PORPHYRIN TREATMENT OF NEURODEGENERATIVE DISEASES

Abstract

Compositions and methods of treating a neurodegenerative disorder are disclosed herein.

Description

BACKGROUND OF THE INVENTION

Neurodegenerative orders affect millions of people worldwide. For example, Parkinson's disease (PD) is an age-related neurodegenerative disease in which the role of reactive oxygen species (ROS) is strongly implicated. There remains a need in the art for effective treatments of neurodegenerative disorders. The present invention provides solutions to these and other needs in the art.

BRIEF SUMMARY OF THE INVENTION

Provided herein, inter alia, are novel methods of treating a neurodegenerative disorder by administering to a patient in need thereof an effective amount of a compound, such as a porphyrin compound disclosed herein.

In one aspect, the compound useful in the methods provided herein has the formula:

In Formula (II), M is a metal e.g. a metal ion. In Formulae (I) and (II), R¹ is independently —C(X¹)₃, —COOR^5A,

R³ is independently —C(X³)₃, —COOR^5B,

R² is independently —C(X²)₃, —COOR^5C, or

R⁴ is independently —C(X⁴)₃, —COOR^5D or)

X¹, X², X³, and X⁴ are independently halogen. R^5A, R^5B, R^5C, R^5D, R^9A, and R^9B are independently hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. R^6A and R^8A are independently hydrogen, halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —CH₂COOH, —COOR^10A, —CH₂COOR^10A, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. R^10A is unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl (e.g. unsubstituted alkyl). R^7A is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —CH₂COOH, —COOR^10B, —CH₂COOR^10B, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. R^10B is unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl (e.g. unsubstituted alkyl). R^6B and R^8B are independently hydrogen, halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —CH₂COOH, —COOR^10C, —CH₂COOR^10C, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. R^10C is unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl (e.g. unsubstituted alkyl). R^7B is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —CH₂COOH, —COOR^10B, —CH₂COOR^10B, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. R^10D is unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl (e.g. unsubstituted alkyl). In some embodiments, R¹, R², R³ and R⁴ are not simultaneously —COOR^5A, —COOR^5B, —COOR^5C, and —COOR^5D, respectively. In some embodiments, if R¹ and R³ are both —CF₃, R² and R⁴ are not both —CO₂CH₃. In some embodiments, if R¹ and R³ are both —CO₂CH₃, R² and R⁴ are not both —CF₃. In some embodiments, if R¹ and R³ are both —CF₃, R² and R⁴ are not both —CO₂CH₂CH₂CH₃. In some embodiments, if R¹ and R³ are both —CO₂CH₂CH₂CH₃, R² and R⁴ are not both —CF₃.

In another aspect, a method is provided for treating a neurodegenerative disorder. The method includes administering to a patient in need thereof an effective amount of a compound provided herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. The concentration of

in the plasma (FIG. 1A) and brains (FIG. 1B) of C57BL/6 mice at different times points after a single dose of AEOL11209 (15 mg/kg) administered by the i.p or p.o. route. Points represent mean+S.E.M. Each point is the average of 3-4 animals.

FIG. 2. The concentration of

in the plasma of the C57BL/6 mice at different times points after a single dose of AEOL11215 (15 mg/kg) administered by the i.p route. Points represent mean+S.E.M. Each point is the average of 3-4 animals.

FIG. 3. The concentration of

in the plasma (FIG. 3A) and brains (FIG. 3B) of C57BL/6 mice at different times points after a single dose of AEOL11216 (15 mg/kg) administered by the i.p. and p.o route. Points represent mean+S.E.M. Bars represent mean+S.E.M. n=3-6 mice per group.

FIG. 4. The histogram of FIG. 4A appears in the order (left to right): vehicle; AEOL 11206 (i.p.). The histogram of FIG. 4B appears in the order (left to right): control; MPTP; MPTP+AEOL 11206 (i.p.). Dopamine levels in the striata (FIG. 4A) number of TH+neurons in the substantia nigra pars compacta (FIG. 4B) of C57BL/6 mice 7 days after injection of MPTP (15 mg/kg×3, s.c., 24 h intervals) alone or in the presence of AEOL11216 15 mg/kg i.p. (1 hr prior to MPTP and daily thereafter). Bars represent mean+S.E.M. n=3-6 mice per group.

FIG. 5. The histograms of FIGS. 5A-5D appear in the order (left to right): control; MPTP; MPTP+AEOL 11216. GSH, GSSG, GSH/GSSG and 3NT/Tyr ratios in the ventral midbrains of C57/B6 mice 24 hours after injection of MPTP (15 mg/kg×3, s.c., 24 h intervals) alone or in the presence of AEOL11216 i.p. (15 mg/kg×3, daily). Bars represent mean+S.E.M. #p<0.01 vs MPTP. One-way, ANOVA, n=6 mice per group.

FIG. 6. The concentration of

in the plasma (FIG. 6A) and brains (FIG. 6B) of C57BL/6 mice at different times points after a single dose of AEOL11203 (15 mg/kg) administered by the i.p. and p.o. route. Points represent mean+S.E.M. Each point is the average of 3-4 animals.

FIG. 7. The histogram of FIG. 7 appears in the order (left to right): control; MPTP; MPTP+AEOL 11203 (i.p.); MPTP+AEOL 11203 (i.o.). Dopamine levels in the striata of C57BL/6 mice 7 days after injection of MPTP (15 mg/kg×3, s.c., 24 h intervals) alone or in the presence of AEOL11203 15 mg/kg i.p or p.o. (1 hr prior to MPTP and daily thereafter). Bars represent mean+S.E.M. n=6-8 mice per group.

FIG. 8. The histograms of FIGS. 8A-8D appear in the order (left to right): control; MPTP; MPTP+AEOL 11203. GSH, GSSG, GSH/GSSG and 3NT/Tyr ratios in the SN of C57/B6 mice 24 hours after injection of MPTP (15 mg/kg×3, s.c., 24 h intervals) alone or in the presence of AEOL11203 i.p. (15 mg/kg×3, daily). Bars represent mean+S.E.M. #p<0.01 vs MPTP. One-way, ANOVA, n=6 mice per group.

FIG. 9. The concentration of

in the plasma (FIG. 9A) and brains (FIG. 9B) of C57BL/6 mice at different times points after a single dose of AEOL1114 (15 mg/kg) administered by the i.p. or p.o. route. Points represent mean+S.E.M. Each point is the average of 4 animals.

FIG. 10. The histogram of FIG. 10 appears in the order (left to right): control; MPTP; MPTP+AEOL 11114B (i.p.); MPTP+AEOL 11114B (i.o.). Dopamine levels in the striata of C57BL/6 mice 7 days after injection of MPTP (15 mg/kg×3, s.c., 24 h intervals) alone or in the presence of AEOL1114B 15 mg/kg i.p or p.o. (1 hr prior to MPTP and daily thereafter×3). Bars represent mean+S.E.M. n=6 mice per group.

FIG. 11. The histograms of FIGS. 11A-11F appear in the order (left to right): control; MPTP; MPTP+AEOL 11114B (i.p.); MPTP+AEOL 11114B (i.o.). GSH, GSSG, GSH/GSSG and 3NT/Tyr ratios in the ventral midbrains of C57/B6 mice 24 hours after last injection of MPTP (15 mg/kg×3, s.c., 24 h intervals) alone or in the presence of AEOL1114 i.p. or p.o. (15 mg/kg×3, daily). Bars represent mean+S.E.M. #p<0.01 vs MPTP. One-way, ANOVA, n=6 mice per group.

FIG. 12. The concentration of

in the plasma of C57BL/6 mice at different times points after a single dose of AEOL11256 (15 mg/kg) administered by the i.p. or p.o. route. Points represent mean+S.E.M. Each point is the average of 4 animals.

FIG. 13. The histogram of FIG. 13 appears in the order (left to right): MPTP; MPTP+AEOL 11207; MPTP+AEOL 11203; MPTP+AEOL 11256; MPTP+AEOL 11114. Striatal MPP+ levels in mice at 3 h after MPTP (15 mg/kg, s.c.) alone or in the presence of AEOL11207, 11203, 11256 and 1114B (15 mg/kg, i.p.) administered 1 h before MPTP treatment. Bars represent mean+S.E.M. n=4-6 mice per group.

FIG. 14. The histogram of FIG. 14 appears in the order (left to right): control; MPTP; MPTP+AEOL 11114 (i.p.); MPTP+AEOL 11114 (i.o.). Tyrosine hydroxylase positive (TH+) cell counts indicative of dopaminergic neuron viability in the substantia nigra pars compacta of C57BL/6 mice 7 days after injection of MPTP (15 mg/kg×3, s.c., 24 h intervals) alone or in the presence of AEOL1114B 15 mg/kg i.p or p.o. (1 hr prior to MPTP and daily thereafter×3). Bars represent mean+S.E.M. n=6.

FIG. 15. The histograms of FIGS. 15A-15C appear in the order (left to right): control; MnCl₂; AEOL 11114; AEOL 11207; AEOL 11203. Behavioral testing after dosing mice with AEOL11207, AEOL11114B or AEOL11203 (MnCl₂ positive control). Mice (6 per group) were divided 5 groups treated with AEOL11207, AEOL11203, AEOL11114B, MnCl₂ (all compound dissolved in 5% DMSO) or 5% DMSO alone by 15 mg/kg i.p. daily for a period of 7 days. At the end of treatment, mice were performed the behavioral tests by open field and accelerating rotorod test in 3-4 h after last injection. The total moving distance (FIG. 15A), moving velocity (FIG. 15B) in 5 minutes measured by open field test and the latency (seconds) from acceleration to fall from the rod (FIG. 15C) in the mice 7 days after injection of vehicle, MnCl₂, AEOL11114, AEOL11207 and AEOL11203 i.p. (15 mg/kg daily). Bars represent mean+S.E.M. One-way, ANOVA, n=6-8 mice per group.

DETAILED DESCRIPTION OF THE INVENTION

I. Definitions

The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched chain, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e., C₁-C₁₀ means one to ten carbons). Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, (cyclohexyl)methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butyryl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (—O—).

The term “alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, —CH₂CH₂CH₂CH₂—. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.

The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N, P, S, and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to: —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH=N—OCH₃, —CH═CH—N(CH₃)—CH₃, —O—CH₃, —O—CH₂—CH₃, and —CN. Up to two heteroatoms may be consecutive, such as, for example, —CH₂—NH—OCH₃.

Similarly, the term “heteroalkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, —CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula —C(O)₂R′— represents both —C(O)₂R′— and —R′C(O)₂—. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as —C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′, and/or —SO₂R′. Where “heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as —NR′R″ or the like, it will be understood that the terms heteroalkyl and —NR′R″ are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as —NR′R″ or the like.

The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.

The terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(C₁-C₄)alkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

The term “acyl” means, unless otherwise stated, —C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

The term “aryl” means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (e.g. from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. The term “heteroaryl” refers to aryl groups (or rings) that contain at least one heteroatom selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Thus, the term “heteroaryl” includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). A 5,6-fused ring heteroaryl refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6-fused ring heteroaryl refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5-fused ring heteroaryl refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An “arylene” and a “heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively.

The term “oxo,” as used herein, means an oxygen that is double bonded to a carbon atom.

The term “alkylsulfonyl,” as used herein, means a moiety having the formula —S(O₂)—R′, where R′ is an alkyl group as defined above. R′ may have a specified number of carbons (e.g., “C₁-C₄ alkylsulfonyl”).

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl,” and “heteroaryl”) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) are as disclosed herein or can be one or more of a variety of groups selected from, but not limited to, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —CN, and —NO₂ in a number ranging from zero to (2m′+1), where m′ is the total number of carbon atoms in such radical. R′, R″, R′″, and R″″ each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound disclosed herein includes more than one R group, for example, each of the R groups is independently selected as are each R′, R″, R′″, and R″″ group when more than one of these groups is present. When R′ and R″ are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, —NR′R″ includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term “alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g., —C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).

Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are disclosed herein or may be selected from, for example: —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —CN, —NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy, and fluoro(C₁-C₄)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R′, R″, R′″, and R″″ are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R′, R″, R′″, and R″″ groups when more than one of these groups is present.

Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)—(CRR′)_q-U-, wherein T and U are independently —NR—, —O—, —CRR′—, or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH₂)_r—B—, wherein A and B are independently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′—, or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula —(CRR′)_s—X′—(C″R′″)_d—, where s and d are independently integers of from 0 to 3, and X′ is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—. The substituents R, R′, R″, and R′″ are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

As used herein, the terms “heteroatom” or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

A “substituent group,” as used herein, means a group selected from the following moieties:

• • (A) —OH, —NH₂, —SH, —CN, —CF₃, —NO₂, oxo, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and
  • (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, substituted with at least one substituent selected from:
    • (i) oxo, —OH, —NH₂, —SH, —CN, —CF₃, —NO₂, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and
    • (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, substituted with at least one substituent selected from:
      • (a) oxo, —OH, —NH₂, —SH, —CN, —CF₃, —NO₂, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and
      • (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, substituted with at least one substituent selected from: oxo, —OH, —NH₂, —SH, —CN, —CF₃, —NO₂, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, and unsubstituted heteroaryl.

A “size-limited substituent” or “ size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C₁-C₂₀ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C₄-C₈ cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 4 to 8 membered heterocycloalkyl.

