COMPOUNDS AND METHODS OF THEIR USE

Abstract

Compounds, compositions, and methods for treating injuries caused by exposure to chemical warfare and similar agents are described herein.

Claims

1. A method for treating a subject having an injury resulting from exposure to a warfare agent, the method comprising administering to the subject a compound described herein.

2. A method of treating an injury in a subject who has been exposed to a chemical warfare agent, the method comprising administering to the subject a compound described herein.

3. A method of treating a subject, the method comprising: identifying a subject that has been exposed to a chemical warfare agent such as a nerve agent or toxin; and administering to the subject a compound described herein.

4. The method of claim 1, wherein the injury is a seizure.

5. The method of claim 4, wherein the injury is a myoclonic seizure.

6. The method of claim 1, wherein the injury is status epilepticus.

7. The method of claim 1, wherein the administration is within 1 week; 6, 5, 4, 3, 2, 1 day; 24, 22, 20, 18, 16, 14, 12, 10, 8, 7, 6, 5, 4, 3, 2, 1 hour, 45, 30, 20, 10, or 5 minutes of exposure to the chemical warfare agent.

8. The method of one of claims 1-3, wherein the compound is administered parenterally.

9. The method of claim 1, wherein the compound is administered by intravenous administration.

10. The method of claim 1, wherein the subject is a human.

11. The method of claim 1, wherein the chemical warfare agent is a nerve agent or toxin.

12. The method of claim 11, wherein the chemical warfare agent is a nerve agent.

13. The method of claim 12, wherein the nerve agent is a phosphorus-containing organic chemical.

14. The method of claim 12, wherein the nerve agent is a G agent.

15. The method of claim 12, wherein the nerve agent is a V agent.

16. The method of claim 11, wherein the toxin is abrin, ricin, or saxitoxin.

17. The method of claim 1, wherein the compound is a compound as described herein.

18. A method for treating disorders related to GABA function in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound, a pharmaceutically acceptable salt thereof, or pharmaceutical composition of a compound of claim 1.

19. A method for treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

20. The method of claim 19, wherein the CNS-related disorder is a sleep disorder, a mood disorder such as depression, a schizophrenia spectrum disorder, a convulsive disorder, epileptogenesis, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, or tinnitus.

21. A kit comprising a solid composition comprising a compound of claim 1 and a sterile diluent.

Description

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

[0099] Compounds and methods of their use for treating subjects (e.g., subjects injured by chemical warfare and similar agents) are described herein.

Chemical Warfare Agents

[0100] A subject may be exposed to a chemical warfare agent. If a compound described herein is administered, the symptoms or injuries resulting from the exposure to the chemical warfare agents can be reduced, prevented, or both. The compounds described herein can be administered to a subject before, during, or following such exposure and is therefore administered within 1 week; 6, 5, 4, 3, 2, 1 day; 24, 22, 20, 18, 16, 14, 12, 10, 8, 7, 6, 5, 4, 3, 2, 1 hour, 45, 30, 20, 10, or 5 minutes before or after such exposure. The compounds described herein can be administered prophylactically, when exposure to an agent is anticipated. It can also be administered after exposure to the chemical warfare agent (e.g., before or after symptoms of injury present in a subject).

[0101] Injuries resulting from the exposure to chemical warfare agents are known in the art and include any physical injuries, such as injuries to the central nervous system and peripheral nervous system. Exemplary symptoms or injuries resulting from the exposure to chemical warfare agents include inflammation, burn, itch, pain, rash, blisters, sweating, muscle twitching, nausea, vomiting, diarrhea, weakness, loss of conciousness, convulsions, muscular twitching, paralysis, secretions (from the mouth, nose, or lung for example), difficulty breating, blurred vision, eye pain, lacrimation, red eyes, shortness of breath, coughing, phlegm production and narrowing of the airways, headaches, tremors, dizziness, numbness or tingling, anxiety, insomnia, depression, emotional instability, and even death. The term “chemical warfare agent” includes all of those agents classified as schedule 1, 2, and 3 agents under the Chemical Weapons Convention of 1993 and may be in liquid form, gas form, solid form, or combinations thereof. Exemplary agents are described in further detail below and include, for example, nerve agents and toxins.

[0102] Nerve agents. Nerve agent poisoning typically leads to contraction of pupils, profuse salivation, convulsions, involuntary urination and defecation, and eventual death by asphyxiation as control is lost over respiratory muscles. For example, nerve agents can be phosphorus-containing organic chemicals (organophosphates) that disrupt the mechanism by which nerves transfer messages to organs. Exemplary agents include G agents such as tabun (GA), sarin (GB), soman (GD), cyclosarin (GF), and GV and V agents such as VE, VG, VM, VX, and Novichok agents.

[0103] Toxins. Exemplary toxins are abrin, ricin, and saxitoxin.

Compounds

[0104] Provided herein are compounds and their methods of use for treating subjects (e.g., subjects injured) by chemical warfare and similar agents.

