JVC SD rats (purchased from Charles River Lab) were monitored daily for body condition and health status during the acclimation period (3-5 days). Rats were randomly assigned to a group (n=4). 2. Day 1 The rats were weighed and orally administered the following doses: Group 1: 13.2 mg / kg A20 (1.32 mg / mL at 10 mL / kg) Group 2: 14.2 mg / kg A22 (1.42 mg / mL at 10 mL / kg) 3. Treated rats were individually housed in metabolic cages and allowed to eat and drink ad libitum. Urine from each rat was collected daily from the metabolic cages and stored on dry ice. 4. Approximately 200 μL of blood samples were collected from each rat before administration (0 min), and 5, 15, 30 min, 1 hour, 2 hours, 8 hours, and 24 hours after administration, and transferred to EDTA tubes. 5. Blood samples in EDTA vials were centrifuged at 6,000 rpm for 10 minutes at 4° C. to obtain approximately 100 μL of plasma per sample. Blood samples were processed as quickly as possible, within 2 minutes at room temperature and within 15 minutes at 4° C. 6. All samples were transferred for bioanalytical assay using LCMS.

[0252] Data from each test are shown below. [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14] [Table 15] [Table 16] [Table 17] [Table 18] [Table 19] [Table 20] [Table 21] [Table 22] [Table 23] [Table 24] [Table 25] [Table 26] [Table 27] [Table 28] [Table 29]

[0253] Although several embodiments have been illustrated and described, one of ordinary skill in the art, upon reading the above specification, may make modifications, equivalent substitutions, and other types of changes to the compounds or salts, pharmaceutical compositions, derivatives, prodrugs, metabolites, tautomers, or racemic mixtures thereof of the present technology described herein, and each of the above aspects and embodiments also includes or incorporates such variations or aspects disclosed with respect to any or all other aspects and embodiments.

[0254] The present technology is also not limited with respect to the specific embodiments described herein, which are intended as examples of individual embodiments of the technology. As will be apparent to one of ordinary skill in the art, many modifications and variations of the present technology can be made without departing from the spirit and scope thereof. Functionally equivalent methods within the scope of the present technology will be apparent to one of ordinary skill in the art from the above description, in addition to those recited herein. Such modifications and variations are intended to be encompassed within the scope of the appended claims. It is understood that the present technology is not limited to specific methods, reagents, compounds, compositions, labeled compounds, or biological systems, which can, of course, vary. It is also understood that the terms used herein are for the purpose of describing particular embodiments only, and are not intended to be limiting. That is, the present specification is intended to be merely exemplary, with the breadth, scope, and spirit of the present technology being indicated only by the appended claims, definitions therein, and any equivalents thereof.

[0255] The embodiments illustratively described herein can be suitably implemented in the absence of any element or limitation not specifically described herein. Thus, for example, terms such as "comprising," "including," and "containing" are to be interpreted broadly and without limitation. Furthermore, the terms and expressions used herein are used as descriptive terms, not limiting terms, and are not intended to be used as terms or expressions that exclude any equivalents of the illustrated and described features or portions thereof, and it is recognized that various modifications are possible within the scope of the claimed technology. In addition, the term "essentially consisting of" is understood to include the elements specifically recited and additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase "consisting of" excludes any elements not specified.

[0256] Additionally, although features or aspects of the disclosure are described as Markush groups, one of skill in the art will recognize that the disclosure is also described thereby with respect to any individual members or subgroups of members of the Markush group. Each of the narrower species and subgroups encompassed by the generic disclosure also form part of the invention. This includes a generic description of the technology with a condition or negative limitation that excludes any subject matter from the genus, regardless of whether the omitted matter is specifically described herein.

[0257] All publications, patent applications, issued patents, and other documents (e.g., journals, articles, and / or textbooks) mentioned herein are incorporated by reference herein as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions contained in sentences incorporated by reference are excluded to the extent that they conflict with definitions in this disclosure.

[0258] Other embodiments are set forth in the following claims, along with the full scope of equivalents to which such claims are entitled.

[0259] While the present invention has been particularly shown and described with reference to preferred and various alternative embodiments, it will be understood by those skilled in the art that various changes in form and detail can be made therein without departing from the spirit and scope of the invention.

[0260] All references, issued patents, and patent applications cited within the body of this specification are hereby incorporated by reference in their entirety for all purposes.