A “lower substituent” or “ lower substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C₁-C₈ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C₅-C₇ cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 5 to 7 membered heterocycloalkyl.

Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbon are within the scope of this invention.

The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

The terms “a,” “an,” or “a(n)”, when used in reference to a group of substituents herein, mean at least one. For example, where a compound is substituted with “an” alkyl or aryl, the compound is optionally substituted with at least one alkyl and/or at least one aryl. Moreover, where a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different.

Description of compounds of the present invention are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.

The term “effective amount” or “therapeutically effective amount” refers to the amount of an active agent sufficient to induce a desired biological result. That result may be alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. The term “therapeutically effective amount” is used herein to denote any amount of the formulation which causes a substantial improvement in a disease condition when applied to the affected areas repeatedly over a period of time. The amount will vary with the condition being treated, the stage of advancement of the condition, and the type and concentration of formulation applied. Appropriate amounts in any given instance will be readily apparent to those skilled in the art or capable of determination by routine experimentation.

As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder. For prophylactic benefit, the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. Treatment includes preventing the disease, that is, causing the clinical symptoms of the disease not to develop by administration of a protective composition prior to the induction of the disease; suppressing the disease, that is, causing the clinical symptoms of the disease not to develop by administration of a protective composition after the inductive event but prior to the clinical appearance or reappearance of the disease; inhibiting the disease, that is, arresting the development of clinical symptoms by administration of a protective composition after their initial appearance; preventing re-occurring of the disease and/or relieving the disease, that is, causing the regression of clinical symptoms by administration of a protective composition after their initial appearance.

The term “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.

A “subject,” “individual,” or “patient,” is used interchangeably herein, which refers to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, murines, simians, humans, farm animals, sport animals, and pets. Tissues, cells and their progeny of a biological entity obtained in vitro or cultured in vitro are also encompassed.

Where a moiety herein is R-substituted (e.g. “R^12A-substituted or unsubstituted alkyl”), that moity may be substituted with a plurality of R groups that are each optionally different (e.g. a plurality of R^12A substituents may be attached to the alkyl moiety wherein each R^12A substituent is optionally different). Moreover, where more than one R group is present (e.g. more than one R^17D), each R group is optionally different (e.g. each R^17D group is independently one of the subistutents provided in its definition or Markush group).

II. Compositions

In some embodiments, the compound useful in the methods provided herein is a porphyrin compound, such as a metalloporphyrin. The compound may have the formula:

In Formula I, the substituted porphyrin may be bound to a metal. The metal may be manganese, iron, cobalt, copper, nickel, zinc, chromium, aluminum, or magnesium, including ions thereof (e.g., Mn²⁺, Mn³⁺, Fe²⁺, Fe³⁺, Co²⁺, Cu²⁺, Ni²⁺, Zn²⁺, Cr²⁺, Cr³⁺, Al³⁺, Mg²⁺). In some embodiments, the compound has the formula of Formula (II), wherein M is a metal (e.g. metal ion):

In some embodiments, M is manganese, iron, cobalt, copper, nickel, zinc, chromium, aluminum, or magnesium, including ions thereof (e.g., Mn²⁺, Mn⁺, Fe²⁺, Fe³⁺, Co²⁺, Cu²⁺, Ni²⁺, Zn²⁺, Cr²⁺, Cr^3°, Al^3°, Mg²⁺). In a specific embodiment, the compound is the compound of formula II, wherein M is manganese. For example, the compound may have the formula:

R¹ may be independently —C(X¹)₃, —COOR^5A,

R³ may be independently —C(X³)₃, —COOR^5B,

R² may be independently —C(X²)₃, —COOR^5C, or

R⁴ may be independently —C(X⁴)₃, —COOR^5D or

In some embodiments, R¹ is —C(X¹)₃ and R³ is —C(X³)₃. In other embodiments, R¹ is —COOR^5A and R³ is —COOR^5B. In some embodiments, R¹ is

and R³

In other embodiments, R¹ is

and R³ is

In other embodiments, R² is —C(X²)₃ and R⁴ is —C(X⁴)₃. In other embodiments, R² is —COOR^5C and R⁴ is —COOR^5D. In some embodiments, R² is

and R⁴

X¹, X², X³ and X⁴ are halogens, such as F, Cl or Br (e.g. F).

In some embodiments, R¹, R², R³ and R⁴ are not simultaneously —COOR^5A, —COOR^5B, —COOR^5C, and —COOR^5D, respectively. In some embodiments, if R² is —COOR^5C and R⁴ is —COOR^5D, R¹ is not

and R³ is not

In some embodiments, if R² is —C(X²)₃ and R⁴ is —C(X⁴)₃, R¹ is not

and R³ is not

In some embodiments, if R¹ and R³ are both —CF₃, then R² and R⁴ are both not —CO₂CH₃. In other words, if R¹ and R³ are both —CF₃, then R² and R⁴ are not simultaneously —CO₂CH₃. In some embodiments, if R¹ and R³ are both —CF₃, then R² and R⁴ are both not —CO₂CH₂CH₂CH₃. In other words, if R¹ and R³ are both —CF₃, then R² and R⁴ are not simultaneously —CO₂ CH₂CH₂CH₃.

In some embodiments, if R¹ and R³ are both —CF₃, then R² and R⁴ are not COOR^5C and COOR^5D, respectively, when R⁵ and R^5D are methyl or propyl. In some embodiments, if R¹ and R³ are both —CF₃, then R² and R⁴ are not COOR^5C and COOR^5D, respectively, when R^5C and R^5D are unsubstituted C₁-C₃ alkyl. In some embodiments, if R¹ and R³ are both —CF₃, then R² and R⁴ are not COOR^5C and COOR^5D, respectively, when R^5C and R^5D are unsubstituted C₁-C₄ alkyl. In some embodiments, if R¹ and R³ are both —CF₃, then R² and R⁴ are not COOR^5C and COOR^5D, respectively, when R^5C and R^5D are unsubstituted C₁-C₅ alkyl. In some embodiments, if R¹ and R³ are both —CF₃, then R² and R⁴ are not COOR^5C and COOR^5D, respectively, when R^5C and R^5D are unsubstituted C₁-C₆ alkyl. In some embodiments, if R¹ and R³ are both —CF₃, then R² and R⁴ are not COOR^5C and COOR^5D, respectively, when R^5C and R^5D are unsubstituted C₁-C₇ alkyl. In some embodiments, if R¹ and R³ are both —CF₃, then R² and R⁴ are not COOR^5C and COOR^5D, respectively, when R^5C and R^5D are unsubstituted C₁-C₈ alkyl.

In some embodiments, if R¹ and R³ are both —CF₃, then R² and R⁴ are not COOR^5C and COOR^5D, respectively, when R^5C and R^5D are substituted or unsubstituted C₁-C₃ alkyl. In some embodiments, if R¹ and R³ are both —CF₃, then R² and R⁴ are not COOR^5C and COOR^5D, respectively, when R^5C and R^5D are substituted or unsubstituted C₁-C₄ alkyl. In some embodiments, if R ¹ and R³ are both —CF₃, then R² and R⁴ are not COOR^5C and COOR^5D, respectively, when R^5C and R^5D are substituted or unsubstituted C₁-C₅ alkyl. In some embodiments, if R¹ and R³ are both —CF₃, then R² and R⁴ are not COOR^5C and COOR5D, respectively, when R^5Cand R^5D are substituted or unsubstituted C₁-C₆ alkyl. In some embodiments, if R¹ and R³ are both —CF₃, then R² and R⁴ are not COOR^5C and COOR^5D, respectively, when R^5C and R^5D are substituted or unsubstituted C₁-C₇ alkyl. In some embodiments, if R¹ and R³ are both —CF₃, then R² and R⁴ are not COOR^5C and COOR^5D, respectively, when R^5C and R^5D are substituted or unsubstituted C₁-C₈ alkyl.

In some embodiments, if R¹ and R³ are both —CF₃, then R² and R⁴ are not COOR^5C and COOR^5D, respectively, when R^5C and R^5D are unsubstituted alkyl. In some embodiments, if R¹ and R³ are both —CF₃, then R ² and R⁴ are not COOR^5C and COOR^5D, respectively, when R^5C and R^5D are substituted or unsubstituted alkyl. In some embodiments, if R¹ and R³ are both —CF₃, then R² and R⁴ are not COOR^5C and COOR^5D.

In other embodiments, if R¹ and R³ are both —CO₂CH₃, R² and R⁴ are both not —CF₃. In other words, if R¹ and R³ are both —CO₂CH₃, R² and R⁴ are not simultaneously —CF₃. In other embodiments, if R¹ and R³ are both —CO₂CH₂CH₂CH₃, R² and R⁴ are both not —CF₃. In other words, if R¹ and R³ are both —CO₂CH₂CH₂CH₃, R² and R⁴ are not simultaneously —CF₃. In some embodiments, if R¹ and R³ are both —CO₂CH₃, R² and R⁴ are not C(X²)₃ and C(X⁴)₃, respectively, when X² and X⁴ are both fluorine. In some embodiments, if R¹ and R³ are both —CO₂CH₃, R² and R⁴ are not C(X²)₃ and C(X⁴)₃, respectively, when X² and X⁴ are both halogen. In some embodiments, if R¹ and R³ are both —CO₂CH₃, R² and R⁴ are not C(X²)₃ and C(X⁴)₃, respectively. In some embodiments, if R¹ and R³ are both —CO₂CH₃, R² and R⁴ are both not alkyl. In some embodiments, if R¹ and R³ are both —CO₂CH₂CH₂CH₃, R² and R⁴ are not C(X²)₃ and C(X⁴)₃, respectively, when X² and X⁴ are both fluorine. In some embodiments, if R¹ and R³ are both —CO₂CH₂CH₂CH₃, R² and R⁴ are not C(X²)₃ and C(X⁴)₃, respectively, when X² and X⁴ are both halogen. In some embodiments, if R¹ and R³ are both —CO₂CH₂CH₂CH₃, R² and R⁴ are not C(X²)₃ and C(X⁴)₃, respectively. In some embodiments, if R¹ and R³ are both —CO₂CH₂CH₂CH₃, R² and R⁴ are both not alkyl.

In some embodiments, if R¹ and R³ are COOR^5A and COOR^5B, respectively, then R² and R⁴ are not —CF₃, when R^5A and R^5B are methyl or propyl. In some embodiments, if R¹ and R³ are COOR^5A and COOR^5B, respectively, then R² and R⁴ are not —CF₃, when R^5A and R^5B are unsubstituted C₁-C₃ alkyl. In some embodiments, if R¹ and R³ are COOR^5A and COOR^5B, respectively, then R² and R⁴ are not —CF₃, when R^5A and R^5B are unsubstituted C₁-C₄ alkyl. In some embodiments, if R ¹ and R³ are COOR^5A and COOR^5B, respectively, then R² and R⁴ are not —CF₃, when R^5A and R^5B are unsubstituted C₁-C₅ alkyl. In some embodiments, if R¹ and R³ are COOR^5A and COOR^5B, respectively, then R² and R⁴ are not —CF₃, when R^5A and R^5B are unsubstituted C₁-C₆ alkyl. In some embodiments, if R¹ and R³ are COOR^5A and COOR^5B, respectively, then R² and R⁴ are not —CF₃, when R^5A and R^5B are unsubstituted C₁-C₇ alkyl. In some embodiments, if R¹ and R³ are COOR^5A and COOR^5B, respectively, then R² and R⁴ are not —CF₃, when R^5A and R^5B are unsubstituted C₁-C₈ alkyl.

In some embodiments, if R¹ and R³ are COOR^5A and COOR^5B, respectively, then R² and R⁴ are not —CF₃, when R^5A and R^5B are substituted or unsubstituted C₁-C₃ alkyl. In some embodiments, if R¹ and R³ are COOR^5A and COOR^5B, respectively, then R² and R⁴ are not —CF₃, when R^5A and R^5B are substituted or unsubstituted C₁-C₄ alkyl. In some embodiments, if R¹ and R³ are COOR^5A and COOR^5B, respectively, then R² and R⁴ are not —CF₃, when R^5A and R^5B are substituted or unsubstituted C₁-C₅ alkyl. In some embodiments, if R¹ and R³ are COOR^5A and COOR^5B, respectively, then R² and R⁴ are not —CF₃, when R^5A and R^5B are substituted or unsubstituted C₁-C₆ alkyl. In some embodiments, if R¹ and R³ are COOR^5A and COOR^5B, respectively, then R² and R⁴ are not —CF₃, when R^5A and R^5B are substituted or unsubstituted C₁-C₇ alkyl. In some embodiments, if R¹ and R³ are COOR^5A and COOR^5B, respectively, then R² and R⁴ are not —CF₃, when R^5A and R^5B are substituted or unsubstituted C₁-C₈ alkyl.

In some embodiments, if R¹ and R³ are COOR^5A and COOR^5B, respectively, then R² and R⁴ are not —CF₃, when R^5A and R^5B are unsubstituted alkyl. In some embodiments, if R¹ and R³ are COOR^5A and COOR^5B, respectively, then R² and R⁴ are not —CF₃, when R^5A and R^5B are substituted or unsubstituted alkyl. In some embodiments, if R¹ and R³ are COOR^5A and COOR^5B, then R² and R⁴ are not —CF₃.