[0105] Various synthetic steroids have also been prepared as neuroactive steroids. See, for example, U.S. Pat. No. 5,232,917, which discloses neuroactive steroid compounds useful in treating stress, anxiety, insomnia, seizure disorders, and mood disorders such as depression, that are amenable to GRC-active agents, such as depression, in a therapeutically beneficial manner. Furthermore, it has been previously demonstrated that these steroids interact at a site or sites on the GRC which is distinct from other known sites of interaction (e.g., barbiturates, benzodiazepines, and GABA) where therapeutically beneficial effects on stress, anxiety, sleep, mood disorders and seizure disorders have been previously elicited (see, e.g., Gee, K. W. and Yamamura, H. I., “Benzodiazepines and Barbiturates: Drugs for the Treatment of Anxiety, Insomnia and Seizure Disorders,” in Central Nervous System Disorders, Horvell, ed., Marcel-Dekker, New York (1985), pp. 123-147; Lloyd, K. G. and Morselli, P. L., “Psychopharmacology of GABAergic Drugs,” in Psychopharmacology: The Third Generation of Progress, H. Y. Meltzer, ed., Raven Press, N.Y. (1987), pp. 183-195; and Gee et al., European Journal of Pharmacology, 136:419-423 (1987). These compounds are desirable for their duration, potency, and oral activity (along with other forms of administration).

[0106] Compounds described herein are generally designed to modulate GABA function, and therefore to act as neuroactive steroids for the treatment and prevention of CNS-related conditions in a subject. Modulation, as used herein, refers to the inhibition or potentiation of GABA receptor function. Accordingly, the compounds and pharmaceutical compositions provided herein find use as therapeutics for preventing and/or treating CNS conditions in mammals including humans and non-human mammals. Thus, and as stated earlier, the present invention includes within its scope, and extends to, the recited methods of treatment, as well as to the compounds for such methods, and to the use of such compounds for the preparation of medicaments useful for such methods.

[0107] In some embodiments, the compounds described herein (e.g., neuroactive steroid described herein) is pregnanolone, allopregnanolone, alphadalone, ganaxolone, or alphaxolone. In some embodiments, the compound (e.g., the neuroactive steroid) is pregnanolone, allopregnanolone, alphadalone, ganaxolone, or alphaxolone. In some embodiments, the neuroactive steroid is allopregnanolone. In some embodiments, the neuroactive steroid is selected from neuroactive steroids that are disclosed in WIPO Publication Nos. WO2013/188792, WO 2013/056181, WO2015/010054, WO2014/169832, WO2014/169836, WO2014/169833, WO2014/169831, WO2015/027227, WO 2014/100228, U.S. Pat. Nos. 5,232,917, 8,575,375 and 8,759,330.

[0108] In one aspect, provided is a compound of Formula (I):

##STR00005##

wherein R.sup.1a is hydrogen, halo, alkyl, alkoxy, —C(O)R.sup.a, —C(O)N(R.sup.b)(R.sup.c), —C(O)OR.sup.a, —N(R.sup.b)(R.sup.c), —OC(O)N(R.sup.b)(R.sup.c), —OC(O)OR.sup.a, —S(O).sub.0-2R.sup.a, —S(O).sub.0-2OR.sup.a, or —S(O).sub.0-2N(R.sup.b)(R.sup.c); R.sup.1b is hydrogen, halo, hydroxy, alkyl, alkoxy, —C(O)R.sup.a, —C(O)N(R.sup.b)(R.sup.c), —C(O)OR.sup.a, —N(R.sup.d)(R.sup.e), —OC(O)N(R.sup.b)(R.sup.c), —OC(O)OR.sup.a, —OC(O)R.sup.a, —S(O).sub.0-2R.sup.a, —S(O).sub.0-2OR.sup.a, or —S(O).sub.0-2N(R.sup.b)(R.sup.c); wherein one of R.sup.1a and R.sup.1b is hydrogen; each R.sup.a is hydrogen or C.sub.1-C.sub.6 alkyl; each R.sup.b and R.sup.c is independently hydrogen or C.sub.1-C.sub.6 alkyl, or R.sup.b and R.sup.c, taken together with the nitrogen atom to which they are attached, form a 3-7-membered (e.g., 5-7-membered) heterocyclic ring; and each R.sup.d and R.sup.e is hydrogen, substituted methyl or C.sub.2-C.sub.6 alkyl, or R.sup.d and R.sup.e, taken together with the nitrogen atom to which they are attached, form a 3-7-membered (e.g., 5-7-membered) heterocyclic ring.

[0109] In some embodiments, R.sup.1a is hydrogen and R.sup.1b is hydroxy, alkyl, or alkoxy. In some embodiments, R.sup.1b is hydroxy or alkoxy. In some embodiments, R.sup.1b is hydroxy. In some embodiments, R.sup.1b is methoxy. In some embodiments, R.sup.1b is alkyl.