[0261] Furthermore, the present invention includes the following aspects. 1. Formula I: [ka] [In the formula, n is 1, 2, 3, 4, 5, 6, 7, 8, or 9; m is 0, 1, 2, 3 or 4; R 1 is amino, substituted amino, alkoxy, substituted alkoxy, C1-C 12 Alkyl, C1-C 12 Substituted Alkyl, C1-C 12 Alkenyl, C1-C 12 Substituted alkenyl, C1-C 12 Alkynyl, C1-C 12 selected from the group consisting of substituted alkynyl, C1-C6 alkylaryl, C1-C6 substituted alkylaryl, C1-C6 alkenylaryl, C1-C6 substituted alkenylaryl, C1-C6 alkynylaryl, C1-C6 substituted alkynylaryl, norleucine, tyrosine, phenylalanine, aspartic acid, arginine, isoleucine, serine, threonine, histidine, glycine, cysteine, methionine, tryptophan, lysine, norvaline, norleucine, ornithine, S-benzylcysteine, O-benzylserine, O-benzylthreonine, cyclohexylalanine, 4-tetrahydropyranyl-glycine, and azaleucine; R 2 is hydrogen, -CH(R a )OPO(OH)2, -CO-Y, [ka] -C(=O)-Y, -CO-U, -C(=O)-(CH2) r is selected from the group consisting of -U, -CH2-V, Where: R a is hydrogen or CH3, Y is -Z-(CH2) q WR b and q is 0 to 4; Z and W are CH2, O, S, NR c and R b are independently selected from the group consisting of R cis selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl; R b is hydrogen, C1-C 12 Alkyl, C1-C 12 Substituted Alkyl, C1-C 12 Alkenyl, C1-C 12 Substituted alkenyl, C1-C 12 Alkynyl, C1-C 12 Substituted alkynyl, C3-C8 cycloalkyl, C3-C8 substituted cycloalkyl, C6-C 10 Aryl, C6-C 10 Substituted aryl, C3-C8 heterocycloalkyl, C3-C8 substituted heterocycloalkyl, C4-C 10 Heteroaryl, and C4-C 10 substituted heteroaryl; r is 0 to 5; U is selected from aryl, heteroaryl, or heterocycloalkyl; V is -OC(=O)-Q-(CH2) r -R d and Where: Q is a bond, O, and N(R c ) selected from the group consisting of R d is C6-C 10 Aryl, C4-C 10 heteroaryl, C3-C8 heterocycloalkyl, hexose, pentose and -(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl), or -C(=)O)-Y forms an amide bond through a nitrogen atom on Y, where Y is selected from the group consisting of glycine, sarcosine, N,N-dimethylglycine, alanine, valine, leucine, isoleucine, lysine, ornithine, arginine, serine and threonine; R 3 and R 4 is hydrogen, C1-C 12 Alkyl, C1-C 12 Substituted Alkyl, C1-C 12 Alkenyl, C1-C12 Substituted alkenyl, C1-C 12 Alkynyl, C1-C 12 Substituted alkynyl, C3-C8 cycloalkyl, C3-C8 substituted cycloalkyl, C6-C 10 Aryl, C6-C 10 Substituted aryl, C3-C8 heterocycloalkyl, C3-C8 substituted heterocycloalkyl, C4-C 10 Heteroaryl, C4-C 10 substituted heteroaryl, [ka] or optionally R 3 and R 4 are linked to form a fused bicyclic or spirocyclic ring system; R 5 is hydrogen, [ka] selected from the group consisting of; R 6 are hydrogen, deuterium, CH3, F, 19 F and 18 F; Optionally, Z and W together represent C3-C8 heterocycloalkyl or C4-C 10 Heteroaryl or one of the rings is C4-C 10 forming a bicyclic ring system which is a heteroaryl; R 1 If present, the amino acid [ka] is covalently bonded to the carbon atom of C(=O) through the nitrogen atom at the N-terminus of the amino acid, or [ka] Together [ka] Just as the C(=O) in represents the amino acid that is the carboxy terminal of the amino acid, 1 The carbon atom of the amino acid is bonded to C(=O); Any and all heterocycles and heteroaryl rings contain up to four heteroatoms selected from the group consisting of O, N and S; however, If both Z and W are heteroatoms, the value of q is not 1; R 2 and R 5 are hydrogen and n is 5, then R 3 or R 4 At least one of them is not hydrogen. or a tautomer thereof and / or a pharma- ceutically acceptable salt thereof.

