WO2017210685A1 - Pyradazinone derivatives and the compositions and methods of treatment regarding the same - Google Patents

Abstract

The present disclosure is directed to pyridazin-3(2H)-one compounds of formula (I), pharmaceutical compositions thereof and methods for modulating or activating a Parkin ligase The present disclosure is also directed to methods of treating and/or reducing the incidence of diseases or conditions related to the activation of Parkin ligase, R²¹, R²², R²³, R²⁴ and R²⁵ are as defined herein.

Description

PYRADAZINONE DERIVATIVES AND THE COMPOSITIONS AND METHODS OF TREATMENT REGARDING THE SAME

REFERENCE TO RELATED APPLICATIONS

[1] This application claims the priority benefit of U.S. Provisional Application No. 62/345,486, filed June 3, 2016, the disclosure of which is incorporated by reference herein in its entirety.

FIELD OF THE INVENTION

[2] The present invention relates to pyridazin-3(2H)-one compounds and their derivatives as well as methods of modulating Parkin ligase or methods of treating various diseases and conditions with the pyridazin-3(2H)-one compounds and their derivatives.

BACKGROUND OF THE INVENTION

[3] Ubiquitin-Proteasome Pathway System (UPS) is a critical pathway that regulates key regulator proteins and degrades misfolded or abnormal proteins. UPS is central to multiple cellular processes, and if defective or unbalanced, it leads to patliogenesis of a variety of diseases. Posttranslational modification of proteins by ubiquitin is a fundamental cellular mechanism that regulates protein stability and activity and underlies a multitude of functions, from almost every aspect of biology. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases. These ligases comprise over 500 different proteins and are categorized into multiple classes defined by the structural element of their E3 functional activity. Specifically, both HECT and RING ligases transfer an activated ubiquitin from a thioester to the e-amino acid group of a lysine residue on a substrate; however, HECT ligases have an active site cysteine that forms an intermediate thioester bond with ubiquitin, while RING ligases function as a scaffold to allow direct ubiquitin transfer from the E2 to substrate. Recent evidence suggests that a subfamily of RING ligases, the RTNG-between-RING (RBR) family, may contain a catalytic cysteine residue 1,2 in addition to a canonical RING domain. (Riley et al. 2013. Nat Commim. 4: 1982, "Riley et al."), which is herein incorporated by reference in its entirety.

[4] Deubiquitmating proteins and ubiquitin-specific proteases (DUBs and USPs) and E3 Ligases play a vital role in the UPS. These proteins are supported by flexible Zinc Finger (ZnF) domains which stabilize the binding of ubiquitin (Ub) for specialized functions. [5] Parkin is a RING-between-RING E3 ligase that functions in the covalent attachment of ubiquitin to specific substrates, and mutations in Parkin are linked to Parkinson's disease, cancer and mycobacterial infection. The individual RING domains for Parkin have been the subject of much debate, in regards to the specific residues that coordinate Zn ions, as well as their relationship to canonical RING crossbrace structures defining classical E2-binding domains. R0 is a novel domain structure, but is more similar to Zn-finger domains than to E3 RING domains (Riley et al. 2013. Nat Commun. 4: 1982}

[6] While many drug discovery programs focus on the UPS, few have been successful due to the lack of selectivity and direct access to enzymatic protein active sites. The present invention is directed towards a novel approach of disrupting Zn-finger domains that provide a therapeutic benefit for various diseases and disorders, including oncology and neurology disorders.

SUMMARY OF THE INVENTION

[7] The compounds of the present disclosure can modulate or active Parkin ligase and may be useful in treating various diseases and conditions as disclosed herein. In one embodiment, the present disclosure provides compounds comprising the structure of formula

(I)

[8] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[9] L⁴ and L⁵ are each independently selected from a bond, alkylene, alkenylene, -0-, - NH-, -NR.⁶-, -NHC(G)-, -NR⁶C(0)~, -CH₂C(0)-, ~C(Q)NH~, ~C(G)NR⁶-, -CH₂C(Q)NH~, - CH₂.C(0)NR⁶-, ~S(0)n~, -S(0)nNH-, -S(0)nNR⁶-, -NHS(0)n-, or -NR⁶S(0)n-;

[10] X is absent, alkylene, alkenylene, divalent cycloalkyl, divalent aryl, divalent heterocyclyl, or divalent monocyclic heteroaryl, wherein cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R⁵;

[11] Y is cycloalkyl, and, heterocyclyl, or heteroaryl, wherein Y is optionally substituted with one or more R⁵;

[12] R¹¹, R¹², and R¹³ are each independently selected from H, I, Br, CI, F, CN, alkyl, haloalkyl, -SH, -S-alkyl, -OH, -O-alkyl, -NH₂, -NHR⁴, -NR⁴R⁴, or -N0₂; or

[13] R⁴ is each independently H, alkyl, aryl, arylalkyl, aryloxyalkyl, heterocyclyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, or heteroaryloxyalkyl, wherein each R⁴ is optionally substituted with one or more R³;

[14] R⁵ is each independently L Br, CI, F, -CN, -CO H2, -CONHR⁶, -C0NR⁶R⁶, -CQGH, -NH2, -M IR'^'. NO2, -NR⁶R⁶, -OH, -OR⁶, -COOR⁶, -OSO3R⁶, oxo, R⁶, -SH, -SO2R⁶, -SO3H, - SO3R⁶, -S(0)nNH2, -S(0)nNHR⁶, -S(0)„NR⁶R⁶, or -SR⁶;

[15] R⁶ is each independently alkyl or cycloalkyl:

[16] n is 0, 1, or 2: and

[17] provided that when L⁴ and L⁵ are each a bond and X is absent, then Y is not unsubstituted phenyl, phenyl substituted with alkyl, halogen or -COOH, or Y is not cycloalkyl or thiazolyl;

[18] provided that when -L⁴~X~L⁵- is -CH2-, then Y is not phenyl, pryidyl, thiophenyl, tliiadiazolyl, dioxolanone, pyrazolyl or oxiranyl;

[19] wherein X is not divalent oxadiazolyl or divalent pyrazolyl:

[20] wherein Y is not pyridyl of tetrahydrofuranyl; and

[21 ] wherein the compound is not 4,5~dichloro~2~((5-(miophen-2~yl)isoxazol-3~ yl)methyl)pyridazin-3(2H)-one, 4,5-Dichloro-2-{2-[4-(diethylamino)phenyl]-2- oxoethyl}pyridazin-3(2H)-one, 2-((4,5-dichloro-6-oxopyridazin-l (6H)-yl)methyl)-l-ethyl- A^r,N-dimethyl-lH-benzo[i ]imidazole-6-sulfonamide, 4-(4-amino-5-chloro-6-oxopyridazin- l(6H)-yl)butyl benzoate, 2-(2-ammo-4-methylthiazol-5-yl)-4,5-dichloropyridazin-3(2H)-one, and/or 2-(2-aminothiazol-4-yl)-4,5-dichloropyridazin-3(2H)-one.

[22] In one embodiment, L⁴ and L⁵ of formula (I) is each independently selected from, a bond, C 1 -C3 alkvlene, C2-C3 alkenylene, -0-, -ΝΗ-, -CH₂C(0)-, -C(0)NH-, -C(0)NR⁶-, - ί i i ( (O)N i -CH2C(0)N ⁶-,-S(0)_n-₅ -S(0)nNH-, or -S(0)nNR⁶-. In another embodiment, L⁴ and L³ is each independently selected from a bond, C 1-C3 alkvlene, C2-C3 alkenylene, -

[23] In one embodiment, L⁴ of formula (I) is -CH2-.

[24] In one embodiment, L³ of formula (1) is a bond.

[25] In one embodiment, X of formula (I) is absent, C1-C3 alkvlene, divalent C3-C6 cycloalkyl, divalent phenyl, divalent 5-6 membered heterocycloalkyl, or divalent 5-6 membered heteroaryl, wherein each of cycloalkyl, phenyl, heterocycloalkyl, or heteroaiyl is optionally substituted with one or more R⁵. In one embodiment, X is absent. In another embodiment, X is C1-C3 alkvlene.

[26] In one embodiment, X of formula (I) is divalent C3-C6 cycloalkyl, divalent phenyl, divalent 5-6 membered heterocycloalkyl, or divalent 5-6 membered heteroaryl, wherem wherein each of cycloalkyi, phenyl heterocycloalkyl, or heteroaiyl is optionally substituted with one or more R⁵. In another embodiment, X is selected from divalent phenyl, divalent oxadsazole, divalent ssoxazole, divalent oxazole, or divalent tlisazole; wherein each of which elected from

wherein each of which are optionally substituted with one or more R⁵.

[27] In one embodiment, X of formula (I) is unsubstituted.

[28] In one embodiment, Y of formula (I) is C3-C6 cycloalkyi, phenyl, 5-6 membered heterocycloalkyl, or 5-10 membered heteroaryl, wherein Y is optionally substituted with one or more R⁵. In another embodiment, Y is phenyl or 5-10 membered heteroaiyl, wherein Y is optionally substituted with one or more R⁵. In one embodiment, Y is phenyl optionally substituted with one or more R³. In some embodiments, Y is 5-6 membered heteroaryl optionally substituted with one or more R⁵. In one embodiment, Y is selected from thiophenyl or isoxazolyl, each of which are optionally substituted with one or more R\

[29] In one embodiment, Y of formula (1) is 9-10 membered bicyclic heteroaryl optionally substituted with one or snore R⁵, In another embodiment, Y is benzoimidazole or benzothiazole, each of which is optionally substituted with one or more R⁵.

[30] In one embodiment of formula (I), X is C1-C3 aikylene, divalent C3-C6 cycloalkyi, divalent phenyl, divalent 5-6 membered heterocycloalkyl, or divalent 5-6 membered heteroaryl, wherein each of cycloalkyi, phenyl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more R³; and Y is C3-C6 cycloalkyi, phenyl, 5-6 membered heterocycloalkyl, or 5-10 membered heteroaiyl, wherein Y is optionally substituted with one or more R⁵.

[31 ] In one embodiment of formula (I), R⁵ is selected from I, Br, CI, F, -CN, R⁶, -

[32] In one embodiment, -L⁴-X-L⁵- of formula (I) is -CH2-. In another embodiment, -L⁴- X-l is \Η(( Η ·) ·0

In one embodiment, R^{1 !} and R¹² of formula (I) are each independently selected from H, I, Br, CI, F, -SH₅ -S-alkyl, -Oi l, -O-alkyl, -NH2, -NH-alkyl, or -NR⁴R⁴. In another embodiment, R^u and Rⁱ² are each independently selected from H, Ci, -S-alkyl, or -NR⁴R⁴.

[33] in one embodiment, R¹³ of formula (I) is H. [34] In one embodiment, compounds of formula (I) has the structure of formula (Γ):

O

R¹³ (Γ)

[35] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[36] L⁴ and \? are each independently selected from a bond, C 1-C3 alkylene, C2-C3 aikenylene, -0-, -NH-, -CH₂C(()h -C(0)NH-, -C(0)NR⁶-, -CH₂C(0)NH-, -CH₂C(0)NR⁶-,- S(0)n-, -S(0)nNH-, or -S(0)nNR⁶-;

[37] X is a divalent cycloalkvi, divalent aryl, divalent heterocycloalkyl, or divalent monocyclic heteroaryl, wherein cycloalkvi, aryl, heterocycloalkyl, or heteroarv'i is optionally substituted with one or more R⁵;

[38] Y is cycloalkvi, aryl, heterocycloalkyl, or heteroaryl, wherein Y is optionally substituted with one or more R^s;

[39] R^{! !}, R^{1 2}, and R^!3 are each independently selected from H, I, Br, CI, F, -CN, alkyl, haloalkyl -SH, -S-alkyi, -OH, -Q-aikyl, -NH2, -NHR⁴, -NR⁴R⁴, or -NO2; or

[40] R⁴ is each independently H, alkyl, aryl, arylalkyl, aryloxyalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, or heteroaryloxyalkyl, wherein each R⁴ is optionally substituted with one or more R³;

[41] ir is each independently I, Br, CI, F, -CN, -CONH2, -CONHR⁶, -CONR⁶R⁶, -COOH, -NH2, -NHR⁶, -NO2, -NR⁶R⁶, -OH, -OR⁶, -COOR⁶, -OSO3R⁶, oxo, R⁶, -SH, -SO2R⁶, -SO 1 1. - SO3R⁶, -S(0)nNH2, -S(0)nNHR⁶, -S(0)„NR⁶R⁶, or -SR⁶;

[42] R⁶ is each independently alkyl or cycloalkvi:

[43] n is 0, 1, or 2: and

[44] wherein X is not divalent oxadiazolyl or divalent pyrazolyl;

[45] wherein Y is not pyridyl of tetrahydrofuranyl; and

[46] wherein the compound is not 4,5-dichloro-2-((5-(thiophen-2-yl)isoxazol-3- yl)methyl)pyridazin-3 (2H)-one .

[47] In one embodiment, L⁴ of formula (Γ) is a bond or -CH2-.

[48] In one embodiment, V of formula (Γ) is a bond or -S(0)»NR⁶-

[49] In one embodiment, X of formula (Γ) is phenyl or 5-6 membered heteroaryl, which are optionally substituted with R⁵.

[50] In one embodiment, Y of formula (Γ) is phenyl or 5-6 membered heteroaryl, which are optionally substituted with R⁵.

[51] In one embodiment, R³ of formula (Γ) is I, Br, CI, F or methyl.

[52] In one embodiment, R¹¹ and R^!2 of formula (Γ) are each independently selected from

H, CI, -S-alkyl, or -NR⁴R .

[53] In one embodiment, R^l3 of formula (Γ) is H.

[54] In one embodiment, compounds of formula (I) has the structure of formula (Γ'):

[55] or a pharmaceutically acceptable salt or solvate thereof, wherein ;

[56] -L⁴-X-L⁵ is a bond or C 1-C3 alkyiene;

[57] Y is cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, wherein Y is optionally substituted with one or more R³;

[58] R^{! !}, R^{1 2}, and R^!3 are each independently selected from H, I, Br, CI, F, -CN, alkyl, haloalkyl, -SH, -S-alkyl, -OH, -O-aikyl, -NH₂, -NHR⁴, -NR⁴R⁴, or -NO2; or

[59] R⁴ is each independently H, alkyl, aryl, arylalkyl, aryloxyalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, or heteroaryloxyalkyl, wherein each R⁴ is optionally substituted with one or more R³;

[60] ir is each independently I, Br, CI, F, -CN, -CONH2, -CONHR⁶, -CONR⁶R⁶, -COOH, -NH2, -NHR⁶, -NO2, ~NR⁶R⁶, -OH, -OR⁶, -COOR⁶, -OSO3R⁶, oxo, R⁶, -SH, -SO2R⁶, -SO 1 1. - SO3R⁶, -S(0)nNH2, -S(0)nNHR⁶, -S(0)„NR⁶R⁶, or -SR⁶;

[61] R⁶ is each independently alkyl or cycloalkyl:

[62] n is 0, 1, or 2: and

[63] provided that when L⁴ and L⁵ are each a bond and X is absent, then Y is not unsubstituted phenyl, phenyl substituted with alkyl, halogen or -COOH, or Y is not cycloalkyl or thiazoly 1;

[64] provided that when -L ~X~L⁵- is -CH2-, then Y is not phenyl, pryidyl, thiophenyl, thiadiazolyl, dioxolanone, pyrazolyl or oxiranyl;

[65] wherein Y is not pyridyl of tetrahydrofuranyl; and

[66] wherein the compound is not 2-((4,5-dichloro-6-oxopyridazin-l(6H)-yl)methyl)-l- ethy]-NN-dimethyl-lH-benzo[i ]imidazole-6-sulfonamide.

[67] In one embodiment, Y of formula (I") is phenyl or heteroaryl, wherein Y is optionally substituted with one or more R³. In another embodiment, Y is phenyl substituted with -

S(0)JINH2 and optionally substituted with one or more R⁵. In some embodiments, Y is 5-6 membered heteroaryl, wherein Y is optionally substituted with one or more R⁵.

[68] In one embodiment, R⁵ is of formula (I") is I, Br, CI, F or methyl.

[69] In one embodiment, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and a compound of formula (I):

[70] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[71] L⁴ and L³ are each independently selected from a bond, alkylene, alkenylene, -0-, -

M l-. -N .'^' -. -\ ! !( ( ))-. -X R' ·(())-. -Π W (0)~. -C(0)NH-, -C(0)NR⁶-, ~CH₂C(0)NH-, -

CH₂C(0)NR⁶-, -S(0)_n-, -S(0)„NH-, -S(0)„NR⁶-, -NHS(0)n-, or - R⁶S(0)n-;

[72] X is absent, alkylene, alkenylene, divalent cycloalkyl, divalent aryl, divalent heterocycloalkvl, or divalent monocyclic heteroaryl, wherein cycloalkyl, aryl, heterocycloalkvl, or heteroaryl is optionally substituted with one or more R³;

[73] Y is cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, wherein Y is optionally substituted with one or more R⁵:

[74] R^{! i}, R^!2, and R^!3 are each independently selected from H, I, Br, CL F, CN, alkyl, haloalkyl, -SH, -S-alkyl, -OH, -O-alkyL -NFI2, -NHR⁴, -NR⁴R⁴, or -NO2; or

[75] R⁴ is each independently H, alkyl, aryl, arylalkyl, aryloxyalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, or heteroaiyloxyaikyl, wherein each R⁴ is optionally substituted with one or more R. ^':

[76] R⁵ is each independently I, Br, CI, F, -CN, -CONH2, -CONHR⁶, -CONR⁶R⁶, -COOH, -Nth, -NHR⁶, NO2, -NR⁶R⁶, -OH, -OR⁶, -COOR⁶, -OSO3R⁶, oxo, R⁶, -SH, -SO2R⁶, -SO3H, - SQ3R⁶, -S(0)nNH₂, -S(0)nNHR⁶, ~S(0)nNR⁶R⁶, or -SR.⁶:

[77] R⁶ is each independently alkyl or cycloalkyl;

[78] n is 0, 1, or 2; and

[79] provided that when L⁴ and L³ are each a bond and X is absent, then Y is not unsubstituted phenyl, phenyl substituted with alkyl, halogen or -COOH:

[80] provided that when -L⁴~X~L³- is -CH2-, then Y is not phenyl, pryidyl, or thiophenyl;;

[81] wherein Y is not pyridyl; and [82] wherein the compound is not 4,5-dichloro-2-((5-(thiophen-2-yl)isoxazol-3- yl)methyl)pyridazin-3(2H)-one or 2-((4,5-dichloro-6-oxopyridazin-l(6H)-yl)methyl)-l-ethyl-

NN-dimethyl-lH-benzo[rf]imidazole-6-sijlfonamide.

[83] In one embodiment of the pharmaceutical composition described herein comprising a compound of formula (I), L⁴ and L³ are each independently selected from a bond, C 1-C3 alkylene, C2-C3 alkenylene, -0-, -ΝΗ-, -CHiCiQ)-, -C(0)NH-, -C(0)NR⁶-, -CH2C(0)NH-, - CH2C(0)NR⁶-,-S(0)_a-, -S(0)nNH-, or -S(G)_ANR⁶-. In another embodiment, L⁴ and L⁵ is each independently selected from a bond, C1-C3 alkylene, C2-C3 alkenylene, -0-, -NH-, or -

[84] In one embodiment of the pharmaceutical composition described herein comprising a compound of formula (I), L⁴ of formula is -CH2-.

[85] In one embodiment of the pharmaceutical composition described herein comprising a compound of formula (I), L⁵ is a bond.

[86] In one embodiment of the pharmaceutical composition described herein comprising a compound of formula (I), X is absent, C1-C3 alkylene, divalent C3-C6 cycloalkyi, divalent phenyl, divalent 5-6 membered heterocycloalkyl, or divalent 5-6 membered heteroaryl, wherein each of cycloalkyi, phenyl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more R⁵. In one embodiment, X is absent. In another embodiment, X is C1-C3 alkylene.

[87] In one embodiment of the pharmaceutical composition described herein comprising a compound of formula (I), X is divalent C3-C6 cycloalkyi, divalent phenyl, divalent 5-6 membered heterocycloalkyl, or divalent 5-6 membered heteroarv'l, wherein wherein each of cycloalkyi, phenyl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more R⁵. In anotlier embodiment, X is selected from divalent phenyl, divalent oxadiazoie, divalent isoxazole, divalent oxazole, or divalent thiazole; wherein each of which are optionally

wherein each of which are optionally substituted with one or more R⁵.

[88] In one embodiment of the pharmaceutical composition described herein comprising a compound of formula (I), X is unsubstituted.

[89] In one embodiment of the pharmaceutical composition described herein comprising a compound of formula (I), Y is C3-C6 cycloalkyi, phenyl, 5-6 membered heterocycloalkyl, or 5-10 membered heteroaiyl, wherein Y is optionally substituted with one or more R⁵. In another embodiment, Y is phenyl or 5-10 membered heteroaiyl, wherein Y is optionally substituted with one or more R⁵. In one embodiment, Y is phenyl optionally substituted with one or more R³. In some embodiments, Y is 5-6 membered heteroaiyl optionally substituted with one or more R⁵. In one embodiment, Y is selected from thiophenyl or isoxazolyl, each of which are optionally substituted with one or more R:\

[90] In one embodiment of the pharmaceutical composition described herein comprising a compound of formula (I), Y is 9- 10 membered bicyclic heteroaiyl optionally substituted with one or more R³. In another embodiment, Y is benzoimidazole or benzothiazole, each of which is optionally substituted with one or more R⁵,

[91] In one embodiment of the pharmaceutical composition described herein comprising a compound of formula (I), X is C 1-C3 aikylene, divalent C3-C6 cycloalkyi, divalent phenyl, divalent 5-6 membered heterocycloalkyl, or divalent 5-6 membered heteroaryl, wherein each of cycloalkyi, phenyl, heterocycloalkyl, or heteroaiyl is optionally substituted with one or more R³; and Y is C3-C6 cycloalkyi, phenyl, 5-6 membered heterocycloalkyl, or 5-10 membered heteroaryl, wherein Y is optionally substituted with one or more R⁵.

[92] In one embodiment of the pharmaceutical composition described herein comprising a compound of formula (I), R³ is selected from I, Br, CI, F, -CN, R⁶, -S(0)nNH2.

[93] In one embodiment of the pharmaceutical composition described herein comprising a compound of formula (I), -L⁴-X-L⁵- is -CH2-, In another embodiment, -L -X-L⁵- is -

\ 1 Ι! ( Ή ·) ·0 .

[94] In one embodiment of the pharmaceutical composition described herein comprising a compound of formula (I), R¹¹ and R¹² are each independently selected from H, 1, Br, CI, F, - SH, -S-alkyl, -OH, -O-alkyl, -NH2, -NH-alkyl, or -NR⁴R⁴. In another embodiment, R^u and R^!2 are each independently selected from H, CI, -S-alkyl, or - R⁴R⁴.

[95] In one embodiment of the pharmaceutical composition described herein comprising a compound of formula (I), R ^: is 1 1

[96] In one embodiment, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and a compound of formula (Γ):

[97] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[98] L⁴ and L⁵ are each independently selected from a bond, C1-C3 alkylene, C2-C3 alkenylene, -0-, -NH-, -CH₂C(0)-, ~C(0)NH~, -C(0)NR⁶-, -CH₂C(0)NH-, ~CH₂C(0)NR⁶-,- S(0)n-, -S(0)nNH-, or -S(0)«NR⁶-;

[99] X is a divalent cycioaikyl, divalent aiyl, divalent heterocycloalkyi, or divalent monocyclic heteroaryl, wherein cycioaikyl, aryl, heterocycloalkyi, or heteroaryl is optionally substituted with one or more R⁵;

[100] Y is cycioaikyl, aryl, heterocycloalkyi, or heteroaryl, wherein Y is optionally substituted with one or more R³:

[101] R^{! !}, R¹², and R¹³ are each independently selected from H, I, Br, CI, F, -CN, alkyl, haloalkyl, -SH, -S-alkyl, -OH, -O-alkyl, -NH₂, -NHR⁴, -NR⁴R⁴, or -NO2; or

[102] R⁴ is each independently H, alkyl, aryl, arylalkyi, aryloxyalkyl, heterocycloalkyi, heteroaryl, heteroarylalkyl, or heteroaryloxyalkyl, wherein each R⁴ is optionally substituted with one or more R⁵;

[103] R⁵ is each independently I, Br, CI, F, -CN, -CONH2, -CONFIR⁶, -CON ⁶R⁶, -COOFI,

-NH2, -NHR⁶, -\0 ·. -NR⁶R⁶, -OH, -O ⁶, -COOR⁶, -QSG3R⁶, oxo, R⁶, -SH, -SO2R⁶, -SO3H, -

SO3R⁶, ~S(0)nNH₂, ~S(0)nNHR⁶, -S(0)nNR⁶R⁶, or -SR.⁶:

[104] R⁶ is each independently alkyl or cycioaikyl:

[105] n is 0, 1, or 2: and

[106] wherein Y is not pyridyl; and

[107] wherein the compound is not 4,5-dichloro-2-((5-(tliiophen-2-y])isoxazo]-3- yl)methy l)pyridazin-3 (2H)-one .

[108] In one embodiment of the pharmaceutical composition described herein comprising a compound of formula (Γ), L⁴ is a bond or -CH₂~.

[109] In one embodiment of the pharmaceutical composition described herein comprising a compound of formula (Γ), L⁵ is a bond or -S(0)nNR⁶-

[110] In one embodiment of the pharmaceutical composition described herein comprising a compound of formula (Γ), X is phenyl or 5-6 membered heteroaryl, which are optionally substituted with R⁵. [1111 I^{n one} embodiment of the pharmaceutical composition described herein comprising a compound of formula (Γ), Y is phenyl or 5-6 membered heteroaryl, which are optionally substituted with R⁵.

[112] In one embodiment of the pharmaceutical composition described herein comprising a compound of formula (Γ), R⁵ is I, Br, CI, F or methyl.

[113] In one embodiment of the pharmaceutical composition described herein comprising a compound of formula (Γ), Rⁿ and R¹² are each independently selected from H, CI, -S-alkyl, or -NR⁴R⁴.

[114] In one embodiment of the pharmaceutical composition described herein comprising a compound of formula (Γ), R^1J is H.

[115] In one embodiment, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and a compound of formula (Γ):

[1 6] or a pharmaceutically acceptable salt or solvate thereof, wherein ;

[117] -L⁴-X-L⁵ is a bond or C1-C3 alkyiene;

[118] Y is cycloalkyi, aryl, heterocycloalkyi, or heteroaryl, wherein Y is optionally substituted with one or more R⁵;

[119] R^{! !}, R^{1 2}, and R¹³ are each independently selected from H, I, Br, CI, F, -CN, alkyl, haloalkyl, -SH, -S-alkyl, -OH, -Q-aikyl, -NH2, -NHR⁴, -NR⁴R⁴, or -NO2: or

[120] R⁴ is each independently H, alkyl, aryl, arylalkyl, aryloxyalkyl, heterocycloalkyi, heteroaryl, heteroarylalky], or heteroaryloxyalkyl, wherein each R⁴ is optionally substituted with one or more R³;

[121] R⁵ is each independently I, Br, CI, F, -CN, -CQNH2, -CQNHR⁶, -CONR⁶R⁶, -COOH, -NH2, -NHR⁶, -NO2, -NR⁶R⁶, -OH, -OR⁶, -COOR⁶, -OSO3R⁶, oxo, R⁶, -SH, -SO2R⁶, -SO3H, - SO3R⁶, -S(0)nNH2, -S(0)nNHR⁶, -S(0)n R⁶R⁶, or -SR⁶;

[122] R⁶ is each independently alkyl or cycloalkyi:

[123] n is 0, 1, or 2: and

[124] provided that when L⁴ and L⁵ are each a bond and X is absent, then Y is not unsubstituted phenyl, phenyl substituted with alkyl, halogen or -COOH; [125] provided that when ~-L⁴-X-L³- is -CH2-, then Y is not phenyl, pryidyl, or thiophenyi:;

[126] wherein Y is not pyridyl; and

[127] wherein the compound is not 2-((4,5-dichloro-6-oxopyridazin-l(6H)-yl)methyl)-l- ethyl-N,N-dimethyl-lH-benzo[i ]imidazole-6-sulfonan ide.