[0110] In some embodiments, R.sup.1b is hydrogen and R.sup.1a is alkyl or alkoxy. In some embodiments, R.sup.1a is alkoxy. In some embodiments, R.sup.1a is methoxy.

[0111] In some embodiments, the compound is of the Formula (Ia):

##STR00006##

wherein R.sup.1a is hydrogen, halo, alkyl, alkoxy, —C(O)R.sup.a, —C(O)N(R.sup.b)(R.sup.c), —C(O)OR.sup.a, —N(R.sup.b)(R.sup.c), —OC(O)N(R.sup.b)(R.sup.c), —OC(O)OR.sup.a, —S(O).sub.0-2R.sup.a, —S(O).sub.0-2OR.sup.a, or —S(O).sub.0-2N(R.sup.b)(R.sup.c); R.sup.1b is hydrogen, halo, hydroxy, alkyl, alkoxy, —C(O)R.sup.a, C(O)N(R.sup.b)(R.sup.c), —C(O)OR.sup.a, —N(R.sup.d)(R.sup.e), —OC(O)N(R.sup.b)(R.sup.c), —OC(O)OR.sup.a, —OC(O)R.sup.a, —S(O).sub.0-2R.sup.a, —S(O).sub.0-2OR.sup.a, or —S(O).sub.0-2N(R.sup.b)(R.sup.c); wherein one of R.sup.1a and R.sup.1b is hydrogen; each R.sup.a is hydrogen or C.sub.1-C.sub.6 alkyl; each R.sup.b and R.sup.c is independently hydrogen or C.sub.1-C.sub.6 alkyl, or R.sup.b and R.sup.c, taken together with the nitrogen atom to which they are attached, form a 3-7-membered (e.g., 5-7-membered) heterocyclic ring; and each R.sup.d and R.sup.e is hydrogen, substituted methyl or C.sub.2-C.sub.6 alkyl, or R.sup.d and R.sup.e, taken together with the nitrogen atom to which they are attached, form a 3-7-membered (e.g., 5-7-membered) heterocyclic ring.

[0112] In some embodiments, R.sup.1a is hydrogen and R.sup.1b is hydroxy, alkyl, or alkoxy. In some embodiments, R.sup.1b is hydroxy or alkoxy. In some embodiments, R.sup.1b is hydroxy. In some embodiments, R.sup.1b is methoxy. In some embodiments, R.sup.1b is alkyl.

[0113] In some embodiments, R.sup.1b is hydrogen and R.sup.1a is alkyl or alkoxy. In some embodiments, R.sup.1a is alkoxy. In some embodiments, R.sup.1a is methoxy.

[0114] In some embodiments, the compound is of the Formula (Ib):

##STR00007##

[0115] In some embodiments, R.sup.1a is hydrogen and R.sup.1b is hydroxy, alkyl, or alkoxy. In some embodiments, R.sup.1b is hydroxy or alkoxy. In some embodiments, R.sup.1b is hydroxy. In some embodiments, R.sup.1b is methoxy. In some embodiments, R.sup.1b is alkyl.

[0116] In some embodiments, R.sup.1b is hydrogen and R.sup.1a is alkyl or alkoxy. In some embodiments, R.sup.1a is alkoxy. In some embodiments, R.sup.1a is methoxy.

[0117] In one aspect, provided is a compound selected from:

##STR00008##

[0118] In some embodiments, the compound is selected from:

##STR00009##

[0119] In some embodiments, the compound is selected from:

##STR00010##

[0120] In one aspect, provided is a compound of the Formula (II):

##STR00011##

wherein R.sup.2a is hydrogen, halo (e.g., chloro. fluoro. bromo. iodo). hydroxy, alkyl, methoxy, substituted ethoxy, C.sub.3-C.sub.6 alkoxy, —C(O)R.sup.a, —C(O)N(R.sup.b)(R.sup.c), —C(O)OR.sup.a, —N(R.sup.f)(R.sup.g), —OC(O)N(R.sup.b)(R.sup.c), —OC(O)OR.sup.a, —OC(O)R.sup.a, —S(O).sub.0-2R.sup.a, −S(O).sub.0-2OR.sup.a, or —S(O).sub.0-2N(R.sup.b)(R.sup.c); R.sup.2b is hydrogen, halo, hydroxy, alkyl, methoxy. substituted ethoxy. C.sub.3-C.sub.6 alkoxy, —C(O)R.sup.a, —C(O)N(R.sup.b)(R.sup.c), —C(O)OR.sup.a, —N(R.sup.b)(R.sup.c). —OC(O)N(R.sup.b)(R.sup.c), —OC(O)OR.sup.a, —OC(O)R.sup.a, —S(O).sub.0-2R.sup.a, —S(O).sub.0-2OR.sup.a, or —S(O).sub.0-2N(R.sup.b)(R.sup.c); wherein one of R.sup.2a and R.sup.2b is hydrogen; each R.sup.a is hydrogen or C.sub.1-C.sub.6 alkyl; each R.sup.b and R.sup.c is independently hydrogen or C.sub.1-C.sub.6 alkyl, or R.sup.b and R.sup.c, taken together with the nitrogen atom to which they are attached, form a 3-7-membered (e.g., 5-7-membered) heterocyclic ring; and each R.sup.f and R.sup.g is independently hydrogen or C.sub.1-C.sub.6 alkyl, or R.sup.f and R.sup.g, taken together with the nitrogen atom to which they are attached, form a 3-7-membered (e.g., 5-7-membered) heterocyclic ring optionally comprising one additional heteroatom selected from nitrogen, oxygen and sulfur.