In other embodiments, if R¹ and R³ are both —CF₃, R² and R⁴ are both not —CO₂CH₃. In other words, if R¹ and R³ are both —CF₃, R² and R⁴ are not simultaneously —CO₂CH₃. In other embodiments, if R¹ and R³ are both —CF₃, R² and R⁴ are both not —CO₂CH₂CH₂CH₃. In other words, if R¹ and R³ are both —CF₃, R² and R⁴ are not simultaneously —CO₂CH₂CH₂CH₃. In some embodiments, if R¹ and R³ are C(X¹)₃ and C(X³)₃, respectively, R² and R⁴ are not —CO₂CH₃, when X¹ and X³ are both fluorine. In some embodiments, if R¹ and R³ are C(X¹)₃ and C(X³)₃, respectively, R² and R⁴ are not —CO₂CH₃, when X² and X⁴ are both halogen. In some embodiments, if R¹ and R³ are C(X¹)₃ and C(X³)₃, respectively, R² and R⁴ are not —CO₂CH₃. In some embodiments, if R¹ and R³ are both alkyl, R² and R⁴ are not —CO₂CH₃. In some embodiments, if R¹ and R³ are C(X¹)₃ and C(X³)₃, respectively, R² and R⁴ are not —CO₂CH₂CH₂CH₃, when X¹ and X³ are both fluorine. In some embodiments, if R¹ and R³ are C(X¹)₃ and C(X³)₃, respectively, R² and R⁴ are not —CO₂CH₂CH₂CH₃, when X¹ and X³ are both halogen. In some embodiments, if R¹ and R³ are C(X¹)₃ and C(X³)₃, R² and R⁴ are not —CO₂CH₂CH₂CH₃. In some embodiments, if R¹ and R³ are both alkyl, R² and R⁴ are not —CO₂CH₂CH₂CH₃.

In some embodiments, the compounds as provided herein do not include substituted porphyrins as set forth in FIG. 1A-C of issued patent U.S. Pat. No. 6,479,477 (Crapo et al.). More specifically, the compounds according to the embodiments provided herein do not include compound AEOL-11201, AEOL-11202, AEOL-11203, AEOL-11204, AEOL-11205, AEOL-11-206, AEOL-11207, AEOL-11212, AEOL-11215, AEOL-11216, AEOL-11217, AEOL-11218, AEOL-11219, AEOL-11220, AEOL-11221, AEOL-11223, AEOL-11225, AEOL-11229, AEOL-11230, AEOL-11231, AEOL-11232, AEOL-11233, or AEOL-11234.

In some embodiments, the porphyrin compositions disclosed herein (e.g. of Formula (I)-(III)) do not include a compound having the formula:

In formula (XII), X², X⁴, R^5A and R^5B are as defined herein (including embodiments thereof). In some embodiments, R^5A and R^5B are both methyl, X² and X⁴ are both fluorine and M is a metal such as metal ions (e.g. Mn²⁺, Mn³⁺). In other embodiments, the composition does not include a compound of formula (XII), wherein R^5A and R^5B are both propyl, and X² and X⁴ are both fluorine. In some embodiments, the composition does not include a compound of formula (XII), wherein R^5A and R^5B are both unsubstituted C₁-C₃ alklyl, and X² and X⁴ are both fluorine. In some embodiments, the composition does not include a compound of formula (XII), wherein R^5A and R^5B are both substituted or unsubstituted C₁-C₃ alklyl, and X² and X⁴ are both fluorine. In some embodiments, the composition does not include a compound of formula (XII), wherein R^5A and R^5B are both unsubstituted C₁-C₄ alklyl, and X² and X⁴ are both fluorine. In some embodiments, the composition does not include a compound of formula (XII), wherein R^5A and R^5B are both substituted or unsubstituted C₁-C₄ alklyl, and X² and X⁴ are both fluorine. In some embodiments, the composition does not include a compound of formula (XII), wherein R^5A and R^5B are both unsubstituted C₁-C₅ alklyl, and X² and X⁴ are both fluorine. In some embodiments, the composition does not include a compound of formula (XII), wherein R^5A and R^5B are both substituted or unsubstituted C₁-C₅ alklyl, and X² and X⁴ are both fluorine. In some embodiments, the composition does not include a compound of formula (XII), wherein R^5A and R^5B are both unsubstituted C₁-C₆ alklyl, and X² and X⁴ are both fluorine. In some embodiments, the composition does not include a compound of formula (XII), wherein R^5A and R^5B are both substituted or unsubstituted C₁-C₆ alklyl, and X² and X⁴ are both fluorine. In some embodiments, the composition does not include a compound of formula (XII), wherein R^5A and R^5B are both unsubstituted C₁-C₇ alklyl, and X² and X⁴ are both fluorine. In some embodiments, the composition does not include a compound of formula (XII), wherein R^5A and R^5B are both substituted or unsubstituted C₁-C₇ alklyl, and X² and X⁴ are both fluorine. In some embodiments, the composition does not include a compound of formula (XII), wherein R^5A and R^5B are both unsubstituted C₁-C₈ alklyl, and X² and X⁴ are both fluorine. In some embodiments, the composition does not include a compound of formula (XII), wherein R^5A and R^5B are both substituted or unsubstituted C₁-C₈ alklyl, and X² and X⁴ are both fluorine. In some embodiments, the composition does not include a compound of formula (XII), wherein R^5A and R^5B are both unsubstituted alklyl, and X² and X⁴ are both fluorine. In some embodiments, the composition does not include a compound of formula (XII), wherein R^5A and R^5B are both substituted or unsubstituted alklyl, and X² and X⁴ are both fluorine.

In other embodiments, the composition does not include a compound of formula (XII), wherein R^5A and R^5B are both methyl, and X² and X⁴ are both halogen. In other embodiments, the composition does not include a compound of formula (XII), wherein R^5A and R^5B are both propyl, and X² and X⁴ are both halogen. In other embodiments, the composition does not include a compound of formula (XII), wherein R^5A and R^5B are both methyl, and X² and X⁴ are both halogen. In other embodiments, the composition does not include a compound of formula (XII), wherein R^5A and R^5B are both propyl, and X² and X⁴ are both halogen.

In some embodiments, the porphyrin compositions disclosed herein (e.g. of Formula (I)-(III)) do not include a compound having the formula: do not include a compound of Formula

In formula (XIII), X¹, X³, R^5D and R^5C are as defined herein (including embodiments thereof). In some embodiments, R^5C and R^5D are both methyl, and X¹ and X³ are both fluorine and M is a metal including ions thereof (e.g. Mn²⁻, Mn³⁺). In other embodiments, the composition does not include a compound of formula (XIII), wherein R^5C and R^5D are both propyl, and X¹ and X³ are both fluorine. In some embodiments, the composition does not include a compound of formula (XIII), wherein R^5C and R^5D are both unsubstituted C₁-C₃ alklyl, and X¹ and X³ are both fluorine. In some embodiments, the composition does not include a compound of formula (XIII), wherein R^5C and R^5D are both substituted or unsubstituted C₁-C₃ alklyl, and X¹ and X³ are both fluorine. In some embodiments, the composition does not include a compound of formula (XIII), wherein R^5C and R^5D are both unsubstituted C₁-C₄ alklyl, and X¹ and X³ are both fluorine. In some embodiments, the composition does not include a compound of formula (XIII), wherein R^5C and R^5D are both substituted or unsubstituted C₁-C₄ alklyl, and X¹ and X³ are both fluorine. In some embodiments, the composition does not include a compound of formula (XIII), wherein R^5C and R^5D are both unsubstituted C₁-C₅ alklyl, and X¹ and X³ are both fluorine. In some embodiments, the composition does not include a compound of formula (XIII), wherein R^5A and R^5B are both substituted or unsubstituted C₁-C₅ alklyl, and X¹ and X³ are both fluorine. In some embodiments, the composition does not include a compound of formula (XIII), wherein R^5C and R^5D are both unsubstituted C₁-C₆ alklyl, and X¹ and X³ are both fluorine. In some embodiments, the composition does not include a compound of formula (XIII), wherein R⁵ and R^5D are both substituted or unsubstituted C₁-C₆ alklyl, and X¹ and X³ are both fluorine. In some embodiments, the composition does not include a compound of formula (XIII), wherein R⁵ and R^5D are both unsubstituted C₁-C₇ alklyl, and X¹ and X³ are both fluorine. In some embodiments, the composition does not include a compound of formula (XIII), wherein R⁵ and R^5D are both substituted or unsubstituted C₁-C₇ alklyl, and X¹ and X³ are both fluorine. In some embodiments, the composition does not include a compound of formula (XIII), wherein R⁵ and R^5D are both unsubstituted C₁-C₈ alklyl, and X¹ and X³ are both fluorine. In some embodiments, the composition does not include a compound of formula (XIII), wherein R⁵ and R^5D are both substituted or unsubstituted C₁-C₈ alklyl, and X¹ and X³ are both fluorine. In some embodiments, the composition does not include a compound of formula (XIII), wherein R⁵ and R^5D are both unsubstituted alklyl, and X¹ and X³ are both fluorine. In some embodiments, the composition does not include a compound of formula (XIII), wherein R⁵ and R^5D are both substituted or unsubstituted alklyl, and X¹ and X³ are both fluorine.

In other embodiments, the composition does not include a compound of formula (XIII), wherein R^5C and R^5D are both methyl, and X¹ and X³ are both halogen. In other embodiments, the composition does not include a compound of formula (XIII), wherein R^5C and R^5D are both propyl, and X¹ and X³ are both halogen. In other embodiments, the composition does not include a compound of formula (XIII), wherein R^5C and R^5D are both methyl, and X¹ and X³ are both halogen. In other embodiments, the composition does not include a compound of formula (XIII), wherein R^5C and R^5D are both propyl, and X¹ and X³ are both halogen.

A person of ordinary skill will immediately understand that the compounds provided herein may have a net charge (e.g. a net positive charge). In such cases, it is understood that any appropriate counterion may be present (e.g. chlorine). For example, the compounds provided herein may be present as a pharmaceutically acceptable salt. Thus,for example, where the compound overall or R¹, R², R³, and R⁴ contain a positive charge, one of skill will immediately recognize that an anionic compound or molecule will be present where the compound is in solution. Any applicable anionic compound or molecule may be used as a counterion to the positively charged substituents, including for example chloride, fluoride, sulfide, a sulfate, a carbonate, or a phosphate.

Each R^6A and R^8A may be the same or different and may each independently be hydrogen, halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —CH₂COOH, —COOR^10A, —CH₂COOR^10A, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl.

R^10A may be unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. R^10A may also be substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In certain embodiments, R^10A is R^11A-substituted or unsubstituted alkyl, R^11A-substituted or unsubstituted heteroalkyl, R^11A-substituted or unsubstituted cycloalkyl, R^11A-substituted or unsubstituted heterocycloalkyl, R^11A-substituted or unsubstituted aryl, or R^11A-substituted or unsubstituted heteroaryl. R^10A may also be R^11A-substituted or unsubstituted alkyl, R^11A-substituted or unsubstituted heteroalkyl, R^11A-substituted or unsubstituted cycloalkyl, R^11A-substituted or unsubstituted heterocycloalkyl, R^11A-substituted or unsubstituted aryl, or R^11A-substituted or unsubstituted heteroaryl. In some embodiments, R^10A is an unsubstituted alkyl such as unsubstituted C₁-C₁₀ alkyl (e.g., —CH₃ or unsubstituted C₁-C₅ alkyl).

In some embodiments, R^6A and R^8A are each independently hydrogen, halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —CH₂COOH , —COOR^10A, —CH₂COOR^10A, substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In some embodiments, one or both of R^6A and R^8A is unsubstituted. In one embodiment, R^6A and R^8A are independently hydrogen or substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆ or C₁-C₃) alkyl. In one embodiment, R^6A and R^8A are independently hydrogen or unsubstituted C₁-C₁₀ (e.g., unsubstituted C₁-C₆ or unsubstituted C₁-C₃) alkyl.

In one embodiment, R^6A and R^8A are hydrogen, halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —CH₂COOH, —COOR^10A, —CH₂COOR^10A, R^11A-substituted or unsubstituted alkyl, R^11A-substituted or unsubstituted heteroalkyl, R^11A-substituted or unsubstituted cycloalkyl, R^11A-substituted or unsubstituted heterocycloalkyl, R^11A-substituted or unsubstituted aryl, or R^11A-substituted or unsubstituted heteroaryl.