[128] In one embodiment of the pharmaceutical composition described herein comprising a compound of formula (I"), Y is phenyl or heteroaiyl, wherein Y is optionally substituted with one or more R⁵. In another embodiment, Y is phenyl substituted with -S(0)nNH2 and optionally substituted with one or more R³, In some embodiments, Y is 5-6 membered heteroaiyl, wherein Y is optionally substituted with one or more R⁵.

[129] In one embodiment of the pharmaceutical composition described herein comprising a compound of formula (I"), R³ is I, Br, CI, F or methyl.

[130] In another embodiment, the pharmaceutical composition comprising a compound of formula (I), (Γ), or (I"), or a pharmaceutically acceptable salt or solvate thereof further comprises one additional therapeutically active agent.

[131] In one embodiment of the present disclosure, a method of modulating a Parkin ligase is provided, comprising administering to a subject in need thereof an effective amount of a compound of fonnula (I):

[132] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[133] L⁴ and L⁵ are each independently selected from a bond, alkylene, alkenylene, -0-, -

NH-, -NR⁶-, -M !( · {))·. -NR '^''(^'( (>)·-. ··( ! !■( (())·. -C(0)NH-, -C(0)NR⁶-, -CI 1.>(^'{ί> ·\! ! ·. -

CH₂C(0)NR⁶-, -S(0)n-, -S(0)nNH-, -S(G)nNR⁶-, -NHS(0)n-, or -NR⁶S(0)„~:

[134] X is absent, alkylene, alkenylene, divalent cycloalkyl, divalent aryl, divalent heterocycloalkyl, or divalent monocyclic heteroaiyl, wherein cycloalkyl, aryl, heterocycloalkyl, or heteroaiyl is optionally substituted with one or more R³;

[135] Y is cycloalkyl, aryl, heterocycloalkyl, or heteroaiyl, wherein Y is optionally substituted with one or more R³;

[136] R^{1 1}, Rⁱ², and Rⁱ³ are each independently selected from H, I, Br, CI, F, CN, alkyi, haloalkyl, ~SH, -S-alkyl, -OH, -O-alkyl, - H2, -NHR⁴, -NR⁴R⁴, or -NO2; or

[137] R⁴ is each independently H, alkyl, aryl, arylalkyl, aryloxyalkyl, heterocycloalkyl, heteroaiyl, heteroarylalkyl, or heteroaryloxyaikyl, wherein each R⁴ is optionally substituted with one or more ³;

[1381 R⁵ is each independently L Br, CI, F, -CN, -CONH2, -CONHR⁶, -CONR⁶R⁶, -CQGH, -NH2, - HR⁶, O2, -NR⁶R⁶, -OH, -OR⁶, -COOR⁶, -OSO3R⁶, oxo, R⁶, -SH, -SO2R⁶, -SO3H, - SO3R⁶, -S(0)nNH2, -S(0)nNHR⁶, -S(0)n R⁶R⁶, or -SR⁶;

[139] R⁶ is each independently alkyl or cycloalkyl: and

[140] n is O, L or 2.

[141] In one embodiment, the method disclosed herein comprises administering to a subject a compound of formula (I), L⁴ and L³ are each independently selected from a bond, C1-C3 alkylene, C2-C3 alkenylene, -0-, -NH-, -CH_C(0)-, -C(0)NH-₅ -C(())NR⁶-, -CH2C(0)NH-, - CH2C(0)NR⁶-,-S(0)n-, -S(0)nNH-, or -S(0)nNR⁶-. In another embodiment, L⁴ and L⁵ is each independently selected from a bond, C1-C3 alkylene, C2-C3 alkenylene, -0-, -NH-, or - S(0)„NH-.

[142] In one embodiment, the method disclosed herein comprises administering to a subject a compound of formula (I), L⁴ is -CH2-.

[143] In one embodiment, the method disclosed herein comprises administering to a subject a compound of formula (I), L³ is a bond.

[144] In one embodiment, the method disclosed herein comprises administering to a subject a compound of formula (I), X is absent, C1 -C3 alkylene, divalent C3-C6 cycloalkyl, divalent phenyl, divalent 5-6 membered heterocycloalkyl, or divalent 5-6 membered heteroaryl, wherein each of cycloalkyl, phenyl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more R⁵. In one embodiment, X is absent. In another embodiment, X is C1-C3 alkylene.

[1451 I^{n one} embodiment, the method disclosed herein comprises administering to a subject a compound of formula (I), X is divalent C3-C6 cycloalkyl, divalent phenyl, divalent 5-6 membered heterocycloalkyl, or divalent 5-6 membered heteroaryl, wherein wherein each of cycloalkyl, phenyl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more R³. In another embodiment, X is selected from divalent phenyl, divalent oxadiazole, divalent isoxazole, divalent oxazole, or divalent thiazole; wherein each of which are optionally substituted with one or more R⁵. In one embodiment, X is selected from

wherein each of which are optionally substituted with one or more R⁵. [146] In one embodiment, the method disclosed herein comprises administering to a subject a compound of formula (I), X is unsubstituted.

[147] In one embodiment, the method disclosed herein comprises administering to a subject a compound of formula (I), Y is C3-C6 cycloalkyl, phenyl, 5-6 membered heterocycloalkyl, or 5-10 membered heteroaryl, wherein Y is optionally substituted with one or more R³. In another embodiment, Y is phenyl or 5-10 membered heteroaryl, wherein Y is optionally substituted with one or more R⁵. In one embodiment, Y is phenyl optionally substituted with one or more R⁵. In some embodiments, Y is 5-6 membered heteroaryl optionally substituted with one or more R⁵. In one embodiment, Y is selected from thiophenyl or isoxazolyl, each of which are optionally substituted with one or more R⁵.

[148] In one embodiment, the method disclosed herein comprises administering to a subject a compound of formula (I), Y is 9-10 membered bicyclic heteroaryl optionally substituted with one or more R⁵. In another embodiment, Y is benzoimidazole or benzothiazole, each of which is optionally substituted with one or more R^b.

[149] In one embodiment, the method disclosed herein comprises administering to a subject a compound of formula (I), X is C 1-C3 alkyiene, divalent C3-C6 cycloalkyl, divalent phenyl, divalent 5-6 membered heterocycloalkyl, or divalent 5-6 membered heteroaryl, wherein each of cycloalkyl, phenyl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more R⁵; and Y is C3-C6 cycloalkyl, phenyl, 5-6 membered heterocycloalkyl, or 5-10 membered heteroaryl, wherein Y is optionally substituted with one or more R⁵.

[150] In one embodiment, the method disclosed herein comprises administering to a subject a compound of formula (I), R⁵ is selected from ΐ, Br, CI, F, -CN, R⁶, -S(0)nNH2.

[151 ] In one embodiment, the method disclosed herein comprises administering to a subject a compound of formula (I), -L⁴-X-L⁵- is -CH2-. In another embodiment, -L⁴-X-L⁵- is -

ΝΊ ΗΟ ί.Ή⁾ .

[152] In one embodiment, the method disclosed herein comprises administering to a subject a compound of formula (I), R^{! 1} and R¹² are each independently selected from H, I, Br, CI, F, - SH, -S-alkyl, -OH, -O-alkyl, -NH2, -NH-alkyl, or -NR⁴R⁴. In another embodiment, R^{! !} and R¹² are each independently selected from H, CI, -S-alkyl, or -NR⁴R⁴.

[153] In one embodiment, the method disclosed herein comprises administering to a subject a compound of formula (I), R^1J is H.

[154] In one embodiment of the present disclosure, a method of modulating a Parkin ligase is provided, comprising administering to a subject in need thereof an effective amount of a compound of formula (Γ):

[155] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[156] L⁴ and L⁵ are each independently selected from a bond, C1-C3 alkylene, C2-C3 alkenylene, -0-, -NH-, -CH₂C(0)-, ~C(0)NH~, -C(0)NR⁶-, -CH₂C(0)NH-, ~CH₂C(0)NR⁶-,- S(0)n-, -S(0)nNH-, or -S(0)nNR⁶-;

[157] X is a divalent cycioaikyl, divalent aryl, divalent heterocycloalkyi, or divalent monocyclic heteroaryl, wherein cycioaikyl, aryl, heterocycloalkyi, or heteroaiyl is optionally substituted with one or more R⁵;

[158] Y is cycioaikyl, aryl, heterocycloalkyi, or heteroaryl, wherein Y is optionally substituted with one or more R³:

[159] R^{1 1}, R¹², and R¹³ are each independently selected from H, I, Br, CI, F, -CN, alkyl, haloalkyl, -SH, -S-alkyl, -OH, -O-alkyl, -NH₂, -NHR⁴, -NR⁴R⁴, or -NO2; or

[160] R⁴ is each independently H, alkyl, aryl, arylalkyi, aryloxyalkyl, heterocycloalkyi, heteroaiyl, heteroarylalkyl, or heteroaryloxyalkyl, wherein each R⁴ is optionally substituted with one or more R⁵;

[161 ] R⁵ is each independently I, Br, CI, F, -CN, -CONFI₂, -CONFIR⁶, -CON ⁶R⁶, -COOH, -NH2, -NHR⁶, -\0 ·. -NR⁶R⁶, -OH, -OR⁶, -COOR⁶, -QSG3R⁶, oxo, R⁶, -SH, -SO2R⁶, -SO3H, - SO3R⁶, ~S(0)nNH₂, ~S(0)nNHR⁶, -S(0)nNR⁶R⁶, or -SR.⁶:

[162] R⁶ is each independently alkyl or cycioaikyl: and

[163] n is 0, 1, or 2.

[164] In one embodiment, the method disclosed herein comprises administering to a subject a compound of formula (Γ), L⁴ of formula (Γ) is a bond or -CH2-.

[165] In one embodiment, the method disclosed herein comprises administering to a subject a compound of formula (Γ), L³ of formula (Γ) is a bond or -S(0)r.NR⁶-

[166] In one embodiment, the method disclosed herein comprises administering to a subject a compound of formula (Γ), X of formula (Γ) is phenyl or 5-6 membered heteroaiyl, which are optionally substituted with R⁵.

[167] In one embodiment, the method disclosed herein comprises administering to a subject a compound of formula (Γ), Y of formula (Γ) is phenyl or 5-6 membered heteroaiyl, which are optionally substituted with R⁵. [168] In one embodiment, the method disclosed herein comprises administering to a subject a compound of formula (Γ), R⁵ of formula (Γ) is I, Br, CI, F or methyl.

[169] In one embodiment, the method disclosed herein comprises administering to a subject a compound of formula (Γ), R^{1 1} and R¹² of formula (Γ) are each independently selected from H, CI, -S-alkyl, or -NR⁴R⁴.

[170] In one embodiment, the method disclosed herein comprises administering to a subject a compound of formula (Γ), R of formula (Γ) is H,

[171] In one embodiment of the present disclosure, a method of modulating a Parkin ligase is provided, comprising administering to a subject in need thereof an effective amount of a compound of formula (!"):

[172] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[173] -L⁴-X-L⁵ is a bond or CI-C3 alkyiene;

[174] Y is cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, wherein Y is optionally substituted with one or more R⁵;

[175] R¹¹, R¹², and R¹³ are each independently selected from H, I, Br, CI, F, -CN, alkyl, haloalkyl, -SI I. -S-alkyl, -OH, -O-alkyl, -\! ί ·. -NHR⁴, -S R 'R '. or -NO:: or

[176] R⁴ is each independently H, alkyl, aryl, arylalkyl, aryloxyalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, or heteroaryloxyalkyl, wherein each R⁴ is optionally substituted with one or more R⁵;

[177] R⁵ is each independently I, Br, CI, F, -CN, -CONHz, -CONUR⁶, -CONR⁶R⁶, -COOH, - I-I2, -NHR⁶, -NO2, -NR⁶R⁶, -OH, -OR⁶, -COOR⁶, -OSO3R⁶, oxo, R⁶, -SH, -SO2R⁶, -SO3H, - SO3R⁶, -S(0)nNH2, -S(0)nNHR⁶, -S(0),,NR⁶R⁶, or -SR⁶;

[178] R⁶ is each independently alkyl or cycloalkyl; and

[179] n is 0, 1, or 2.

[180] In one embodiment, the method disclosed herein comprises administering to a subject a compound of formula (I"), Y is phenyl or heteroaryl, wherein Y is optionally substituted with one or more R⁵. In another embodiment, Y is phenyl substituted with -S(0)nNH2 and optionally substituted with one or more R⁵. In some embodiments, Y is 5-6 membered heteroaryl, wherein Y is optionally substituted with one or more R⁵. [181] In one embodiment, the method disclosed herein comprises administering to a subject a compound of formula (I"), R⁵ is I, Br, CI, F or methyl.

[182] In another embodiment of the present disclosure, a method of treating a disease or a condition is provided comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I):

[183] or a pharmaceutically acceptable salt or solvate thereof, wherein :

[184] L⁴ and L³ are each independently selected from a bond, alkylene, alkenylene, -0-, -

NH-, -NR.⁶-, -NHC(O)-, -NR⁶C(0)-, -CH₂C(0)-, -C(0)NH-, -C(())NR⁶-, --(^'I K (O)NH-. -

CH₂C(0)NR⁶-, -S(0)n-, -S(0)nNH-₅ -S(0)nNR⁶-, -NHS(Q)n-, or -NR⁶S(G)„-;

[185] X is absent, alkylene, alkenylene, divalent cycloalkyl, divalent aryl, divalent heterocycloalkyl, or divalent monocyclic heteroaryl, wherein cycloalkyl, aryl, heterocycloalkyi, or heteroaryl is optionally substituted with one or more R⁵:

[186] Y is cycloalkyl, aryl, heterocycloalkyi, or heteroaryl, wherem Y is optionally substituted with one or more R⁵;

[187] R¹¹, R^!2, and R^!3 are each independently selected from H, I, Br, CI, F, CN, alkyl, haloalkyl, -SH, -S-alkyi, -OH, -O-alkyl, -NH2, -NHR⁴, -NR⁴R⁴, or -NO -: or

[188] R⁴ is each independently H, alkyl, aryl, arylalkyl, aryloxyalkyl, heterocycloalkyl, heteroaryl, heteroan'ialkyl, or heteroaryloxyalkyl, wherein each R⁴ is optionally substituted with one or more R⁵;

[189] R⁵ is each independently 1, Br, CI, F, -CN, -CONH2, -CQNHR⁶, -CQNR⁶R⁶, -COOH, -ΝΉ2, -NHR.⁶, NO2, -NR.⁶R⁶, -OH, -OR⁶, -COOR⁶, -OSO3R.⁶, oxo, R⁶, -SH, -SO2R⁶, -SO3H, - SO3R⁶, -S(0)nNH₂, -S(0)nNHR⁶, -S(0),,NR⁶R⁶, or -SR⁶;

[190] R⁶ is each independently alkyl or cycloalkyl; and

[191] n is 0, 1, or 2;

[192] wherein the disease or the condition is selected from the group consisting of cancer, neurological disease, a disorder characterized by abnormal accumulation of -synuclein, a disorder of an aging process, cardiovascular disease, bacterial infection, viral infection, mitochondrial related disease, mental retardation, deafness, blindness, diabetes, obesity, autoimmune disease, glaucoma, Leber's Hereditary Optic Neuropathy, and rheumatoid arthritis. [193] In another embodiment of the present disclosure, a method of treating a disease or a condition is provided comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (Γ):

[194] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[195] L⁴ and V are each independently selected from a bond, C1-C3 alkylene, C2-C3 alkenylene, -0-, -Ni k -CH₂C(0)-, -C(0)NH-, -C(0)NR⁶-, -CH₂C(Q)NH~, -CH₂C(Q)NR⁶-,~ S(0)„-, -S(0)nNH-₅ or -S(0)nNR⁶-;

[196] X is a divalent cycloalkyl, divalent aryl, divalent heterocycloalkyi, or divalent monocyclic heteroaryi, wherein cycloalkyl, aryi, heterocycloalkyi, or heteroaryi is optionally substituted with one or more R^s;

[197] Y is cycloalkyl, and, heterocycloalkyi, or heteroaryi, wherein Y is optionally substituted with one or more R⁵;

[198] R^{! !}, R¹², and R^!3 are each independently selected from H, I, Br, CL F, -CN, alkyl, haloalkyl, ~SH, -S-alkyl, -OH, -O-alkyl, -NH₂, -NHR⁴, -NR⁴R⁴, or -N0₂; or

[199[ R⁴ is each independently H, alkyl, and, arylalkyl, aiyloxyalkyl, heterocycloalkyi, heteroaryi, heteroarylalkyl, or heieroaryloxyaikyl, wherein each R⁴ is optionally substituted with one or more R⁵;

[200] R⁵ is each independently I, Br, CI, F, -CN, -CONFfc, -CONHR⁶, -CONR⁶R⁶, -COOH, -NH2, -NHR⁶, -NO2, -NR⁶R⁶, -OH, -OR⁶, -COOR⁶, -OSO3R⁶, oxo, R⁶, -SH, -S0₂R⁶, -SO3H, - SO3R⁶, -S(G)_nNH₂, -S(G)_nNHR⁶, -S(0)nNR⁶R⁶, or -SR⁶;

[201] R⁶ is each independently alkyl or cycloalkyl; and

[202] n is 0, l, or 2;

[203] wherein the disease or the condition is selected from the group consisting of cancer, neurological disease, a disorder characterized by abnormal accumulation of a-synuclein, a disorder of an aging process, cardiovascular disease, bacterial infection, viral infection, mitochondrial related disease, mental retardation, deafness, blindness, diabetes, obesity, autoimmune disease, glaucoma, Leber's Hereditary Optic Neuropathy, and rheumatoid arthritis.

[204] In another embodiment of the present disclosure, a method of treating a disease or a condition is provided comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (Γ):

[205] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[206] -L⁴-X-L³ is a bond or C 1 -C3 alkylene;

[207] Y is cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, wherem Y is optionally substituted with one or more R⁵;

[208] R^Li, R¹², and Rⁱ³ are each independently selected from H, I, Br, CI, F, -CN, alkyl, haloalkyl, -SH, -S-alkyi, -OH, -O-aikyl, -Nth, -NHR⁴, -NR⁴R⁴, or -NO2; or

[209[ R⁴ is each independently H, alkyl, aryl, arylalkyi, aryloxyalkyl, heterocycloalkyl, heteroaiyl, heteroaryl alkyl, or heteroaryloxyalkyl, wherein each R⁴ is optionally substituted with one or more R⁵;

[210] R⁵ is each independently 1, Br, CI, F, -CN, -CONH2, -CQNHR⁶, -CGNR⁶R⁶, -COOH, -NH2, -NHR⁶, -NO2, -NR⁶R⁶, -OH, -OR⁶, -COOR⁶, -OSO3R⁶, oxo, R⁶, -SH, -SO2R⁶, -SO3H, - SO3R⁶, -S(0)_aNH₂, -S(0)nNHR⁶, -S(0)nNR⁶R⁶, or -SR⁶;

[211] R⁶ is each independently alkyl or cycloalkyl; and

[212] n is 0, 1, or 2;

[213] wherein the disease or the condition is selected from, the group consisting of cancer, neurological disease, a disorder characterized by abnormal accumulation of cc-synuclein, a disorder of an aging process, cardiovascular disease, bacterial infection, viral infection, mitochondrial related disease, mental retardation, deafness, blindness, diabetes, obesity, autoimmune disease, glaucoma, Leber's Hereditary- Optic Neuropathy, and rheumatoid arthritis.

BRIEF DESCRIPTION OF THE FIGURES

[214] Figure 1 indicates that 4,5-dichloro-2-((5-(thiophen-2-yl)isoxazol-3- yl)methyl)pyridazin-3(2H)-one (Compound B) increases the Parkin Ligase reaction with the Activity-based Ubiquitin vinyl sulfone probe. [215] Figure 2 indicates that compound 4,5-dichloro-2-((5-(thiophen-2-yl)isoxazol-3- yl)methyl)pyridazinen-3(2H)~one (Compound B) increases Parkin activity in an auto- ubiquitination assay.

[216] Figure 3 shows mitophagy cell assay result for 4,5-dichloro-2-((5-(thiophen-2- yl)isoxazol-3-yl)me1hyl)pyridazinen-3(2H)-one (Compound B).

[217] Figure 4 indicates that 4,5-dichloro-2-((2-phenylthiazol-4-yl)methyl)pyridazin- 3(2H)-one (Compound G) increases the Parkin Ligase reaction with the Activity-based Ubiquitin vinyl sulfone probe.

[218] Figure 5 indicates that compound 4,5-dichloro-2-((2-phenylthiazol-4- yl)methyl)pyridazin-3(2H)-one (Compound G) increases Parkin activity in an auto- ubiquitination assay.

[219] Figure 6 shows mitophagy cell assay result for 4,5-dichloro-2-((2-phenylthiazol-4- yl)methyl)pyridazin-3(2H)-one (Compound G).

DETAILED DESCRIPTION

[220] All publications, patents and patent applications, including any drawings and appendices therein are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent or patent application, drawing, or appendix was specifically and individually indicated to be incorporated by reference in its entirety for ail purposes.

DEFINITIONS

[221] While the following terms are believed to be well understood by one of ordinary skill m the art, the following definitions are set forth to facilitate explanation of the presently disclosed subject matter.

[222] Throughout the present specification, the terms '"about^" and/or '"approximately" may^¬ be used in conjunction with numerical values and/or ranges. The term ^"'about" is understood to mean those values near to a recited value. For example, "about 40 [units]" may mean within ± 25% of 40 (e.g., from 30 to 50), within ± 20%, ± 15%, ± 10%, ± 9%, ± 8%, ± 7%, ± 6%, ± 5%, ± 4%, ± 3%, ± 2%, ± 1%, less than ± 1%, or any other value or range of values therein or therebelow. Furthermore, the phrases "less than about [a value]" or "greater than about [a value]" should be understood in view of the detinition of the term "about" provided herein. The terms "about" and "approximately" may be used interchangeably. [223] Throughout the present specification, numerical ranges are provided for certain quantities. It is to be understood that these ranges comprise all subranges therein. Thus, the range "from 50 to 80" includes all possible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values within a given range may be an endpoint for the range encompassed thereby (e.g., the range 50-80 includes the ranges with endpoints such as 55-80, 50-75, etc.).

[224] The term "a" or "an" refers to one or more of that entity; for example, "a kinase inhibitor" refers to one or more kinase inhibitors or at least one kinase inhibitor. As such, the terms "a" (or "an"), "one or more" and "at least one" are used interchangeably herein. In addition, reference to "an inhibitor" by the indefinite article "a" or "an" does not exclude the possibility that more than one of the inhibitors is present, unless the context clearly requires that there is one and only one of the inhibitors.

[225] As used herein, the verb "comprise" as is used in this description and in the claims and its conjugations are used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded. The present invention may suitably "comprise", "consist of, or "consist essentially of, the steps, elements, and/or reagents described in the claims.

[226] It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely", "only" and the like in connection with the recitation of claim elements, or the use of a "negative" limitation.

[227] The term "pharmaceutically acceptable salts" include those obtained by reacting the active compound functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Those skilled in the art will further recognize that acid addition salts may^¬ be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.

[228] The term "treating" means one or more of relieving, alleviating, delaying, reducing, reversing, improving, or managing at least one symptom of a condition in a subject. The term "treating" may also mean one or more of arresting, delaying the onset (i.e., the period prior to clinical manifestation of the condition) or reducing the risk of developing or worsening a condition. [229] An "effective amount" means the amount of a formulation according to the invention that, when administered to a patient for treating a state, disorder or condition is sufficient to effect such treatment. The "effective amount" will vary depending on the active ingredient, the state, disorder, or condition to be treated and its severity, and the age, weight, physical condition and responsiveness of the mammal to be treated.

[230] The term "therapeutically effective" applied to dose or amount refers to that quantity of a compound or pharmaceutical formulation that is sufficient to result in a desired clinical benefit after administration to a patient in need thereof.

[231 ] All weight percentages (i.e., "% by weight" and "wt. %" and w/w) referenced herein, unless otherwise indicated, are measured relative to the total weight of the pharmaceutical composition.

[232] As used herein, "substantially" or "substantial" refers to the complete or nearly complete extent or degree of an action, characteristic, property, state, structure, item, or result. For example, an object that is "substantially" enclosed would mean that the object is either completely enclosed or nearly completely enclosed. The exact allowable degree of deviation from absolute completeness may in some cases depend on the specific context. However, generally speaking, the nearness of completion will be so as to have the same overall result as if absolute and total completion were obtained. The use of "substantially" is equally applicable when used in a negative connotation to refer to the complete or near complete lack of action, characteristic, property, state, structure, item, or result. For example, a composition that is "substantially free of other active agents would either completely lack other active agents, or so nearly completely lack other active agents that the effect would be the same as if it completely lacked other active agents. In other words, a composition that is "substantially free of an ingredient or element or another active agent may still contain such an item, as long as there is no measurable effect thereof

[233] As used herein, the "alignment" of two or more protein/amino acid sequences may be performed using the alignment program C3ustalW2, available at www.ebi.ac.uk/Tools/msa/ciustalw2/. The following default parameters may be used for Pairwise alignment: Protein Weight Matrix = Gonnet; Gap Open = 10; Gap Extension = 0.1.

[234] "Ubiquitin Proteasome Pathway System (UPS)" as used herein relates to the ubiquitin proteasome pathway, conserved from yeast to mammals, and is required for the targeted degradation of most short-lived proteins in the eukaryotic cell Targets include cell cycle regulatory proteins, whose timely destruction is vital for controlled cell division, as well as proteins unable to fold properly within the endoplasmic reticulum. Ubiquitin modification is an ATP -dependent process carried out by three classes of enzymes. An "ubiquitin activating enzyme'¹ (El) forms a thio-ester bond with ubiquitin, a highly conserved 76-amino acid protein. This reaction allows subsequent binding of ubiquitin to a "ubiquitin conjugating enzyme" (E2), followed by the formation of an isopeptide bond between the carboxy- terminus of ubiquitin and a lysine residue on the substrate protein. The latter reaction requires a "ubiquitin ligase" (E3). E3 ligases can be single- or multi-subunit enzymes. In some cases, the ubiquitin-binding and substrate binding domains reside on separate polypeptides brought together by adaptor proteins or culling. Numerous E3 ligases provide specificity in that each can modify only a subset of substrate proteins. Further specificity is achieved by post- translational modification of substrate proteins, including, but not limited to, phosphorylation. Effects of monoubiquitination include changes in subcellular localization. However, multiple ubiquitination cycles resulting in a polyubiquitin chain are required for targeting a protein to the proteasome for degradation. The muitisubunit 26S proteasome recognizes, unfolds, and degrades polyubiquitinated substrates into small peptides. The reaction occurs within the cylindrical core of the proteasome complex, and peptide bond hydrolysis employs a core threonine residue as the catalytic nucleophile. It has been shown that an additional layer of complexity, in the form of multiubiquitin chain receptors, may lie between the polyubiquitination and degradation steps. These receptors react with a subset of polyubiquitinated substrates, aiding in their recognition by the 26S proteasome, and thereby promoting their degradation. This pathway is not only important in cellular homeostasis, but also in human disease. Because ubiquitin/proteasome-dependent degradation is often employed in control of the cell division cycle and cell growth, researchers have found that proteasome inhibitors hold some promise of being developed into potential cancer therapeutic agents.