[0121] In some embodiments, R.sup.2a is hydrogen and R.sup.2b is alkyl. In some embodiments, R.sup.2b is alkyl. In some embodiments, R.sup.2b is methyl. In some embodiments, R.sup.2b is methoxy.

[0122] In some embodiments, R.sup.2b is hydrogen and R.sup.2a is alkyl, methoxy. substituted ethoxy, or C.sub.3-C.sub.6 alkoxy. In some embodiments, R.sup.2b is alkyl. In some embodiments, R.sup.2a is methyl. In some embodiments, R.sup.2a is ethyl. In some embodiments, R.sup.2a is methoxy. In some embodiments, R.sup.2a is —OCF.sub.3. In some embodiments, R.sup.2a is substituted ethoxy. In some embodiments, R.sup.2a is —OCH.sub.2CH.sub.2OMe. In some embodiments, R.sup.2a is —OCH.sub.2CH.sub.2OH. In some embodiments, R.sup.2a is —OCH.sub.2CF.sub.3. In some embodiments, R.sup.2a is C.sub.3-C.sub.6 alkoxy. In some embodiments, R.sup.2a is propoxy. In some embodiments, R.sup.2a is —OCH(CH.sub.3).sub.2. In some embodiments, R.sup.2a is —OCH.sub.2CH(CH.sub.3).sub.2. In some embodiments, R.sup.2a is cyclopropoxy.

[0123] In some embodiments, the compound is of the Formula (IIa):

##STR00012##

wherein R.sup.2a is hydrogen, halo (e.g., chloro. fluoro. bromo. iodo). hydroxy, alkyl, methoxy. substituted ethoxy, C.sub.3-C.sub.6 alkoxy, —C(O)R.sup.a, —C(O)N(R.sup.b)(R.sup.c), —C(O)OR.sup.a, —N(R.sup.f)(R.sup.g), —OC(O)N(R.sup.b)(R.sup.c), —OC(O)OR.sup.a, —OC(O)R.sup.a, —S(O).sub.0-2R.sup.a, —S(O).sub.0-2OR.sup.a, or —S(O).sub.0-2N(R.sup.b)(R.sup.c); R.sup.2b is hydrogen, halo, hydroxy, alkyl, methoxy, substituted ethoxy. C.sub.3-C.sub.6 alkoxy, —C(O)R.sup.a, —C(O)N(R.sup.b)(R.sup.c), —C(O)OR.sup.a, —N(R.sup.b)(R.sup.c), —OC(O)N(R.sup.b)(R.sup.c), —OC(O)OR.sup.a, —OC(O)R.sup.a, —S(O).sub.0-2R.sup.a, —S(O).sub.0-2OR.sup.a, or —S(O).sub.0-2N(R.sup.b)(R.sup.c); wherein one of R.sup.2a and R.sup.2b is hydrogen; each R.sup.a is hydrogen or C.sub.1-C.sub.6 alkyl; each R.sup.b and R.sup.c is independently hydrogen or C.sub.1-C.sub.6 alkyl, or R.sup.b and R.sup.c, taken together with the nitrogen atom to which they are attached, form a 3-7-membered (e.g., 5-7-membered) heterocyclic ring; and each R1 and R.sup.g is independently hydrogen or C.sub.1-C.sub.6 alkyl, or R.sup.f and R.sup.g, taken together with the nitrogen atom to which they are attached, form a 3-7-membered (e.g., 5-7-membered) heterocyclic ring optionally comprising one additional heteroatom selected from nitrogen, oxygen and sulfur.

[0124] In some embodiments, R.sup.2a is hydrogen and R.sup.2b is alkyl. In some embodiments, R.sup.2b is alkyl. In some embodiments, R.sup.2b is methyl. In some embodiments, R.sup.2b is methoxy.

[0125] In some embodiments, R.sup.2b is hydrogen and R.sup.2a is alkyl, methoxy, substituted ethoxy, or C.sub.3-C.sub.6 alkoxy. In some embodiments, R.sup.2a is alkyl. In some embodiments, R.sup.2a is methyl. In some embodiments. R.sup.2a is ethyl. In some embodiments, R.sup.2a is methoxy. In some embodiments, R.sup.2a is —OCF.sub.3. In some embodiments, R.sup.2a is substituted ethoxy. In some embodiments, R.sup.2a is —OCH.sub.2CH.sub.2OMe. In some embodiments, R.sup.2a is —OCH.sub.2CH.sub.2OH. In some embodiments, R.sup.2a is —OCH.sub.2CF.sub.3. C.sub.3-C.sub.6 alkoxy. In some embodiments, R.sup.2a is propoxy. In some embodiments, R.sup.2a is —OCH(CH.sub.3).sub.2. In some embodiments, R.sup.2a is —OCH.sub.2CH(CH.sub.3).sub.2. In some embodiments, R.sup.2a is cyclopropoxy.