In one embodiment, R^6A and R^8A are independently hydrogen, halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —COOR^10A, —CH₂COOH, —CH₂COOR^10A, R^11A-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^11A-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^11A-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^11A-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^11A-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^11A-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^11A is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —COOR^15A, —CH₂COOR^15A, —CH₂COOH, R^12A-substituted or unsubstituted alkyl, R^12A-substituted or unsubstituted heteroalkyl, R^12A-substituted or unsubstituted cycloalkyl, R^12A-substituted or unsubstituted heterocycloalkyl, R^12A-substituted or unsubstituted aryl, or R^12A-substituted or unsubstituted heteroaryl. In certain embodiments, R^11A is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —COOR^15A, —CH₂COOR^15A, R^12A-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^12A-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^12A-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^12A-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^12A-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^12A-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^15A may be a unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. R^15A may also be substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In some embodiments, R^15A is R^12A-substituted or unsubstituted alkyl, R^12A-substituted or unsubstituted heteroalkyl, R^12A-substituted or unsubstituted cycloalkyl, R^12A-substituted or unsubstituted heterocycloalkyl, R^12A-substituted or unsubstituted aryl, or R^12A-substituted or unsubstituted heteroaryl. R^15A may also be R^12A-substituted or unsubstituted C ₁-C₁₀ (e.g., C₁-C₆) alkyl, R^12A-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^12A-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^12A-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^12A-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^12A-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^12A is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —COOR^16A, —CH₂COOR^16A, —CH₂COOH, R^13A-substituted or unsubstituted alkyl, R^13A-substituted or unsubstituted heteroalkyl, R^13A-substituted or unsubstituted cycloalkyl, R^13A-substituted or unsubstituted heterocycloalkyl, R^13A-substituted or unsubstituted aryl, or R^13A-substituted or unsubstituted heteroaryl. In one embodiment, R^12A is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —COOR^16A, —CH₂COOR^16A, R^13A-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^13A-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^13A-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^13A-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^13A-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^13A-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^16A may be a unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. R^16A may also be substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In some embodiments, R^16A is R^13A-substituted or unsubstituted alkyl, R^13A-substituted or unsubstituted heteroalkyl, R^13A-substituted or unsubstituted cycloalkyl, R^13A-substituted or unsubstituted heterocycloalkyl, R^13A-substituted or unsubstituted aryl, or R^13A-substituted or unsubstituted heteroaryl. R^16A may also be R^13A-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^13A-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^13A-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^13A-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^13A-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^13A-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^13A is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —COOR^17A, —CH₂COOR^17A, —CH₂COOH, R^14A-substituted or unsubstituted alkyl, R^14A-substituted or unsubstituted heteroalkyl, R^14A-substituted or unsubstituted cycloalkyl, R^14A-substituted or unsubstituted heterocycloalkyl, R^14A-substituted or unsubstituted aryl, or R^14A-substituted or unsubstituted heteroaryl. In one embodiment, R^13A is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —COOR^17A, —CH₂COOR^17A, R^14A-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^14A-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^14A-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^14A-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^14A-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^14A-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. R^14A is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —COOR^10A, —CH₂COOR^10A, —CH₂COOH, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

R^17A may be a unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. R^17A may also be substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In some embodiments, R^17A is R^14A-substituted or unsubstituted alkyl, R^14A-substituted or unsubstituted heteroalkyl, R^14A-substituted or unsubstituted cycloalkyl, R^14A-substituted or unsubstituted heterocycloalkyl, R^14A-substituted or unsubstituted aryl, or R^14A-substituted or unsubstituted heteroaryl. R^17A may also be R^14A-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^14A-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^14A-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^14A-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^14A-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^14A-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^7A may be hydrogen, halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —CH₂COOH, —COOR^10B, —CH₂COOR^10B, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl.

R^10B may be unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. R^10B may also be substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In certain embodiments, R^10B is R^11B-substituted or unsubstituted alkyl, R^11B-substituted or unsubstituted heteroalkyl, R^11B substituted or unsubstituted cycloalkyl, R^11B-substituted or unsubstituted heterocycloalkyl, R^11B-substituted or unsubstituted aryl, or R^11B-substituted or unsubstituted heteroaryl. R^10B may also be R^11B-substituted or unsubstituted alkyl, R^11B-substituted or unsubstituted heteroalkyl, R^11B-substituted or unsubstituted cycloalkyl, R^11B-substituted or unsubstituted heterocycloalkyl, R^11B-substituted or unsubstituted aryl, or R^11B-substituted or unsubstituted heteroaryl. In some embodiments, R^10B is an unsubstituted alkyl such as C₁-C₁₀ alkyl (e.g., —CH₃ or a C₁-C₅ alkyl).

In some embodiments, R^7A is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —CH₂COOH , —COOR^10B, —CH₂COOR^10B, substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In some embodiments, R^7A is unsubstituted. In one embodiment, R^7A is hydrogen or substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆ or C₁-C₃) alkyl. In one embodiment, R^7A is hydrogen or unsubstituted C₁-C₁₀ (e.g., unsubstituted C₁-C₆ or unsubstituted C₁-C₃) alkyl.

In one embodiment, R^7A is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —CH₂COOH, —COOR^10B, —CH₂COOR^10B, R^11B-substituted or unsubstituted alkyl, R^11B-substituted or unsubstituted heteroalkyl, R^11B-substituted or unsubstituted cycloalkyl, R^11B-substituted or unsubstituted heterocycloalkyl, R^11B-substituted or unsubstituted aryl, or R^11B-substituted or unsubstituted heteroaryl.

In one embodiment, R^7A is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —COOR^10B, —CH₂COOH, —CH₂COOR^10B, R^11B-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^11B-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^11B-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^11B-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^11B-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^11B-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^11B is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —COOR^15B, —CH₂COOR^15B, —CH₂COOH, R^12B-substituted or unsubstituted alkyl, R^12B-substituted or unsubstituted heteroalkyl, R^12B-substituted or unsubstituted cycloalkyl, R^12B-substituted or unsubstituted heterocycloalkyl, R^12B-substituted or unsubstituted aryl, or R^12B-substituted or unsubstituted heteroaryl. In certain embodiments, R^11B is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —COOR^15B, —CH₂COOR^15B, R^12B-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^12B-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^12B-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^12B-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^12B-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^12B-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^15B may be a unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. R^15B may also be substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In some embodiments, R^15B is R^12B-substituted or unsubstituted alkyl, R^12B-substituted or unsubstituted heteroalkyl, R^12B-substituted or unsubstituted cycloalkyl, R^12B-substituted or unsubstituted heterocycloalkyl, R^12B-substituted or unsubstituted aryl, or R^12B-substituted or unsubstituted heteroaryl. R^15B may also be R^12B-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^12B-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^12B-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^12B-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^12B-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^12B-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^12B is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —COOR^16B, _CH₂COOR^16B, —CH₂COOH, R^13B-substituted or unsubstituted alkyl, R^13B-substituted or unsubstituted heteroalkyl, R^13B-substituted or unsubstituted cycloalkyl, R^13B-substituted or unsubstituted heterocycloalkyl, R^13B-substituted or unsubstituted aryl, or R^13B-substituted or unsubstituted heteroaryl. In one embodiment, R^12B is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —COOR^16B, —CH₂COOR^16B, R^13B-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^13B-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^13B-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^13B-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^13B-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^13B-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^16B may be a unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. R^16B may also be substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In some embodiments, R^16B is R^13B-substituted or unsubstituted alkyl, R^13B-substituted or unsubstituted heteroalkyl, R^13B-substituted or unsubstituted cycloalkyl, R^13B-substituted or unsubstituted heterocycloalkyl, R^13B-substituted or unsubstituted aryl, or R^13B-substituted or unsubstituted heteroaryl. R^16B may also be R^13B-substituted or unsubstituted C ₁-C₁₀ (e.g., C₁-C₆) alkyl, R^13B-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^13B-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^13B-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^13B-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^13B-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^13B is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —COOR^17B, —CH₂COOR^17B, —CH₂COOH, R^14B-substituted or unsubstituted alkyl, R^14B-substituted or unsubstituted heteroalkyl, R^14B-substituted or unsubstituted cycloalkyl, R^14B-substituted or unsubstituted heterocycloalkyl, R^14B-substituted or unsubstituted aryl, or R^14B-substituted or unsubstituted heteroaryl. In one embodiment, R^13B is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —COOR^17B, —CH₂COOR^17B, R^14B-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^14B-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^14B-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^14B-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^14B-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^14B-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. R^14B is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —COOR^10B, —CH₂COOR^10B, —CH₂COOH, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

R^17B may be a unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. R^17B may also be substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In some embodiments, R^17B is R^14B-substituted or unsubstituted alkyl, R^14B-substituted or unsubstituted heteroalkyl, R^14B-substituted or unsubstituted cycloalkyl, R^14B-substituted or unsubstituted heterocycloalkyl, R^14B-substituted or unsubstituted aryl, or R^14B-substituted or unsubstituted heteroaryl. R^17B may also be R^14B-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^14B-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^14B-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^14B-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^14B-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^14B-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

Each R^6B and R^8B may be the same or different and may each independently be hydrogen, halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —CH₂COOH, —COOR^10C, —CH₂COOR^10C, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl.

R^10C may be unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. R^10C may also be substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In certain embodiments, R^10C is R^11C-substituted or unsubstituted alkyl, R^11C-substituted or unsubstituted heteroalkyl, R^11C-substituted or unsubstituted cycloalkyl, R^11C-substituted or unsubstituted heterocycloalkyl, R^11C-substituted or unsubstituted aryl, or R^11C-substituted or unsubstituted heteroaryl. R^10C may also be R^11C-substituted or unsubstituted alkyl, R^11C-substituted or unsubstituted heteroalkyl, R^11C-substituted or unsubstituted cycloalkyl, R^11C-substituted or unsubstituted heterocycloalkyl, R^11C-substituted or unsubstituted aryl, or R^11C-substituted or unsubstituted heteroaryl. In some embodiments, R^10C is an unsubstituted alkyl such as C₁-C₁₀ alkyl (e.g., —CH₃ or a C₁-C₅ alkyl).

In some embodiments, R^6B and R^8B are each independently hydrogen, halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —CH₂COOH, —COOR^10C, —CH₂COOR^10C, substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In some embodiments, one or both of R^6B and R^8B is unsubstituted. In one embodiment, R^6B and R^8B are independently hydrogen or substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆ or C₁-C₃) alkyl.

In one embodiment, R^6B and R^8B are hydrogen, halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —CH₂COOH, —COOR^10C, —CH₂COOR^10C, R^11C-substituted or unsubstituted alkyl, R^11C-substituted or unsubstituted heteroalkyl, R^11C-substituted or unsubstituted cycloalkyl, R^11C-substituted or unsubstituted heterocycloalkyl, R^11C-substituted or unsubstituted aryl, or R^11C-substituted or unsubstituted heteroaryl.

In one embodiment, R^6B and R^8B are independently hydrogen, halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —COOR^10C, —CH₂COOH, —CH₂COOR^10C, R^11C-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^11C-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^11C-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^11C-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^11C-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^11C-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^11C is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —COOR^15C, —CH₂COOR^15C, —CH₂COOH, R^12C-substituted or unsubstituted alkyl, R^12C-substituted or unsubstituted heteroalkyl, R^12C-substituted or unsubstituted cycloalkyl, R^12C-substituted or unsubstituted heterocycloalkyl, R^12C-substituted or unsubstituted aryl, or R^12C-substituted or unsubstituted heteroaryl. In certain embodiments, R^11C is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —COOR^15C, —CH₂COOR^15C, R^12C-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^12C-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^12C-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^12C-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^12C-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^12C-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^15C may be a unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. R^15C may also be substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In some embodiments, R^15C is R^12C-substituted or unsubstituted alkyl, R^12C-substituted or unsubstituted heteroalkyl, R^12C-substituted or unsubstituted cycloalkyl, R^12C-substituted or unsubstituted heterocycloalkyl, R^12C-substituted or unsubstituted aryl, or R^12C-substituted or unsubstituted heteroaryl. R^15C may also be R^12C-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^12C-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^12C-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^12C-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^12C-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^12C-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^12C is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —COOR^16C, —CH₂COOR^16C, —CH₂COOH, R^13C-substituted or unsubstituted alkyl, R^13C-substituted or unsubstituted heteroalkyl, R^13C-substituted or unsubstituted cycloalkyl, R^13C-substituted or unsubstituted heterocycloalkyl, R^13C-substituted or unsubstituted aryl, or R^13C-substituted or unsubstituted heteroaryl. In one embodiment, R^12C is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —COOR^16C, —CH₂COOR^16C, R^13C-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^13C-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^13C-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^13C-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^13C-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^13C-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^16C may be a unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. R^16C may also be substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In some embodiments, R^16C is R^13C-substituted or unsubstituted alkyl, R^13C-substituted or unsubstituted heteroalkyl, R^13C-substituted or unsubstituted cycloalkyl, R^13C-substituted or unsubstituted heterocycloalkyl, R^13C-substituted or unsubstituted aryl, or R^13C-substituted or unsubstituted heteroaryl. R^16C may also be R^13C-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^13C-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^13C-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^13C-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^13C-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^13C-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^13C is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —COOR^17C, —CH₂COOR^17C, —CH₂COOH, R^14C-substituted or unsubstituted alkyl, R^14C-substituted or unsubstituted heteroalkyl, R^14C-substituted or unsubstituted cycloalkyl, R^14C-substituted or unsubstituted heterocycloalkyl, R^14C-substituted or unsubstituted aryl, or R^14C-substituted or unsubstituted heteroaryl. In one embodiment, R^13C is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —COOR^17C, —CH₂COOR^17C, R^14C-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^14C-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^14C-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^14C-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^14C-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^14C-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. R^14C is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —COOR^10C, —CH₂COOR^10C, —CH₂COOH, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

R^17C may be a unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. R^17C may also be substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In some embodiments, R^17C is R^14C-substituted or unsubstituted alkyl, R^14C-substituted or unsubstituted heteroalkyl, R^14C-substituted or unsubstituted cycloalkyl, R^14C-substituted or unsubstituted heterocycloalkyl, R^14C-substituted or unsubstituted aryl, or R^14C-substituted or unsubstituted heteroaryl. R^17C may also be R^14C-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^14C-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^14C-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^14C-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^14C-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^14C-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^7B may be hydrogen, halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —CH₂COOH, —COOR^10D, —CH₂COOR^10D, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl.