[0262] 2. Formula II: [ka] [In the formula, n is 1, 2, 3, 4, 5, 6, 7, 8 or 9; m is 0, 1, 2, 3 or 4; R 1 is C1-C 12 Alkyl, C1-C 12 Substituted Alkyl, C1-C 12 Alkenyl, C1-C 12 Substituted alkenyl, C1-C 12 Alkynyl and C1-C 12 substituted alkynyl; R 2 is hydrogen, [ka] -C(=O)-Y and -CO-U; Where: Y is -Z-(CH2) q WR b and q is 0 to 4; Z and W are CH2, O, S, NR cand R b are independently selected from the group consisting of R c is selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl; R b is hydrogen, C1-C 12 Alkyl, C1-C 12 or -C(=)O)-Y forms an amide bond through a nitrogen atom on Y, where Y is selected from the group consisting of glycine, sarcosine, N,N-dimethylglycine, alanine, valine, leucine, isoleucine, lysine, ornithine, arginine, serine and threonine; U is selected from the group consisting of pyridine, 1,4-dihydropyridine, N-alkyl-1,4-dihydropyridine and C-imidazole, or U is selected from aryl, heteroaryl or heterocycloalkyl; R 3 and R 4 is hydrogen, C1-C 12 Alkyl, C1-C 12 Substituted Alkyl, C1-C 12 Alkenyl, C1-C 12 Substituted alkenyl, C1-C 12 Alkynyl and C1-C 12 substituted alkynyl, or optionally R 3 and R 4 are linked to form a fused bicyclic or spirocyclic ring system; R 6 are hydrogen, deuterium, CH3, F, 19 F and 18 F; Optionally, Z and W together represent C3-C8 heterocycloalkyl or C4-C 10 Heteroaryl or one of the rings is C4-C 10 forming a bicyclic ring system which is a heteroaryl; Any and all heterocycles and heteroaryl rings contain up to four heteroatoms selected from the group consisting of O, N and S; however, If both Z and W are heteroatoms, the value of q is not 1; R 2 If is hydrogen, R 3 or R 4 At least one of them is not hydrogen. or a tautomer thereof and / or a pharma- ceutically acceptable salt thereof.

[0263] 3. Formula III: [ka] [In the formula, R 1 is C1-C 12 Alkyl or C1-C 12 is a substituted alkyl; R 2 is hydrogen, [ka] and -C(=O)-Y; Where: Y is -Z-(CH2) q WR b and q is 0 to 4; Z and W are CH2, O, S, NR c and R b are independently selected from the group consisting of R c is selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl; R b is hydrogen, C1-C 12 Alkyl, C1-C 12 selected from the group consisting of substituted alkyl, C3-C8 cycloalkyl, C3-C8 substituted cycloalkyl, C3-C8 heterocycloalkyl, and C3-C8 substituted heterocycloalkyl; R 3 and R4 is hydrogen, C1-C 12 Alkyl, C1-C 12 Substituted Alkyl, C1-C 12 Alkenyl, C1-C 12 Substituted alkenyl, C1-C 12 Alkynyl and C1-C 12 substituted alkynyl, or optionally R 3 and R 4 are linked to form a fused bicyclic or spirocyclic ring system, wherein the fused rings are C3-C8 heterocycloalkyl or C6-C 10 Aryl or C4-C 10 is heteroaryl; Optionally, Z and W together represent C3-C8 heterocycloalkyl or C4-C 10 Heteroaryl or one of the rings is C4-C 10 forming a bicyclic ring system which is a heteroaryl; Any and all heterocycles and heteroaryl rings contain up to four heteroatoms selected from the group consisting of O, N and S; however, If both Z and W are heteroatoms, the value of q is not 1; R 2 If is hydrogen, R 3 or R 4 At least one of them is not hydrogen. or a tautomer thereof and / or a pharma- ceutically acceptable salt thereof.