[0126] In some embodiments, the compound is of the Formula (IIb):

##STR00013##

wherein R.sup.2a is hydrogen, halo (e.g., chloro, fluoro, bromo, iodo), hydroxy, alkyl, methoxy, substituted ethoxy, C.sub.3-C.sub.6 alkoxy, —C(O)R.sup.a, —C(O)N(R.sup.b)(R.sup.c), —C(O)OR.sup.a, —N(R.sup.f)(R.sup.g), —OC(O)N(R.sup.b)(R.sup.c), —OC(O)OR.sup.a, —OC(O)R.sup.a, —S(O).sub.0-2R.sup.a, —S(O).sub.0-2OR.sup.a, or —S(O).sub.0-2N(Rb)(R.sup.c); —R.sup.2b is hydrogen, halo, hydroxy, alkyl, methoxy, substituted ethoxy, C.sub.3-C.sub.6 alkoxy, —C(O)R.sup.a, —C(O)N(R.sup.b)(R.sup.c), —C(O)OR.sup.a, —N(R.sup.b)(R.sup.c), —OC(O)N(R.sup.b)(R.sup.c), —OC(O)OR.sup.a, —OC(O)R.sup.a, —S(O).sub.0-2R.sup.a, —S(O).sub.0-2OR.sup.a, or —S(O).sub.0-2N(R.sup.b)(R.sup.c); wherein one of R.sup.2a and R.sup.2b is hydrogen; each R.sup.a is hydrogen or C.sub.1-C.sub.6 alkyl; each R.sup.b and R.sup.c is independently hydrogen or C.sub.1-C.sub.6 alkyl, or R.sup.b and R.sup.c, taken together with the nitrogen atom to which they are attached, form a 3-7-membered (e.g., 5-7-membered) heterocyclic ring; and each R.sup.f and R.sup.g is independently hydrogen or C.sub.1-C.sub.6 alkyl, or R.sup.f and R.sup.g, taken together with the nitrogen atom to which they are attached, form a 3-7-membered (e.g., 5-7-membered) heterocyclic ring optionally comprising one additional heteroatom selected from nitrogen, oxygen and sulfur.

[0127] In some embodiments, R.sup.2a is hydrogen and R.sup.2b is alkyl. In some embodiments, R.sup.2b is alkyl. In some embodiments, R.sup.2b is methyl. In some embodiments, R.sup.2b is methoxy.

[0128] In some embodiments, R.sup.2b is hydrogen and R.sup.2a is alkyl, methoxy, substituted ethoxy, or C.sub.3-C.sub.6 alkoxy. In some embodiments, R.sup.2a is alkyl. In some embodiments, R.sup.2a is methyl. In some embodiments, R.sup.2a is ethyl. In some embodiments, R.sup.2a is methoxy. In some embodiments, R.sup.2a is —OCF.sub.3. In some embodiments, R.sup.2a is substituted ethoxy. In some embodiments, R.sup.2a is —OCH.sub.2CH.sub.2OMe. In some embodiments, R.sup.2a is —OCH.sub.2CH.sub.2OH. In some embodiments, R.sup.2a is —OCH.sub.2CF.sub.3. C.sub.3-C.sub.6 alkoxy. In some embodiments, R.sup.2a is propoxy. In some embodiments, R.sup.2a is —OCH(CH.sub.3).sub.2. In some embodiments, R.sup.2a is —OCH.sub.2CH(CH.sub.3).sub.2. In some embodiments, R.sup.2a is cyclopropoxy.

[0129] In one aspect, provided is a compound selected from:

##STR00014## ##STR00015## ##STR00016##

[0130] In some embodiments, the compound is selected from:

##STR00017## ##STR00018## ##STR00019##

[0131] In some embodiments, the compound is selected from:

##STR00020## ##STR00021##

[0132] In one aspect, provided is a compound of the Formula (III):