R^10D may be unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. R^10D may also be substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In certain embodiments, R^10D is R^11D-substituted or unsubstituted alkyl, R^11D-substituted or unsubstituted heteroalkyl, R^11D-substituted or unsubstituted cycloalkyl, R^11D-substituted or unsubstituted heterocycloalkyl, R^11D-substituted or unsubstituted aryl, or R^11D-substituted or unsubstituted heteroaryl. R^10D may also be R^11D-substituted or unsubstituted alkyl, R^11D-substituted or unsubstituted heteroalkyl, R^11D-substituted or unsubstituted cycloalkyl, R^11D-substituted or unsubstituted heterocycloalkyl, R^11D-substituted or unsubstituted aryl, or R^11D-substituted or unsubstituted heteroaryl. In some embodiments, R^10D is an unsubstituted alkyl such as C ₁-C₁₀ alkyl (e.g., —CH₃ or a C₁-C₅ alkyl).

In some embodiments, R^7B is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —CH₂COOH , —COOR^10D, —CH₂COOR^10D, substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In some embodiments, R^7D is unsubstituted. In one embodiment, R^7D is hydrogen or substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆ or C₁-C₃) alkyl.

In one embodiment, R^7D is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —CH₂COOH, —COOR^10D, —CH₂COOR^10D, R^11D-substituted or unsubstituted alkyl, R^11D-substituted or unsubstituted heteroalkyl, R^11D-substituted or unsubstituted cycloalkyl, R^11D-substituted or unsubstituted heterocycloalkyl, R^11D-substituted or unsubstituted aryl, or R^11D-substituted or unsubstituted heteroaryl.

In one embodiment, R^7D is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —COOR^10D, —CH₂COOH, —CH₂COOR^10D, R^11D-substituted or unsubstituted C ₁-C₁₀ (e.g., C₁-C₆) alkyl, R^11D-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^11D-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^11D-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^11D-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^11D-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^11D is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —COOR^15D, —CH₂COOR^15D, —CH₂COOH, R^12D-substituted or unsubstituted alkyl, R^12D-substituted or unsubstituted heteroalkyl, R^12D-substituted or unsubstituted cycloalkyl, R^12D-substituted or unsubstituted heterocycloalkyl, R^12D-substituted or unsubstituted aryl, or R^12D-substituted or unsubstituted heteroaryl. In certain embodiments, R^11D is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —COOR^15D, —CH₂COOR^15D, R^12D-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^12D-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^12D-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^12D-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^12D-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^12D-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^15D may be a unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. R^15D may also be substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In some embodiments, R^15D is R^12D-substituted or unsubstituted alkyl, R^12D-substituted or unsubstituted heteroalkyl, R^12D-substituted or unsubstituted cycloalkyl, R^12D-substituted or unsubstituted heterocycloalkyl, R^12D-substituted or unsubstituted aryl, or R^12D-substituted or unsubstituted heteroaryl. R^15D may also be R^12D-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^12D-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^12D-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^12D-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^12D-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^12D-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^12D is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —COOR^16D, _CH₂COOR^16D, —CH₂COOH, R^13D-substituted or unsubstituted alkyl, R^13D-substituted or unsubstituted heteroalkyl, R^13D-substituted or unsubstituted cycloalkyl, R^13D-substituted or unsubstituted heterocycloalkyl, R^13D-substituted or unsubstituted aryl, or R^13D-substituted or unsubstituted heteroaryl. In one embodiment, R^12D is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —COOR^16D, —CH₂COOR^16D, R^13D-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^13D-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^13D-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^13D-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^13D-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^13D-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^16D may be a unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. R^16D may also be substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In some embodiments, R^16D is R^13D-substituted or unsubstituted alkyl, R^13D-substituted or unsubstituted heteroalkyl, R^13D-substituted or unsubstituted cycloalkyl, R^13D-substituted or unsubstituted heterocycloalkyl, R^13D-substituted or unsubstituted aryl, or R^13D-substituted or unsubstituted heteroaryl. R^16D may also be R^13D-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^13D-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^13D-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^13D-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^13D-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^13D-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^13D is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —COOR^17D, —CH₂COOR^17D, —CH₂COOH, R^14D-substituted or unsubstituted alkyl, R^14D-substituted or unsubstituted heteroalkyl, R^14D-substituted or unsubstituted cycloalkyl, R^14D-substituted or unsubstituted heterocycloalkyl, R^14D-substituted or unsubstituted aryl, or R^14D-substituted or unsubstituted heteroaryl. In one embodiment, R^13D is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —COOR^17D, —CH₂COOR^17D, R^14D-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^14D-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^14D-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^14D-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^14D-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^14D-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. R^14D is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, —COOR^10D, —CH₂COOR^10D, —CH₂COOH, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

R^17D may be a unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. R^17D may also be substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In some embodiments, R^17D is R^14D-substituted or unsubstituted alkyl, R^14D-substituted or unsubstituted heteroalkyl, R^14D-substituted or unsubstituted cycloalkyl, R^14D-substituted or unsubstituted heterocycloalkyl, R^14D-substituted or unsubstituted aryl, or R^14D-substituted or unsubstituted heteroaryl. R^17D may also be R^14D-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^14D-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^14D-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^14D-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^14D-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^14D-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^5A may be hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. In some embodiments, R^5A is hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. R^5A may also be substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In some embodiments, R^5A is R¹⁸-substituted or unsubstituted alkyl, R¹⁸-substituted or unsubstituted heteroalkyl, R¹⁸-substituted or unsubstituted cycloalkyl, R¹⁸-substituted or unsubstituted heterocycloalkyl, R¹⁸-substituted or unsubstituted aryl, or R¹⁸-substituted or unsubstituted heteroaryl. R^5A may also be R¹⁸-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R¹⁸-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R¹⁸-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R¹⁸-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R¹⁸-substituted or unsubstituted C₅-C_g (e.g., C₅-C₆) aryl, or R¹⁸-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R¹⁸ is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂, —COOH, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. R¹⁸ may also be hydrogen, halogen, —CN, —CF₃, —OH, —NH₂, —COOH, substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In some embodiments, R¹⁸ is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, R¹⁹-substituted or unsubstituted alkyl, R¹⁹-substituted or unsubstituted heteroalkyl, R¹⁹-substituted or unsubstituted cycloalkyl, R¹⁹-substituted or unsubstituted heterocycloalkyl, R¹⁹-substituted or unsubstituted aryl, or R¹⁹-substituted or unsubstituted heteroaryl. R¹⁸ may also be halogen, —CN, —CF₃, —OH, —NH₂, —COOH, R¹⁹-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R¹⁹-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R¹⁹-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R¹⁹-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R¹⁹-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R¹⁹-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R¹⁹ is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. R¹⁹ may also be halogen, —CN, —CF₃, —OH, —NH₂, —COOH, substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In some embodiments, R¹⁹ is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, R²⁰-substituted or unsubstituted alkyl, R²⁰-substituted or unsubstituted heteroalkyl, R²⁰-substituted or unsubstituted cycloalkyl, R²⁰-substituted or unsubstituted heterocycloalkyl, R²⁰-substituted or unsubstituted aryl, or R²⁰-substituted or unsubstituted heteroaryl. R¹⁹ may also be halogen, —CN, —CF₃, —OH, —NH₂, —COOH, R²⁰-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R²⁰-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R²⁰-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R²⁰-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R²⁰-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R²⁰-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R²⁰ is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. R²⁰ may also be halogen, —CN, —CF₃, —OH, —NH₂, —COOH, substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In some embodiments, R²⁰ is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, R²¹-substituted or unsubstituted alkyl, R²¹-substituted or unsubstituted heteroalkyl, R²¹-substituted or unsubstituted cycloalkyl, R²¹-substituted or unsubstituted heterocycloalkyl, R²¹-substituted or unsubstituted aryl, or R²¹-substituted or unsubstituted heteroaryl. R²⁰ may also be halogen, —CN, —CF₃, —OH, —NH₂, —COOH, R²¹-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R²¹-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R²¹-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R²¹-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R²¹-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R²¹-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R²¹ is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or an unsubstituted heteroaryl.

R^5B may be hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. In some embodiments, R^5B is hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. R^5B may also be substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In some embodiments, R^5B is R^18A-substituted or unsubstituted alkyl, R^18A-substituted or unsubstituted heteroalkyl, R^18A-substituted or unsubstituted cycloalkyl, R^18A-substituted or unsubstituted heterocycloalkyl, R^18A-substituted or unsubstituted aryl, or R^18A-substituted or unsubstituted heteroaryl. R^5B may also be R^18A-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^18A-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^18A-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R¹⁸-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^18A-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^18A-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^18A is hydrogen, halogen, —CN, —CF₃, —OH, —NH₂, —COOH, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. In some embodiments, R^18A is unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. R^18A may also be halogen, —CN, —CF₃, —OH, —NH₂, —COOH, substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In some embodiments, R^18A is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, R^19A-substituted or unsubstituted alkyl, R^19A-substituted or unsubstituted heteroalkyl, R^19A-substituted or unsubstituted cycloalkyl, R^19A-substituted or unsubstituted heterocycloalkyl, R^19A-substituted or unsubstituted aryl, or R^19A-substituted or unsubstituted heteroaryl. R^18A may also be halogen, —CN, —CF₃, —OH, —NH₂, —COOH, R^19A-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^19A-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^19A-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^19A-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^19A-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^19A-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^19A is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. In some embodiments, R^19A is unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. R^19A may also be halogen, —CN, —CF₃, —OH, —NH₂, —COOH, substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In some embodiments, R^19A is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, R^20A-substituted or unsubstituted alkyl, R^20A-substituted or unsubstituted heteroalkyl, R^20A-substituted or unsubstituted cycloalkyl, R^20A-substituted or unsubstituted heterocycloalkyl, R^20A-substituted or unsubstituted aryl, or R^20A-substituted or unsubstituted heteroaryl. R^19A may also be halogen, —CN, —CF₃, —OH, —NH₂, —COOH, R^20A-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^20A-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^20A-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^20A-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^20A-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^20A-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^20A is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. In some embodiments, R^20A is unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. R^20A may also be halogen, —CN, —CF₃, —OH, —NH₂, —COOH, substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In some embodiments, R^20A is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, R^21A-substituted or unsubstituted alkyl, R^21A-substituted or unsubstituted heteroalkyl, R^21A-substituted or unsubstituted cycloalkyl, R^21A-substituted or unsubstituted heterocycloalkyl, R^21A-substituted or unsubstituted aryl, or R^21A-substituted or unsubstituted heteroaryl. R^20A may also be halogen, —CN, —CF₃, —OH, —NH₂, —COOH, R^21A-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^21A-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^21A-substituted or unsubstituted C₃-C_g (e.g., C₅-C₇) cycloalkyl, R^21A-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^21A-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^21A-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl

R^21A is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or an unsubstituted heteroaryl.

Each R^5C and R^9A may be the same or different and may each independently be hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. In some embodiments, R^5C and R^9A are independently hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. R^5C and R^9A may also be independently substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In some embodiments, R^5C and R^9A are R^18B-substituted or unsubstituted alkyl, R^18B-substituted or unsubstituted heteroalkyl, R^18B-substituted or unsubstituted cycloalkyl, R^18B-substituted or unsubstituted heterocycloalkyl, R^18B-substituted or unsubstituted aryl, or R^18B-substituted or unsubstituted heteroaryl. R^5C and R^9A may also be R^18B-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^18B-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^18B-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^18B-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^18B-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^18B-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^18B is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. In some embodiments, R^18B is unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. R^18B may also be halogen, —CN, —CF₃, —OH, —NH₂, —COOH, substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In some embodiments, R^18B is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, R^19B-substituted or unsubstituted alkyl, R^19B-substituted or unsubstituted heteroalkyl, R^19B-substituted or unsubstituted cycloalkyl, R^19B-substituted or unsubstituted heterocycloalkyl, R^19B-substituted or unsubstituted aryl, or R^19B-substituted or unsubstituted heteroaryl. R^18B may also be halogen, —CN, —CF₃, —OH, —NH₂, —COOH, R^19B-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^19B-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^19B-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^19B-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^19B-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^19B-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^19B is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. In some embodiments, R^19B is unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. R^19B may also be halogen, —CN, —CF₃, —OH, —NH₂, —COOH, substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In some embodiments, R^19B is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, R^20B-substituted or unsubstituted alkyl, R^20B-substituted or unsubstituted heteroalkyl, R^20B-substituted or unsubstituted cycloalkyl, R^20B-substituted or unsubstituted heterocycloalkyl, R^20B-substituted or unsubstituted aryl, or R^20B-substituted or unsubstituted heteroaryl. R^19B may also be halogen, —CN, —CF₃, —OH, —NH₂, —COOH, R^20B-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^20B-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^20B-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^20B-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^20B-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^20B-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^20B is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. In some embodiments, R^20B is unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. R^20B may also be halogen, —CN, —CF₃, —OH, —NH₂, —COOH, substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In some embodiments, R^20B is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, R^21B-substituted or unsubstituted alkyl, R^21B-substituted or unsubstituted heteroalkyl, R^21B-substituted or unsubstituted cycloalkyl, R^21B-substituted or unsubstituted heterocycloalkyl, R^21B-substituted or unsubstituted aryl, or R^21B-substituted or unsubstituted heteroaryl. R^20B may also be halogen, —CN, —CF₃, —OH, —NH₂, —COOH, R^21B-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^21B-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^21B-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^21B-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^21B-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^21B-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^21B is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or an unsubstituted heteroaryl.