[235] Protein degradation through the ubiquitin-proteasome system is the major pathway of non-lysosomal proteolysis of intracellular proteins. It plays important roles in a variety of fundamental cellular processes such as regulation of ceil cycle progression, division, development and differentiation, apoptosis, cell trafficking, and modulation of the immune and inflammatory responses. The central element of this system is the covalent linkage of ubiquitin to targeted proteins, which are then recognized by the 26S proteasome, an adenosine triphosphate-dependent, multi-catalytic protease. Damaged, oxidized, or misfolded proteins as well as regulatory proteins that control many critical cellular functions are among the targets of this degradation process. Aberration of this system leads to the dysregulation of cellular homeostasis and the development of multiple diseases (Wang et al. Cell Mol Immunol. 2006 Aug; 3(4):255-61).

[236] "Parkin ligase" or "Parkin" as used herein relates to a protein which in humans is encoded by the PARK2 gene. ( Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shirnizu N (April 1998). "Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism". Nature 392 (6676): 605-608. doi: 10.1038/33416. PMID 9560156. Matsumine I I. Yamamura Y, Hattori N, Kobayashi 1 . Kitada T, Yoritaka A, Mizuno Y (April 1998), "A microdeletion of D6S305 in a family of autosomal recessive juvenile parkinsonism (PARK2)". Genomics 49 (1): 143-146. doi: 10.1006/geno. l997.5196. PMID 9570960. The protein is a component of a multiprotein E3 ubiquitin ligase complex which in turn is part of the ubiquitin-proteasome system that mediates the targeting of proteins for degradation. Mutations in the PARK2 gene are known to cause a familial form of Parkinson's disease known as autosomal recessive juvenile Parkinson's disease (AR-JP).

[237] "Ligase" as used herein, is an enzyme that can catalyze the joining of two or more compounds or biomolecules by bonding them togetlier with a new chemical bond. The "ligation" of the two usually with accompanying hydrolysis of a small chemical group dependent to one of the larger compounds or biomolecules, or the enzyme catalyzing the linking togetlier of two compounds, e.g., enzymes that catalyze joining of groups C-O, C-S, C-N, etc. Ubiquitin-protein (E3) ligases are a large family of highly diverse enzymes selecting proteins for ubiquitination.

[238] "Ub Ligases" are involved in disease pathogenesis for oncology, inflammation & infectious disease. E3 ligase belonging to the RTNG-between-RING (RBR) family of E3 ligases containing both canonical RING domains and a catalytic cysteine residue usually restricted to HECT E3 ligases; termed 'RING HECT hybrid' enzymes. Mutations in Parkin linked to Parkinson's disease, cancer and mycobacterial infection. Parkin is recognized as a neuroprotective protein with a role in mitochondrial integrity . Human genetic data implicate loss of Parkin activity as a mechanism for pathogenesis of Parkinson's disease (PD).

[239] "Zinc Finger (ZnF) Domain" as used herein relates to a protein structure characterized by coordinating zinc ions to stabilize the functional activity. ZnF stabilize the binding of Ub, Deubiquitinating Enzymes (DUBs), and Ligases (E3) in the UPS.

[240] "Ligands" as used herein bind to metal via one or more atoms in the ligand, and are often termed as chelating ligands. A ligand that binds through two sites is classified as bidentate, and three sites as tridentate. The "bite angle" refers to the angle between the two bonds of a bidentate chelate. Chelating ligands are commonly formed by linking donor groups via organic linkers. A classic bidentate ligand is ethylenediamine, which is derived by the linking of two ammonia groups with an ethylene (-CH2CH2-) linker. A classic example of a polydentate ligand is the hexadentate chelating agent EDTA, which is able to bond through six sites, completely surrounding some rnetals. The binding affinity of a chelating system depends on the chelating angle or bite angle. Many ligands are capable of binding metal ions through multiple sites, usually because the ligands have lone pairs on more than one atom. Some ligands can bond to a metal center through the same atom but with a different number of lone pairs. The bond order of the metal ligand bond can be in part distinguished through the metal ligand bond angle (M~X~R). This bond angle is often referred to as being linear or bent with further discussion concerning the degree to which the angle is bent. For example, an imido ligand in the ionic form has three lone pairs. One lone pair is used as a sigma X donor, the other two lone pairs are available as L type pi donors. If both lone pairs are used in pi bonds then the M-N-R geometry is linear. However, if one or both of these lone pairs are non-bonding then the M-N-R bond is bent and the extent of the bend speaks to how much pi bonding there may be. It was found that few heteroatoms, such as nitrogen, oxygen, and sulfur atoms, interacted with zinc, ideal distances between the zinc and these heteroatoms were identified. Whereas carboxylates bound to the zinc via both monodentate and bidentate interactions, the hydroxamates bound dominantly in a bidentate manner. These results aid in the design of new inhibitors with the potential to interact with zinc in the target protein. Virtually every molecule and every ion can serve as a ligand for (or "coordinate to") metals. Monodentate ligands include virtually all anions and all simple Lewis bases. 11ms, the halides and pseudohalides are important anionic ligands whereas ammonia, carbon monoxide, and water are particularly common charge -neutral ligands. Simple organic species are also very common, be they anionic (RO^~ and RCO2^") or neutral (R2O, R2S, R3-xNHx, and R3P). Complexes of polydentate ligands are called chelate complexes. They tend to be more stable than complexes derived from monodentate ligands. This enhanced stability, the chelate effect, is usually attributed to effects of entropy, which favors the displacement of many ligands by one polydentate ligand. When the chelating ligand forms a large ring that at least partially surrounds the central atom and bonds to it, leaving the central atom at the center of a large ring. The more rigid and the higher its denticity, the more inert will be the macrocyclic complex.

[241] '^"Chelator^" as used herein relates to a binding agent that suppresses chemical activity by forming a chelate (a coordination compound in which a metal atom or ion is bound to a ligand at two or more points on the ligand, so as to form, for example, a heterocyclic ring containing a metal atom).

[242] "Chelation" as used herein relates to a particular way that ions and molecules bind metal ions. According to the International Union of Pure and Applied Chemistry (IUPAC), chelation involves the formation or presence of two or more separate coordinate bonds between a polydentate (multiple bonded) ligand and a single central atom. Usually these ligands are organic compounds, and are called chelants, chelators, chelating agents, or sequestering agents.

[243] "Electrophile" as used herein relates to species that is attracted to an electron rich center. In chemistry, an electrophile is a reagent attracted to electrons. It participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carries a partial positive charge, or have an atom that does not have an octet of electrons.

[244] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[245] "Amino" refers to the -NH2 radical.

[246] "Cyano" refers to the -CN radical.

[247] "Halo" or "halogen" refers to bromo, chloro, ffuoro or iodo radical.

[248] "Hydroxy" or "hydroxyl" refers to the -OH radical

[249] "Imino" refers to the =NH substituent.

[250] "Nitro" refers to the -NO2 radical.

[251] "Oxo" refers to the =0 substituent.

[252] "Thioxo" refers to the =^:S substituent.

[253] "Alky!" or "alkyl group" refers to a fully saturated, straight or branched hydrocarbon chain radical having from one to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond. Alkyls comprising any number of carbon atoms from 1 to 12 are included. An alkyl comprising up to 12 carbon atoms is a C1-C12 alkyl, an alkyl comprising up to 10 carbon atoms is a C1-C10 alkyl, an alkyl comprising up to 6 carbon atoms is a Ci-Ce alkyl and an alkyl comprising up to 5 carbon atoms is a C1-C5 alkyl. A C1-C5 alkyl includes C5 alkyls, C4 alkyls, C3 alkyls, C2 alkyls and Ci alkyl (i. e., methyl). A i-Ce alkyl includes all moieties described above for C1-C5 alkyls but also includes C& alkyls. A C1-C10 alkyl includes all moieties described above for C1-C5 alkyls and Ci-Ce alkyls, but also includes C?, Cs, C9 and Cio alkyls. Similarly, a Ci-Ci2 alkyl includes all the foregoing moieties, but also includes Cii and C12 alkyls. Non-limiting examples of C1-C12 alkyl include methyl, ethyl, ^-propyl, /^'- propyl, sec-propyl, «-butyi, /^'-butyl, sec-butyl, i-butyl, o-pentyl, i-amyl, M-hexyl, «-heptyl, n- octyl, n-nonyl, n-decyl, «-undecyl, and H-dodecyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.

[254] "Alkylene" or "alkylene chain" refers to a fully saturated, straight or branched divalent hydrocarbon chain radical, and having from one to twelve carbon atoms. Non- limiting examples of C1-C12 alkylene include methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, «-butenylene, propynylene, n-butynylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain can be optionally substituted.

[255] "Alkenyl" or "alkenyl group" refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl group comprising any number of carbon atoms from. 2 to 12 are included. An alkenyl group comprising up to 12 carbon atoms is a C'2~Ci2 alkenyl, an alkenyl comprising up to 10 carbon atoms is a C2-C10 alkenyl, an alkenyl group comprising up to 6 carbon atoms is a C2- Ce alkenyl and an alkenyl comprising up to 5 carbon atoms is a C2-C5 alkenyl. A C2-C5 alkenyl includes Cs alkenyls, C& alkenyls, C3 alkenyls, and C2 alkenyls. A C2-C6 alkenyl includes all moieties described above for C2-C5 alkenyls but also includes Ce alkenyls. A C2- Cio alkenyl includes all moieties described above for C2-C5 alkenyls and C2 alkenyls, but also includes i, Cs, C¾ and C10 alkenyls. Similarly, a C2-C12 alkenyl includes all the foregoing moieties, but also includes C11 and C12 alkenyls. Non-limiting examples of C2-C12 alkenyl include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l - propenyl, 1-butenyi, 2-butenyl, 3-butenyl, i-pentenyl, 2-pentenyl, 3-pentenyi, 4-pentenyl, i- hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyi, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4- heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6- octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7- nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyi, 5-decenyl, 6-decenyi, 7- decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-imdecenyl, 4-undecenyl, 5- undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1 -dodecenyl, 2-dodecenyi, 3-dodecenyi, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8- dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11 -dodecenyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.

[256] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Non-limiting examples of C2-C12 alkenylene include ethene, propene, butene, and the like. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkenylene chain can be optionally substituted.

[257] 'Alkynvl" or "alkynyl group" refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. Alkynyl group comprising any number of carbon atoms from 2 to 12 are included. An alkynyl group comprising up to 12 carbon atoms is a C2-C12 alkynyl, an alkynyl comprising up to 10 carbon atoms is a C2-C10 alkynyl, an alkynyl group comprising up to 6 carbon atoms is a C -Ce alkynyl and an alkynyl comprising up to 5 carbon atoms is a C2-C5 alkynyl. A C2-C5 alkynyl includes Cs alkynyls, Ca alkyny!s, C3 alkynyls, and C2 alkynyls. A C2-C6 alkynyl includes all moieties described above for C2-C5 alkynyls but also includes Ce alkynyls. A C2-C10 alkynyl includes all moieties described above for C2-C5 alkynyls and C2-C6 alkynyls, but also includes C7, Cs, C9 and Go alkynyls. Similarly, a C2-C12 alkynyl includes ail the foregoing moieties, but also includes C11 and C12 alkynyls. Non-limiting examples of C2-G2 alkenyl include ethynyl, propynyl, butynyl, pentynyl and the like. Unless stated otherwise specifically m the specification, an alkyl group can be optionally substituted.

[258] 'Aikynyiene" or "aikynyiene chain" refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Non-limiting examples of C2-C12 aikynyiene include ethynylene, propargylene and the like. The aikynyiene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the aikynyiene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an aikynyiene chain can be optionally substituted.

[259] "Alkoxy" refers to a radical of the formula -OR?, where Ra is an alkyl, alkenyl or aiknyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted.

[260] "Alkylamino" refers to a radical of the formula -NHRa or -NRaRa where each ¾ is, independently, an alkyi, alkenyl or aikynvi radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkylamino group can be optionally substituted.

[261] "Alky carbonyi" refers to the -C(=0)Ra moiety, wherein Ra is an alkyi, alkenyl or alkynyl radical as defined above. A non-limiting example of an alkyi carbonyl is the methyl carbonyl ("acetal") moiety. Alkylcarbonyl groups can also be referred to as "Cw-Cz acyl" where w and z depicts the range of the number of carbon in Ra, as defined above. For example, "C l-Cio acyl" refers to alkylcarbonyl group as defined above, where Ra is Ci~Cio alkyi, Ci-Cio alkenyl, or Ci-Cio alkynyl radical as defined above. Unless stated otherwise specifically in the specification, an alkyi carbonyl group can be optionally substituted.

[262] '^"Aryl" refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring. For pusposes of this invention, the aryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthryleme, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, os-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, the term "aryl" is meant to include aryl radicals that are optionally substituted.

[263] "Aralkyl" or "arylalkyl" refers to a radical of the fonnula -Rb-Rc where Rb is an alkylene group as defined above and R_c is one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl and the like. Unless stated otherwise specifically in the specification, an aralkyl group can be optionally substituted.

[264] 'Aralkenyl" or "arylalkenyl" refers to a radical of the formula -Rb-Rc where Rb is an alkenylene o group as defined above and Rc is one or more aryl radicals as defined above. Unless stated otherwise specifically in the specification, an aralkenyl group can be optionally substituted.

[265] "Aralkynyl" or "arylalkynyl" refers to a radical of the fonnula -Rb-Rc where Rt. is an alkynylene group as defined above and Rc is one or more aryl radicals as defined above. Unless stated otherwise specifically in the specification, an aralkynyl group can be optionally substituted.

[266] "Carbocyclyl," "carbocyclic ring" or "carbocycle" refers to a rings structure, wherein the atoms which form the ring are each carbon. Carbocyclic rings can comprise from 3 to 20 carbon atoms in the ring. Carbocyclic rings include aryls and cycloalkyl. cycioaikenyi and cycloalkynyl as defined herein. Unless stated otherwise specifically in the specification, a carbocyclyl group can be optionally substituted.

[267] '"Cycloalkyl" refers to a stable non-aromatic monocyclic or poly cyclic fully saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, which can include fused or bridged ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyciohexyl, cycloheptyl, and cyciooctyl. Polycyclic cycloalkyl radicals include, for example, adamant}⁷!, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2. Ijheptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group can be optionally- substituted.

[268] '^"Cycioalkenyr¹ refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon double bonds, which can include fused or bridged ring systems, having from three to twenty- carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycioaikenyi radicals include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cycloctenyl, and the like. Polycyclic cycioaikenyi radicals include, for example, bicyclo[2.2.1]hept-2-enyl and the like. Unless otherwise stated specifically in the specification, a cycioaikenyi group can be optionally substituted.

[269] "Cycloalkynyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds, which can include fused or bridged ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkynyl radicals include, for example, cycioheptynyl, cyclooctynyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkynyl group can be optionally substituted.

[270] "Cycloalkylalky!" refers to a radical of the formula -Rb-Rd where Rb is an alkylene, alkenylene, or alkynylene group as defined above and Rd is a cycloalkyl, cycioaikenyi, cycloalkynyl radical as defined above. Unless stated otherwise specifically in the specification, a cycloalkylalky! group can be optionally substituted.

[271] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyi, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyi group can be optionally substituted.

[272] "Haloalkenyl" refers to an alkenyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g. , 1-fluoropropenyl, 1,1-difluorobutenyl, and the like. Unless stated otherwise specifically in the specification, a haloalkenyl group can be optionally substituted.

[273] "Haloalkynyl" refers to an alkynyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., 1-ffuoropropynyl, 1-fluorobutynyl, and the like. Unless stated otherwise specifically in the specification, a haloalkenyl group can be optionally substituted.

[274] "Heterocyciyl," "heterocyclic ring" or "heterocycle" refers to a stable 3- to 20-membered non-aromatic, partially aromatic, or aromatic ring radical which consists of two to twelve carbon atoms and from, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Heterocyclycl or heterocyclic rings include heteroaryls as defined below. Unless stated otherwise specifically in the specification, the heterocyciyl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyciyl radical can be optionally oxidized: the nitrogen atom can be optionally quateraized; and the heterocyciyl radical can be partially or fully saturated. Examples of such heterocyciyl radicals include, but are not limited to, dioxolanyl, thienyl[l ,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidmyl, morphoHny], octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidmyl, 2-oxopyrrolidinyl, oxazolidinyi, piperidmyi, piperazinyi, 4-piperidonyl, pyrrolidinyl, pyrazoiidinyl, quinuclidinyi, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, tiiiamorpholinyl, 1-oxo-thiomorpholinyl, and 1 ,1-dioxo-thiomoipholinyl. Unless stated otherwise specifically in the specification, a heterocyciyl group can be optionally substituted.

[275] "HeterocyclySalkyl" refers to a radical of the formula -Rb-Re where is an alkylene group as defined above and R_e is a heterocyciyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocyclylalkyl group can be optionally substituted.

[276] "Heterocyclylalkenyl" refers to a radical of the formula -Rb-Re where R is an alkenylene group as defined above and Re is a heterocyciyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocyclylalkenyl group can be optionally substituted.

[277] "Heterocyclylalkynyl" refers to a radical of the formula -R -Re where Rb is an alkynylene group as defined above and R_e is a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocyclylalkynyl group can be optionally substituted.

[278] 'W-heterocyciyi" refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. Unless stated otherwise specifically in the specification, a N-heterocyclyl group can be optionally substituted.

[279] "Heteroaryl" refers to a 5- to 20-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring. For purposes of this invention, the heteroaryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[Z>][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, mdazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindoiinyl, isoquinolyl, indoiizinyl, isoxazoiyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, l-oxidopyridinyl, 1 -oxidopyrimidinyl, 1- oxidopyrazinyl, 1 -oxidopyridazinyl, 1 -phenyl- lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazoiyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyi, quinuclidinyl, isoquinoimyl, tetrahydroquinolinyl, thiazoiyl, thiadiazolyl, triazolyl, tetrazolyi, triazinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group can be optionally substituted.

[280] "N-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. Unless stated otherwise specifically in the specification, an N-heteroaryl group can be optionally substituted. [281 ] "Heteroarylalkyl" refers to a radical of the formula -Rb-Rr where Rb is an alkylene chain as defined above and Rf is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkyl group can be optionally substituted.

[282] "Heteroarylalkenyi" refers to a radical of the formula -Rb-Rf where Rb is an aikenylene, chain as defined above and Rf is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkenyi group can be optionally substituted.

[283] "Heteroarylalkynyl" refers to a radical of the formula -Rb-Rf where Rb is an alkynylene chain as defined above and Rf is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkynyl group can be optionally substituted.

[284] "Thioaikyl" refers to a radical of the formula -SRa where Ra is an aikyl, aikenyl, or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, a thioaikyl group can be optionally substituted.

[285] The term "substituted" used herein means any of the above groups (i.e., alkyi, alkylene, aikenyl, aikenylene, alkynyl, alkynylene, alkoxy, alkylamino, alkyicarbonyi, thioaikyl, aryl, aralkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, CI, Br, and I; an oxygen atom in groups such as hydroxy! groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioaikyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, aikylarylamines, di arylamines, N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. "Substituted^"' also means any of the above groups in w hich one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, ^"'substituted^"' includes any of the above groups in which one or more hydrogen atoms are replaced

with -NRgRh, -NR,( ( 0)Ri,.

¾ -ORg, -SR_& -SORg, -SO Rg, -OSOzRg, -SCbQRg, -NSGiRg, and -SOiNRgft,. "Substituted also means any of the above groups in which one or more hydrogen atoms are replaced with ··( ( 0)R,. -C! OlOR:, ·( { 0)NR_r.R». -CFfcSQiRg, -CHiSOiNRgfe. In the foregoing, Rg and Rh are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylaikyl. "Substituted" furtlier means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyi, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylaikyl group. In addition, each of the foregoing substituents can also be optionally substituted with one or more of the above substituents.

[286] As used herein, the symbol '^* 4 I- ' (hereinafter can be referred to as "a point of attachment bond") denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond. For example, " indicates that the chemical entity "XY" is bonded to another chemical entity via the point of attachment bond. Furthermore, the specific point of attachment to the non-depicted chemical entity can be specified by inference. For example, the compound

CH3-R³, wherein R³ is H or † " infers that when R³ is "XY" ^',, the point of attachment bond is the same bond as the bond by which R^J is depicted as being bonded to CH3.

[287] The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed inventions, or that any publication specifically or implicitly referenced is prior art.

Compounds of the Present Disclosure

[288] The compound of the present disclosure can be useful for modulating Parkin ligase. Further, the compound of the present disclosure can be useful for treating various diseases and conditions including, but not limited to, cancer, neurological disease, a disorder characterized by abnormal accumulation of a-synuclein, a disorder of an aging process, cardiovascular disease, bacterial infection, viral infection, mitochondrial related disease, mental retardation, deafness, blindness, diabetes, obesity, autoimmune disease, glaucoma, Leber's Hereditary Optic Neuropathy, and rheumatoid arthritis. In one embodiment, the present disclosure provides compounds having the structure of formula (Ϊ):

[289] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[290] L⁴ and L⁵ are each independently selected from a bond, alkylene, alkenylene, -0-, - NH-, ~NR⁶~, -NHC(O)-, -NR⁶C(0)-, -CH₂C(0)-, -C(0)NH-, -C(0)N ⁶-, -CH₂C(0)NH~, - C(())NHCH₂-, -CH₂C(0)NR⁶-, -S(0)_n-, -S(0)„NH-, -S(0)„NHCH₂-, -S(C))_nNHCH₂CH₂-, - S(0)nNR⁶-, -NHS(0)_n-, or -NR⁶S(0)_n-;

[291] X is absent, alkylene, alkenylene, divalent cycloalkyl, divalent aryl, divalent heterocyclyl, or divalent monocyclic heteroaryl, wherein cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more

[292] Y is cycloalkyl, aryl, heterocyclyl, or heteroaryl, wherein Y is optionally substituted with one or more R⁵;

[293] R¹¹, R^!2, and R^!3 are each independently selected from H, I, Br, CI, F, CN, alkyi, haloalkyl, -SH, -SR⁴, -OH, -OR⁴, -NH₂, -NHR⁴, -NR⁴R⁴, or -NQ₂; or

[294] R⁴ is each independently H, alkyi, aryl, arylalkyl, aryloxyalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, or heteroaryloxyalkyl, wherein each R⁴ is optionally substituted with one or more R⁵:

[295] R⁵ is each independently 1, Br, CI, F, -CN, -CONH₂, -CQNHR⁶, -CQNR⁶R⁶, -COOH,

-NH2, -NHR⁶, N0₂, -NR⁶R⁶, -OH, -OR⁶, -COOR⁶, -OSO3R⁶, oxo, R⁶, -SH, -SO2R⁶, -SO3H, -

SO3R⁶, -S(0)nNH₂, -S(0)nNHR⁶, -S(0),,NR⁶R⁶, or -SR⁶;

[296] R⁶ is each independently alkyi, haloalkyl, or cycloalkyl: and

[297] n is O, l, or 2.

[298] In one embodiment of formula (I), when L⁴ and L³ are each a bond and X is absent, then Y is not unsubstituied phenyl, phenyl substituted with alkyi, halogen or ---COOH, or Y is not cycloalkyl or thiazolyl.

[299] In one embodiment of formula (I), when -L⁴-X-L⁵- is -CH2-, then Y is not phenyl, pryidyl, thiophenyl, thiadiazolyl, dioxolanone, pyrazolyl or oxiranyl.

[300] In one embodiment of formula (I), X is not divalent oxadiazolyl or divalent pyrazolyl. [301] In one embodiment of formula (I), Y is not pyridyl or tetrahydrofuranyl.

[302] In one embodiment, compounds of formula (1) is not 4,5-dichloro-2-((5-(thiophen-2- yl)isoxazol-3-yl)me1hyl)pyridazm-3(2H)-orie, 4,5-Diehloro-2-{2-[4-(diethy3amino)phenyl]~2- oxoethyl}pyridazin-3(2H)-one, 2-((4,5-dichloro-6-oxopyridazin-l (6H)-yl)methyl)-l-ethyl- N^-dimethyl-lH-benzo[i ]imidazole-6-sulfonamide, 4-(4-amino-5-chloro-6-oxopyridazin- l(6H)-yl)butyl benzoate, 2-(2-ammo-4-methylthiazol-5-yl)-4,5-dichloropyridazin-3(2H)-one, and/or 2~(2-amino4iazol-4~yi)-4,5-dichloropyridazin~3(2H)-one.

[303] In one embodiment, L⁴ and L³ of formula (I) is each independently selected from a bond, C1 -C3 alkylene, C2-C3 alkenylene, -0-, -ΝΗ-, -CH₂C(0)-, -C(0)NH-, -C(0)N ⁶-, - CH₂C(0)NH-, -CH2C(0)NR⁶-,-S(0)n-, -S(G)_nNH~, or -S(0)nNR⁶-. In another embodiment, L⁴ and L³ is each independently selected from a bond, C 1 -C3 alkylene, C2-C3 alkenylene, -

[304] In one embodiment, L⁴ of formula (1) is a bond. In one embodiment, L⁴ is C1-C3 alkylene. In one embodiment, L⁴ is -CH2-. In another embodiment, L⁴ is -CH2CH2-. In another embodiment, L⁴ is -CH2C(0)NH-.

[305] In one embodiment, L³ of formula (I) is a bond. In one embodiment, L⁵ is -0-. In one embodiment, L³ is -NH-. In one embodiment, L⁵ is -S(0)nNH-. In one embodiment, L³ is - S(0)₂NH-. In one embodiment, L⁵ is -S(0)nNR⁶-. In one embodiment, L^s is -S(0)₂NR⁶-. In one embodiment, L³ is ---8(())2Ν((¾)-.Ιη one embodiment, L⁵ is -S(0)u-. In another embodiment, ³ is -S(0)₂-. In one embodiment, L⁵ is -C(0)NH-. In one embodiment, L⁵ is - C(0)NHCH2~. In another embodiment, L⁵ is -C(0)NR⁶-. In one embodiment, L⁵ is - C(0)N(CH3)-. In one embodiment, L⁵ is C 1 -C3 alkylene. In one embodiment, L³ is -CH2-. In another embodiment, L³ is -CH2CH2-.

[306] In one embodiment, X of formula (1) is absent, C 1-C3 alkylene, divalent C3-C6 cycloalky!, divalent phenyl, divalent 5-6 membered heterocyciyi, or divalent 5-6 membered heteroaryl, wherein each of cycloalkyl, phenyl, heterocyciyi, or heteroaryl is optionally- substituted with one or more R³. In one embodiment, X is absent. In another embodiment, X is C1-C3 alkylene.

[307] In one embodiment, X of formula (I) is divalent C3-C6 cycloalkyl, divalent phenyl, divalent 5-6 membered heterocyciyi, or divalent 5-6 membered heteroaryl, wherein each of cycloalkyl, phenyl, heterocyciyi, or heteroaryl is optionally substituted with one or more R⁵. In another embodiment, X is selected from divalent phenyl, divalent oxadiazole, divalent isoxazole, divalent oxazole, or divalent thiazole; wherein each of which are optionally- substituted with one or more R⁵. In one embodiment, X is selected from

wherein each of which are optionally substituted with one or more R⁵.