##STR00022##

wherein one of R.sup.1a and R.sup.1b is halo (e.g., chloro, fluoro, bromo, iodo), hydroxy, alkyl, alkoxy, —C(O)R.sup.a, —C(O)N(R.sup.b)(R.sup.c), —C(O)OR.sup.a, —N(R.sup.h)(R.sup.i), —OC(O)N(R.sup.b)(R.sup.c), —OC(O)OR.sup.a, —OC(O)R.sup.a, —S(O).sub.0-2R.sup.a, —S(O).sub.0-2OR.sup.a, or —S(O).sub.0-2N(R.sup.b)(R.sup.c), and the other one is hydrogen; or R.sup.1a and R.sup.1b are taken together with the carbon to which they are attached to form C(═O); one of R.sup.2a and R.sup.2b is chloro, fluoro, hydroxy, alkyl, alkoxy, —C(O)R.sup.a, —C(O)N(R.sup.b)(R.sup.c), —C(O)OR.sup.a, —N(R.sup.f)(R.sup.g), —OC(O)N(R.sup.b)(R.sup.c), —OC(O)OR.sup.a, —OC(O)R.sup.a, —S(O).sub.0-2R.sup.a, —S(O).sub.0-2OR.sup.a, or —S(O).sub.0-2N(R.sup.b)(R.sup.c), and the other one is hydrogen; R.sup.3 is hydrogen or C.sub.1-C.sub.6 alkyl; each R.sup.a is hydrogen or C.sub.1-C.sub.6 alkyl; each R.sup.b and R.sup.c is independently hydrogen or C.sub.1-C.sub.6 alkyl, or R.sup.b and R.sup.c, taken together with the nitrogen atom to which they are attached, form 3-7-membered (e.g., 5-7-membered) heterocyclic ring; each R.sup.f and R.sup.g is independently hydrogen or C.sub.1-C.sub.6 alkyl, or R.sup.f and R.sup.g, taken together with the nitrogen atom to which they are bound to form a 3-7-membered (e.g., 5-7-membered) heterocyclic ring optionally comprising one additional heteroatom selected from nitrogen, oxygen and sulfur; and each R.sup.h is unsubstituted C.sub.1-C.sub.4 alkyl; each R.sup.i is hydrogen, substituted methyl or C.sub.2-C.sub.6 alkyl, or R.sup.h and R.sup.i, together with the nitrogen atom to which they are attached, form a 3-7-membered (e.g., 5-7-membered) heterocyclic ring.

[0133] In some embodiments, R.sup.1a is hydrogen and R.sup.1b is hydroxy, alkyl, or alkoxy.

[0134] In some embodiments, R.sup.1b is hydrogen and R.sup.1a is hydroxy, alkyl, or alkoxy. In some embodiments, R.sup.1a is hydroxy. In some embodiments, R.sup.1a is alkoxy. In some embodiments, R.sup.1a is methoxy.

[0135] In some embodiments, R.sup.1a and R.sup.1b are taken together with the carbon to which they are attached to form C(═O).

[0136] In some embodiments, R.sup.2a is hydrogen and R.sup.2b is hydroxy, alkyl, or alkoxy. In some embodiments, R.sup.2b is hydroxy. In some embodiments, R.sup.2b is alkyl. In some embodiments, R.sup.2b is methyl. In some embodiments, R.sup.2b is alkoxy.

[0137] In some embodiments, R.sup.2b is hydrogen and R.sup.2a is hydroxy, alkyl, or alkoxy. In some embodiments, R.sup.2a is hydroxy. In some embodiments, R.sup.2a is alkyl. In some embodiments, R.sup.2a is methyl. In some embodiments, R.sup.2a is alkoxy. In some embodiments, R.sup.2a is methoxy. In some embodiments, R.sup.2a is ethoxy. In some embodiments, R.sup.2a is propoxy. In some embodiments, R.sup.2a is —OCH.sub.2CH.sub.2OCH.sub.3. In some embodiments, R.sup.2a is —OCH(CH.sub.3).sub.2.

[0138] In some embodiments, R.sup.3 is alkyl (e.g., C.sub.1-C.sub.6 alkyl) or alkoxy (e.g., C.sub.1-C.sub.6 alkoxy).

[0139] In some embodiments, the compound is a compound of Formula (IIIa):

##STR00023##

wherein one of R.sup.1a and R.sup.1b is halo, hydroxy, alkyl, alkoxy, —C(O)R.sup.a, —C(O)N(R.sup.b)(R.sup.c), —C(O)OR.sup.a, —N(R.sup.h)(R.sup.i), —OC(O)N(R.sup.b)(R.sup.c), —OC(O)OR.sup.a, —OC(O)R.sup.a, —S(O).sub.0-2R.sup.a, —S(O).sub.0-2OR.sup.a, or —S(O).sub.0-2N(R.sup.b)(R.sup.c), and the other one is hydrogen; or R.sup.1a and R.sup.1b are taken together with the carbon to which they are attached to form C(═O); one of R.sup.2a and R.sup.2b is halo (e.g., chloro, fluoro, bromo, iodo), hydroxy, alkyl, alkoxy, —C(O)R.sup.a, —C(O)N(R.sup.b)(R.sup.c), —C(O)OR.sup.a, —N(R.sup.f)(R.sup.g), —OC(O)N(R.sup.b)(R.sup.c), —OC(O)OR.sup.a, —OC(O)R.sup.a, —S(O).sub.0-2R.sup.a, —S(O).sub.0-2OR.sup.a, or —S(O).sub.0-2N(R.sup.b)(R.sup.c), and the other one is hydrogen; R.sup.3 is hydrogen or C.sub.1-C.sub.6 alkyl; each R.sup.a is hydrogen or C.sub.1-C.sub.6 alkyl; each R.sup.b and R.sup.c is independently hydrogen or C.sub.1-C.sub.6 alkyl, or R.sup.b and R.sup.c, taken together with the nitrogen atom to which they are attached, form 3-7-membered (e.g., 5-7-membered) heterocyclic ring; each R.sup.f and R.sup.g is independently hydrogen or C.sub.1-C.sub.6 alkyl, or R.sup.f and R.sup.g, taken together with the nitrogen atom to which they are attached, form a 3-7-membered (e.g., 5-7-membered) heterocyclic ring optionally comprising one additional heteroatom selected from nitrogen, oxygen and sulfur; and each R.sup.h is unsubstituted C.sub.1-C.sub.4 alkyl; each R.sup.i is hydrogen, substituted methyl or C.sub.2-C.sub.6 alkyl, or R.sup.h and R.sup.i, together with the nitrogen atom to which they are attached, form a 3-7-membered (e.g., 5-7-membered) heterocyclic ring.