[0264] 4. Formula IV: [ka] [In the formula, n is 1, 2, 3, 4, 5, 6, 7, 8, or 9; m is 0, 1, 2, 3 or 4; R 2 is hydrogen, -CH(R a )OPO(OH)2, -CO-Y, [ka] -C(=O)-Y, -CO-U, -C(=O)-(CH2) r is selected from the group consisting of -U, -CH2-V, Where: R a is hydrogen or CH3, Y is -Z-(CH2) q WR b and q is 0 to 4; Z and W are CH2, O, S, NR c and R b are independently selected from the group consisting of R c is selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl; R b is hydrogen, C1-C 12 Alkyl, C1-C 12 Substituted Alkyl, C1-C 12 Alkenyl, C1-C 12 Substituted alkenyl, C1-C 12 Alkynyl, C1-C 12 Substituted alkynyl, C3-C8 cycloalkyl, C3-C8 substituted cycloalkyl, C6-C 10 Aryl, C6-C 10 Substituted aryl, C3-C8 heterocycloalkyl, C3-C8 substituted heterocycloalkyl, C4-C 10 Heteroaryl, and C4-C 10 substituted heteroaryl; r is 0 to 5; U is selected from aryl, heteroaryl, or heterocycloalkyl; V is -OC(=O)-Q-(CH2) r -R d and Where: Q is a bond, O, and N(R c ) selected from the group consisting of R d is C6-C 10 Aryl, C4-C 10heteroaryl, C3-C8 heterocycloalkyl, hexose, pentose and -(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl), or -C(=)O)-Y forms an amide bond through a nitrogen atom on Y, where Y is selected from the group consisting of glycine, sarcosine, N,N-dimethylglycine, alanine, valine, leucine, isoleucine, lysine, ornithine, arginine, serine and threonine; R 3 and R 4 is hydrogen, C1-C 12 Alkyl, C1-C 12 Substituted Alkyl, C1-C 12 Alkenyl, C1-C 12 Substituted alkenyl, C1-C 12 Alkynyl and C1-C 12 substituted alkynyl, or optionally R 3 and R 4 are linked to form a fused bicyclic or spirocyclic ring system; R 6 are hydrogen, deuterium, CH3, F, 19 F and 18 F; Optionally, Z and W together represent C3-C8 heterocycloalkyl or C4-C 10 Heteroaryl or one of the rings is C4-C 10 forming a bicyclic ring system which is a heteroaryl; Any and all heterocycles and heteroaryl rings contain up to four heteroatoms selected from the group consisting of O, N and S; however, If both Z and W are heteroatoms, the value of q is not 1; R 2 If is hydrogen, R 3 or R 4 At least one of them is not hydrogen. or a tautomer thereof and / or a pharma- ceutically acceptable salt thereof.

[0265] 5. Formula V: [ka] [In the formula, m is 0, 1, 2, 3 or 4; R 2 is hydrogen, [ka] and -C(=O)-Y; Where: Y is -Z-(CH2) q WR b and q is 0 to 4; Z and W are CH2, O, S, NR c and R b are independently selected from the group consisting of R c is selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl; R b is hydrogen, C1-C 12 Alkyl, C1-C 12 or -C(=)O)-Y forms an amide bond through a nitrogen atom on Y, where Y is selected from the group consisting of glycine, sarcosine, N,N-dimethylglycine, alanine, valine, leucine, isoleucine, lysine, ornithine, arginine, serine, and threonine; R 3 and R 4 is hydrogen, C1-C 12 Alkyl, C1-C 12 Substituted Alkyl, C1-C 12 Alkenyl, C1-C 12 Substituted alkenyl, C1-C 12 Alkynyl and C1-C 12 substituted alkynyl, or optionally R 3 and R 4are linked to form a fused bicyclic or spirocyclic system, the fused rings being C3-C8 heterocycloalkyl or C6-C 10 Aryl or C4-C 10 is heteroaryl; R 6 are hydrogen, deuterium, CH3, F, 19 F and 18 F; Optionally, Z and W together represent C3-C8 heterocycloalkyl or C4-C 10 Heteroaryl or one of the rings is C4-C 10 forming a bicyclic ring system which is a heteroaryl; Any and all heterocycles and heteroaryl rings contain up to four heteroatoms selected from the group consisting of O, N and S; however, If both Z and W are heteroatoms, the value of q is not 1; R 2 If is hydrogen, R 3 or R 4 At least one of them is not hydrogen. or a tautomer thereof and / or a pharma- ceutically acceptable salt thereof.