Each R^5D and R^9B may be the same or different and may each independently be hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. In some embodiments, R^5D and R^9B are independently hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. R^5D and R^9B may also be independently substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In some embodiments, R^5D and R^9B are R^18C-substituted or unsubstituted alkyl, R^18C-substituted or unsubstituted heteroalkyl, R^18C-substituted or unsubstituted cycloalkyl, R^18C-substituted or unsubstituted heterocycloalkyl, R^18C-substituted or unsubstituted aryl, or R^18C-substituted or unsubstituted heteroaryl. R^5D and R^9B may also be R^18C-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^18C-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^18C-substituted or unsubstituted C₃-C_g (e.g., C₅-C₇) cycloalkyl, R^18C-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^18C-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^18C-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^18C is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. In some embodiments, R^18C is unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. R^18C may also be halogen, —CN, —CF₃, —OH, —NH₂, —COOH, substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In some embodiments, R^18C is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, R^19C-substituted or unsubstituted alkyl, R^19C-substituted or unsubstituted heteroalkyl, R^19C-substituted or unsubstituted cycloalkyl, R^19C-substituted or unsubstituted heterocycloalkyl, R^19C-substituted or unsubstituted aryl, or R^19C-substituted or unsubstituted heteroaryl. R^18C may also be halogen, —CN, —CF₃, —OH, —NH₂, —COOH, R^19C-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^19C-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^19C-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^19C-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^19C-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^19C-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^19C is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. In some embodiments, R^19C is unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. R^19C may also be halogen, —CN, —CF₃, —OH, —NH₂, —COOH, substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In some embodiments, R^19C is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, R^20C-substituted or unsubstituted alkyl, R^20C-substituted or unsubstituted heteroalkyl, R^20C-substituted or unsubstituted cycloalkyl, R^20C-substituted or unsubstituted heterocycloalkyl, R^20C-substituted or unsubstituted aryl, or R²⁰ substituted or unsubstituted heteroaryl. R^19C may also be halogen, —CN, —CF₃, —OH, —NH₂, —COOH, R^20C-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^20C-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^20C-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^20C-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^20C-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^20C-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^20C is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. In some embodiments, R^20C is unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. R^20C may also be halogen, —CN, —CF₃, —OH, —NH₂, —COOH, substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl. In some embodiments, R^20C is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, R^21C-substituted or unsubstituted alkyl, R^21C-substituted or unsubstituted heteroalkyl, R^21C-substituted or unsubstituted cycloalkyl, R^21C-substituted or unsubstituted heterocycloalkyl, R^21C-substituted or unsubstituted aryl, or R^21C-substituted or unsubstituted heteroaryl. R^20C may also be halogen, —CN, —CF₃, —OH, —NH₂, —COOH, R^21C-substituted or unsubstituted C₁-C₁₀ (e.g., C₁-C₆) alkyl, R^21C-substituted or unsubstituted 2 to 10 membered (e.g., 2 to 6 membered) heteroalkyl, R^21C-substituted or unsubstituted C₃-C₈ (e.g., C₅-C₇) cycloalkyl, R^21C-substituted or unsubstituted 3 to 8 membered (e.g., 3 to 6 membered) heterocycloalkyl, R^21C-substituted or unsubstituted C₅-C₈ (e.g., C₅-C₆) aryl, or R^21C-substituted or unsubstituted 5 to 8 membered (e.g., 5 to 6 membered) heteroaryl.

R^21C is halogen, —CN, —CF₃, —OH, —NH₂, —COOH, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or an unsubstituted heteroaryl.

In some embodiments, R¹ is —C(X¹)₃ and R³ is —C(X³)₃. In other embodiments, R¹ is —COOR^5A and R³ is —COOR^5B. In some embodiments, R¹ is

and R³ is

In other embodiments, R¹ is

and R³ is

In other embodiments, R² is —C(X²)₃ and R⁴ is —C(X⁴)₃. In other embodiments, R² is —COOR^5C and R⁴ is —COOR^5D. In some embodiments, R² is

and R⁴ is

In some embodiments, X¹, X², X³ and X⁴ are fluorine.

In a more specific embodiment, R¹ is —COOR^5A, R³ is —COOR^5B, R² is

R⁴ is

and R^5A, R^5B, R^9A, and R^9B are independently substituted or unsubstituted alkyl. In some embodiments, each R^5A, R^5B, R^9A, and R^9B may be the same or different and may each independently be a substituted or unsubstituted alkyl (e.g. unsubstituted alkyl), and particularly a substituted or unsubstituted C₁-C₂₀ alkyl (e.g. unsubstituted C₁-C₂₀ alkyl), more particularly a substituted or unsubstituted C₁-C₁₀ alkyl (e.g. unsubstituted C₁-C₁₀ alkyl), more particularly a substituted or unsubstituted C₁-C₆ alkyl (e.g. unsubstituted C₁-C₆ alkyl), and even more particularly a substituted or unsubstituted C₁-C₄ alkyl (e.g. unsubstituted C₁-C₄ alkyl), and even more particularly, hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted propyl.

In a specific embodiment, the metalloporphyrin compound has the formula:

In another specific embodiment, R¹ is Error! Objects cannot be created from editing field codes., R³ is Error! Objects cannot be created from editing field codes., R² is Error! Objects cannot be created from editing field codes., R⁴ is Error! Objects cannot be created from editing field codes., and

R^6A, R^6B, R^7A, R^7B, R^9A and R^9B are independently substituted or unsubstituted alkyl (e.g. unsubstituted alkyl). In some embodiments, each R^6A, R^6B, R^7A, R^7B, R^9A and R^9B may be the same or different and may each independently be substituted or unsubstituted C₁-C₂₀ alkyl (e.g. unsubstituted C₁-C₂₀ alkyl), more particularly a substituted or unsubstituted C₁-C₁₀ (e.g. unsubstituted C₁-C₁₀ alkyl), more particularly a substituted or unsubstituted C₁-C₆ alkyl (e.g. unsubstituted C₁-C₆ alkyl), and even more particularly a substituted or unsubstituted C₁-C₄ alkyl (e.g. unsubstituted C₁-C₄ alkyl), and even more particularly, a hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted propyl.

In a specific embodiment, the metalloporphyrin compound of the invention may have the formula:

In a another specific embodiment, R¹ is —C(X¹)₃, R³ is —C(X³)₃, R² is

R⁴ is

and R^9A and R^9B are independently substituted or unsubstituted alkyl. In some embodiments, R^9A and R^9B may be independently particularly substituted or unsubstituted C₁-C₂₀ alkyl (e.g. unsubstituted C₁-C₂₀ alkyl), more particularly substituted or unsubstituted C₁-C₁₀ alkyl (e.g. unsubstituted C₁-C₁₀ alkyl), more particularly substituted or unsubstituted C₁-C₆ alkyl (e.g. unsubstituted C₁-C₆ alkyl), and even more particularly substituted or unsubstituted C₁-C₄ alkyl (e.g. unsubstituted C₁-C₄ alkyl), and even more particularly, hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted propyl. In some embodiments, X¹ and X³ are fluorine.

In a specific embodiment, the metalloporphyrin compound of the invention may have the formula:

In a another specific embodiment, R¹ is —C(X¹)₃, R² is —C(X²)₃, R³ is —C(X³)₃ and R⁴ is —C(X⁴)₃. In some embodiments, X¹, X², X³ and X⁴ are fluorine.

In a specific embodiment, the metalloporphyrin compound of the invention may have the formula:

In a another specific embodiment, R¹ is

R³ is

R² is —C(X²)₃, R⁴is —C(X⁴)₃, and R^6A, R^6B, R^7A and R^7B are independently substituted or unsubstituted alkyl (e.g. unsubstituted alkyl). In some embodiments, each R^6A, R^6B, R^7A and R^7B may be the same or different and may each independently be an alkyl, and particularly a substituted or unsubstituted C₁-C₂₀ alkyl (e.g. unsubstituted C₁-C₂₀ alkyl), more particularly a substituted or unsubstituted C₁-C₁₀ alkyl (e.g. unsubstituted C₁-C₁₀ alkyl), more particularly a substituted or unsubstituted C₁-C₆ alkyl (e.g. unsubstituted C₁-C₆ alkyl), and even more particularly a substituted or unsubstituted C₁-C₄ alkyl (e.g. unsubstituted C₁-C₄ alkyl), and even more particularly, a hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted propyl. In some embodiments, X² and X⁴ are fluorine.

In a specific embodiment, the metalloporphyrin compound of the invention may have the formula:

In a another specific embodiment, R¹

is, R³ is

R² is —COOR^5C, R⁴ is —COOR^5D, and R^6A, R^6B, R^7A and R^7B are independently substituted or unsubstituted alkyl (e.g. unsubstituted alkyl). In some embodiments, each R^6A, R^6B, R^7A and R^7B may be the same or different and may each independently be an alkyl, and particularly a substituted or unsubstituted C₁-C₂₀ alkyl (e.g. unsubstituted C₁-C₂₀ alkyl), more particularly a substituted or unsubstituted C₁-C₁₀ alkyl (e.g. unsubstituted C₁-C₁₀ alkyl), more particularly a substituted or unsubstituted C₁-C₆ alkyl (e.g. unsubstituted C₁-C₆ alkyl),and even more particularly a substituted or unsubstituted C₁-C₄ alkyl (e.g. unsubstituted C₁-C₄ alkyl), and even more particularly, a hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted propyl.

In a specific embodiment, the metalloporphyrin compound of the invention may have the formula:

In a another specific embodiment, R¹ is

R³ is

R² is —COOR^5C, R⁴ is —COOR^5D, and R^5C, R^5D, R^8A and R^8B are independently substituted or unsubstituted alkyl (e.g. unsubstituted alkyl). In some embodiments, each R^5C, R^5D, R^8A and R^8B may be the same or different and may each independently be an alkyl, and particularly a substituted or unsubstituted C₁-C₂₀ alkyl (e.g. unsubstituted C₁-C₂₀ alkyl), more particularly a substituted or unsubstituted C₁-C₁₀ alkyl (e.g. unsubstituted C₁-C₁₀ alkyl), more particularly a substituted or unsubstituted C₁-C₆ alkyl (e.g. unsubstituted C₁-C₆ alkyl), and even more particularly a substituted or unsubstituted C₁-C₄ alkyl (e.g. unsubstituted C₁-C₄ alkyl), and even more particularly, a hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted propyl.

In a specific embodiment, the metalloporphyrin compound of the invention may have the formula:

In a another specific embodiment, R¹ is

R³ is,

R² is —C(X²)₃, R⁴ is —C(X⁴)₃, and R^8A and R^8B are independently substituted or unsubstituted alkyl (e.g. unsubstituted alkyl). In some embodiments, R^8A and R^8B may be an alkyl, and particularly a substituted or unsubstituted C₁-C₂₀ alkyl (e.g. unsubstituted C₁-C₂₀ alkyl), more particularly a substituted or unsubstituted C₁-C₁₀ alkyl (e.g. unsubstituted C₁-C₁₀ alkyl), more particularly a substituted or unsubstituted C₁-C₆ alkyl (e.g. unsubstituted C₁-C₆ alkyl), and even more particularly a substituted or unsubstituted C₁-C₄ alkyl (e.g. unsubstituted C₁-C₄ alkyl), and even more particularly, a hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted propyl. In some embodiments, X² and X⁴ are fluorine.

In a specific embodiment, the metalloporphyrin compound of the invention may have the formula:

In some embodiments, each substituted group described in the compounds above (e.g., Formulae (I)-(III)) is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, described in the compounds above (e.g., Formulae (I)-(III)) are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. Alternatively, at least one or all of these groups are substituted with at least one lower substituent group.

In other embodiments of the compounds described above (e.g., Formulae (I)-(III)) each substituted or unsubstituted alkyl is a substituted or unsubstituted C₁-C₂₀ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈ cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl.

In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C₁-C₈ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C₅-C₇ cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 5 to 7 membered heterocycloalkyl.

III. Methods

Provided herein are methods of treating a neurodegenerative disorder comprising administering to a patient in need thereof an effective amount of a porphyrin compound described herein (e.g., porphyrin or metalloporphyrin compounds described in Section II) or a pharmaceutically acceptable salt thereof. In some embodiments, the neurodegenerative disease is an acute or chronic neurodegenerative disease. In some embodiments, the neurodegenerative disease is neurodegenerative disorder is Parkinson's disease, Alzheimer's disease, Pick's disease, Huntington's disease, amyotrophic lateral sclerosis, prion diseases, dystonia, dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, Friedreich's Ataxia, temporal lobe epilepsy, stroke, traumatic brain injury, or a mitochondrial encephalopathiy.