[308] In one embodiment, X of formula (I) is phenyl optionally substituted with one or more R³. In one embodiment, X is phenyl optionally substituted with one or more selected from I, Br, CI, F, CN, C1-C3 alkyl, 3-6 membered cycloalkyl, -S(0)_NH2, or -S(0)2NH(C 1- C6 alkyl). In one embodiment, X is divalent monocyclic heteroaryl optionally substituted with one or more R⁵. In one embodiment, X is divalent monocyclic heteroaryl optionally substituted with one or more selected from I, Br, CI, F, CN, C1-C3 alkyl, 3-6 membered cycloalkyl, -S(0)2NH2, or -S(0)2 H(C 1-C6 alkyl). In one embodiment, X is divalent oxadiazole, divalent isoxazole, divalent oxazole, or divalent thiazole.

[309] In one embodiment, X of formula (I) is unsubstituted.

[310] In one embodiment, X of formula (I) is absent.

[311] In one embodiment, Y of formula (I) is C3-C6 cycloalkyl, phenyl, 5-6 membered heterocyclyl, or 5-10 membered heteroaryl, wherein Y is optionally substituted with one or more R⁵. In another embodiment, Y is phenyl or 5-10 membered heteroaryl, wherein Y is optionally substituted with one or more R³. In one embodiment, Y is phenyl optionally substituted with one or more R⁵. In some embodiments, Y is 5-6 membered heteroaryl optionally substituted with one or more R³. In one embodiment, Y is selected from thiophenyl or isoxazolyl, each of which is optionally substituted with one or more R³.

[312] In one embodiment, Y of formula (I) is phenyl optionally substituted with one or more R³. In one embodiment, Y is phenyl optionally substituted with one or more selected from I, Br, Ci, F, CN, C1-C3 alkyl, 3-6 membered cycloalkyl, -Sf O NI k or -S(0)₂NH(C1- C6 alkyl). In some embodiments, Y is phenyl optionally substituted with one or two groups selected from I, Br, CI, F, CN, C1-C3 alkyl, 3-6 membered cycloalkyl, -S(0)2NH2, or - -C6 alkyl). In one embodiment, Y is selected from:

; which are each further optionally substituted with one or more selected from I, Br, CI, F, CN, C1-C3 alkyl, 3-6 membered cycloaikyl, -S(0)₂NH₂, or -S(0)2NH(C1-C6 alkyi).

[313] In one embodiment, Y of fonnula (1) is C3-C6 cycloaikyl, optionally substituted with one or more R:\ In one embodiment, Y is cyclopentyl optionally substituted with one or more selected from I, Br, CI, F, CN, C1-C3 alkyl, 3-6 membered cycloaikyl, -S(0)2NH2, or - S(0)2NH(C1-C6 alkyl). In one embodiment, Y is cyclohexyl optionally substituted with one or more selected from I, Br, CI, F, CN, C1-C3 alkyl, 3-6 membered cycloaikyl, -S(0)₂NH2, or -S(0)₂NH(C1-C6 alkyl).

[314] In one embodiment, Y of formula (I) is 5-10 membered heteroaryi, optionally substituted with one or more R⁵. In one embodiment, Y is 5-6 membered heteroaryi, optionally substituted with one or more selected from I, Br, CI, F, CN, C1-C3 alkyl, 3-6 membered cycloaikyl, -S(())₂NH₂, or -S(0)₂NH(C 1-C6 alkyl). In one embodiment Y is 5- membered heteroaryi optionally substituted with one or more selected from I, Br, Ci, F, CN, C1-C3 alkyl, 3-6 membered cycloaikyl, -S(0)₂NH₂, or -S(0)₂NH(C 1 -C6 alkyl). In one embodiment, Y is 6-membered heteroaryi optionally substituted with one or more selected from I, Br, Ci, F, CN, C1-C3 alkyl, 3-6 membered cycloaikyl, -8(0)₂ΝΗ₂, or -S(0)₂NH(CI-

; which are each optionally substituted with one or more selected from I, Br, CI, F, CN, C1-C3 alkyl, 3-6 membered cycloaikyl, -S(0)₂NH¾ or -S(0)₂NH(C1-C6 alkyl).

[315] In one embodiment, Y of formula (I) is 5-6 membered heterocyclyl, optionally substituted with one or more R³. In one embodiment, Y is 5-membered heteroaryi, optionally substituted with one or more selected from I, Br, CI, F, CN, C1-C3 alkyl, 3-6 membered cycloaikyl, -S(0)2NH2, or -S(0)2NH(C1-C6 alkyl). In one embodiment, Y is 6-membered heteroaryi, optionally substituted with one or more selected from I, Br, Ci, F, CN, C1-C3 alkyl, 3-6 membered cycloaikyl, -S(0)2NH2, or -S(0)₂NH(C1-C6 alkyl). In some embodiments, Y is piperidine, optionally substituted with one or more selected from I, Br, CI, F, CN, C1-C3 alkyl, 3-6 membered cycloaikyl, -S(0)2NH₂, or -S(0)_NH(C1-C6 alkyi). In another embodiment, Y is selected from:

I, F,

CN, C1-C3 alkyl, 3-6 membered cycloalkyl, -S(0):Nl k or -S(G)₂NH(C1-C6 alkyl).

[316] In one embodiment, Y of formula (I) is 9-10 membered bicyclic heteroaryl optionally substituted with one or more R³, In one embodiment, Y is 9-membered bicyclic heteroaryl optionally substituted with one or more groups selected from 1, Br, Ci, F, CN, C1-C3 alkyl, 3- 6 membered cycloalkyl, -S(0)2 H2, or -S(0)2NH(C1-C6 alkyl). In another embodiment, Y is 10-membered bicyclic heteroaryl optionally substituted one or more groups selected from I, Br, CI, F, CN, C1 -C3 alkyl, 3-6 membered cycloalkyl, -S(0)2NH₂, or -S(0)₂NH(C1-C6 alkyl). In another embodiment, Y is benzoimidazole or benzothiazole, each of which is optionally substituted with one or more groups selected from L Br, CI, F, CN, C1-C3 alkyl, 3- 6 membered cycloalkyl, -S(0)2NH₂, or -S(0)2NH(C1-C6 alkyl). In one embodiment, Y is selected from:

K or

; which are each optionally substituted with one or more selected from I, Br, CI, F, CN, C1-C3 alkyl, 3-6 membered cycloalkyl, -S(0)2NH₂, or - S(0)_NH(C1-C6 alkyl).

[317] In one embodiment of formula (I), X is C1-C3 alkylene, divalent C3-C6 cycloalkyl, divalent phenyl, divalent 5-6 membered heterocyclyl, or divalent 5-6 membered heteroarv'i, wherein each of cycloalkyl, phenyl, heterocyclyl, or heteroaryl is optionally substituted with one or more R⁵; and Y is C3-C6 cycloalkyl, phenyl, 5-6 membered heterocyclyl, or 5-10 membered heteroaryl, wherein Y is optionally substituted with one or more R\

[318] In one embodiment of formula (I), R⁵ is selected from I, Br, CI, F, -CN, R⁶, - S(0)nNH₂, or -S(0)j)NHR⁶. In another embodiment, R⁵ is selected from 1, Br, Ci, F, CN, Cl- C3 alkyl, 3-6 membered cycloalkyl, ~S(0)A H \ or -S(0)2NH(C1-C6 alkyl). In some embodiments, R⁵ is selected from T, Br, Ci, F, CN, C 1 -C3 alkyl, or cyclopropyl .

[319] In one embodiment, -L⁴-X-L⁵- of formula (I) is -CHj-. In another embodiment, -L⁴- X-L⁵- is -NH(CH2)20-. In another embodiment, -L⁴-X-L⁵- is -CH₂.C(0)NH-. In another embodiment, -L⁴-X-L⁵- is -CH2C(0)NHCH2-. In another embodiment, -L⁴-X-IA- is a bond.

[320] In one embodiment, R¹¹ and R^!2 of formula (I) are each independently selected from H, I, Br, CI, F, -SH, -S-alkyl, -OH, -O-alkyl, -NH2, -NH-alkyl, or -NR⁴R⁴. In another embodiment, R^{! 1} and Rⁱ² are each independently selected from H, CI, -S-aikyl, or -NR⁴R⁴.

[321] In one embodiment, K ^; of formula (I) is CI. In one embodiment, K of formula (I) is H. In one embodiment, Rⁿ is -OH. In one embodiment, R^{1 !} is -O-alkyl. In one embodiment, R^{! 1} is -OMe. In one embodiment, R¹¹ is -S-alkyl. In one embodiment, R¹¹ is -SMe. In some embodiments, R¹¹ is -NR⁴R⁴. In some embodiments, R¹¹ is -NHR⁴. In other embodiments, R¹¹ is -NHR⁴, wherein R⁴ is arylalkyl. In other embodiments, R^{i !} is -NHCH2CH2PI1. In some embodiments, R^{! !} is -N(CH3)2.

[322] In one embodiment, R¹² of formula (I) is CI. In one embodiment, R¹² is H. In one embodiment, R¹² is ~OH. In one embodiment, R¹² is -O-alkyl. In one embodiment, R^!2 is - OMe. In one embodiment, R¹² is -S-alkyl. In one embodiment, Rⁱ² is -SMe. In some embodiments, R^{1 2} is -NR⁴R⁴. In some embodiments, R¹² is -NHR⁴. In other embodiments, R^!2 is -NHR⁴, wherem R⁴ is arylalkyl. In oilier embodiments, R¹² is -NHCH2CH2PI1. In some embodiments, R¹² is MCI \^■■).·.

[323] In one embodiment, R'³ of formula (I) is H.

[324] In one embodiment, compounds of formula (I) has the structure of formula (Γ):

[325] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[326] L⁴ and L³ are each independently selected from a bond, C1-C3 alkylene, C2-C3 alkenylene, -0-, -M i- . -CH₂C(0)-, -C(0)NH-, ·( (0)\ ! Κ 1 · ·. -C(0)NR⁶-, ·(^'! i C( {))M !··. - CH2C(0)NR⁶-,-S(0)_n-, -S(0)_nNH-, or -S(0)_nNR⁶-;

[327] X is a divalent cycloalkyl, divalent aryl, divalent heterocyciyl, or divalent monocyclic heteroaryl, wherein cycloalkyl, aryl, heterocyciyl, or heteroaryl is optionally substituted with one or more R⁵;

[328] Y is cycloalkyl, aryl, heterocyciyl, or heteroaryl, wherein Y is optionally substituted with one or more R⁵;

[329] R^{1 1}, R¹², and R¹³ are each independently selected from H, I, Br, CI, F, -CN, alkyl, haloalkyl, -SH, -SR⁴, -OH, -OR⁴, -NH2, -NHR⁴, -NR⁴R⁴, or -NO2; or

[330] R⁴ is each independently H, alkyl, aryl, arylalkyl, aryloxyalkyl, heterocyciyl, heterocyclylalkyi, heteroaryl, heteroaiylalkyl, or heteroaryloxyalkyl, wherein each R⁴ is optionally substituted with one or more R³;

[3311 R⁵ is each independently I, Br, CI, F, -CN, -C j >. -CONHR⁶, -CONR⁶R⁶, -CQGH, -NH2, -NHR⁶, -NO2, -NR⁶R⁶, -OH, -OR⁶, -COOR⁶, -OSO3R⁶, oxo, R⁶, -SH, -SG2R⁶, -SO3H, - SO3R⁶, -S(0)nNH₂, -S(0)nNHR⁶, -S(0)n R⁶R⁶, or -SR⁶;

[332] R⁶ is each independently alkyl or cycloalkyi: and

[333] n is O, L or 2.

[334] In one embodiment, L⁴ of formula (Γ) is a bond or O 1

[335] In one embodiment, L⁵ of formula (Γ) is a bond or -S(0)nNR⁶-.

[3361 ^{m one} embodiment, L⁵ of formula (Γ) is a bond or -S(0)2NH-, -C(0)NH-, or -

C(0)NHCH₂-,

[337] In one embodiment, X of formula (Γ) is phenyl or 5-6 membered heteroaryl, which are optionally substituted with R³.

[338] In one embodiment, Y of formula (Γ) is phenyl, 5-6 membered heteroaryl, or 5-6 membered heteroeycly!, which are optionally substituted with R⁵.

[339] In one embodiment, R³ of formula (Γ) is I, Br, CI, F or methyl. In one embodiment, R⁵ of formula (Γ) is R⁶, wherein R⁶ is cycloalkyi. In one embodiment, R⁵ of formula (Γ) is cycloalkyi.

[340] In one embodiment, R^{1 !} and Rⁱ² of formula (Γ) are each independently selected from H, CI, -S-alkyl, or -NR⁴R⁴. In some embodiments, R^{! !} is -NHR⁴. In other embodiments, R^{1 ]} is -NHR⁴, wherein R⁴ is arylaikyl. In other embodiments, Rⁿ is -NHCH2CH2PI1. In some embodiments, R¹² is -NHR⁴. In other embodiments, R¹² is -NHR⁴, wherein R⁴ is arylaikyl . In other embodiments, R¹ -' is - HCH2CH2Ph.

[341] In one embodiment, R^!3 of formula (Γ) is H.

[342] In one embodiment, compounds of formula (I) has the structure of formula (Γ):

[343] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[344] -L⁴-X-L⁵ is a bond or C 1 -C3 alkylene;

[345] Y is cycloalkyi, aryl, heterocyciyi, or heteroaryl, wherein Y is optionally substituted with one or more R⁵;

[346[ R¹¹, R¹², and R¹³ are each independently selected from H, I, Br, CI, F, -CN, alkyl, haloalkyl, -SH, -SR⁴, -OH, -OR⁴, -NH2, -NHR⁴, -NR⁴R⁴, or -NO?.; or

[347] R⁴ is each independently H, alkyl, aryl, arylalkyl, aryloxyalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, or heteroaryloxyalkyl, wherein each R⁴ is optionally substituted with one or more R⁵;

[348] R⁵ is each independently I, Br, CI, F, -CN, -CONH2, -CONHR⁶, -CONR⁶R⁶, -COOH, -NH2, -NHR⁶, -NO2, - R⁶R⁶, -OH, -OR⁶, -CQGR⁶, -OSO3R⁶, oxo, R⁶, -SH, -SO2R⁶, -SO3H, - SO3R⁶, -S(0)_aNH2, -S(0)nNHR⁶, -S(0)nNR¾⁶, or -SR⁶;

[349] R⁶ is each independently alkyl or cycloalkyl; and

[350] n is 0, l, or 2.

[351] In on embodiment, Y of formula (I") is phenyl or heteroaryl, wherein Y is optionally substituted with one or more R⁵. In another embodiment, Y is phenyl substituted with -

S(0)nNH2 and optionally substituted with one or more R⁵. In some embodiments, Y is 5-6 membered heteroaryl, wherein Y is optionally substituted with one or more R⁵.

[352] In one embodiment, R⁵ is of formula (I") is I, Br, CI, F or methyl,

[353] Various embodiments as described above for fonnula (I) also applies to formula (Γ), and formula (I").

[354] In one embodiment, the compound of formula (1) or (I") is not where when L⁴ and L⁵ are each a bond and X is absent, then Y is not unsubstituted phenyl, phenyl substituted with alkyl, halogen or -COOH, or Y is not cycloalkyl or thiazolyl.

[355] In one embodiment, the compound of formula (1) or (I") is not where when -L⁴-X-L⁵- is -CH2-, then Y is not phenyl, pryidyi, thiophenyl, thiadiazoiyl, dioxolanone, pyrazolyl or oxiranyl;

[356] In one embodiment, the compound of formula (I) or (Γ), X is not divalent oxadiazolyl or divalent pyrazolyl:

[357] In one embodiment, the compound of formula (I), (Γ), or (I"), Y is not pyridyl of tetrahydrofuranyl; and

[358] In one embodiment, the compound of formula (I), the compound is not 4,5-dichloro- 2~((5-(tliiophen-2~yl)isoxazo3-3~yl)methy3)pyridazin-3(2H)-one 4,5-Dichloro-2-{2-[4- (diethylamino)phenyl]-2-oxoethyl}pyridazin-3(2H)-one, 2-((4,5-dichloro-6-oxopyridazin- l(6H)-yl)me1hyl)-l-emyl-N^-dimethyl-lH-benzo[if]imidazole-6-sulfonamide, 4-(4-amino-5- chloro-6-oxopyridazin-l(6H)-yl)butyl benzoate, 2-(2-amino-4-metliylthiazoI-5-yl)-4,5- dichloropyridazin-3(2H)-one, and/or 2-(2-aminothiazol-4-yl)-4,5-dichloropyridazin-3(2H)- one.

[359] In one embodiment, the compound of formula (Γ), the compound is not 4,5-dichloro- 2-((5-(thiophen-2-yl)isoxazol-3-yl)methyl)p3'ridazin-3(2H)-one.

[360J In one embodiment, the compound of formula (I"), the compound is not 2-((4,5- dichloro-6-oxopy ridazin- 1 (6H)-yl)methyl)- 1 -ethyl -N,iV~dimethyl-lH-benzo[d imidazole~6- sulfonamide.

[361] In one embodiment, the compound of formula (I), (Γ), or (I") is selected from Table 1 below, or a pharmaceutically acceptable salt or solvate thereof.



[362] In one embodiment, the compound of formula (I), ( ! ^'}. or (I") is selected from. Table 2 below, or a pharmaceutically acceptable salt or solvate thereof.

[364] In one embodiment, the compound of formula (I), (Γ), or ( !") exclude

[365] In one embodiment, the present disclosure relates to the following compound:

Methods

[366] Ubiquitination is crucial for a plethora of physiological processes, including cell survival and differentiation and innate and adaptive immunity. Proteins are built-up to cater for the structural and biochemical requirements of the cell and they are also broken-down in a highly -regulated process serving more purposes than just destruction and space management. Proteins have different half-lives, determined by the nature of the amino acids present at their N-termini. Some will be long-lived, while other will rapidly be degraded. Proteolysis not only enables the cell to dispose of misfolded or damaged proteins, but also to fine-tune the concentration of essential proteins within the cell, such as the proteins involved in the cell cycle. This rapid, highly specific degradation can be achieved through the addition of one to several ubiquitin molecules to a target protein. The process is called ubiquitinatioii.

[367] In recent years, considerable progress has been made in the understanding of the molecular action of ubiquitin in signaling pathways and how alterations in the ubiquitin system lead to the development of distinct human diseases. It has been shown that ubiquitination plays a role in the onset and progression of cancer, metabolic syndromes, neurodegenerative diseases, autoimmunity, inflammatory disorders, infection and muscle dystrophies (Popovic et al. Nature Medicine 20, 1242-1253 (2014)),

[368] Ubiquitin-protein (E3) ligases are a large family of enzymes that select various proteins for ubiquitination. These ubiquitin ligases, called "Ub ligases" are known to have a role in various diseases and conditions, including but not limited to, cancer, inflammation and infectious diseases.

[369] One specific Ub ligase is Parkin iigase. Parkin ligase is a component of a multiprotein "E3" ubiquitin ligase complex, which in turn is part of the ubiquitin-proteasome system that mediates the targeting of proteins for degradation. Although the specific function of Parkin iigase is not known, mutations in Parkin ligase are linked to various diseases, such as Parkinson's disease, cancer and mycobacterial infection. Parkin ligase is thus an attractive target for therapeutic intervention.

[370] Further, there are various known methods for regulating ligases known in the art. Many ligases, particularly ligases involved in the Ubiquitin-Proteasome Pathway System (UPS), are known to have Zinc Finger (ZnF) domains that stabilize critical protein binding regions in that ligase.

[371] ZnF domains coordinate zinc ions and this coordination stabilizes functional activity of the protem. The functional activity provided by proteins with ZnF domains can include the regulation of important cellular signaling pathways, such as recognizing ubiquitins, regulation of DNA, such as transcription and repair, and acting as cellular redox sensors. The binding of zinc to ZnF domains, or simply just regulating how zinc interacts with the ZnF domains, are essential to ligases involved in the UPS.

[372] Parkin ligase is known to have one or more ZnF domains. The present disclosure focuses on two different strategies for modulating ZnF domains in Parkin ligase. One strategy of the present disclosure includes using chelating compounds that bind to the ZnF domains and thus disallowing the binding of zinc, or causing the dissociation of zinc, such as Zn, or Zn²⁺, from the ZnF domain. Another strategy of the present disclosure includes using compounds that bind or react with a cysteine amino acid residue in the ZnF domain. One or more cysteine residues (and sometimes with the assistance of histidine residues) are essential in ZnF domains for binding to and/or coordinating to the zinc ion. The zinc ion (usually Znⁱ⁺) can coordinate with multiple cysteine or histidine residues. The more cysteine residues there are in the domain, the more flexible is the ZnF domain. Ligases, such as Parkin ligase are thought to have multiple cysteine residues coordinated with zinc in their ZnF domains. This flexibility in the ZnF domains of Parkin ligase is thought to allow the domain to be reversible, and is thus is one possible mechanism for regulating Parkin ligase. For example, efforts directed to this approach are disclosed in U.S. Patent Application No. 14,961,285; U.S. Provisional Application No. 62/237,400; U.S. Provisional Application No. 62/222,008, and U.S. Provisional Application No. 62/087,972, all of which are hereby incorporated by reference in their entirety.

[373] The present disclosure relates to the use of one or more agents or one or more compounds of formula (I), (Γ), or (I"), or a pharmaceutically acceptable salt or solvate thereof, which have electrophilic, chelation or both electrophilic and chelation properties that can interact with the zinc ion and/or the cysteine residue(s) in a Parkin ligase. In one embodiment, compounds of the present disclosure modulate Parkin iigase's activity. Specifically, without bound to any theory, it is believed that not allowing a zinc ion to coordinate in at least one of Parkin Iigase's ZnF domains induces its activity. The present disclosure is thus directed to a method for activating or modulating Parkin ligase by the chelation of Zn followed by its removal from the ZnF domain, or through electrophilic attack at the cysteine amino acid(s) that holds the Zn in place.

[374] Accordingly, in one embodiment of the present disclosure, a method of modulating or activating a Parkin ligase comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of formula (I), (Γ), or (I"), or a pharmaceutically acceptable salt or solvate thereof, is disclosed. In another embodiment, a method of modulating or activating a Parkin ligase comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of fonnuia (I), (Γ), or (I"), or a pharmaceutically acceptable salt or solvate thereof, that disaipt at least one Parkin ligase zinc finger is disclosed. In another embodiment, a method of activating a Parkin ligase comprising administering to a subject two or more compounds that disrupt at least one Parkin ligase zinc finger is disclosed, wherein at least one of the compound is selected from a compound of formula (I), (Γ), or (I"), or a pharmaceutically acceptable salt or sol vate thereof.

[375] In a specific embodiment, the compounds of the present disclosure can be an electrophile or a chelator. In another embodiment, the compounds of the present disclosure can function as both an electrophile and as a chelator. For example, the compounds of the present disclosure can include multiple functional groups wherein at least one functional group has chelating properties and at least one other functional group has electrophilic properties.

[376] In another specific embodiment, the compound useful for methods in modulating or activating Parkin ligase as disclosed herein is selected from Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[377] In another embodiment, the compound of the present disclosure is useful in a method to increase the Parkin ligase reaction with the Activity-based Ubiquitin vinyl suifone probe. See e.g., Example 2.

[378] In another embodiment, the one or more compounds of the present disclosure can coordinate with a Zn ion, and/or bind or react with one or more cysteine residues. In a specific embodiment the Zn ion may be either a Zn^4" or a Zn²⁺ ion. In another embodiment, the compound can coordinate to a Zn ion is a monodentate, bidentate, or tridentate ligand. [379] In another embodiment, the compound of the present disclosure can bind and/or react with a thiol group in more than one cysteine residues. In another embodiment, the compound can bind and/or react with a thiol group in two cysteine residues. In another embodiment, the compound can bind and/or react with a thiol group in three cysteine residues. In another embodiment, the compound can bind and/or react with a thiol group in four cysteine residues. In another specific embodiment, the compound can bind or react with one or more cysteine residues in one or more domains selected from the group consisting amino acids 1 1-225, amino acids 238-293, amino acids 313-377, and amino acids 418-449 of human Parkin ligase. See http://www.uniprot.org uniprot/O60260.

[380] The methods of the present disclosure also include activating auto-ubiquitinization of a Parkin ligase by administering to a subject in need thereof a therapeutically effective amount of one or more compounds of formula (I), ( ), or (I"), or a pharmaceutically acceptable salt or solvate thereof.

[381] In a specific embodiment, the one or more compounds of the present disclosure can disrupt at least one Parkin ligase zinc finger. For example, Phospho Ubiquitin (pUB), an endogenous cellular regulator of Parkin, can be added to Parkin ligase which can activate Parkin ligase and its auto-ubiquitinization. In one embodiment, one or more compounds can be administered to a subject in need thereof that acts synergistically with Phospho Ubiquitin (pUB) in activating the Parkin ligase. See, e.g.. Example 3. In one embodiment, the one or more compounds that acts synergistically with pUB in activating the Parkin ligase is a compound of formula (I), (Γ), or (I"), or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, one or more compounds of the present disclosure can be administered with pUB to synergistically increase the activation of Parkin ligase and/or its auto-ubiquitinization.

[382] In another specific embodiment, the activation of the Parkin ligase treats or reduces the incidence of one or more diseases or ailments selected from the group consisting of Alzheimer's Dementia, Parkinson's disease, Huntington Disease, Amyotrophic Lateral Sclerosis (ALS), Freidreich's ataxia, Spinocerebellar Ataxia, Multiple Systems Atrophy, PSP, Tauopathy, Diffuse Lewy Body Disease, Lewy Body dementia, any disorder characterized by abnormal accumulation of cc-synuclein, disorders of the aging process, stroke, bacterial infection, viral infection, Mitochondrial related disease, mental retardation, deafness, blindness, diabetes, obesity, cardiovascular disease, multiple sclerosis, Sjogrens syndrome, lupus, glaucoma, including pseudoexfoliation glaucoma, Leber's Hereditary Optic Neuropathy, and rheumatoid arthritis. [383] In a specific embodiment, the bacterial infection is Mycobacterium infection. In another specific embodiment the viral infection is HIV, Hepatitis B infection or Hepatitis C infection. Another embodiment of the present invention includes methods of treating and/or reducing the incidence of cancer, specifically comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds that disrupt at least one Parkin ligase zinc finger and induces Parkin ligase activity. In a specific embodiment, the activated Parkin ligase suppresses the growth of one or more tumors and/or prevents metastasis of one or more tumors.