[0266] 6. Formula VI: [ka] [In the formula, R 2 is hydrogen, [ka] and -C(=O)-Y; Where: Y is -Z-(CH2) q WR b and q is 0 to 4; Z and W are CH2, O, S, NR c and R b are independently selected from the group consisting of Rc is selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl; R b is hydrogen, C1-C 12 Alkyl, C1-C 12 selected from the group consisting of substituted alkyl, C3-C8 cycloalkyl, C3-C8 substituted cycloalkyl, C3-C8 heterocycloalkyl, and C3-C8 substituted heterocycloalkyl; Optionally, Z and W together represent C3-C8 heterocycloalkyl or C4-C 10 Heteroaryl or one of the rings is C4-C 10 forming a bicyclic ring system which is a heteroaryl; Any and all heterocycles and heteroaryl rings contain up to four heteroatoms selected from the group consisting of O, N and S; However, when both Z and W are heteroatoms, the value of q is not 1. or a tautomer thereof and / or a pharma- ceutically acceptable salt thereof.

[0267] 7. R 1 C1-C 12 is alkyl, R 3 and R 4 are both hydrogen and R 5 The compound according to item 1, wherein is hydrogen.

[0268] 8. m is 0 and R 1 C1-C 12 is alkyl, R 3 and R 4 and together form a spiro ring system.

[0269] 9. m is 1 or 2 and R 1 C1-C 12 is alkyl, R 3 and R 4 together form a spiro ring system, and R 6 are hydrogen, deuterium, F, 19 F and 18Item 3. The compound according to item 2, wherein each of the compounds is independently selected from the group consisting of F.

[0270] 10. R 1 C1-C 12 is alkyl, R 2 is -C(=O)-Y, and R 3 and R 4 The compound according to item 3, wherein both are hydrogen.

[0271] 11. R 1 C1-C 12 is alkyl, R 2 -C(=O)-(CH(NH2) i Pr and R 3 and R 4 The compound according to item 3, wherein both are hydrogen.

[0272] 12. R 1 C1-C 12 is alkyl, R 2 -C(=O)-(CH(NH2) i Pr and R 3 and R 4 are both hydrogen, m is 1 or 2, and R 6 The compound according to item 3, wherein

[0273] 13. R 1 C1-C 12 is alkyl, R 2 but [ka] and R 3 and R 4 The compound according to item 3, wherein both are hydrogen.

[0274] 14. m is 1 and R 3 and R 4 are both hydrogen and R 6 The compound according to item 4, wherein

[0275] 15. m is 0 and R 3 and R4 The compound according to item 4, wherein both are hydrogen.

[0276] 16. m is 1 and R 2 is -C(=O)-Y, and R 6 The compound according to item 5, wherein is F.

[0277] 17. m is 1 and R 2 but [ka] and R 6 but 19 The compound according to item 5, wherein F is

[0278] 18. R 2 The compound according to item 6, wherein Z and W together form a C3-C8 heterocycloalkyl.

[0279] 19. R 2 but [ka] Item 7. The compound according to item 6, wherein

[0280] 20. The structure: [ka] [ka] [ka] [ka] [ka] A compound selected from:

[0281] 21. The structure: [ka] A compound selected from:

[0282] 22. A composition comprising at least one compound according to any one of items 1 to 21.

[0283] 23. The composition according to item 22, comprising a plurality of compounds according to any one of items 1 to 21.

[0284] 24. A pharmaceutical composition comprising at least one compound according to any one of items 1 to 21 and a pharma- ceutically acceptable carrier or excipient.

[0285] 25. The pharmaceutical composition according to item 24, comprising a plurality of compounds according to any one of items 1 to 21.

[0286] 26. The pharmaceutical composition according to claim 24 or 25, further comprising a basic structure.

[0287] 27. A method for treating a disease condition, comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition described in any one of items 1 to 21.

[0288] 28. The method according to paragraph 27, wherein the disease is a neurodegenerative disease.

[0289] 29. The method according to paragraph 28, wherein the disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, other dementias and neurodegenerative diseases, spinal cord injury, traumatic brain injury, sensorineural hearing loss and vision loss.

[0290] 30. The method according to item 28, wherein the disease is Alzheimer's disease.

[0291] 31. The method according to item 28, wherein the disease is Parkinson's disease.

[0292] 32. The method of any one of paragraphs 27 to 31, wherein the route of administration is selected from the group consisting of enteral, parenteral, inhalation, and topical, including but not limited to oral, intravenous, subcutaneous, intrathecal, and intracerebroventricular administration.

[0293] 33. The method according to paragraph 32, wherein the administration is intravenous administration.

[0294] 34. The method of paragraph 27, wherein administration is performed in vitro.

[0295] 35. Use of a compound according to any one of clauses 1 to 21 in the manufacture of a medicament for treating any of the diseases according to clause 29.

Claims

[Claim 1] The invention as described herein or in any drawings.

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