As used herein, the term “neuronal” or “neuron” refers to one or more cells that are a morphologic and functional unit of the brain, spinal column, and peripheral nerves consisting of nerve cell bodies, dendrites, and axons. Neuron cell types can include, but are not limited to, typical nerve cell body showing internal structure, horizontal cell from cerebral cortex, Martinotti cell, bipolar cell, unipolar cell, Purkinje cell, and pyramidal cell of motor area of cerebral cortex. Exemplary neuronal cells can include, but are not limited to, cholinergic, adrenergic, noradrenergic, dopaminergic, serotonergic, glutaminergic, GABAergic, and glycinergic.

As used herein, the term “neurodegenerative disease,” “neurodegenerative disorder” or “degenerative disease” is defined as a disease or condition in which there is a progressive loss of neurons or loss of neuronal function. Thus, a neurodegenerative disorder or neurodegenerative disease, as used in the current context, should be obvious to one skilled in the art, but is meant to include any abnormal physical or mental behavior or experience where the death of neuronal cells is involved in the etiology of the disorder, or is affected by the disorder. As used herein, neurodegenerative diseases encompass disorders affecting the central and peripheral nervous systems, and include such afflictions as memory loss, stroke, dementia, personality disorders, gradual, permanent or episodic loss of muscle control. Examples of neurodegenerative disorders or diseases for which the current invention can be used preferably include, but are not limited to, Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, amyotrophic lateral sclerosis (ALS), Pick's disease, prion diseases, dystonia, dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, Friedreich's Ataxia, temporal lobe epilepsy, stroke, traumatic brain injury, mitochondrial encephalopathies, Guillain-Barre syndrome, multiple sclerosis, epilepsy, myasthenia gravis, chronic idiopathic demyelinating disease (CID), neuropathy, ataxia, dementia, chronic axonal neuropathy and stroke.

As used herein, the term “neurodegeneration” refers to the progressive loss or function of at least one neuron or neuronal cell. One of skill in the art realizes that the term progressive loss can refer to cell death or cell apoptosis.

As used herein, the term “neuronal cell loss” refers to the loss of neuronal cells. The loss of neuronal cells may be a result of a genetic predisposition, congenital dysfunction, apoptosis, ischemic event, immune-mediated, free-radical induced, chemical induced, or any injury that results in a loss of neuronal cells, as well as a progressive loss of neuronal cells.

In some embodiments, the present invention is directed to methods for treating Parkinson's disease in a subject by administering to the subject in need thereof an effective amount of a metalloporphyrin compound, a derivative or a pharmaceutically acceptable salt thereof. As used herein, the term “Parkinson's disease” refers to a neurological disorder characterized by muscle rigidity, tremor, bradykinesia, and akinesia that is caused by the decreased stimulation of the motor cortex by the basal ganglia due to insufficient formation and action of dopamine on the dopamine receptors in the brain. The term “Parkinson's disease” includes chronic progressive parkinsonism, primary parkinsonism, idiopathic parkinsonism, secondary parkinsonism induce by drugs, trauma or other medical disorders and Parkinson-plus syndromes (e.g., multiple symptom atrophy, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies and olivopontocerebellar atrophy).

The methods of inhibiting neuron degeneration can be used to inhibit or prevent neuron degeneration in patients newly diagnosed as having a neurodegenerative disease (e.g., Parkinson's disease) or at risk of developing a new neurodegenerative disease (e.g., Parkinson's disease). On the other hand, the methods of inhibiting neuron degeneration can also be used to inhibit or prevent further neuron degeneration in patients who are already suffering from, or have symptoms of, a neurodegenerative disease (e.g., Parkinson's disease). Preventing neuron degeneration includes decreasing or inhibiting neuron degeneration, which may be characterized by complete or partial inhibition of neuron degeneration. This can be assessed, for example, by analysis of neurological function.

IV. Pharmaceutical Compositions

In some embodiments, the metalloporphyrin compounds may from part of a pharmaceutical composition. The pharmaceutical composition may include a a porphyrin compound described herein (e.g., porphyrin or metalloporphyrin compounds described in Section II) or a pharmaceutically acceptable salt thereof (also referred to herein as a “treatment compound”), and a pharmaceutically acceptable excipient. A “pharmaceutically acceptable excipient” includes pharmaceutically and physiologically acceptable, organic or inorganic carrier substances suitable for enteral or parenteral administration that do not deleteriously react with the active agent. Suitable pharmaceutically acceptable carriers include water, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, and carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, and polyvinyl pyrrolidone. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the active agent.

In one embodiment, the treatment compound (e.g., porphyrin or metalloporphyrin compounds described in Section II) forms part of a pharmaceutical composition, wherein the pharmaceutical composition comprises said treatment compound and a pharmaceutical acceptable excipient. In one embodiment, the pharmaceutical composition includes a permeabilizer (e.g., a salicylate, a fatty acid, or a metal chelator).

The pharmaceutical composition can be formulated for any route of administration, including enteral, oral, sublingual, buccal, parenteral, ocular, intranasal, pulmonary, rectal, intravaginal, transdermal, and topical routes. Parenteral administration includes, but is not limited to, intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal, intrastemal, intraarterial injection and infusion.

The pharmaceutical composition can be formulated for immediate release or modified release, e.g., modified, sustained, extended, delayed, or pulsatile release, using known methods and excipients.

In one embodiment, the pharmaceutical composition is formulated as a topical composition, an injectable composition, an inhalant, a sustained release composition, or an oral composition. The treatment compound is preferably formulated for parenteral administration, e.g., by subcutaneous injection. If subcutaneous or an alternative type of administration is used, the compounds may be derivatized or formulated such that they have a protracted profile of action.

In another embodiment, the pharmaceutical composition is formulated as a peptide micelle, a targeted micelle, a degradable polymeric dosage form, a porous microsphere, a polymer scaffold, a liposome, or a hydrogel.

The treatment compound may be formulated according to known methods to prepare pharmaceutically useful compositions. An exemplary formulation would be one that is a stable lyophilized product that is reconstituted with an appropriate diluent or an aqueous solution of high purity with optional pharmaceutically acceptable carriers, preservatives, excipients or stabilizers (Remington's Pharmaceutical Sciences 16th edition (1980)). The pharmaceutical composition may include a pharmaceutically acceptable buffer to achieve a suitable pH for stability and for administration.

For parenteral administration, the treatment compound is formulated in a unit dosage injectable form (solution, suspension, or emulsion) with a pharmaceutically acceptable carrier. Preferably, one or more pharmaceutically acceptable anti-microbial agents may be added, such as phenol, m-cresol, and benzyl alcohol.

In one embodiment, one or more pharmaceutically acceptable salts (e.g., sodium chloride), sugars (e.g., mannitol), or other excipients (e.g., glycerin) may be added to adjust the ionic strength or tonicity.

The dosage of the composition of the invention to be administered can be determined without undue experimentation and will be dependent upon various factors including the nature of the active agent (including whether metal bound or metal free), the route of administration, the patient, and the result sought to be achieved. A suitable dosage of mimetic to be administered IV or topically can be expected to be in the range of about 0.01 to 50 mg/kg/day, preferably, 0.1 to 10 mg/kg/day, more preferably 0.1 to 6 mg/kg/day. For aerosol administration, it is expected that doses will be in the range of 0.001 to 5.0 mg/kg/day, preferably, 0.01 to 1 mg/kg/day. Suitable doses will vary, for example, with the compound and with the result sought.

The concentration of mimetic presentation in a solution used to treat cells/tissues/organs in accordance with the methods of the invention can also be readily determined and will vary with the active agent, the cell/tissue/organ and the effect sought.

Certain aspects of the invention can be described in greater detail in the non-limiting Example that follows.

EXAMPLES

The following examples illustrate certain specific embodiments of the invention and are not meant to limit the scope of the invention.

Embodiments herein are further illustrated by the following examples and detailed protocols. However, the examples are merely intended to illustrate embodiments and are not to be construed to limit the scope herein. The contents of all references and published patents and patent applications cited throughout this application are hereby incorporated by reference.

Example 1

Optimizing Metalloporphyrins for Clinical Development in Parkinson's Disease—AEOL11209

FIG. 1 shows the concentration of AEOL11209 in the plasma (A) and brains (B) of C57BL/6 mice at different times points after a single dose of AEOL11209 (15 mg/kg) administered by the intraperitoneal (i.p.) or oral (p.o.) route. Points represent mean±S.E.M. Each point is the average of 3-4 animals.

Purity analysis by mass spectrometry: Mass spectrometric analysis of AEOL11209 revealed a compound of appropriate mass in a single peak confirming its purity.

Pharmacokinetic analysis in plasma and brain via i.p. and p.o. route: a) Plasma concentrations were low but achievable after i.p. administration but not after p.o. administration. b) The concentration of AEOL11209 in the brain after i.p. or p.o. administration was variable and relatively low. c) Solubility of AEOL11209 was a major issue and necessitated high concentrations of DMSO which made animals sick.

Alternate approach: To synthesize an analog of AEOL11209 that is more water soluble (AEOL1114B), determine its pharmacokinetic properties and efficacy in the MPTP mouse model.

Example 2

Optimizing Metalloporphyrins for Clinical Development in Parkinson's Disease—AEOL11215

FIG. 2 shows the concentration of AEOL11215 in the plasma of the C57BL/6 mice at different times points after a single dose of AEOL11215 (15 mg/kg) administered by the i.p route. Points represent mean±S.E.M. Each point is the average of 3-4 animals.

Results: AEOL11215 achieved moderate levels in the plasma after i.p. administration. AEOL11215 was not reliably detectable in brain following i.p. administration. AEO111215 was not reliably detected plasma after p.o. administration at any time point.

Alternate approach: To test an alternate compound from Dr. Day's library, AEOL11203 which has shorter meso-substituted side chains (see below).

Example 3

Optimizing Metalloporphyrins for Clinical Development in Parkinson's Disease—AEOL11216

FIG. 3 shows the concentration of AEOL11216 in the plasma (A) and brains (B) of C57BL/6 mice at different times points after a single dose of AEOL11216 (15 mg/kg) administered by the i.p. and p.o route. Points represent mean+S.E.M. Bars represent mean+S.E.M. n=3-6 mice per group. FIG. 4 shows dopamine levels in the striata (A) number of TH+ neurons in the substantia nigra pars compacta (B) of C57BL/6 mice 7 days after injection of MPTP (15 mg/kg×3, s.c., 24 h intervals) alone or in the presence of AEOL11216 15 mg/kg i.p. (1 hr prior to MPTP and daily thereafter). Bars represent mean+S.E.M. n=3-6 mice per group. FIG. 5 shows GSH, GSSG, GSH/GSSG and 3NT/Tyr ratios in the ventral midbrains of C57/B6 mice 24 hours after injection of MPTP (15 mg/kg×3, s.c., 24 h intervals) alone or in the presence of AEOL11216 i.p. (15 mg/kg×3, daily). Bars represent mean+S.E.M. #p<0.01 vs MPTP. One-way, ANOVA, n=6 mice per group.

Results: AEOL11216 achieved high plasma concentrations after i.p. administration but not after p.o. administration. AEOL11216 penetrated the BBB and remained stable at more than 100 nM in the brain for 24 hr after i.p. administration. AEOL11216 did not significantly prevent MPTP-induced striatal dopamine depletion after i.p. administration. AEOL11216 significantly protected against MPTP-induced dopaminergic neuronal loss in the substantial nigra pars compacta after i.p. administration. The dopamine neurons (TH positive neurons) were counted by an investigator blinded to the treatment of mice with stereological methods. AEOL11216 significantly protected against MPTP-induced alteration of GSH/GSSG and 3-NT/tyrosine ratio after i.p. administration.

Example 4

Optimizing Metalloporphyrins for Clinical Development in Parkinson's Disease—AEOL11203

AEOL11203's bioavailability and efficacy were tested to overcome solubility issues related to AEOL11209 and poor bioavailability of AEOL11215. FIG. 6 shows the concentration of AEOL11203 in the plasma (A) and brains (B) of C57BL/6 mice at different times points after a single dose of AEOL11203 (15 mg/kg) administered by the i.p. and p.o. route. Points represent mean±S.E.M. Each point is the average of 3-4 animals. FIG. 7 shows dopamine levels in the striata of C57BL/6 mice 7 days after injection of MPTP (15 mg/kg×3, s.c., 24 h intervals) alone or in the presence of AEOL11203 15 mg/kg i.p or p.o. (1 hr prior to MPTP and daily thereafter). Bars represent mean+S.E.M. n=6-8 mice per group. FIG. 8 shows GSH, GSSG, GSH/GSSG and 3NT/Tyr ratios in the SN of C57/B6 mice 24 hours after injection of MPTP (15 mg/kg×3, s.c., 24 h intervals) alone or in the presence of AEOL11203 i.p. (15 mg/kg×3, daily). Bars represent mean+S.E.M. #p<0.01 vs MPTP. One-way, ANOVA, n=6 mice per group.

Results: AEOL11203's solubility properties were good. The concentration in the plasma after i.p. administration was relative high. AEOL11203 penetrated the BBB and remain stable (>100 nM) in the brain for 24 hr after i.p. administration and ˜50 nM in the brain for 24 hr after p.o. administration. AEOL11203 achieved relatively high plasma concentrations (˜5 μM) after administration via the p.o. route. AEOL11203 showed a statistically significant protection against MPTP-induced striatal dopamine depletion by i.p. administration. AEOL11203 significantly protected against MPTP-induced increased GSH/GSSG and 3-NT/tyrosine ratio after i.p. administration.