[384] In another embodiment the cancer may be selected from one or more of the group consisting of Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Adrenocortical Carcinoma, AIDS-Related Cancers, Kaposi Sarcoma, Lymphoma, Anal Cancer, Appendix Cancer, Astrocytomas, Childhood Atypical Teratoid/Rhabdoid Tumor, Basal Cell Carcinoma, Skin Cancer (Nonmelanoma), Childhood Bile Duct Cancer, Extrahepatic Bladder Cancer, Bone Cancer, Ewing Sarcoma Family of Tumors, Osteosarcoma and Malignant Fibrous Histiocytoma, Brain Stem Glioma, Brain Tumors, Embryonal Tumors, Germ Cell Tumors, Craniopharyngioma, Ependymoma, Bronchial Tumors, Burkitt Lymphoma (Non-Hodgkin Lymphoma), Carcinoid Tumor, Gastrointestinal Carcinoma of Unknown Primary, Cardiac (Heart) Tumors, Lymphoma, Primary, Cervical Cancer, Childhood Cancers, Chordoma, Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, Chronic Myeloproliferative Neoplasms Colon Cancer, Colorectal Cancer, Cutaneous T-Cell Lymphoma, Ductal Carcinoma In Situ, Endometrial Cancer, Ependymoma, Esophageal Cancer, Esthesioneuroblastoma, Ewing Sarcoma, Extracranial Germ Cell Tumor, Extragonadal Germ Ceil Tumor, Extrahepatic Bile Duct Cancer, Eye Cancer, Intraocular Melanoma, Retinoblastoma, Fibrous Histiocytoma of Bone, Malignant, and Osteosarcoma, Gallbladder Cancer, Gastric (Stomach) Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumors, Extragonadal Cancer, Ovarian Cancer, Testicular Cancer, Gestational Trophoblastic Disease, Glioma, Brain Stem Cancer, Hairy Cell Leukemia, Head and Neck Cancer, Heart Cancer, Hepatocellular (Liver) Cancer, Histiocytosis, Langerhans Cell Cancer, Hodgkin Lymphoma, Hypopharyngeal Cancer, Intraocular Melanoma, Islet Cell Tumors, Pancreatic Neuroendocrine Tumors, Kaposi Sarcoma, Kidney Cancer, Renal Cell Cancer, Wilms Tumor and Other Childhood Kidney Tumors, Langerhans Cell Histiocytosis, Laryngeal Cancer, Leukemia, Chronic Lymphocytic Cancer, Chronic Myelogenous Cancer, Hairy Ceil Cancer, Lip and Oral Cavity Cancer, Liver Cancer (Primary), Lobular Carcinoma In Situ (LCIS), Lung Cancer, Non-Small Cell Cancer, Small Cell Cancer, Lymphoma, Cutaneous T-Cell (Mycosis Fungoides and Sezary Syndrome), Hodgkin Cancer, Non- Hodgkin Cancer, Macroglobulinemia, Waldenstrom, Male Breast Cancer, Malignant Fibrous Histiocytoma of Bone and Osteosarcoma, Melanoma, Intraocular (Eye) Cancer, Merkel Cell Carcinoma, Mesothelioma, Malignant, Metastatic Squamous Neck Cancer with Occult Primary, Midline Tract Carcinoma Involving NUT Gene, Mouth Cancer, Multiple Endocrine Neoplasia Syndromes, Multiple Myeloma/Plasma Cell Neoplasm, Mycosis Fungoides, Myelodysplastic Syndromes, Myelodysplastic/MyeloproSiferative Neoplasms, Myelogenous Leukemia, Chronic, Myeloid Leukemia, Acute, Myeloma Multiple, Chronic Myeloproliferative Neoplasms, Nasal Cavity and Paranasal Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer, Oral Cavity Cancer, Lip and Oropharyngeal Cancer, Osteosarcoma and Malignant Fibrous Histiocytoma of Bone, Epithelial Cancer, Low Malignant Potential Tumor, Pancreatic Cancer, Pancreatic Neuroendocrine Tumors (Islet Cell Tumors), Papillomatosis, Paraganglioma, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer, Pheochromocytoma, Pituitary Tumor, Plasma Cell Neoplasm/Multiple Myeloma, Pleuropulmonary Blastema, Primary Central Nervous System Lymphoma, Rectal Cancer, Renal Cell (Kidney) Cancer, Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Cancer, Sarcoma, Ewing Cancer, Kaposi Cancer, Osteosarcoma (Bone Cancer), Soft Tissue Cancer, Uterine Cancer, Sezary Syndrome, Skin Cancer, Childhood Melanoma, Merkel Cell Carcinoma, Nonmelanoma, Small Ceil Lung Cancer, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Cell Carcinoma, Skin Cancer (Nonmelanoma), Childhood Squamous Neck Cancer with Occult Primary, Metastatic Cancer, Stomach (Gastric) Cancer, T-Cell Lymphoma, Cutaneous Cancer, Testicular Cancer, Throat Cancer, Thymoma and Thymic Carcinoma, Thyroid Cancer, Transitional Ceil Cancer of the Renal Pelvis and Ureter, Unknown Primary, Carcinoma of Childhood, Unusual Cancers of Childhood, Urethral Cancer, Uterine Cancer, Endometrial Cancer, Uterine Sarcoma, Vaginal Cancer, Vulvar Cancer, Waldenstrom Macroglobulinemia, Wilms Tumor, and Women's Cancers.

[385] In a specific embodiment, the cancer is glioblastoma, small cell lung carcinoma, breast cancer and/or prostate cancer. In another embodiment, the administration of the Parkin ligase suppresses one or more tumors in the subject.

[386] In another specific embodiment, the compound eliminates damaged mitochondria, increases cell viability during cellular stress, decreases tumor transformation and/or mitigates alpha-synuclein in cells. [387] In another embodiment, the methods of the present disclosure include treating and/or reducing the incidence of Parkinson^'s disease, specifically by administering to a subject in need thereof a therapeutically effective amount of one or more compounds that disrupt at least one Parkin ligase zinc fmger and induces Parkin ligase activity, wherein the compound can coordinate with a Zn ion and/or react with a thiol group in a cysteine(s). In one embodiment, the compound that disrupts at least one Parkin ligase zinc fmger and incudes Parkin ligase activity in the above mentioned method is selected from compound of formula (I), (Γ), or (I"), or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, the one or more compounds eliminate damaged mitochondria, increases cell viability during cellular stress and/or mitigates alpha-synuclein in cells. "Somatic Mutations of the Parkinson's disease-associated gene PARK 2 in glioblastoma and other human malignancies" {Nature Genetics Jan 2010 42(1 )77-82). In one embodiment, the compound that eliminate damaged mitochondria, increase cell viability during cellular stress and/or mitigates alpha-synuclein in cells in the above mentioned method is a selected from compound of formula (I), (Γ), or (I"), or a pharmaceutically acceptable salt or solvate thereof.

[388] In another embodiment, the Parkin ligase activation alters ubiquitmation . Specifically, the alteration of ubiquitination is caused by the ability of Parkin to modify a substrate protein by covaient attachment of Ubiquitin, a substrate protein being Parkin itself, or another protein such as Mitofusion 1 or 2, FBW7, or other publicly reported substrates of Parkin ligase.

[389] Further embodiments of the present disclosure relate to methods of treating, preventing, or ameliorating one or more symptoms associated with neurological diseases or disorders including but not limited to Alzheimer's Dementia, Parkinson's disease, Huntington Disease, Amyotrophic Lateral Sclerosis (ALS), Freidreich's ataxia, Spinocerebellar Ataxia, Multiple Systems Atrophy, PSP, Tauopathy, Diffuse Lewy Body Disease, Lewy Body dementia, any disorder characterized by abnormal accumulation of a-synuclein, disorders of the aging process, and stroke.

[390] Other embodiments of the present disclosure relate to methods of treating, preventing, or ameliorating one or more symptoms associated with but not limited to mental retardation, deafness, blindness, diabetes, obesity, cardiovascular disease, and autoimmune diseases such as multiple sclerosis, Sjogrens syndrome, lupus, glaucoma, including pseudoexfoliation glaucoma, Leber's Hereditary Optic Neuropathy, and rheumatoid arthritis.

[391] Further embodiments of the present disclosure of the present invention relate to methods of treating, preventing, or ameliorating one or more symptoms associated with but not limited to Mitochondrial Related Diseases or Capsules as follows: Alpers Disease

Bartli Syndrome / LiC (Lethal Infantile Cardiomyopathy) Beta-oxidation Defects

Carnitine-Acyl-Carnitine Deficiency

Carnitine Deficiency

Creatine Deficiency Syndromes

Co-Enzyme Q10 Deficiency

Complex ΐ Deficiency

Complex II Deficiency

Complex III Deficiency

Complex IV Deficiency / COX Deficiency- Complex V Deficiency

CPEO

CPT I Deficiency

CPT II Deficiency

KSS

Lactic Acidosis

LBSL - Leukodystrohpy

LCAD

LCHAD

Leigh Disease or Syndrome

Luft Disease

MAD / Glutaric Aciduria Type II

MCAD

MELAS

MER F

MIRAS

Mitochondrial Cytopathy

Mitochondrial DNA Depletion

M itochondrial Encephalopathy

Mitochondrial Myopathy

MNGIE NARP

Pearson Syndrome Pyruvate Carboxylase Deficiency

Pyruvate Dehydrogenase Deficiency

POLG Mutations

Respiratory Chain

SCAD

SCHAD

VLCAD.

[392] In one embodiment, the methods of the present disclosure include treating and/or reducing the incidence of cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), (Γ), or (I"), or a pharmaceutically acceptable salt or solvate thereof. The compound of the present disclosure can disrupts at least one Parkin ligase zinc finger and induces Parkin ligase activity, wherein the compound can coordinate with a zinc ion and/or bind or react with a cysteine. In a specific embodiment, the Parkin ligase suppresses the growth of one or more tumors and/or prevents metastasis of one or more tumors. In another embodiment, the compound of formula (I), (Γ), or (I"), or a pharmaceutically acceptable salt or solvate thereof eliminates damaged mitochondria, increases cell viability during cellular stress, decreases tumor transformation and/or mitigates alpha-synuclein in cells. In another embodiment, the cancer is glioblastoma, small cell lung carcinoma, breast cancer or prostate cancer.

[393] In a specific embodiment, the methods of the present disclosure include treating and/or reducing the incidence of Parkinson's disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), (Γ), or (I"), or a pharmaceutically acceptable salt or solvate thereof that disrupts at least one Parkin ligase zinc finger and induces Parkin ligase activity, wherein the compound can coordinate with a zinc ion and/or bind or react with a cysteine. In a specific embodiment, the compound of the present disclosure eliminates damaged mitochondria, increases cell viability during cellular stress and/or mitigates alpha-synuclein in cells.

Pharmaceutical Compositions and Formulations

[394] Hie present disclosure also includes pharmaceutical compositions for modulating or activating a Parkin ligase in a subject. In one embodiment, a pharmaceutical composition comprises one or more compounds of formula (I), (Γ), or (I"), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, one or more compounds of formula (1), (Γ), or (I"), or a pharmaceutically acceptable salt or solvate thereof, in a pharmaceutical composition as described herein disrupts at least one Parkin ligase zinc finger. In another embodiment, one or more compounds of formula (I), (Γ), or (I"), or a pharmaceutically acceptable salt or solvate thereof, in a pharmaceutical composition as described herein coordinates with a Zn ion, and/or react with at least one thiol group in a cysteine.

[395] In one embodiment of the present disclosure, a pharmaceutical composition comprises a tlierapeuticallv effective amounts of one or more compounds of formula (1), (Γ), or (I"), or a pharmaceutically acceptable salt or solvate thereof.

[396] In a specific embodiment, a pharmaceutical composition, as described herein, comprises one or more compounds selected from Table 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, a pharmaceutical composition as described herein comprise one or more compounds selected from Table 2, or a pharmaceutically acceptable salt or solvate thereof.

herein does not contain:

[397] In one embodiment, a pharmaceutical composition, as described herein, comprising one or more compounds of formula (I), (Γ), or (I"), or a pharmaceutically acceptable salt or solvate thereof, further comprises one or more additional therapeutically active agents. In one embodiment, one or more additional therapeutically active agents are selected from therapeutics useful for treating cancer, neurological disease, a disorder characterized by abnormal accumulation of a-synuclein, a disorder of an aging process, cardiovascular disease, bacterial infection, viral infection, mitochondrial related disease, mental retardation, deafness, blindness, diabetes, obesity, autoimmune disease, glaucoma, Leber's Hereditary Optic Neuropathy, and rheumatoid arthritis.

[398] In a further embodiment of the present disclosure, a pharmaceutical composition comprising one or more compounds of formula (I), (F), or (I"), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient or adjuvant is provided. The pharmaceutically acceptable excipients and adjuvants are added to the composition or formulation for a variety of purposes. In another embodiment, a pharmaceutical composition comprising one or more compounds of formula (I), (Γ), or (!"), or a pharmaceutically acceptable salt or solvate thereof, further comprises a pharmaceutically acceptable carrier. In one embodiment, a pharmaceutically acceptable carrier includes a pharmaceutically acceptable excipient, binder, and/or diluent. In one embodiment, suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffsn, hydroxymethyicellulose and polyvinylpyrrolidone.

[399] In certain embodiments, the pharmaceutical compositions of the present disclosure may additionally contain other adjunct components conventionally found in pharmaceutical compositions, at their art-established usage levels. Thus, for example, the pharmaceutical compositions may contain additional, compatible, pharmaceutically-active materials such as, for example, antipruritics, astringents, local anesthetics or anti-inflammatory agents, or may contain additional materials useful in physically formulating various dosage forms of the compositions of the present invention, such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers. However, such materials, when added, should not unduly interfere with the biological activities of the components of the compositions of the present invention . The formulations can be sterilized and, if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously interact with the oligonucleotide(s) of the formulation.

[400] For the purposes of this disclosure, the compounds of the present disclosure can be formulated for administration by a variety of means including orally, parenterally, by inhalation spray, topically, or rectally in formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used here includes subcutaneous, intravenous, intramuscular, and intraarterial injections with a variety of infusion techniques, intraarterial and intravenous injection as used herein includes administration through catheters.

[401] The compounds disclosed herein can be formulated in accordance with the routine procedures adapted for desired administration route. Accordingly, the compounds disclosed herein can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formuiatory agents such as suspending, stabilizing and/or dispersing agents. The compounds disclosed herein can also be formulated as a preparation for implantation or injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (e.g., as a sparingly soluble salt). Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Suitable formulations for each of these methods of administration can be found, for example, in Remington: The Science and Practice of Pharmacy, A. Genna.ro, ed., 20^th edition, Lippincott, Williams & Wilkins, Philadelphia, PA.

[402] n certain embodiments, a pharmaceutical composition of the present disclosure is prepared using known techniques, including, but not limited to mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes.

[403] In one embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I), ( !').. or (Γ), or a pharmaceutically acceptable salt or solvate thereof, as disclosed herein, combined with a pharmaceutically acceptable earner. In one embodiment, suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions. Pharmaceutically acceptable earners are well known to those skilled in the art and include, but are not limited to, from about 0.01 to about 0.1 M and preferably 0.05M phosphate buffer or 0.8% saline. Such pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non-aqueous solvents suitable for use in the present application include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.

[404] Aqueous carriers suitable for use in the present application include, but are not limited to, water, ethanol, alcoholic/aqueous solutions, glycerol, emulsions or suspensions, including saline and buffered media. Oral carriers can be elixirs, syrups, capsules, tablets and the like.

[405[ Liquid carriers suitable for use in the present application can be used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compounds. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.

[406[ Liquid carriers suitable for use in the present application include, but are not limited to, water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also include an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form comprising compounds for parenteral administration. The liquid carrier for pressurized compounds disclosed herein can be halogenated hydrocarbon or other pharmaceutically acceptable propellent.

[407] Solid carriers suitable for use in the present application include, but are not limited to, inert substances such as lactose, starch, glucose, methyl-cellulose, magnesium stearate, dicalcium phosphate, mannitol and the like. A solid carrier can further include one or more substances acting as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents: it can also be an encapsulating material . In powders, the carrier can be a finely divided solid which is in admixture with the finely divided active compound. In tablets, the active compound is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active compound. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.

[408] Parenteral carriers suitable for use in the present application include, but are not limited to, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, iactated Ringer's and fixed oils. Intravenous carriers include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose and the like. Preservatives and other additives can also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like. [409] Carriers suitable for use in the present application can be mixed as needed with disinte grants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known in the art. The carriers can also be sterilized using methods that do not deleteriously react with the compounds, as is generally known in the art.

[410] Diluents may be added to the formulations of the present invention. Diluents increase the bulk of a solid pharmaceutical composition and/or combination, and may make a pharmaceutical dosage form containing the composition and/or combination easier for the patient and care giver to handle. Diluents for solid compositions and/or combinations include, for example, microcrystaliine cellulose (e.g., AVICEL), rnicrofme cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., EUDRAGIT® ), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[411] Additional embodiments relate to the pharmaceutical fonnulations wherein the formulation is selected from the group consisting of a solid, powder, liquid and a gel. In certain embodiments, a pharmaceutical composition of the present invention is a solid (e.g., a powder, tablet, a capsule, granulates, and/or aggregates). In certain of such embodiments, a solid pharmaceutical composition comprising one or more ingredients known in the art, including, but not limited to, starches, sugars, diluents, granulating agents, lubricants, binders, and disintegrating agents.

[412] Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions and/or combinations include acacia, alginic acid, carbomer (e.g., carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, gum tragacanth, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., KLUCEL), hydroxypropyl methyl cellulose (e.g., METHOCEL), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g., KOLLIDON, PLASDONE), pregelatinized starch, sodium alginate, and starch.

[413] The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition and/or combination. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., AC-DI-SOL and PRIMELLOSE), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., KOLLIDON and POLYPLASDONE), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystaliine cellulose, polacrilin potassium, powdered cellulose, pregelatmized starch, sodium alginate, sodium starch glycolate (e.g., EXPLOTAB), potato starch, and starch.

[414] Glidants can be added to improve the flowability of a non-compacted solid composition and/or combination and to improve the accuracy of dosing. Excipients that may- function as giidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

[415] When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition and/or combination to reduce adhesion and ease tlie release of tlie product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl paimitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl furnarate, stearic acid, talc, and zinc stearate.

[416] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that may^¬ be included in the composition and'or combination of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[417] Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level .

[418] In certain embodiments, a pharmaceutical composition of the present invention is a liquid (e.g., a suspension, elixir and/or solution), in certain of such embodiments, a liquid pharmaceutical composition is prepared using ingredients known in the art, including, but not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.

[419] Liquid pharmaceutical compositions can be prepared using compounds of formula (I), (Γ), or (I"), or a pharmaceutically acceptable salt or solvate thereof, and any other solid excipients where the components are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.

[420] For example, formulations for parenteral administration can contain as common excipients sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like. In particular, biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene- polyoxypropylene copolymers can be useful excipients to control the release of active compounds. Other potentially useful parenteral delivery systems include ethyiene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation administration contain as excipients, for example, lactose, or can be aqueous solutions containing, for example, polyoxyethylene-9-auryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally. Formulations for parenteral administration can also include glycocholate for buccal administration, methoxysalicylate for rectal administration, or citric acid for vaginal administration.

[421] Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition and/or combination an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that may be useful in liquid compositions and/or combinations of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.

[422] Liquid pharmaceutical compositions can also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxy-propyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, and xanthan gum.

[423] Sweetening agents such as aspartame, lactose, sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar may be added to improve the taste.

[424] Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxy! toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability.

[425] A liquid composition can also contain a buffer such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field. [426] In one embodiment, a phannaceuticai composition is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, etc.). In certain of such embodiments, a pharmaceutical composition comprises a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. In certain embodiments, other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives). In certain embodiments, injectable suspensions are prepared using appropriate liquid carriers, suspending agents and the like. Certain phannaceuticai compositions for injection are presented in unit dosage form, e.g., in ampoules or in multi-dose containers. Certain pharmaceutical compositions for injection are suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Certain solvents suitable for use in pharmaceutical compositions for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, such suspensions may also contain suitable stabilizers or agents that increase the solubility of the phannaceuticai agents to allow for the preparation of highly concentrated solutions.

[427] The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenteral!}⁷ acceptable diluent or solvent, such as a solution in 1,3- butane-diol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables. Formulations for intravenous administration can comprise solutions in sterile isotonic aqueous buffer. Where necessary, the formulations can also include a solubilizing agent and a local anesthetic to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampule or sachet indicating the quantity of active agent. Where the compound is to be administered by infusion, it can be dispensed in a formulation with an infusion bottle containing sterile pharmaceutical grade water, saline or dextrose/water. Where the compound is administered by injection, an ampule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.

[428] Suitable formulations further include aqueous and non-aqueous sterile injection solutions that can contain antioxidants, buffers, bacteriostats, bactericidal antibiotics and solutes that render the formulation isotonic with the bodily fluids of the intended recipient; and aqueous and non-aqueous sterile suspensions, which can include suspending agents and thickening agents.

[429] In certain embodiments, a pharmaceutical composition of the present invention is formulated as a depot preparation. Certain such depot preparations are typically longer acting than non-depot preparations. In certain embodiments, such preparations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. In certain embodiments, depot preparations are prepared using suitable polymeric or hydrophobic materials (for example an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[430] In certain embodiments, a pharmaceutical composition of the present invention comprises a delivery system. Examples of delivery systems include, but are not limited to, liposomes and emulsions. Certain delivery systems are useful for preparing certain pharmaceutical compositions including those comprising hydrophobic compounds. In certain embodiments, certain organic solvents such as dimethyl sulfoxide are used.

[431] In certain embodiments, a pharmaceutical composition of the present invention comprises a co-solvent system. Certain of such co-solvent systems comprise, for example, benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. In certain embodiments, such co-solvent systems are used for hydrophobic compounds. A non-limiting example of such a co-solvent system is the VPD co-solvent system, which is a solution of absolute ethanol comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80 and 65% w/v polyethylene glycol 300. The proportions of such co-solvent systems may be varied considerably without significantly altering their solubility and toxicity characteristics. Furthermore, the identity of co-solvent components may be varied: for example, other surfactants may be used instead of Polysorbate 80: the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.

[432] In certain embodiments, a pharmaceutical composition of the present invention comprises a sustained-release system. A non-limiting example of such a sustained-release system is a semi-permeable matrix of solid hydrophobic polymers. In certain embodiments, sustained-release systems may, depending on their chemical nature, release pharmaceutical agents over a period of hours, days, weeks or months.

[433] Appropriate pharmaceutical compositions of the present disclosure can be determined according to any clinically-acceptable route of administration of the composition to the subject. The manner in which the composition is administered is dependent, in part, upon the cause and/or location. One skilled in the art will recognize the advantages of certain routes of administration. The method includes administering an effective amount of the agent or compound (or composition comprising the agent or compound) to achieve a desired biological response, e.g., an amount effective to alleviate, ameliorate, or prevent, in whole or in part, a symptom of a condition to be treated, e.g., oncology and neurology disorders. In various aspects, the route of administration is systemic, e.g., oral or by injection. The agents or compounds, or pharmaceutically acceptable salts or derivatives thereof, are administered orally, nasally, transdeimally, pulmonary, inhalationaliy, buccally, sublingually, intraperitoneal 3y, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, intraportally, and parenteral!}'. Alternatively or in addition, the route of administration is local, e.g., topical, intra-tumor and peri-tumor. In some embodiments, the compound is administered orally.

[434] In certain embodiments, a pharmaceutical composition of the present disclosure is prepared for oral administration. In certain of such embodiments, a pharmaceutical composition is formulated by combining one or more agents and pharmaceutically acceptable carriers. Certain of such carriers enable pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject. Suitable excipients include, but are not limited to, fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmetrryl-cellulose, sodium carboxymethylceiiuiose, and/or polyvinylpyrrolidone (PVP). In certain embodiments, such a mixture is optionally ground and auxiliaries are optionally added. In certain embodiments, pharmaceutical compositions are formed to obtain tablets or dragee cores. In certain embodiments, disintegrating agents (e.g., cross-linked polyvinyl pyrroiidone, agar, or alginic acid or a salt thereof, such as sodium alginate) are added.

[435] In certain embodiments, dragee cores are provided with coatings. In certain such embodiments, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to tablets or dragee coatings.

[436] In certain embodiments, pharmaceutical compositions for oral administration are push-fit capsules made of gelatin. Certain of such push-fit capsules comprise one or more pharmaceutical agents of the present invention in admixture with one or more filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In certain embodiments, pharmaceutical compositions for oral administration are soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In certain soft capsules, one or more pharmaceuticai agents of the present invention are be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.

[437] In certain embodiments, pharmaceutical compositions are prepared for buccal administration. Certain of such pharmaceutical compositions are tablets or lozenges formulated in conventional manner.

[438] In certain embodiments, a pharmaceutical composition is prepared for transmucosal administration. In certain of such embodiments penetrants appropriate to the barrier to be permeated are used in the formulation . Such penetrants are generally known in the art.

[439] In certain embodiments, a pharmaceutical composition is prepared for administration by inhalation. Certain of such pharmaceutical compositions for inhalation are prepared in the form of an aerosol spray in a pressurized pack or a nebulizer. Certain of such pharmaceutical compositions comprise a propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In certain embodiments using a pressurized aerosol, the dosage unit may be determined with a valve that delivers a metered amount. In certain embodiments, capsules and cartridges for use in an inhaler or insufflator may be formulated. Certain of such formulations comprise a powder mixture of a pharmaceutical agent of the invention and a suitable powder base such as lactose or starch.

[440] In other embodiments the compound of the present disclosure are administered by the intravenous route. In further embodiments, the parenteral administration may be provided in a bolus or by infusion.

[441 [ In certain embodiments, a pharmaceutical composition is prepared for rectal administration, such as a suppository or retention enema. Certain of such pharmaceutical compositions comprise known ingredients, such as cocoa butter and/or other glycerides. [442] In certain embodiments, a pharmaceutical composition is prepared for topical administration. Certain of such pharmaceutical compositions comprise bland moisturizing bases, such as ointments or creanis. Exemplar}_' suitable ointment bases include, but are not limited to, petrolatum, petrolatum plus volatile silicones, and lanolin and water in oil emulsions. Exemplary suitable cream bases include, but are not limited to, cold cream and hydrophilic ointment.

[443] In certain embodiments, the therapeutically effective amount is sufficient to prevent, alleviate or ameliorate symptoms of a disease or to prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art.

[444] In certain embodiments, one or more compounds of formula (I), (T), or (I"), or a pharmaceutically acceptable salt or solvate thereof are formulated as a prodrug. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically more active form. In certain embodiments, prodrugs are useful because they are easier to administer than the corresponding active form. For example, in certain instances, a prodrug may be more bioavailable (e.g., through oral administration) than is the corresponding active form. In certain instances, a prodrug may have improved solubility compared to the corresponding active fonn. In certain embodiments, prodrugs are less water soluble than the corresponding active form. In certain instances, such prodrugs possess superior transmittal across cell membranes, where water solubility is detrimental to mobility. In certain embodiments, a prodrug is an ester. In certain such embodiments, the ester is metabolically hydrolyzed to carboxylic acid upon administration. In certain instances the carboxylic acid containing compound is the corresponding active form. In certain embodiments, a prodrug comprises a short peptide (polyaminoacid) bound to an acid group. In certain of such embodiments, the peptide is cleaved upon administration to form the corresponding active form.

[445] In certain embodiments, a prodrug is produced by modifying a pharmaceutically active compound such that the active compound will be regenerated upon in vivo administration. The prodrug can be designed to alter the metabolic stability' or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a daig. By virtue of knowledge of pharmacodynamic processes and drug metabolism in vivo, those of skill in this art, once a pharmaceutically active compound is known, can design prodrugs of the compound (see, e.g., Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392).

[446] In various aspects, the amount of the compound of formula (I), (Γ), or (1"), or a pharmaceutically acceptable salt or solvate thereof, or compounds disclosed in Table 1 and/or Table 2, or a pharmaceutically acceptable salt or solvate thereof, can be administered at about 0.001 mg/kg to about 100 mg/kg body weight (e.g., about 0.01 mg/kg to about 10 nig/kg or about 0.1 mg/kg to about 5 mg/kg).

[447] The concentration of a disclosed compound in a pharmaceutically acceptable mixture will vary depending on several factors, including the dosage of the compound to be administered, the pharmacokinetic characteristics of the compound(s) employed, and the route of administration. The agent may be administered in a single dose or in repeat doses. The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. Treatments may be administered daily or more frequently depending upon a number of factors, including the overall health of a patient, and the formulation and route of administration of the selected compound(s). An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the dmg required to prevent, counter or arrest the progress of the condition.

[448] The compounds or pharmaceutical compositions of the present disclosure may be manufactured and/or administered in single or multiple unit dose forms.

[449] Having now generally described the invention, the same will be more readily understood through reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention.