[0140] In some embodiments, R.sup.1a is hydrogen and R.sup.1b is hydroxy, alkyl, or alkoxy.

[0141] In some embodiments, R.sup.1b is hydrogen and R.sup.1a is hydroxy, alkyl, or alkoxy. In some embodiments, R.sup.1a is hydroxy. In some embodiments, R.sup.1a is alkoxy. In some embodiments, R.sup.1a is methoxy.

[0142] In some embodiments, R.sup.1a and R.sup.1b are taken together with the carbon to which they are attached to form C(═O).

[0143] In some embodiments, R.sup.2a is hydrogen and R.sup.2b is hydroxy, alkyl, or alkoxy. In some embodiments, R.sup.2b is hydroxy. In some embodiments, R.sup.2b is alkyl. In some embodiments, R.sup.2b is methyl. In some embodiments, R.sup.2b is alkoxy.

[0144] In some embodiments, R.sup.2b is hydrogen and R.sup.2a is hydroxy, alkyl, or alkoxy. In some embodiments, R.sup.2a is hydroxy. In some embodiments, R.sup.2a is alkyl. In some embodiments, R.sup.2a is methyl. In some embodiments, R.sup.2a is alkoxy. In some embodiments, R.sup.2a is methoxy. In some embodiments, R.sup.2a is ethoxy. In some embodiments, R.sup.2a is propoxy. In some embodiments, R.sup.2a is —OCH.sub.2CH.sub.2OCH.sub.3. In some embodiments, R.sup.2a is —OCH(CH.sub.3).sub.2

[0145] In some embodiments, R.sup.3 is hydrogen. In some embodiments, R.sup.3 is C.sub.1-C.sub.6 alkyl.

[0146] In some embodiments, the compound is a compound of Formula (IIIb):

##STR00024##

wherein one of R.sup.1a and R.sup.1b is halo (e.g., chloro, fluoro, bromo, iodo), hydroxy, alkyl, alkoxy, —C(O)R.sup.a, —C(O)N(R.sup.b)(R.sup.c), —C(O)OR.sup.a, —N(R.sup.h)(R.sup.i), —OC(O)N(R.sup.b)(R.sup.c), —OC(O)OR.sup.a, —OC(O)R.sup.a, —S(O).sub.0-2R.sup.a, —S(O).sub.0-2OR.sup.a, or —S(O).sub.0-2N(R.sup.b)(R.sup.c), and the other one is hydrogen; or R.sup.1a and R.sup.1b are taken together with the carbon to which they are attached to form C(═O); one of R.sup.2a and R.sup.2b is halo (e.g., chloro, fluoro, bromo, iodo), hydroxy, alkyl, alkoxy, —C(O)R.sup.a, —C(O)N(R.sup.b)(R.sup.c), —C(O)OR.sup.a, N(R.sup.f)(R.sup.g), —OC(O)N(R.sup.b)(R.sup.c), —OC(O)OR.sup.a, —OC(O)R.sup.a, —S(O).sub.0-2R.sup.a, —S(O).sub.0-2OR.sup.a, or —S(O).sub.0-2N(R.sup.b)(R.sup.c), and the other one is hydrogen; R.sup.3 is hydrogen or C.sub.1-C.sub.6 alkyl; each R.sup.a is hydrogen or C.sub.1-C.sub.6 alkyl; each R.sup.b and R.sup.c is independently hydrogen or C.sub.1-C.sub.6 alkyl, or R.sup.b and R.sup.c, taken together with the nitrogen atom to which they are attached, form 3-7-membered (e.g., 5-7-membered) heterocyclic ring; each R.sup.f and R.sup.g is independently hydrogen or C.sub.1-C.sub.6 alkyl, or R.sup.f and R.sup.g, taken together with the nitrogen atom to which they are attached, form a 3-7-membered (e.g., 5-7-membered) heterocyclic ring optionally comprising one additional heteroatom selected from nitrogen, oxygen and sulfur; and each R.sup.h is unsubstituted C.sub.1-C.sub.4 alkyl; each R.sup.i is hydrogen, substituted methyl or C.sub.2-C.sub.6 alkyl, or R.sup.h and R.sup.i, together with the nitrogen atom to which they are attached, form a 3-7-membered (e.g., 5-7-membered) heterocyclic ring.