Example 5

Optimizing Metalloporphyrins for Clinical Development in Parkinson's Disease—AEOL1114

A small quantity of an alternate compound (AEOL1114B) was synthesized and evaluated to overcome solubility issues associated with AEOL11209. FIG. 9 shows the concentration of AEOL1114 in the plasma (A) and brains (B) of C57BL/6 mice at different times points after a single dose of AEOL1114 (15 mg/kg) administered by the i.p. or p.o. route. Points represent mean+S.E.M. Each point is the average of 4 animals. FIG. 10 shows dopamine levels in the striata of C57BL/6 mice 7 days after injection of MPTP (15 mg/kg×3, s.c., 24 h intervals) alone or in the presence of AEOL1114B 15 mg/kg i.p or p.o. (1 hr prior to MPTP and daily thereafter×3). Bars represent mean+S.E.M. n=6 mice per group. FIG. 11 shows GSH, GSSG, GSH/GSSG and 3NT/Tyr ratios in the ventral midbrains of C57/B6 mice 24 hours after last injection of MPTP (15 mg/kg×3, s.c., 24 h intervals) alone or in the presence of AEOL1114 i.p. or p.o. (15 mg/kg×3, daily). Bars represent mean+S.E.M. #p<0.01 vs MPTP. One-way, ANOVA, n=6 mice per group.

Results: AEOL1114 showed favorable solubility properties. It achieved very high plasma concentrations (˜20 μM) after administration via the i.p. route and relatively good plasma concentrations (2˜3 μM) after administration via the p.o. route. AEOL1114 penetrated the BBB and remain stable (>200 nM) in the brain for 24 hr after administration via both of i.p. and p.o. route. AEOL 1114 showed a statistically significant protection against MPTP-induced striatal dopamine depletion after administration via both of i.p. and p.o. route. AEOL1114 significantly protected against MPTP-induced alteration of GSH/GSSG and 3-NT/tyrosine ratio after administration via both of i.p. and p.o. route.

Example 6

Optimizing Metalloporphyrins for Clinical Development in Parkinson's Disease—AEOL11256

FIG. 12 shows the concentration of AEOL11256 in the plasma of C57BL/6 mice at different times points after a single dose of AEOL11256 (15 mg/kg) administered by the i.p. or p.o. route. Points represent mean+S.E.M. Each point is the average of 4 animals.

Results: Plasma concentrations were relatively low after i.p. and p.o. administration. The concentration of AEOL11256 in the brain after i.p. or p.o. administration was undetectable. Solubility of AEOL11256 was a major issue and necessitated high concentrations of DMSO which made animals sick.

Example 7

Effects of AEOL Compounds on MPTP Metabolism

FIG. 13 shows striatal MPP+ levels in mice at 3 h after MPTP (15 mg/kg, s.c.) alone or in the presence of AEOL11207, 11203, 11256 and 1114B (15 mg/kg, i.p.) administered 1 h before MPTP treatment. Bars represent mean+S.E.M. n=4-6 mice per group. As indicated in the graph above, none of the AEOL compounds tested altered the levels of MPP+ in the striata suggesting a lack of effect on MPTP metabolism.

Example 8

Optimizing Metalloporphyrins for Clinical Development in Parkinson's Disease

As discussed, the compounds as shown in FIG. 14 showed unfavorable bioavailability in vivo and/or poor solubility. Our attempt to further improve AEOL11207 efficacy by meso-substitution of —CF3 groups in all four positions was unsuccessful based on the poor oral bioavailability (FIG. 12). However, the attempts to overcome the unfavorable pharmacokinetic or oral bioavailability of AEOL11209 and AEOL11215 were successful. As shown in FIG. 15, shortening the side chains of AEOL11215 to the carboxy methyl side chains was met with success. AEOL11203 shows good brain bioavailability following i.p. and p.o. administration and promising efficacy in the MPTP mouse model.

Evaluation of AEOL11209 showed poor bioavailability most likely due to solubility issues. As shown in FIG. 16, the structure of AEOL11209 has two meso-substituted aldehyde groups that were hypothesized to react with cellular macromolecules rendering it poorly absorbed through the gastrointestinal tract. Based on AEOL11207's structure, we hypothesized that substitution of two —CF3 groups in the AEOL11209 structure would improve bioavailability and optimize efficacy. This strategy was met with success demonstrating good pharmacokinetic properties, brain penetration, oral bioavailability and efficacy against MPTP-induced oxidative stress of AEOL1114B.

Example 9

Efficacy Against MPTP Toxicity by Stereological Cell Counting and Assessment of Neurotoxicity Potentially Arising from Manganese Accumulation

Experimental Approach

Assessment of tyrosine hydroxylase (TH) neurons: Free-floating 30 μM mesencephalic serial sections will be processed with antibodies against TH for immunohistochemistry (Vector Laboratories) and counterstained with cresyl violet. Total numbers of TH and cresyl violet-stained neurons in SNpc is counted stereologically with STEREO INVESTIGATOR software.

Stereological analysis and TH immunohistochemistry: The 40-μm sections including the whole SN pars compacta (SNpc) from bregma −2.60 to −3.80 mm is immunostained with a rabbit antibody to TH (Chemicon, Temecula, Calif.) using the ABC method (ABC Elite Kit, Vector Laboratories, Burlingame, Calif.). The number of TH-positive neurons is quantified using stereo investigator software (MicroBrightfield, Williston, Vt.) by a previously described method (West, Trends in Neurosciences 22:51-61, 1999; Liang et al., J Neurosci 27:4326-4333, 2007).

Statistical analyses of the above parameters is conducted using a one-way ANOVA with Tukey's multiple comparison test.

To determine potential adverse effects of AEOL112 compounds due to manganese release: The metalloporphyrins used here have manganese as the metal center for catalyzing redox reactions. Although manganic porphyrins are extremely stable i.e. they have been found to keep the manganese chelated even in the presence of millimolar amounts of EDTA (Day et al., Arch Biochem Biophys 347:256-262, 1997) and several of these compounds have been found to be safe and efficacious when used in both in vitro and in vivo models of neurodegeneration (Patel and Day, Trends Pharmacol Sci 20:359-364, 1999), there is a possibility that chronic presence of these compounds may result in the release of manganese from porphyrin rings and a manganese based neurotoxicity. Therefore, it is important to measure any free manganese in the brain and behavioral deficits indicative of manganese accumulation in the brains of AEOL112-treated mice. Since manganese accumulation is of concern, we plan to measure manganese levels and behavioral effects after the experimental protocol used for the MPTP neurotoxicity (i.e. 1 week of injection).

Experimental approach: Mice (6-10 per groupX3 groups, control+compounds i.e. AEOL11207, AEOL1114B, and AEOL11203) are treated with each compound via the p.o. route in a manner identical to the treatment of drugs for evaluation of the MPTP-induced loss of TH+ cells i.e. once daily for 7 days. At the end of the 1 week period, mice are subjected to behavioral tests (see below). Following completion of behavioral testing, mice are euthanized and brain, blood, kidney and liver collected for determination of manganese levels by inductively coupled plasma mass spectrometry. The dosing regimen is selected based on Aim 2a.

Manganese concentration assay: Tissue samples from mice are measured by Inductively Coupled Plasma—Mass Spectrometry (ICPMS) by WCAS which is a highly sensitive analytical method for trace metal analysis.

Behavioral assessment Neurobehavioral function following treatment with AEOL112 compounds are evaluated using the open field test and the accelerated rotarod. Both tests provide simple assessment for general levels of activity in mice. The open field test not only provides gross locomotor activity, but also exploration habits in mice. Assessment over several days allows habituation to the environment to be evaluated.

Open field test: The test is performed in mice treated with AEOL compounds or vehicle. The assessment is conducted over 2-4 days in a square arena mounted within specially designed sound-proof plexiglass shells. Each day a mouse is placed in the center of the open field arena and allowed to freely move about for 20-60 minutes while being tracked by an automated tracking system.

Motor behavior assessment by accelerating rotarod test follows the protocol of Hamm et al. (Ferret et al., Hepatology 33:1173-1180, 2001). Rotarod test is performed by using an automated rotarod (Ugo Basile, Comerio, Italy) after AEOLs or vehicle injections. Animals are tested two consecutive daily trials (1 hour apart) with an accelerating mode (15, 20, 25, 30, 35 and 40 rpm) in 240 seconds for total 5 days. The average latency to fall from the rod will be recorded. Mice unable to grasp the rotating rod are given a latency value of 0 s.

These studies determine if the AEOL112 compounds increased free manganese levels in tissues and if this results in any adverse effects indicative of manganese toxicity in mice i.e. changes in exploration in open field test or latency in rotarod test. It is unlikely that the manganic porphyrins release any free manganese because of the following reasons. 1). They are extremely stable i.e. they have been found to keep the manganese chelated even in the presence of millimolar amounts of EDTA (Day et al., Arch Biochem Biophys 347:256-262, 1997). 2). Several of these compounds were found to be safe and efficacious when used in both in vitro and in vivo models of neurodegeneration. 3). They can be measured unchanged in the urine.

The proposed studies validate the utility of three additional lead lipophilic metalloporphyrins in a well accepted animal model of parkinsonism. These studies optimize glyoxylate class of metalloporphyrins to identify the best drug candidate for clinical development for PD. These studies specifically define the following parameters: 1) Plasma and brain pharmacokinetic profiles of three two compounds with good bioavailability and 2) antioxidant properties in the mouse MPTP model. To determine if manganese accumulation from metalloporphyrins poses a risk for adverse behavioral effects, brain manganese levels are determined in conjunction with behavioral testing after dosing with AEOL11207, AEOL1114B, AEOL11203 and AEOL11216.

Example 10

AEOL1114B Prevented MPTP-Induced Loss of Dopaminergic Neurons

FIG. 17 shows tyrosine hydroxylase positive (TH+) cell counts indicative of dopaminergic neuron viability in the substantia nigra pars compacta of C57BL/6 mice 7 days after injection of MPTP (15 mg/kg×3, s.c., 24 h intervals) alone or in the presence of AEOL1114B 15 mg/kg i.p or p.o. (1 hr prior to MPTP and daily thereafter×3). Bars represent mean+S.E.M. n=6. The data demonstrates that AEOL1114B prevents MPTP-induced loss of TH+ dopamine neurons in the substantia nigra pars compact when administered either via the oral or i.p. route.

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Example 11

Behavioral Testing After Dosing Mice with AEOL11207, AEOL1114B or AEOL11203 (MnCl₂ Positive Control)

Mice (6 per group) were divided 5 groups treated with AEOL11207, AEOL11203, AEOL11114B, MnCl₂ (all compound dissolved in 5% DMSO) or 5%DMSO alone by 15 mg/kg i.p. daily for a period of 7 days. At the end of treatment, mice were performed the behavioral tests by open field and accelerating rotorod test in 3-4 h after last injection. FIG. 18 shows that no statistically significant differences were observed between any groups in both behavioral tests.

Claims

1. A compound having the formula:

2. The compound of claim 1, wherein the compound has the formula of Formula (II) and M is a metal ion.

3. The compound of claim 1, wherein the compound is the compound of formula II and wherein M is manganese.

4. The compound of claim 1, wherein R1 is —C(X1)3 and R3 is —C(X3)3;R1 is —COOR5A and R3 is —COOR5B;R1 is

5. The compound of claim 1, wherein R2 is —C(X2)3 and R4 is —C(X4)3;R2 is —COOR5c and R4 is —COOR5D; orR2 is

6. The compound of claim 1, wherein X1, X2, X3 and X4 are fluorine.

7. The compound of claim 1, wherein if R2 is —COOR5C and R4 is —COOR5D, R1 is not

8. The compound of claim 1, wherein if R2 is —C(X2)3 and R4 is —C(X4)3, R1 is not

9. The compound of claim 1, wherein R1 is —COOR5A;R3 is —COOR5B;R2 is

10. The compound of claim 9, wherein R5A, R5B, R9A, and R9B are independently a substituted or unsubstituted C1-C20 alkyl.

11. The compound of claim 9, wherein R5A, R5B, R9A, and R9B are independently unsubstituted methyl, unsubstituted ethyl, or unsubstituted propyl.

12. The compound of claim 1, wherein R1 is —C(X1)3;R3 is —C(X3)3;R2 is

13. The compound of claim 12, wherein R9A and R9B are independently substituted or unsubstituted C1-C20 alkyl.

14. The compound of claim 12, wherein R9A and R9B are independently hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted propyl.

15. The compound of claim 12, wherein X1 and X3 are fluorine.

16. The compound of claim 1, wherein R1 is —C(X1)3, R2 is —C(X2)3, R3 is —C(X3)3 and R4 is —C(X4)3.

17. The compound of claim 16, wherein X1, X2, X3 and X4 are fluorine.

18. A method of treating a neurodegenerative disorder comprising administering to a patient in need thereof an effective amount of a compound of claim 1.

19. The method of claim 18, wherein said neurodegenerative disorder is Parkinson's disease, Alzheimer's disease, Pick's disease, Huntington's disease, amyotrophic lateral sclerosis, prion diseases, dystonia, dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, Friedreich's Ataxia, temporal lobe epilepsy, stroke, traumatic brain injury, or a mitochondrial encephalopathy.

20. The method of claim 18, wherein said neurodegenerative disorder is Parkinson's disease.