EXAMPLES

Example 1 : Identification of Parkin activators

Assay principle:

[450] The assay based on the irreversible reaction of an Activity-Based Probe (ABP) with the active site cysteine in the enzyme. ABP consists of a ubiquitin moiety with an epitope tag (e.g. HA tag) at the N-terminus, and a reactive group at the C -terminus. The activity of Parkin-RBR (w/o the R0 inhibitory domain) is significantly higher than the activity of Parkin-RORBR or the activity of full-length Parkin. The covalent attachment of ABP to Parkin can be monitored by Time Resolved Fluorescence Resonance Energy Transfer (TR- FRET)

- Parkin-RORBR, full-length Parkin→ low TR-FRET signal (negative control)

-Parkin RBR --> high TR-FRET signal (positive control)

[451] Compounds increasing the activity of Parkin-RORBR or the activity of full-length - Parkin can be identified by an increase in TR-FRET signal.

Strategy: use of N-terminal His-SUMO tagged constructs of Parkin-RORBR, full-length Parkin and Parkin-RBR. (from Evotec Slides; Based on Riley et al. 2013 , Nat Commun. 4: 1982 & on information provided by E3x Bio; grant Application)

Constructs:

[452] - Full-length Parkin (1-465), RORBR (141-465) and RBR (238-465) expression with N-terminal Hise-SUMO-tag (can potentially be removed during purification using SENP1 protease) in E. cold as described by Riley et al.

-N-terminal Hise-tag enabling TR-FRET-assay --> use of the purified protein that still have the N-terminal His6-SUMO-tags on.

- Small scale tests are conducted for all constructs to evaluate which construct, full-length Parkin or RORBR, give better yield to facilitate an UTS-assay.

Phase 1: Protein Production

[453] - Initiate gene synthesis through third party for full-length Parkin with N-terminal Hise-SUMO, His6-SUMO-R0RBR and Flise-SUMO-RBR, codon-optimized for expression in E. cali and subcloning into a suitable expression vector

- Small scale test expression evaluated by Western Blotting to estimate the yield of soluble protein

- Transform the RBR construct as well as either the full-length Parkin construct or the RORBR construct into BL21(DE3) and express as outlined in Riley et al., in the scale of 6- 24L (depending on outcome of small scale test expression)

- Purification of -10 mg of the RBR construct as well as either the full-length Parkin construct or the RORBR construct as described by Riley et al.*, i.e. IMAC, MonoQ and size exclusion.

Phase 2: Assay Development

[454] Goals: Set-up robust primary screening assays in 1,536-well assay plate format

- Establish assays in 384- ell format with a reasonable dynamic range (e.g. using Parkin +./- the R0 inhibitory domain)

- Optimize assay (e.g. in terms of concentrations of assay components, buffer, additives, order of addition of reagents, and incubation temperature)

- Run time course experiments to define optimal incubation times

- Demonstrate assay robustness (goal: Z'>0.5)

-Demonstrate readout stability

- Test DMSO tolerance

- Demonstrate specificity of the assay signal obtained using the Parkin RBR domain (w/o the R0 inhibitory domain) by titration of Ub (competing with ABP)

- Transfer assay from 384- to final 1,536-well screening plate format; adapt the assay to the EVOscreen™ Mark 111 HTS platform

- If necessary, fine-tune the assay conditions in order to optimize assay robustness in this high density plate format (goal: Z'>0.5) and to demonstrate assay suitability for high- throughput screening (HTS)

- Confirm, stability of assay reagents under screening conditions over time

- Demonstrate plate-to-plate and day-to-day assay robustness

- Estimate and procure the amounts of all assay reagents required for screening and hit profiling.

Phase 3: Screening

[455] Marker Library Screen (MLS):

- Pre-screening of a diverse marker library of approximately 2.5k representative lead-like compounds against the primary screening assay at two concentrations in triplicate

- Statistical analysis of the MLS and hit definition using the 3-sigma-method (plate-based, based on the scatter of compound-free DMSO wells)

- Selection of the optimal compound concentration for primary screening

Primary Screen (PS):

- Screening of approximately 75,000 lead-like compounds against the primary screening assay at one uniform compound concentration i n I s: re-screening of compound plates that do not meet an agreed re-screen criterion (e.g. Z'>0.5)

- Hit definition for the primary screen using the 3-sigma-method (plate-based, based on the scatter of compound-free DMSO wells) Statistical analysis of the primary screen --> Primary Hit Compounds (Parkin activators) Hit Confirmation (HC):

- Selection of a set of up to approximately 750 primary hits for Hit Confirmation

- Cherry picking of the selected compounds and reformatting for testing

- Retesting of the selected cpds against the primary screening assay at the compound screening concentration (n=3)

- Statistical analysis of the Hit Confirmation campaign→ Identification of confirmed small molecule Parkin activators.

Phase 4: HitProfilmg (HP):

- Selection of a set of up to approximately 250 confirmed hit compounds for Hit Profiling

- Cherry picking of the selected compounds and reformatting for concentration-response testing

- Concentration-response testing as 11 -point compound dilution series against the primary screening assay (n=2)

- Automated data fitting of the concentration response cun/es and calculation of the resulting IC50 values

- LC/'MS inspection of the hit compounds to confirm compound identit ⁷ and purity

- Structure-activity relationship analysis (SAR) of the active hit compounds

- Confirmed & profiled small molecule Parkin activators.

Example 2: Activity-Based Probe Assay using an Ubiquitin vinyl sulfone probe

[456] An Ubiquitin vinyl sulfone probe can be used that irreversibly binds to the active site cysteine of Parkm ligase. Covalent attachment of the probe to the Parkm can be monitored by TR-FRET. Candidate activator compounds can be identified by increasing the activity of Parkin iigase due to an increase in TR-FRET signal. Screening for activating compounds can be distinguished from the controls as follows:

100% activation signal = Heat activated Parkin + 100 nM control activator in DMSO.

0% activation signal = Heat activated Parkin + DMSO only.

Parkin activators can be identified by an increase of the 0% activation signal TR-FRET signal.

[457] Assay Conditions:

Materials:

Assay Plate: White 384 well plate (Corning 3572) Enzyme: Parkin-His tagged 203 μΜ (10.5 mg/ml)

Probe: Ubiquitin vinyl-sulfone (HA-Ub-VS Boston Biochem U-212)

DMSO: DMSO (Sigma cat # D4540 -100ML)

Reaction Buffer: 50 mM HEPES (pH 8,5), 150 niM NaCl, 0.01% Tween 20,

Detection Buffer: 50 mM HEPES (pH 8.5), 150 mM NaCl, 0.01% Tween 20, 0, 1% BSA

800mM KF

Detection Reagent A: 2,6 nM Anti-6HIS-Eu cryptate and 40 nM Anti-HA-XL665 in

detection buffer

Eu cryptate: Anti-6HIS-Eu cryptate (CisBio 61HISKLA)

XL665: Anti-HA-XL665^"(CisBio 610HAXLA)

Enzyme Reaction (15min pre incubation Parkin with activator only)

Parkin: 40 n :

HA-Ub-VS Probe: 70 nM

Activator/DMSO: 2X Activator/2% DMSO

Reaction time: 60 minutes

Temperature : 22 °C

Total volume: 10 ui reaction

Take 10 μΐ of Enzyme Reaction above and add 10 μΐ detection Reagent A under the following conditions:

Reaction time: 60 minutes

Temperature : 22 °C

Total volume: 20 ui

[458] Assay procedure (Using HP D-300 compound dispenser and Bravo for the operation):

1) Heat activate Parkin in reaction buffer (500 μΐ /1.5 ml tube: Eppendorf Thermomixer 5 minutes, 400 rpm at 58 °C and put on ice until needed).

2) Load assay plate wells with 4,8 μΐ 84.5 nM Parkin in reaction buffer by use of Bravo.

3) Deliver 0.2 μΐ 200X activator candidates in DMSO by use of HP D-300 compound dispenser. Highest 200X concentration = 20 μιη and then twofold dilutions.

4) Spin 1000 rpm, 2 minutes, at room temp.

5) Incubate plate for 15 minutes at room temp.

6) Add 5 μΐ 140 nM HA-Ub-VS Probe in reaction buffer by use of Bravo.

7) Spin 1000 rpm, 2 minutes, at room temp,

8) Incubate plate for 60 minutes at room temp.

9) Add 10 μΐ 2,6 nM Anti-6HIS-Eu cryptate and 40 nM Anti-HA-XL665 in detection buffer.

10) Spin 1000 rpm, 2 minutes, at room temp.

11 ) Incubate plate for 60 minutes at room temp. 12) Read plates on Perkin Elmer Envision instrument with the following parameters:

LANCE dual laser protocol loaded into the Envision® software

Top Mirror: LANCE/DELFIA Duel/Bias (Bar code 446)

Emission Filter: APC 665 EM (Bar code 205)

2nd Emission Filter: Europium 615 EM (Bar code 203)

Read 655 am (channel 1) and 615nm (channel 2) wavelengths on Envision®

[459] Data Analysis: The Data can be read in CS V files. There are two tables in those CS V files, which are the values of 655nm (channel 1) and 615nm (channel 2) wavelengths respectively. The data is converted to an HTRF Ratio ^:=: (Channel 1 / Channel 2) * 10,000 [460] The average of all the OuM controls (DMSO only) = BKGD (Background - 0% activation). Subtract BKGD from each FITRF Ratio value = HTRF-BKGD. The average of ail the l OOuM ΙΟΟηΜ control activator in DMSO controls = Max (100% activation). The following equation is then used to calculate % Activation for each well/candidate as follows: % Activation = (HTRF-BKGD/Max)* 100.

[461] The % Activation of compound titration can then be used to find activation EC50 or highest % activation if less than 75% activation is seen for the candidate compound.

[462] Graphpad Prisim was used with Transform X values: X = Log(X) and nonlinear regression (dose-response-stimulation): Log(agonist) vs Response - variable slope (four parameters) with constrains set to Bottom = 0 and Top = 100.

[463] The Activity-Based Probe Assay was performed with various compounds in Table 1 and/or Table 2. As shown in Table 3, the compounds indicated range of increasing Parkin activity with the activity-based probe Ubiquitin-vinyl sulfone, with the average value provided for each. This is also demonstrated in Figs. 1 and 4 for Compounds B and G. Each ceil ratings assay is presented

[464] Tabk 3

Probe Assay Aiito-ubiq

Compound Cell Ratings

EC50 {μΜ} EC50 l Μ) m [Example 4]

[Example 2] [Example 3]

+

E 63, 10 67.60

++

F 36.20 >40 NA

++

G 3.40 10.10

++

++

H— ί—*

H 3.60 30.50

+ +

++

1 13.80 15.40

+

J >100 >40 NA

K >100 >40 NA

L 5.20 4.70

++

M >100 >40 NA

N 52.00 5.60

++

+

0 16.70 5.10

+

+

P 62.90 19.50 +

+

Q 9.60 3.20

++

++

R 4.20 2.60 ++

++

S 16.40 8.70

T 17,90 5.30

++

+ u 26.90 9.30

-

V 7.00 3.70 w 3.00 1.90

+ Probe Assay Aiito-ubiq

Compound Cell Ratings

EC50 {μΜ} EC50 l Μ) m [Example 4]

[Example 2] [Example 3]

-

X 41.90 4.00

+

-

Y 6.30 9.60

+

AA 4.80 3.50

+ +

BB 8.60 3.40

CC >100 >40 NA

DD 53.80 >40 NA

EE 7.00 3.40

+

FF 11.00 1.80

+

++

GG 22.7 1.10 +

+ +

HH 4.1 0.83

II >100 9.60

JJ 4.2 3.20

+

KK 4.3 1.60

++ Probe Assay Aiito-ubiq

Compound Cell Ratings

EC50 {μΜ} EC50 l Μ) m [Example 4]

[Example 2] [Example 3]

-

++ ++

LL 18.5 10.80

++/-

MM 41.9 >40 ++/+

NN >100 >40 NA

00 >100 >40 NA

++ ++

PP 20.7 4.50

-

Q.Q. 52,6 11.80

++

RR 16.9 4.00

+

+

SS 3.2 2.20

-

TT >100 39.40

uu >100 >40 NA

- vv >100 6.00

WW 52.1 6.40

-

XX 27.1 12.70

YY 0.4 0.40 - zz 1.1 1.70 -

A3 4.4 2.10 -

B3 3.2 1.90 +

C3 1.9 2.30 -

D3 1.5 1.50 -

E3 43.2 23.30 NA

F3 9.8/4.0 8.00/4.00 NA Probe Assay Aiito-ubiq

Compound Cell Ratings m EC50 (μΜ) EC50 (μΜ)

[Example 4] [Example 2] [Example 3]

G3 6,8 6.80 NA

H3 >100 >40 NA

13 15.2 22.80 NA

J3 >100 >40 NA

K3 >100 >40 NA

L3 16,2 19.90 NA

M3 2,5 6.10 NA

N3 48,3 >40 NA

03 >100 >40 NA

P3 22.0 >40 NA

Q3 1.7 17.60 NA

R3 25.3 17.90 NA

S3 25.0 >40 NA

T3 >100 >40 NA

U3 47.5 >40 NA

V3 5.7 7.80 NA

W3 >100 >40 NA

X3 >100 >40 NA

Y3 5.8 6.90 NA

Z3 >100 >40 NA

A4 9,6 13.90 NA

B4 >100 >40 NA

C4 19,6 >20 NA

D4 9,2 19.90 NA

E4 41,0 >40 NA

F4 40.5 19.50 NA

G4 60.3 >40 NA

H4 20,8 >40 NA

14 >100 >40 NA Probe Assay Aiito-ubiq

Compound Cell Ratings m EC50 (μΜ) EC50 (μΜ)

[Example 4] [Example 2] [Example 3]

J4 >100 >40 NA

K4 >100 >40 NA

L4 62,7 >40 NA

M4 >100 >40 NA

N4 4.4 8.90 NA

04 >100 >40 NA

P4 >100 >40 NA

Q4 0.4 7.00 NA

R4 1.5/2.0 8.87/13.00 NA

S4 74.0 >40 NA

T4 9.0 22.00 NA

U4 5.0 7.00 NA

V4 13.0 >20 NA

W4 >100 16.00 NA

X4 0.9 >0.625 NA

Y4 3.0 20.00 NA

Z4 20.0 33.00 NA

AS 11.0 14.00 NA

B5 8.0 >40 NA

C5 14,0 >40 NA

D5 5.0 9.00 NA

E5 9.0 >40 NA

F5 32,0 >40 NA

G5 53.0 >40 NA

H5 36.0 >40 NA

15 9.0 >10 NA

J5 >100 >40 NA

K5 17.0 >40 NA

L5 3.0 29.00 NA Probe Assay Aiito-ubiq

Compound Cell Ratings

EC50 {μΜ} EC50 (μΜ) m [Example 4]

[Example 2] [Example 3] 5 1,0 >20 NA

IMS >100 >40 NA

05 >25 >40 NA

P5 78.0 >40 NA

Q5 29,5 >40 NA

R5 15.0 18.00 NA

S5 50.0 >40 NA

T5 >100 >40 NA

U5 1.0 9.00 NA

V5 23.0 >40 NA

W5 >100 >40 NA

X5 29.0 >40 NA

Y5 11.0 >40 NA

Z5 18,0 19.00 NA

A6 7,0 5.00/5.30 NA

B6 15.7 14.00 NA

C6 19,0 16.00 NA

D6 9,0 9.60 NA

E6 22.0 17.00 NA

F6 20,0 9.60 NA

G6 18.0 12.70 NA

H6 68.2 >40 NA

16 15,0 10.50 NA

J6 52.0 >40 NA

K6 11.0 5.00 NA

L6 27.0 20.00 NA 6 13.0 15.00 NA

N6 52.0 >40 NA

06 8.0 5.00 NA Probe Assay Aiito-ubiq

Compound Cell Ratings m EC50 (μΜ) EC50 (μΜ)

[Example 4] [Example 2] [Example 3]

P6 38.0 >40 NA

Q6 19.0 10.00 NA

R6 31.0 >40 NA

So 15.0 NA NA

T6 4.0 NA NA

U6 6.0 NA NA

V6 13.0 NA NA

W6 9.0 NA NA

X6 25.0 NA NA

Y6 12.0 NA NA

Z6 14.0 NA NA

A7 15.0 NA NA

B7 >100 NA NA

C7 19.0 NA NA

D7 6.0 NA NA

E7 48.0 NA NA

F7 25.0 NA NA

G7 21.0 NA NA

H7 4.0/7.0 NA NA

17 41,0 NA NA

J7 20.0 NA NA

K7 8.0 NA NA

L7 21,0 NA NA

M7 5.0 NA NA

N7 7.0 NA NA

07 5.0 NA NA

P7 3,0 NA NA

Q7 14.0 NA NA

R7 19.0 NA NA Probe Assay Aiito-ubiq

Compound Cell Ratings

EC50 (μΜ) EC50 l Μ)

m [Example 4]

[Example 2] [Example 3]

S7 27.0 NA NA

T7 5.0 NA NA

U7 13.0 NA NA

V7 24.0 NA NA

W7 8.0 NA NA

X7 43.0 NA NA

+++ >70% effect at 10 μ.Μ; ++ 69%-31% effect at 10 μΜ; + <30% effect at 10 μ.Μ; - negative at 10 μΜ; NA = not available; any cell assay indicated with a "/" shows the cell activity/dose response ,

Example 3: Parkin pUB Auto-uhiquitmyiatiera Assay

[465] A Parkin pUB Auto-ubiquitinylation Assay is used to evaluate a compound's potency to activate Parkin^'s ability to Auto-ubiquitmylate itself.

[466] The principle of this assay is that the E3 Ligase Parkin catalyzes the transfer of Ubiquitin to target proteins, but also has the ability to auto-ubiquitmylate itself. The phospho- Ubiquition (pUb) added to the assay alters the Parkin to a state where small molecule activators can enable the Parkin to auto-ubiquitinylate though the El - E2 cascade reaction. The use of a Eu cryptate Ubiquition and anti 6His-d2 that binds to the His tagged Parkin will give a signal when the Eu cryptate Ubiquition is auto-ubiquitinylate onto the Parkin which can be monitored by TR-FRET.

[467] Similar to the Activity-based probe assay in Example 2, screening for activating compounds can be distinguished from the controls as follows:

100% activation signal = pUb activated Parkin + 40 nM control activator in DMSO.

0% activation signal = pUb activated Parkin + DMSO only.

Parkin activators can be identified by an increase of the 0% activation signal TR-FRET signal.

Assay Plate: White 384 well plate (Corning 3572)

Enzyme 1 : El (Ubiquitin-activating enzyme/UBEl Boston Biochem E-305)

Enzyme 2: E2 (UBcH7/Ube2L3 Boston Biochem E2-640)

Enzyme 3: Parkin-His tagged 203 μΜ (10.5 mg/ml)

pUb: Phospho-Ubiquitin (S65) (Boston Biochem U-102)

Eu Cryptate Reagent: Ubiquitin Eu (CisBio 61 UBIKLA)

DMSO: DMSO (Sigma-34869-2.5L)

Reaction Buffer: 50 mM HEPES, 50 mM NaCl, 1 mM Mj 0.005% Tween 20, 0.1%

PF-127 (Fisher Scientific 50-310-494), pH 8.5 Detection Buffer: 50 mM HEPES, 50 mM NaCl, 800 mM KF, 5 mM EDTA, 0.005% Tween 20, 0.1% PF-127, pFI 8.5

Detection Reagent Z: 13.4 nM Anti-6His-d2 in detection buffer

d2 Reagent: Anti-6His-d2 (CisBio 61HISDLA)

[468] Assay Conditions:

[469] Enzyme Reaction { i in in re -incubation with Parkin, pUb and activator only)

El: nM

E2: 50 nM

Ubiquitin Eu: 8.8 nM

Reaction time: 120 minutes

Temperature: 22 °C

Total volume: 10 ul reaction

Take 10 μΐ of Enzyme Reaction above and add 10 μΐ detection Reagent Z under the following conditions:

Reaction time: 60 minutes

Temperature: 22 °C

Total volume: 20 μΐ

[471] Assay Procedure:

1) Load assay plate wells with 4.9 μΐ 400.0 nM Parkin, 400 nM pUb in reaction buffer by use of Eppendorf 12-channel pipette.

2) Deliver 0.1 μ3 100X activator candidates in DMSO by use of Echo 555 compound dispenser. Highest 100X concentration = 100 μηι and then twofold dilutions. Add each compound and control in duplicate wells.

3) Spin 1000 rpm, 2 minutes, at room temp.

4) Incubate plate for 15 minutes at room temp.

5) Add 5μ1 10 n : El, 100 nM E2, 17.6 nM Ubiquitin Eu and 2 mM ATP in Reaction Buffer by use of Eppendorf 12-channel pipette.

6) Spin 1000 rpm, 2 minutes, at room temp.

7) Incubate plate for 120 minutes at room temp.

8) Add 10 μΐ 13.4 nM and his d2 in detection buffer by use of Eppendorf 12-channel pipette.

9} Spin 1000 rpm, 2 minutes, at room temp.

10) Incubate plate for 120 minutes at room temp.

11) Read plates on Perkm Elmer Envision instrument with the following parameters: LANCE dual laser protocol loaded into the Envision® software

Top Mirror: LANCE/DELFIA Duel/Bias (Bar code 446)

Emission Filter: APC 665 EM (Bar code 205)

2nd Emission Filter: Europium 615 EM (Bar code 203)

Read 655 nm (channel 1) and 615mn (channel 2) wavelengths on Envision®

[472] Data Analysis: The Data can be read in CSV files. There are two tables in those CSV files, which are the values of 655mm (channel 1) and 615nm (channel 2) wavelengths respectively. The data is converted to an HTRF Ratio = (Channel 1 / Channel 2) * 10,000 [473] The average of all the OuM controls (DMSO only) = BKGD (Background - 0% activation). Subtract BKGD from each HTRF^" Ratio value = HTRF -BKGD. The average of all the !OOuM control activator in DMSO controls = Max (100% activation). The following equation is then used to calculate % Activation for each well/candidate as follows: % Activation = (HTRF-BKGD/Max)* 100.

[474] The % Activation of compound titration can then be used to find activation EC50 or highest % activation if less than 75% activation is seen for the candidate compound.

[475] XLFIT5 model 205 was applied for the data analysis. EC50 fit model (4 Parameter

Logistic Model/Sigmoidal dose-Response Model); fit = (A+((B-A)/(l+((C/x)^AD)))): res = (y- fit). The parameters are:

A: Bottom

B: Top

C: Relative EC50

D: Hill Slope

Constrains set to Bottom = 0 and Top =^: 100.

[476] The Parkin pUB auto-ubiquitinyiation Assay was performed with various compounds in Table 1 and/or Table 2. The compounds indicated a range of increasing Parkin activity in an auto-ubiquitination assay as shown in Table 3. This is also demonstrated in Figs. 2 and 5 for Compounds B and G.

Example 4: Cell Rating Experiments

[477] Compounds: All compounds were dissolved in DMSO to a concentration of 25 mM and stored at -20 °C. Compound 1 is N \^r'-( l -phenyl- iH- i,2,4-triazoie-3, 5 -diyi)dibenzamide.

[478] Cell Culture: S-HeLa stably expressing a YFP-Parkin fusion protein (kindly donated by Prof. Richard J. Youle, Porter Neuroscience Research Center, Bethesda, MD, USA) were utilised to assess Parkin-dependent induction of mitophagy. 4000 cells were seeded in each well of a 96 well plate (Parkin Elmer ViewPlate-96 F TC, cat. N. 6005182) and left to grow for 2/4 hours.

[479] Subsequently cells were incubated with vehicle (DMSO) or 6 μΜ CCCP for 1 hour prior to adding increasing concentrations of compound(l, 2.5, 5, 10 uM), each condition run in replicate of five. After 20 hours cells were processed for immunofluorescence.

[480] Immunofluorescence: Samples were fixed in 4% PFA for 25 minutes RT and permeabilized with PBS 0.1% Triton-Xl OO for 3 minutes on ice, blocked with PBS 3% BSA, 0.3% Triton-XlOO for 2 hours RT, followed by overnight incubation with primary antibody at 4° C (0.5 ug/ml rabbit Tomiti20 antibody FL-145; Santa Cruz Biotechnology) diluted in PBS 0.1 % BSA, 0.3% Triton-XlOO. The secondar ' goat anti-rabbit antibody conjugated with Dy Light 649 (Jackson ImmunoResearch) was applied for 1 hour at room temperature at a concentration of 2.8 ug/ml in conjunction with 1 ug/ml Hoechst33342.

[481] Cells were imaged using an Olympus ScanR automated microscope equipped with motorised stage and 20x APO planar objective. 18 images were acquired for each well using the following combination of excitation/emission filters: Hoechst33342 was excited through a 350/50 nm band pass filter and fluorescence intensity was collected through a 460/30 band pass filter, YFP was excited through a 500/20 nm band pass filter and fluorescence intensity- was collected through a 540/35 band pass filter. Dy Light 649 was excited through a 640/30 nm band pass filter and fluorescence intensity was collected through 700/75 band pass filter. Images were processed and analysed as described in the Image Analysis section.

[482] Image analysis: Images were processed and analysed using Columbus HCS Analysis software (Version 2.5.Ο., PerkinElmer) as follows:

[483] Tomm20 fluorescence intensity was corrected using the parabola algorithm. Hoechst 33342 fluorescence was used to identify and count cells. Cells were segmented according to Tomm20 fluorescence intensity. Spot detection was optimized to recognize number and total cellular area of Tomm20 stained clusters (mitochondria).

[484] Tomm20 staining intensity, spot numbers and spot area were used to train a linear classifier algorithm that discriminated between Tomm20 positive (high intensity, spot numbers and spot area) and Tomm20 negative cells (low intensity, spot numbers and spot area).

[485] Bar graphs were generated reporting the number of Tomm20 negative cells expressed as percentage of total cells imaged for each well (Figs. 3 and 6). Results were shown as mean ± SD of a representative experiment performed in triplicate. +++ indicates >70% effect at 10 μΜ; ++ indicates 69%-31 % effect at 10 μΜ; + indicates <30% effect at 10 μΜ; - indicates negative at 1 μΜ; NA ^:=: not available.

Example 5: Metabolic Stability in Rat Liver Microsomes (RLM) and Human Liver

Microsomes (HLM)

[486] Compounds were also tested for metabolic stability in both rat liver microsomes (RLM) and human liver microsomes (HLM) and their half-life caicuiated (See Table 4). The assay was performed as follows. The total volume for each incubation was 250 \ L. A 100 μΜ DMSO solution of compound (diluted from 10 mM stock solution) was spiked into 50 mM KH2PO4 (pH 7.4) buffer containing liver microsome at a concentration of 1.0 mg/mL. The reaction was initiated by the addition of 50 μΐ. of 1 mM NADPH. The final concentration of each compound was 1 μΜ (1 % DMSO). The positive controls, phenacetin for CYP 1A2, diclofenac for CYP2C9, omeprazole for CYP2C19, dextromethorphan for CYP2D6 and midazolam for CYP3A4 were added to a separate tube with the final substrate concentrations of 1 μ.Μ (1 % DMSO) for evaluating the enzyme activities in the liver microsomes. At 0, 15, 30 and 60 min, an aliquot of 15 \iL reaction mixtures were removed and 200 uL of methanol (with internal standard of 25 mg/mL propranolol) was added to quench the reaction. The resulting mixture was centrifuged and supernatant was used for LC- MS/MS analysis.

[487] The signals for each compound, or the metabolites for the probe substrates and the internal standard were integrated and the peak area ratios to internal standard were generated. Percent parent remaining at a specified timepomt was calculated based on the peak area ratios at time 0 (as 100%) for in vitro metabolic stability studies in liver microsome and hepatocyte. The observed rate constant (kobs) for the metabolism of substrates was calculated by plotting the natural log of percentage substrate remaining versus time of incubation with the slope being kobs. The half-life (T1/2) was calculated according to the following equation:

[488] Table 4

Compound

HLM ti/₂ (min) RUV! ti/₂ {min) ID

PP 2.1 1.6

E3 68.6 13.4

G3 30.0 9.2

13 69.0 41.0

L3 29.1 10.1

M3 4.1 0.8

P3 17.5 9.5

V3 25.4 1.3

Y3 15.4 1.7

A4 NA 9.0

C4 NA 22.0

D4 198.0 23.3

H4 IMA 59.0

N4 NA 3.0

Q4 NA 70.0

R4 IMA 2.0

T4 NA 10.0

U4 NA 11.0

V4 IMA 2.0

W4 NA 2.0

X4 NA 28.0

Y4 IMA 4.0

Z4 NA 80,0

A5 NA <1

B5 NA 5.0

C5 NA 5.0

D5 NA 3.0

E5 NA 9.0

15 198.0 124.0 Compound

HLM ti/₂ (min) RUV! ti/₂ {min) ID

K5 NA 28.0

L5 NA 12.0

M5 NA 29,0

Q.5 NA 25.0

R5 IMA 23.0

U5 NA 4.0

V5 NA 33.0

Y5 NA 24.0

Z5 NA 23.0

A6 NA 193.0

B6 NA 267.0

C6 NA 88.0

D6 NA 92.0

E6 NA 151.0

F6 NA 193.0

G6 NA 81.0

H6 NA 128.0

16 NA 198.0

K6 NA 495.0

L6 NA 347.0

M6 NA 289.0

06 NA 365.0

Q6 NA >500

S6 NA 20.0

U6 NA 88.0

V6 NA 13.0

W6 NA 52.0

Y6 NA 8.0

Z6 NA 13.0 Compound

HLM ti/₂ (min) UV! ti/₂ {min)

ID

A7 NA 75.0

C7 IMA 90.0

D7 NA 110.0

G7 NA 107.0

J7 IMA 128.0

K7 NA 61,0

L7 NA 5.0

7 NA 26.0

N7 NA 17.0

07 NA 15.0

P7 NA 131.0

Q7 NA 32.0

R7 NA 95.0

S7 NA 239.0

T7 NA 3.0

U7 NA 38.0

V7 NA 35.0

W7 NA 2.5

Example 6: Synthesis of 4-chloro-5-(dimethylamino)-2-[[5-(2-thienyl)isoxazol-3- yl]methyl]pyridazin-3-one (Compound F)

s ep a O s ep

s p

[489] Step a: Synthesis of ethyl-(Z)-2-hydroxy-4-oxo-4-(2-thienyl)but-2-enoate

[490] To a solution of l-(2-thienyl)ethanone (5.00 g, 39.63 mmol, 4.27 mL, 1.00 eq) in toluene ( 120 mL) at 0 °C was added potassium fe -butoxide (4.45 g, 39.63 mmol, 1.00 e ). Then diethyl oxalate (5.79 g, 39.63 mmol, 5.41 mL, 1.00 eq) was added dropwise within 0.5 h. The reaction mixture was stirred at 15 °C for 13.5 h . One main peak wrth the desired mass was detected by LC-MS. The mixture was filtered and the solid was collected. The solid was dissolved with ethyl acetate (200 mL), washed with aq. HCl solution (1 M, 100 mL * 2), dried over anhydrous a2S0 , filtered and concentrated in vacuo to afford crude ethyl-(Z)-2- hydroxy-4-oxo-4-(2-thienyl)but-2-enoate (5.50 g, 22.85 mmol, 58% yield, 94% purity) as a brown solid, which was used directly in the next step without further purification. LC-MS (ESI): m/z 227.1 ( M i l) .

[491 ] Step b: Synthesis of ethyl-5-(2-tliienyl)isoxazole-3-carboxylate

[492] A solution of ethyl-(Z)-2-hydroxy-4-oxo-4-(2-thienyl)but-2-enoate (2.50 g, 1 1.05 mmol, 1.00 eq) in EtOH (120 mL) at 15 °C was added NHzOH-HCl (3.00 g, 43.17 mmol, 3.91 eq). Then the mixture was stirred at 80 °C for 3 h. One main peak with desired MS was detected by LC-MS. The mixture was concentrated under reduced pressure to give a crude residue. The residue was diluted with H2O (80 mL), adjusted to pH = 7 by adding 33 wt% NH4OH (5 mL). The precipitate was filtered and dissolved in DCM (50 mL), and the aqueous layer was extracted with DCM (50 mL). The combined organic layers were dried over anhydrous Na.-SO i. filtered and concentrated in vacuum to etliyl-5-(2-thienyi)isoxazoie- 3-carboxylate (2.30 g, 9.17 mmol, 83% yield, 89% purity) as a brown solid. LC-MS (ESI): m/z 224.2 ⁽ W - WY .

[493] Step c: Synthesis of [5-(2-thienyl)isoxazol-3-yl]methanol [494] To a solution of ethyl-5-(2-thienyl)isoxazole-3-carboxylate (2.00 g, 8.96 mrnoi, 1.00 eq) in EtOH (40 mL) was added NaBH4 (678 mg, 17.92 mmol, 2.00 eq). Then the mixture was stirred at 80 °C for 2 h. TLC (33% ethyl acetate/petroleum ether) indicated the starting material was consumed completely. Sat. aq. NH4CI solution (80 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 10 min. After removal of ethanol under vacuum, the reaction mixture was extracted with DCM (120 mL). The organic layer was concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent of 0-50% ethyl acetate/petroleum ether gradient @60 niL/min) to afford [5-(2- thienyl)isoxazo3-3~yi]methanol (1.45 g, 7.52 mmol, 84% yield, 94% purity) as a yellow oil. LC-MS (ESI): m/z 182.2 { M i l) .

[495] Step d: Synthesis of [5-(2-thienyl)isoxazol-3-yl]methanol

[496] A solution of 4,5-dichloro-lH-pyridazin-6-one (500 mg, 3.03 mmol, 1.00 eq) in DMF (10 mL) was stirred at 140 °C for 24 h. One peak with the desired mass was detected by LC- MS. The mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (17-100% ethyl acetate/petroleum ether) to afford 5-chloro-4-(dimetliylamino)-lH-pyridazin-6-one (180 mg, 985.02 ;./mol, 33% yield, 95% purity at 254 ran) as a yellow solid. LC-MS (ESI): m/z 174.1 (M+H)⁺.

[497] Step d: Synthesis of 4-chloro-5-(dimethylamino)-2-[[5-(2-thienyl)isoxazol-3- yl jmethyl]pyridazin-3 -one

[498] To a solution of 5-chloro-4-(dimethylammo)-lH-pyridazin-6-one (80 mg, 460.83 ηιοΐ, 1.00 eq) and [5-(2-thienyl)isoxazol-3-yl]methanol (108 mg, 599.08 μπιοΧ, 1.30 eq) in TI-IF (2 mL) at 0 °C was added PPI13 (170 mg, 645.16 mnol, 1.40 eq) and DIAD (280 mg, 1.38 mmol, 268.80 L, 3.00 eq). Then the reaction mixture was stirred at 10 °C for 14 h. One peak with the desired mass was detected by LC-MS. The mixture was concentrated under reduced pressure to give a crude product. The crude product was slurried with EtOH (6 mL) twice. The solids were collected and dried to afford 4~chloro-5-(dimethyiamino)-2-[| 5- (2-thienyl)isoxazoi-3-yl]methyi]pyridazin-3-one (10.3 mg, 29.05 μη\ο\, 6.3% yield, 95% purity) as a white solid. ^!H NM (400 MHz, DMSQ-cfe) δ ppm: 7.94 (s, lH), 7.82-7.8 ! (m, 1H), 7.71-7.70 (m, 1H), 7.26-7.20 (rn, i l l). 6.74 (s, H i). 5.29 (s, 2H), 3.10 (s, 6H); ¹³C NMR (100 MHz, DMSO-flfc) δ ppm: 165.2, 161.2, 157.9, 148.3, 131.6, 130.1, 129.1, 128.6, 128.4, 109.4, 99.6, 47.0, 42.1. LC-MS (ESI): m/z 337.0 (M+l)^'", 339.0 (M+2) ^'. Example 7: Synthesis of 4,5-dic !oro~2-[(5-phe5iySisoxazo!~3-yl)niethy!]pyridazm-3-one (Compound I)

[499] Step a: Synthesis of ethyl-(Z)-2 -hydroxy -4-oxo-4-phenyl-but-2-enoate

[500] To a solution of 1-phenylethanone (5.00 g, 41.61 mmol, 4.85 mL, 1.00 eq) in toluene (60 mL) at 0 °C was added potassium, fe.* -butoxide (4.67 g, 41.61 mmol, 1.00 eq). Then diethyl oxalate (6.08 g, 41.61 mmol, 5.68 mL, 1.00 eq) was added dropwise at 0 °C within 0.5 h. The reaction mixture was stirred at 15 °C for 3.5 h. TLC (50% ethyl acetate/petroleum ether) indicated the starting material was consumed completely. The mixture was filtered, and then the filter cake was collected and dissolved in ethyl acetate (150 mL). The resulting solution was washed with aq. HQ solution (1 M, 80 mL x 2), dried over anhydrous Na?.S04, filtered and concentrated in vacuo to give ethyl-(Z)-2-hydroxy-4-oxo-4-phenyl-but-2-enoate (7.00 g, 28.61 mmol, 69% yield, 90% purity) as a yellow liquid, which was used in the next step without further purification, I . ( -.MS (ESI): m/z 22 1 . 1 (M i l) .

[501 [ Step b: Synthesis of ethyl-5-phenylisoxazole-3-carboxylate

[S02[ To a solution of ethyl~(Z)"2-hydroxy-4~oxo-4-phenyl~but-2~enoate (500 mg, 2.27 mmol, 1.00 eq) in EtOH (20 mL) at 10 °C was added NHtOH'HCl (631 mg, 9.08 mmol, ,00 eq). Tire reaction mixture was stirred at 80 °C for 3 h. TLC (ethyl acetate) indicated the starting material was consumed completely. The mixture was concentrated under reduced pressure to give a residue. Water (20 mL) was added to the residue and then the pH adjusted to 7 with 30 wt% ΝΗ3Ή2Ο (2 mL). The resulting solution was extracted with DCM (50 mL x 2). The organic layers were combined, washed with brine (30 mL), dried over anhydrous Na?,S04, filtered and concentrated in vacuo to give ethyl-5-phenylisoxazole-3-carboxylate (430 mg, 1.72 mmol, 76% yield) as a brown solid, which was used in the next step without further purification, LC-MS (ESI): ;;/ r 2 ! 8. i (M i l) .

[503] Step c: Synthesis of (5-phenylisoxazol-3-yl)methanol [504] To a mixture of ethyl-5-phenylisoxazole-3-carboxylate (430 mg, 1.98 mmol, 1.00 eg) in EtOH (10 ml) at 10 °C was added NaBHU (150 mg, 3.96 mmol, 2.00 eg). The mixture was stirred at 10 °C for 3 h. TLC (33% ethyl acetate/petroleum ether) indicated the starting material was consumed completely. Sat. aq. NH₄C1 solution (15 mL) was added to the reaction mixture. The mixture was concentrated under reduced pressure to remove ethanol. Then the resulting solution was extracted with DCM (40 mL < 2) and concentrated under reduced pressure to afford a residue, which was purified by column chromatography on silica gel (0-80% ethyl acetate/petroleum ether) to afford (5~phenylisoxazol-3-yl)methanol (280 mg, 1.57 mmol, 79% yield) as a white solid. LC-MS (ESI): m/z 176.2 (M+H)⁺.

[SOS] Step d: Synthesis of 4,5-dichloro-2-[(5-pheny3isoxazo3-3~yi)niethy3]pyridazin-3-one [506] To a mixture of (5-phenylisoxazol-3-yl)methanol (140 mg, 800 μχηο], 1 .32 eg), 4,5- dichloro-lH-pyridazin- 6-one (100 mg, 606.13 / mol, 1.00 eg) and PPh₃ (223 mg, 848.58 μπιοϊ, 1.40 eg) 111 THF (2.00 mL) at 0 °C was added DIAD (368 mg, 1.82 mmol, 353.56 iL, 3.00 eg). The mixture was stirred at 10 °C for 14 h. TLC (33% ethyl acetate/petroleum ether) indicated the starting material was consumed completely. The mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica (0-80% ethyl acetate/petroleum ether) to give a crude product. Then MeOH (6 mL) was added to the crude product and the resulting mixture was stirred at 10 °C for 1 h, filtered and the filter cake was collected and dried to afford 4,5-dichloro-2-[(5- phenylisoxazol-3-yl)methyl^"|pyridazin-3-one (29.2 mg, 88.83 μπιοΐ, 15% yield, 98% purity) as a white solid, ¾ NMR (400 MHz, DMSO-tfe) 5 ppm: 8.30 (s, 1H), 7.86-7.84 (m, 2H), 7.56-7.5 ! (m, 3H), 7.00 (s, 1H), 5,43 (s, 2H); ^l3C NMR (100 MHz, DMSO-ifc) δ ppm: 170.0, 160.5, 156.2, 137.1 , 133.7, 131.1, 129.7, 127.0, 126.1, 100.4, 48.2. LC-MS (ESI): m/z 322.0 ( M i l) . 324.0 (M l ! .?) . 326.0 < M 1 1 4 ·

[S07]

[508] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.

[509] While the invention has been described in connection with proposed specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth and as follows in the scope of the appended claims.

Claims

WHAT IS CLAIMED IS:

1. A compound of formula (I):

(I)

or a pharmaceutically acceptable salt or solvate thereof, wherein:

L⁴ and I ." are each independently selected from a bond, alkylene, alkenylene, ~0-, ~ NH-, - R⁶-, -NHC(O)-, -NR⁶C(0)-, -CH₂C(0)-, -C(0)NH-, -C(0)NR⁶-, -CH ( ! 0}\ ! !-. - ( iO)NS !( ! ! · ·. ^•(^'! ! C( ())N R '- . -S(0)_rt-. -S(0)nNH-, -S{0}«N R(^'R ··-. ·8(() )Λ 1 Κ Ί I 'CI i -. - S(0)n R⁶-, -NHS(0)_n-, or -NR⁶S(0)n-;

X is absent, alkylene, alkenylene, divalent cycloalkyl, divalent aryl, divalent heterocyclyl, or divalent monocyclic heteroaryi, wherein cycloalkyl, aryl, heterocyclyl, or heteroaryi is optionally substituted with one or more R⁵;

Y is cycloalkyl, aryl, heterocyclyl, or heteroaryi, wherein Y is optionally substituted with one or more R⁵;

R¹¹, R¹², and R^{l j} are each independently selected from H, I, Br, CI, F, CN, alkyl, haloalkyl, -SH, -SR⁴, -OH, -OR⁴, -NH2, -NHR⁴, -NR⁴R⁴, or -NO?.; or

R⁴ is each independently H, alkyl, aryl, arylalkyl, aryioxyaikyi, heterocyclyl, heterocyclylalkyl, heteroaryi, heteroarylalkyl, or heieroaryloxyaikyl, wherein each R⁴ is optionally substituted with one or more R⁵:

R⁵ is each independently I, Br, CI, F, -CN, -CONH2, -CONHR⁶, -CONR⁶R⁶, -COOH, -NFI2, -NHR⁶, NO2, -NR⁶R⁶, -OH, -OR⁶, -COOR⁶, -OSO3R⁶, oxo, R⁶, -SH, -SO2R⁶, -SO3H, - SO3R⁶, -S(0)nNH₂, -S(0)nNHR⁶, -S(0),,NR⁶R⁶, or -SR⁶;

R⁶ is each independently alkyl, haloalkyl, or cycloalkyl:

n is 0, 1, or 2;

provided that when L⁴ and V are each a bond and X is absent, then Y is not unsubstituted phenyl, pheny l substituted with alkyl, halogen or ---COOH, or Y is not cycloalkyi or thiazolyi; and

provided that when -L⁴-X-L⁵- is -CH2-, then Y is not phenyl, pryidyl, thiophenyl, thiadiazolyl, dioxolanone, pyrazolyl or oxiranyl;

wherein X is not divalent oxadiazolyl or divalent pyrazolyl;

wherein Y is not pyridyl of tetrahydrofuranyl: and wherein the compound is not 4,5-dichloro-2-((5-(thiophen-2-yl)isoxazol-3- yl)methyl)pyridazin-3(2H)-one, 4,5~Dichloro-2~{2-| 4-(diethylamino)phenyl |-2- oxoethyl}pyridazin-3(2H)-one, 2-((4,5-dichloro-6-oxopyridazin-l (6H)-yl)methyl)-l-ethyl- A^r,N-dimethyl-lH-benzo[i ]imidazole-6-sulfonamide, 4-(4-amino-5-chloro-6-oxopyridazin- l(6H)-yl)butyl benzoate, 2-(2-amino-4-methylthiazol-5-yl)-4,5-dichloropyridazin-3(2H)-one, or 2-(2-aminothiazol-4-yl)-4,5-dichloropyridazin-3(2H)-one.

2. The compound of claim 1, wherein L⁴ and L⁵ is each independently selected from a bond, C1-C3 alkylene, C2-C3 alkenylene, -0-, -ΝΗ-, -CH₂C(0)-, -C(0)NH-, -C(0)N ⁶-, -

CH₂C(0)NH-, ~C(G)NHCH₂-, ~CH₂C(G) RS-S(G)_n-, -S(0)_nNH-, ~S(0)_nNHCH₂-, - S(0)nNHCH₂CH₂-, or -S(0)nNR⁶-.

3. The compound of claim 1 or 2, wherein L⁴ and L⁵ is each independently selected from a bond, C1-C3 alkylene, C2-C3 alkenylene, -0-, ΛΉ-. or -S(0)nNH-.

4. The compound of claim 1 or 2, wherein L⁴ is -CH2-.

5. The compound of claim 3, wherein L³ is a bond.

6. The compound of any one of claims 1-5, wherein: X is absent, C1-C3 alkylene, divalent C3-C6 cycloalkyl, divalent phenyl, divalent 5-6 membered heterocyclyl, or divalent 5-6 membered heteroaryl, wherein each of cycloalkyl, phenyl, heterocyclyl, or heteroaryl is optionally substituted with one or more R³,

7. The compound of any one of claims 1-6, wherein X is absent.

8. The compound of any one of claims 1-6, wherein X is C1-C3 alkylene.

9. The compound of any one of claims 1-6, wherein X is divalent C3-C6 cycloalkyl, divalent phenyl, divalent 5-6 membered heterocyclyl, or divalent 5-6 membered heteroaryl, wherein wherein each of cycloalkyl, phenyl, heterocyclyl, or heteroaryl is optionally substituted with one or more R⁵.

10. The compound of any one of claims 1-6 or 9, wherein X is selected from divalent phenyl, divalent oxadiazole, divalent isoxazoie, divalent oxazole, or divalent thiazole;

wherein each of which are optionally substituted with one or more R⁵.

11. The compound of any one of claims 1-6, 9, or 10, wherein X is selected from

wherein each of which are optionally substituted with one or more R³.

12. The compound of claim 11, wherein X is unsubstituted.

13. The compound of any one of claims 1 -12, wherein Y is C3-C6 cycloalkyl, phenyl, 5-6 membered heterocyclyl, or 5-10 membered heteroaryl, wherein Y is optionally substituted with one or more R⁵.

14. The compound of any one of claims 1-12, wherein Y is phenyl or 5-10 membered heteroaryl, wherein Y is optionally substituted with one or more R⁵.

15. The compound of any one of claims 1-13, wherein Y is phenyl optionally substituted with one or more R⁵.

16. The compound of any one of claims 1-13, wherein Y is 5-6 membered heteroaryl optionally substituted with one or more R\

17. The compound of claim 16, wherein Y is selected from thiophenyl or isoxazoiyl, each of which are optionally substituted with one or more R³.

18. The compound of any one of claims 1-13, wherein Y is 9-10 membered bicyclic heteroaryl optionally substituted with one or more R³.

19. The compound of claim 18, wherem Y is benzoimidazole or benzothiazole, each of which are optionally substituted with one or more R⁵.

20. The compound of any one of claims 1 -5, wherein:

X is C1-C3 alkylene, divalent C3-C6 cycloalkyl, divalent phenyl, divalent 5-6 membered heterocyclyl, or divalent 5-6 membered heteroaryi, wherein each of cycloalkyl, phenyl, heterocyclyl, or heteroaryi is optionally substituted with one or more R⁵; and

Y is C3-C6 cycloalkyl, phenyl, 5-6 membered heterocyclyl, or 5-10 membered heteroaryi, wherein Y is optionally substituted with one or more R⁵.

21. The compound of any one of claims 1 -20, wherem R⁵ is selected from ΐ, Br, CI, F, -

22. The compound of claim 1 wherein -L -X-L⁵~ is -CH2-,

23. Hie compound of claim 1 wherein -L⁴-X-L⁵- is -ΝΗ(Ο¾)20-.

24. The compound of any one of claims 1-23, wherein Rⁿ and R¹² are each independently selected from H, I, Br, CI, F, -SH, -S-aikyl, -OH, -O-alkyl, -NH2, -NH-alkyi, or -NR⁴R⁴.

25. The compound of any one of claim s 1-24, wherein R¹¹ and R^!2 are each independently selected from H, CI, -S-alkyl, or -NR⁴R⁴.

26. The compound of any one of claims 1-25, wherein R¹³ is H.

The compound of claim 1 , wherein the compound has the structure of formula (Γ)

L⁴ and L³ are each independently selected from a bond, C1-C3 alkylene, C2-C3 aikenylene, -0-, -NH-, -QhbCiQ -C(0)NH-, -C(0)NR⁶-, -Π K i<))\! 1~. ·( (O sNI !( ! ! ··. -

CH2C(0)NR⁶~,-S(0)n-, -S(Q)nNH~, or ~S(0)nNR⁶-;

X is a divalent cycloalkyl, divalent aryl, divalent heterocyclyl, or divalent monocyclic heteroaryi, wherein cycloalkyl, aryl, heterocyclyl, or heteroaryi is optionally substituted with one or more R³;

Y is cycloalkyl, and, heterocyclyl, or heteroaryi, wherein Y is optionally substituted with one or more R³;

R¹¹, R¹², and R^{l j} are each independently selected from H, I, Br, CI, F, -CN, alkyl, haloalky!, -SH, -S-alkyl, -OH, -O-alkyl, -NH₂, -NHR⁴, ~\ \V\V. or -NO2; or

R⁴ is each independently H, alkyl, aryl, arylalkyl, aiyloxyalkyl, heterocyclyl, heterocyclylalkyl, heteroaryi, heteroarylalkyl, or heteroaryloxyaikyl, wherein each R⁴ is optionally substituted with one or more R⁵:

R³ is each independently I, Br, CI, F, -CN, -CONH2, -CONHR⁶, -CONR⁶R⁶, -COOH, - H2, -NHR⁶, -NO2, -NR⁶R⁶, -OH, -OR⁶, -COOR⁶, -OSO3R⁶, oxo, R⁶, -SH, -SO2R⁶, -SO3H, - SO3R⁶, -S(0)nNH2, -S(0)nNHR⁶, -S(0)nNR⁶R⁶ ₅ or -SR⁶;

R⁶ is each independently alkyl, haloalkyl, or cycloalkyl: and

n is 0, 1, or 2.

28. The compound of claim 27, wherein L⁴ is a bond or -CH2-.

29. The compound of claim 27 or 28, wherein L⁵ is a bond, -S(0)nNR⁶-, -S(0)2NH-, - C(0)NH-, or -C(0)NHCH₂-.

30. The compound any one of claims 27-29, wherein X is phenyl or 5-6 membered heteroaryi, which are optionally substituted with R⁵.

31. The compound of any one of claims 27-30, v, herein Y is phenyl or 5-6 membered heteroaryi, which are optionally substituted with R³.

32. The compound of any one of claims 27— 31, wherein R⁵ is 1, Br, Ci, F, methyl, or cycloalkyl.

33. The compound of any one of claims 27-32, wherein R¹¹ and R^{1 2} are each

independently selected from H, CI, -S-alkyl, or -NR⁴R⁴.

34. The compound of any one of claims 27-33, wherein R¹³ is H.

35. The compound of claim 1, wherein the compound has the structure of formula (I")

(1")

or a pharmaceutically acceptable salt or solvate thereof, wherein:

-L⁴-X-L⁵ is a bond or C 1 -C3 alkylene;

Y is cycloalkyl, aryl, heierocyclyl, or heteroaiyl, wherein Y is optionally substituted with one or more R⁵;

R^{! !}, R¹², and R¹³ are each independently selected from H, I, Br, CI, F, -CN, alkyl, haloalky], -SH, -S-alkyl, -OH, -O-alkyl, -NH₂, -NHR⁴, -NR⁴R⁴, or -NO2; or

R⁴ is each independently H, alkyl, aryl, arylalkyi, aiyloxyalkyl, heierocyclyl, heterocyclylalkvl, heteroaryl, heteroarylalkyl, or heteroaryloxyaiky 1, wherein each R⁴ is optionally substituted with one or more R⁵;

R⁵ is each independently I, Br, CI, F, -CN, -CONH2, -CONHR⁶, -CONR⁶R⁶, -COOH, -NH2, -NHR⁶, -NO '. -NR⁶R⁶, -OH, -OR⁶, -COOR⁶, -OSO3R⁶, oxo, R⁶, -SH, -SO2R⁶, -SO3H, - SO3R⁶, -S(0)_nNH2, -S(0)_nNHR⁶, -S(0)nNR⁶R⁶, or -SR.⁶;

R⁶ is each independently alkyl or cycloalkyl; and

n is 0, 1, or 2.

36. The compound of claim. 35, wherein Y is phenyl or heteroaryl, wherein Y is optionally substituted with one or more R⁵.

37. The compound of claim 35 or 36, wherein Y is phenyl substituted with -S(0)nNH₂ and optionally substituted with one or more R⁵.

38. The compound of claim 35 or 4361, wherein Y is 5-6 membered heteroaiyl, wherein Y is optionally substituted with one or more R⁵.

I l l

39. The compound of any one of claims 35-38, wherein R⁵ is I, Br, CI, F or methyl.

40, A pharmaceutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and a compound of formula (I):

(D

or a pharmaceutically acceptable salt or solvate thereof, wherein:

L⁴ and L⁵ are each independently selected from a bond, alkylene, alkenyiene, -0-, - M l-. -NR⁶-, -M I( (())-. -NR⁶C(0)-, -CH₂C(0)-, -C(0)NH-, -C(0)NR⁶-, -( H i {0 .\! !-. - C(0)NHCH₂-, CH₂C(0)N ⁶-, -S(0)«-, -S(0)„NH-, S(0)_DNHCH₂-, -S(0)nNHCH₂CH₂-, - S(0)nNR⁶~, -NHS(Q),,-, or -NR⁶S(0)n-;

X is absent, alkylene, alkenyiene, divalent cycloaikyi, divalent aryl, divalent heterocyclyl, or divalent monocyclic heteroaryl, wherein cycloaikyi, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R⁵;

Y is cycloaikyi, aryl, heterocyclyl, or heteroaryl, wherein Y is optionally substituted with one or more R⁵;

R^{! !}, R¹², and R¹³ are each independently selected from H, I, Br, CI, F, -CN, alkyl, haloalkyl, -Si I. -SR⁴, -OH, -OR⁴, -Ntb, -NHR⁴, -NR⁴R⁴, or -\^'0 <: or

R⁴ is each independently H, alkyl, aryl, arylalkyl, aryloxyalkyl, heterocyclyl, heterocyclylaikyl, heteroaryl, heteroarylalkyl, or heteroar doxyalkyl, wherein each R⁴ is optionally substituted with one or more R³;

R⁵ is each independently 1, Br, CI, F, -CN, -CONH2, -CONHR⁶, -CONR⁶R⁶, -COOH, -NH2, -NHR⁶, AO > . -NR⁶R⁶, -OH, -OR⁶, -COOR⁶, -OSO3R⁶, oxo, R⁶, -SH, -SO2R⁶, -SO3H, - SO3R⁶, -S(0)nNH2, -S(0)_SiNHR⁶, -S(0)„NR⁶R⁶, or -SR⁶;

R⁶ is each independently alkyl, haloalkyl or cycloaikyi;

n is 0, 1, or 2:

provided that when L⁴ and L⁵ are each a bond and X is absent, then Y is not unsubstituted phenyl, phenyl substituted with alkyl, halogen or -COOH; and

provided that when -L⁴-X-L³- is -CH2-, then Y is not phenyl, pryidyl, or thiophenyl;

wherein Y is not pyridyi; and wherein the compound is not 4,5-Dichloro-2-{2-[4-(diethylamino)phenyl]-2- oxoethyl}pyridazin-3(2H)-one, or 2-((4,5-dichloro-6-oxopyridazin-l(6H)-}'l)methyl)-l-ethyl- N^-dimethyl-lH-benzo[i ]imidazole-6-sulfonamide.

41. The composition of claim 40, wherein L⁴ and L³ is each independently selected from a bond, C1-C3 aikylene, C2-C3 alkenylene, -0-, -ΝΗ-, -CH₂C(0)-, ·( (0)\1 Ι·. -C(0)NR⁶-, - CH2C(0)NH~, -C(0)NHCH2-, -CH₂C(0)NR⁶~,-S(0)n-, -S(Q)nNH~, -, -S(0)n HCH₂-, - SiOj ! K i K Ή -. or -S(0)nNR⁶-.

42. The composition of claim. 40 or 4 , wherein L⁴ and L⁵ is each independently selected from a bond, C1-C3 aikylene, C2-C3 alkenylene, -0-, -NH-, or -S(0)nNH-.

43. The composition of any one of claims 40-42, wherein L⁴ is -CH2-.

44. The composition of any one of claims 40-43 wherein L³ is a bond.

45. The composition of any one of claims 40-44, wherein: X is absent, C 1-C3 aikylene, divalent C3-C6 cycloalkyl, divalent phenyl, divalent 5-6 membered heterocyclyl, or divalent 5-6 membered heteroaiyl, wherein each of cycloalkyl, phenyl, heterocyclyl, or heteroaryi is optionally substituted with one or more R⁵.

46. The composition of any one of claims 40-45, wherein X is absent.

47. The composition of any one of claims 40-45, wherein X is C1-C3 aikylene.

48. The composition of any one of claims 40-45, wherein X is divalent C3-C6 cycloalkyl, divalent phenyl, divalent 5-6 membered heterocyclyl, or divalent 5-6 membered heteroaryi, wherein wherein each of cycloalkyl, phenyl, heterocyclyl, or heteroaiyl is optionally substituted with one or more R⁵.

49. The composition of any one of claims 40-45 or 48, wherein X is selected from divalent phenyl, divalent oxadiazole, divalent isoxazole, divalent oxazole, or divalent thiazole; wherein each of which are optionally substituted with one or more R⁵ The composition of any one of claims 40-45, 48 or 49, wherein X is selected from

wherein each of which are optionally substituted with one or more R⁵.

51. The composition of claim 50, wherein X is unsubstituted.

52. The composition of any one of claims 40-51 , wherein Y is C3-C6 cyeloalkyl, phenyl, 5-6 membered heterocyciyl, or 5-10 membered heteroaryl, wherein Y is optionally substituted with one or more R⁵.

53. The composition of any one of claims 40-51, wherein Y is phenyl or 5- 10 membered heteroaryl, wherein Y is optionally substituted with one or more R³.

54. The composition of any one of claims 40-53, wherein Y is phenyl optionally substituted with one or more R⁵.

55. The composition of any one of claims 40-53, wherein Y is 5-6 membered heteroaryl optionally substituted with one or more R⁵.

56. The composition of claim 55, wherein Y is selected from thiophenyl or isoxazoiyi, each of which are optionally substituted with one or more R³.

57. The composition of any one of claims 40-53, wherein Y is 9-10 membered bicvclic heteroaryl optionally substituted with one or more R⁵.

58. The composition of claim 57, wherein Y is benzoimidazole or benzothiazole, each of which are optionally substituted with one or more R³.

59. The composition of any one of claims 40-44, wherein: X is C 1 -C3 alkylene, divalent C3-C6 eycloalkyl, divalent phenyl, divalent 5-6 membered heterocyclyL or divalent 5-6 membered heteroaryi, wherein each of eycloalkyl, phenyl, heterocyclyl, or heteroaryi is optionally substituted with one or more R⁵: and

Y is C3-C6 eycloalkyl, phenyl, 5-6 membered heterocyclyl, or 5-10 membered heteroaryi, wherein Y is optionally substituted with one or more R³.

60. The composition of any one of claims 40-59, wherein R⁵ is selected from I, Br, CI, F,

61. The composition of claim 40 wherein -L⁴-X-L⁵- is -CH2-.

62. The composition of claim 40 wherein -L⁴-X-L⁵- is -NH(CH2)2()-.

63. The composition of any one of claims 40-62, wherein R¹¹ and R^!2 are each independently selected from H, I, Br, CI, F, -SH, -S-aikyL -OH, -O-alkyl, -NH2, -NH-alkyl, or -S lV lV.

64. The composition of any one of claims 40-63, wherein R^1! and R^!2 are each independently selected from H, CI, -S-alkyl, or -NR⁴R⁴.

65. The composition of any one of claims 40-64, wherein R^1J is H.

66. The composition of claim 40, wherein the compound has the structure of formula (Γ)

L⁴ and L³ are each independently selected from a bond, C1-C3 alkylene, C2-C3 alkenylene, -0-, -NH-, -( ! ! ·( ({))-. -C(0)NH-, -C(0)NR⁶-, -CH₂C(0)NH-, -C(0)NHCH₂-, - CH2C(0)NR⁶-,-S(0)n-₅ -S(0)nNH-, or -S(0)_nNR⁶-; X is a divalent cvcloalkyi, divalent aryi, divalent heterocyclyl, or divalent monocvchc heteroaryi, wherein cvcloalkyi, aryi, heterocyclyl, or heteroaryl is optionally substituted with one or more R⁵;

Y is cycloalkyl, aryi, heterocyclyl, or heteroaryl, wherein Y is optionally substituted with one or more R⁵;

R^{! !}, R¹², and R¹³ are each independently selected from H, I, Br, CI, F, -CN, alkyl, haloalkyl, -SH, -SR⁴, -OH, -OR⁴, -NH2, -NHR⁴, -NR⁴R⁴, or -NO -: or

R⁴ is each independently H, alkyl, aryi, arylalkyl, aryloxyalkyl, heterocyclyl, heterocyciylalkyi, heteroaryl, heteroarylalkyl, or heteroaryloxyalkyl, wherein each R⁴ is optionally substituted with one or more R³;

R⁵ is each independently I, Br, CI, F, -CN, -CONH2, -CONHR⁶, -CONR⁶R⁶, -COOH, -NH₂, -NHR⁶, -NO2, -NR⁶R⁶, -OH, -OR⁶, -COOR⁶, -OSO3R⁶, oxo, R⁶, -SH, -SO2R⁶, -SO3H, - SO3R⁶, -S(0)nNH2, -S(0)nNHR⁶, -S(0)nNR⁶R⁶, or -SR⁶;

R⁶ is each independently alkyl, haloalkyl or cvcloalkyi; and

n is 0, 1, or 2,

67. The composition of claim 66, wherein L⁴ is a bond or -CH2-.

68. The composition of claim 66 or 67, wherein L5 is a bond, -S(0)nNR⁶-, -S(0)2NH-, - C(G)NH~, or -C(0)NHCH₂-.

69. The composition any one of claims 66-68, wherein X is phenyl or 5-6 membered heteroaryl, which are optionally substituted with R⁵.

70. The composition of any one of claims 66-69, wherein Y is phenyl or 5-6 membered heteroaryi, which are optionally substituted with R⁵.

71. The composition of any one of claims 66-70, wherein R⁵ is I, Br, CL F or methyl.

72. The composition of any one of claims 66-71 , wherein R^u and R¹² are each independently selected from H, CI, -S-alkyl, or -NR⁴R⁴.

73. The composition of any one of claims 66-72, wherein R^{] i} is H.

74. The composition of claim 45, wherein the compound has the structure of formula (I")

d")

or a pharmaceutically acceptable salt or solvate thereof, wherein:

-L⁴-X-L⁵ is a bond or C1-C3 alkyiene;

Y is cycloalkyi, and, heterocyclvl, or heteroaryi, wherein Y is optionally substituted with one or more R³;

R^u, R¹², and R^{1 J} are each independently selected from H, 1, Br, Ci, F, -CN, alkyi, haloalky!, -SH, -SR⁴, -OH, -OR⁴, ~NH₂, -NHR⁴, -NR⁴R⁴, or -NO2; or

R⁴ is each independently H, alkyl, aryl, arylalkyl, aryloxyalkyl, heterocyclvl, heterocyclylalkyl, heteroaryi, heteroarylalkyl, or heteroaryloxyaikyl, wherein each R⁴ is optionally substituted with one or more R⁵:

R⁵ is each independently I, Br, CI, F, -CN, -CONH2, -CONHR⁶, -CONR⁶R⁶, -COOH, - H2, -NHR⁶, -NO2, -NR⁶R⁶, -OH, -OR⁶, -COOR⁶, -OSO3R⁶, oxo, R⁶, -SH, -SO2R⁶, -SO3H, - SO3R⁶, -S(0)nNH2, -S(0)nNHR⁶, -S(0),,NR⁶R⁶, or -SR⁶;

R⁶ is each independently alkyl, haloalkyl, or cycloalkyi: and

n is 0, 1, or 2.

75. The composition of claim 74, wherein Y is phenyl or heteroaryi, wherein Y is optionally substituted with one or more R⁵.

76. The composition of claim 74 or 75, wherein Y is phenyl substituted with -S(0)nNH₂ and optionally substituted with one or more R⁵.

77. The composition of claim 74 or 75, wherein Y is 5-6 membered heteroaryi, wherein Y is optionally substituted with one or more R⁵.

78. The composition of any one of claims 74-77, wherein R⁵ is I, Br, CI, F or methyl.

79. A method of modulating a Parkin ligase, comprising administering to a subject in need thereof an effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

L⁴ and L⁵ are each independently selected from a bond, alkylene, alkenylene, -0-, - NH-, -NR⁶-, -\! !(^'(()}·. -\ R^:f !())··. -CI I■( {():···. -C(0)NH-, -C(0)NR⁶-, -CH₂C(Q)NH-, - C(Q)NHCH₂~, -CH₂C(0)NR⁶~, -S(0)n-, -S(0)nNH-, -S(0)_nNHCH₂-, -S(G)nNHCH₂CH₂-, - S(0)nN ⁶-, -NHS(O)i)-, or -NR⁶S(0)n-;

X is absent, alkylene, alkenylene, divalent cycloalkyl, divalent aryl, divalent heterocyclyl, or divalent monocyclic heteroaryl, wherein cycloalkyl, aryl, heterocyciyL or heteroaryl is optionally substituted with one or more R⁵;

Y is cycloalkyl, aryl, heterocyclyl, or heteroaryl, wherein Y is optionally substituted with one or more R⁵;

R^{! !}, R¹², and R¹³ are each independently selected from H, I, Br, CI, F, -CN, alkyl, haloalkyl, -SH, -SR⁴, -OH, -OR⁴, -NH₂, -NHR⁴, -NR⁴R⁴, or -NO -: or

R⁴ is each independently H, alkyl, aryl, arylalkyi, aryloxyalkyl, heterocyclyl, heterocyclylalkvl, heteroaryl, heteroarylalkyl, or heteroaryloxyaikyl, wherein each R⁴ is optionally substituted with one or more R⁵;

R⁵ is each independently I, Br, CI, F, -CN, -CONH2. -CONHR⁶, -CONR⁶R⁶, -COOH, -NH2, -NHR⁶, -NO2, -NR⁶R⁶, -OH, -OR⁶, -COOR⁶, -OSO3R⁶, oxo, R⁶, -SH, -SO2R⁶, -SO3H, - SO3R⁶, -S(0)_nNH₂, -S(0)_nNHR⁶, -S(G)nNR⁶R⁶, or -SR⁶;

R⁶ is each independently alkyl, haloalkyl or cycloalkyl; and

n is 0, 1, or 2.

80, The method of claim. 79, wherein L⁴ and V is each independently selected from a bond, C1-C3 alkylene, C2-C3 alkenylene, -0-, -NH-, -CH₂C(0)-₅ -C(0)NH-, -C(0)NR⁶-, - CH₂C(0)NH-, -( {Ο ίΜ !( ! ! ··. -CH₂C(0)NR⁶-,-S(0)_n-, -S(0)„NH-, -S(0)„NHCH2-, - S(0)nNHCH2CH₂-, or -S(0)_nNR⁶-.

81. Ttie method of claim 79 or 80, wherein L⁴ and L⁵ is each independently selected from a bond, C1-C3 alkylene, C2-C3 alkenylene, -0-, -NH-, or -S(0)„NH-. 82 The method of claim 79 or 80, wherein L⁴ is -CH2-

83, The method of claim. 81 , wherein L⁵ is a bond.

84. The method of any one of claims 79-83, wherein: X is absent, C1-C3 alkyiene, divalent C3-C6 cvcloalkyl, divalent phenyl, divalent 5-6 membered heterocyclyl, or divalent 5-6 membered heteroaryl, wherein each of cvcloalkyl, phenyl, heterocyclyl, or heteroaryl is optionally substituted with one or more R³,

85. The method of any one of claims 79-84, wherein X is absent.

86. The method of any one of claims 79-84, wherein X is C1-C3 alkyiene.

87. The method of any one of claims 79-84, wherein X is divalent C3-C6 cvcloalkyl, divalent phenyl, divalent 5-6 membered heterocyclyl, or divalent 5-6 membered heteroaryl, wherein wherein each of cvcloalkyl, phenyl, heterocyclyl, or heteroaryl is optionally substituted with one or more R³.

88. The method of any one of claims 79-84 or 87, wherein X is selected from divalent phenyl, divalent oxadiazole, divalent isoxazole, divalent oxazole, or divalent thiazole; wherein each of which are optionally substituted with one or more R³

The method of any one of claims 79-84, 87, or 88, wherein X is selected from

wherein each of which are optionally substituted with one or more R⁵.

90. The method of claim 89, wherein X is unsubstituted.

91. The method of any one of claims 79-90, wherein Y is C3-C6 cycloalkyl, phenyl, 5-6 membered heterocyclyi, or 5-10 membered heteroaryi, wherein Y is optionally substituted with one or more R³.

92. The method of any one of claims 79-90, wherein Y is phenyl or 5-10 membered heteroaryi, wherein Y is optionally substituted with one or more R³.

93. The method of any one of claims 79-91 , wherein Y is phenyl optionally substituted with one or more R³.

94. The method of any one of claims 79-90, wherein Y is 5-6 membered heteroaryi optionally substituted with one or more R⁵.

95. The method of claim 94, wherein Y is selected from thioplienyl or isoxazolvl, each of which are optionally substituted with one or more R⁵.

96. The method of any one of claims 79-90, wherein Y is 9-10 membered bicyclic heteroaryi optionally substituted with one or more R⁵.

97. The method of claim 96, wherein Y is benzoimidazole or benzotliiazoie, each of which are optionally substituted with one or more R⁵.

98. The method of any one of claims 79-83, wherein:

X is C1-C3 aikylene, divalent C3-C6 cycloalkyl, divalent phenyl, divalent 5-6 membered heterocyclyi, or divalent 5-6 membered heteroaryi, wherein each of cycloalkyl, phenyl, heterocyclyi, or heteroaryi is optionally substituted with one or more R³; and

Y is C3-C6 cycloalkyl, phenyl, 5-6 membered heterocyclyi, or 5-10 membered heteroaryi, wherein Y is optionally substituted with one or more R³.

99. The method of any one of claims 79-98, wherein R⁵ is selected from I, Br, CI, F, -CN,

The method of claim 79, wherein -L⁴-X-L⁵- is -CH2 The method of claim 79, wherein Ι Χ-Ι - is Χ! !(( Ί !.<).■<)-

102. The method of any one of claims 79-101, wherein R^{! i} and R¹² are each independently selected from H, I, Br, CI, F, -SH, -S-alkyl, -OH, -O-alky!, -NH_, - H-alkyl, or -NR⁴R⁴.

103. The method of any one of claims 79-102 wherein R^{i !} and R¹² are each independently- selected from H, CI, -S-alkyl, or -NR⁴R⁴.

The method of any one of claims 79-103, wherein R¹

The method of claim 79, wherein the compound has the structure of formu

(Γ)

or a pharmaceutically acceptable salt or solvate thereof, wherein:

L⁴ and L⁵ are each independently selected from a bond, C 1-C3 alkylene, C2-C3 aikenylene, -0-, -NH-, -CH₂C(0)-, -C(0)NH-, -C(0)NR⁶-, ·( ! ! (O)Xi 1··. ·( (O sXI !( ! ! ··. -

CH2C(0)NR⁶-,~S(0)n~, -S(Q)nNH~, or -S(0)nNR⁶-;

X is a divalent cycioaikyl, divalent aryl, divalent heterocyclyi, or divalent monocyclic heteroaryl, wherein cycioaikyl, aryl, heterocyclyi, or heteroaryl is optionally substituted with one or more R³;

Y is cycioaikyl, and, heterocyclyi, or heteroaryl, wherein Y is optionally substituted with one or more R³;

R^{! i}, R^!2, and R^1J are each independently selected from H, 1, Br, Ci, F, -CN, alkyi, haloalky!, -SH, -SR⁴, -OH, -OR⁴, -NH_, -NHR⁴, -NR R⁴, or -NO2; or

R⁴ is each independently H, alkyl, aryl, aryialkyl, aryloxyaikyl, heterocyclyi, heterocyclylalkyl, heteroaryl, heteroarylalkyl, or heieroaryloxyaikyl, wherein each R⁴ is optionally substituted with one or more R⁵:

R⁵ is each independently I, Br, CI, F, -CN, -CONH2, -CONHR⁶, -CONR⁶R⁶, -COOH, -Nth, -NHR⁶, -NO2, -NR⁶R⁶, -OH, -OR⁶, -COOR⁶, -OSO3R⁶, oxo, R⁶, -SH, -SO2R⁶, -SO3H, - SQ3R⁶, -S(0)_nNH₂, -S(0)nNHR⁶, -S(0)nNR⁶R⁶, or -SR⁶;

R⁶ is each independently alkyl, haloalkyl or cycioaikyl; and n is 0, 1, or 2.

106. The m ethod of claim. 105 , wh erein L⁴ is a bond or -CH2-.

107. The method of claim 105 or 106, wherein L5 is a bond, -S(0)nNR⁶-, -S(0)₂NH-, - C(G)NH-, or•( ( O iM !Ci l - .

108. The method any one of claims 105-107, wherein X is phenyl or 5-6 membered heteroaryl, which are optionally substituted with R⁵.

109. The method of any one of claims 105-108, wherein Y is phenyl or 5-6 membered heteroaryl, which are optionally substituted with R⁵.

1 10. The method of any one of claims 05-109, wherein R³ is I, Br, CI, F or methyl.

1 11. The method of any one of claims 105-1 10, wherein R¹¹ and R¹² are each independently selected from H, CI, -S-alkyl, or -NR⁴R⁴.

1 12. The method of any one of claims 105-1 1 1, wherein R^!3 is H.

1 13. The method of claim 79, wherein the compound has th e structure of formula (I")

(1")

or a pharmaceutically acceptable salt or solvate thereof, wherein:

-L⁴-X-L³ is a bond or C 1 -C3 alkylene;

Y is cycloalkyl, aryi, heterocyclyl, or heteroaryl, wherein Y is optionally substituted with one or more R⁵;

R ^Li, R¹², and R^{1 3} are each independently selected from H, I, Br, CI, F, -CN, alkyl, haloalkyl, -SH, -SR⁴, -OH, -OR⁴, -NH2, -NHR⁴, -NR⁴R⁴, or -NO2; or R⁴ is each independently H, alkyi, aryl, arylalkyi, aryloxyalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, or heteroaryloxyaikyl, wherein each R⁴ is optionally substituted with one or more R³;

R⁵ is each independently I, Br, CI, F, -CN, -CO H2, -CONHR⁶, -CONR⁶R⁶, -COOH, -NH2, -NHR⁶, -NO2, -NR⁶R⁶, -OH, -OR⁶, -COOR⁶, -OSO3R⁶, oxo, R⁶, S! L -SO2R⁶, -SO3H, - SO3R⁶, -S(0)nNH2, -S(0)nNHR⁶, -S(0)nNR⁶R⁶, or -SR⁶;

R⁶ is each independently alkyl, haloalkyl, or cycloalkyl; and

n is 0, 1, or 2,

114. The method of claim. 113, wherein Y is phenyl or heteroaryl, wherein Y is optionally substituted with one or more R³.

115. The method of claim 113 or 114, wherein Y is phenyl substituted with -S(0)nNtb and optionally substituted with one or more R⁵.

116. The method of claim 113 or 114, wherein Y is 5-6 rnembered heteroaiyl, wherein Y is optionally substituted with one or more R³.

117. The method of any one of claims 113-116, wherein R³ is I, Br, CI, F or methyl.

118. A method of treating a disease or a condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I):

(I)

or a pharmaceutically acceptable salt or solvate thereof, wherein:

L⁴ and L⁵ are each independently selected from a bond, alkylene, aikenylene, -0-, - NH-, -NR⁶-, -NHC(O)-, -NR⁶C(0}-, -( i ! ·( (())-. -C(0)NH-, -C(0) R⁶-, -⁽ H ( (0)\H-. - C(0)NHCH2~, -CH₂C(0)NR⁶-, -S(0)n-, -S(0)nNH-, -S(0)„NHCH₂-, -S(0)nNHCH₂CFi2-, - S(0)_DNRS -NHS(0)n-₅ or -NR⁶S(())„-; X is absent, alkylene, alkenylene, divalent cycloalkyl, divalent aryl, divalent heterocyclyl, or divalent monocyclic heteroaryl, wherein cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R⁵;

Y is cycloalkyl, aryl, heterocyclyl, or heteroaryl, wherein Y is optionally substituted with one or more R⁵;

R^{! !}, R¹², and R¹³ are each independently selected from H, I, Br, CI, F, -CN, alkyl, haloalkyl, -SH, -SR⁴, -OH, -OR⁴, -NH2, -NHR⁴, -NR⁴R⁴, or -NO -: or

R⁴ is each independently H, alkyl, aryl, arylalkyl, aryloxyalkyl, heterocyclyl, heterocyciylalkyi, heteroaryl, heteroarvlalkyl, or heteroaiyloxyalkyl, wherein each R⁴ is optionally substituted with one or more R³;

R⁵ is each independently I, Br, CI, F, -CN, -CO H2, -CONHR⁶, -CONR⁶R⁶, -COOH, -NH2, -NHR⁶, -NO2, -NR⁶R⁶, -OH, -OR⁶, -COOR⁶, -OSO3R⁶, oxo, R⁶, -SH, -SO2R⁶, -SO3H, - SO3R⁶, -S(0)nNH₂, -S(0)nNHR⁶, -S(0)„NR⁶R⁶, or -SR⁶;

R⁶ is each independently alkyl, haloalkyl, or cycloalkyl;

n is 0, 1, or 2; and

R⁶ is each independently alkyl;

wherein the disease or the condition is selected from the group consisting of cancer, neurological disease, a disorder characterized by abnormal accumulation of a-synuclein, a disorder of an aging process, cardiovascular disease, bacterial infection, viral infection, mitochondrial related disease, mental retardation, deafness, blindness, diabetes, obesity, autoimmune disease, glaucoma, Leber's Hereditary Optic Neuropathy, and rheumatoid arthritis.

119. The method of claim 118, wherein the compound has the structure of formula (Γ)

L⁴ and L^s are each independently selected from a bond, C1-C3 alkylene, C2-C3 alkenylene, -0-, -NH-, -CH₂C(0K -C(0)NH-, -C(0)NR⁶-, -(^'! H ( 0)\1 k -C(0)NHCH₂-, - CH2C(0)NR⁶-,-S(0)_n-, -S(0)„NH-, or -S(0)nNR⁶-; X is a divalent cvcloalkyi, divalent aryi, divalent heterocyclyl, or divalent monocyclic heteroaryi, wherein cvcloalkyi, aryi, heterocyclyl, or heteroaryl is optionally substituted with one or more R⁵;

Y is cvcloalkyi, aryi, heterocyclyl, or heteroaryl, wherein Y is optionally substituted with one or more R⁵;

R¹¹, R¹², and l ¹³ are each independently selected from H, I, Br, CI, F, -CN, alkyi, haloalkyl, -SH, ~SR⁴, -OH, -OR⁴, -NH2, -NHR⁴, -NR⁴R⁴, or -NO -: or

R⁴ is each independently H, alkyl, aryi, arylalkyl, aryloxyalkyl, heterocyclyl, heterocyciylalkyi, heteroaryl, heteroarylalkyl, or heteroaiyloxyalkyl, wherein each R⁴ is optionally substituted with one or more R³;

R⁵ is each independently I, Br, CI, F, -CN, -CONH2, -CONHR⁶, -CONR⁶R⁶, -COOH, -NH₂, -NHR⁶, -NO2, -NR⁶R⁶, -OH, -OR⁶, -COOR⁶, -OSO3R⁶, oxo, R⁶, -SH, -SO2R⁶, -SO3H, - SO3R⁶, -S(0)nNH2, -S(0)nNHR⁶, -S(0)nNR⁶R⁶, or -SR⁶;

R⁶ is each independently alkyl, haloalkyl, or cvcloalkyi; and

n is 0, 1, or 2,

The method of claim 118, wherein the compound has the structure of formula (I")

(1")

or a pharmaceutically acceptable salt or solvate thereof, wherein:

-L -X-L⁵ is a bond or C1-C3 alkylene;

Y is cvcloalkyi, aryi, heterocyclyl, or heteroaryl, wherein Y is optionally substituted with one or more R³;

Rⁿ, Rⁱ², and R¹³ are each independently selected from. H, I, Br, CI, F, -CN, alkyl, haloalkyl, -SH, -SR⁴, -OH, -OR⁴, -NH2, -NHR⁴, -NR⁴R⁴, or -NO2; or

R⁴ is each independently H, alkyi, aryi, arylalkyl, aryloxyalkyl, heterocyclyl, heterocyciylalkyi, heteroaryl, heteroarylalkyl, or heteroaryioxyalkyi, wherein each R⁴ is optionally substituted with one or more R³;

R⁵ is each independently I, Br, CI, F, -CN, -CONH2, -CONHR⁶, -CONR⁶R⁶, -COOH, -NH2, -NHR⁶, -NO2, -NR⁶R⁶, -OH, -OR⁶, -COOR⁶, -OSQ3R⁶, oxo, R⁶, -SH, -SO2R⁶, -SO3H, - SQ3R⁶, -S(0)nNH₂, -S(0)nNHR⁶, -S(0)nNR⁶R⁶, or -SR⁶; R⁶ is each independently alkyl, haloalkyl, or cycloalkyi: and n is 0, 1, of 2.