[0147] In some embodiments, R.sup.1a is hydrogen and R.sup.1b is hydroxy, alkyl, or alkoxy.

[0148] In some embodiments, R.sup.1b is hydrogen and R.sup.1a is hydroxy, alkyl, or alkoxy. In some embodiments, R.sup.1a is hydroxy. In some embodiments, R.sup.1a is alkoxy. In some embodiments, R.sup.1a is methoxy.

[0149] In some embodiments, R.sup.1a and R.sup.1b are taken together with the carbon to which they are attached to form C(═O).

[0150] In some embodiments, R.sup.2a is hydrogen and R.sup.2b is hydroxy, alkyl, or alkoxy. In some embodiments, R.sup.2b is hydroxy. In some embodiments, R.sup.2b is alkyl. In some embodiments, R.sup.2b is methyl. In some embodiments, R.sup.2b is alkoxy.

[0151] In some embodiments, R.sup.2b is hydrogen and R.sup.2a is hydroxy, alkyl, or alkoxy. In some embodiments, R.sup.2a is hydroxy. In some embodiments, R.sup.2a is alkyl. In some embodiments, R.sup.2a is methyl. In some embodiments, R.sup.2a is alkoxy. In some embodiments, R.sup.2a is methoxy. In some embodiments, R.sup.2a is ethoxy. In some embodiments, R.sup.2a is propoxy. In some embodiments, R.sup.2a is —OCH.sub.2CH.sub.2OCH.sub.3. In some embodiments, R.sup.2a is —OCH(CH.sub.3).sub.2.

[0152] In some embodiments, R.sup.3 is hydrogen. In some embodiments, R.sup.3 is C.sub.1-C.sub.6 alkyl.

[0153] In one aspect, provided is a compound selected from:

##STR00025## ##STR00026## ##STR00027##

[0154] In one aspect, provided is a compound selected from:

##STR00028## ##STR00029##

[0155] In one aspect, provided is a compound of the Formula (IV):

##STR00030##

wherein one of R.sup.1a and R.sup.1b is halo, hydroxy, alkyl, alkoxy, —C(O)R.sup.a, —C(O)N(R.sup.b)(R.sup.c), —C(O)OR.sup.a, —N(R.sup.b)(R.sup.c), —OC(O)N(R.sup.b)(R.sup.c), —OC(O)OR.sup.a, —OC(O)R.sup.a, —S(O).sub.0-2R.sup.a, —S(O).sub.0-2OR.sup.a, or —S(O).sub.0-2N(R.sup.b)(R.sup.c), and the other one is hydrogen; or R.sup.1a and R.sup.1b are taken together with the carbon to which they are attached to form C(═O); R.sup.3 is alkyl or alkoxy; each R.sup.a is hydrogen or C.sub.1-C.sub.6 alkyl; each R.sup.b and R.sup.c is independently hydrogen or C.sub.1-C.sub.6 alkyl, or R.sup.b and R.sup.c, together with the nitrogen atom to which they are bound to form a 3-7-membered (e.g., 5-7-membered) heterocyclic ring.

[0156] In some embodiments, R.sup.1b is hydrogen and R.sup.1a is hydroxy, alkyl, or alkoxy. In some embodiments, R.sup.1a is hydroxy. In some embodiments, R.sup.1a is alkyl. In some embodiments, R.sup.1a is alkoxy. In some embodiments, R.sup.1a is methoxy.

[0157] In some embodiments, R.sup.1a and R.sup.1b are taken together with the carbon to which they are attached to form C(═O).

[0158] In some embodiments, R.sup.3 is alkyl. In some embodiments, R.sup.3 is methyl.

[0159] In some embodiments, provided is a compound selected from:

##STR00031##

[0160] In one aspect, provided is a compound of the Formula (V):

##STR00032##

wherein R.sup.3 is alkyl or alkoxy.

[0161] In some embodiments, R.sup.3 is alkyl. In some embodiments, R.sup.3 is methyl or ethyl.

[0162] In some embodiments, provided is a compound selected from:

##STR00033##

[0163] In one aspect, provided is a pharmaceutical composition comprising a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), or (V) and a pharmaceutically acceptable excipient.

[0164] In one aspect, provided is a solvate, isotopic variant, or tautomer of a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), or (V).

[0165] In one aspect, provided herein is a compound having the structure of Formula (VI):

##STR00034##

or a pharmaceutically acceptable salt thereof; [0166] wherein:

[0167] R.sub.1 is selected from (C.sub.1-C.sub.4 alkyl)-O (e.g., methoxy, ethoxy, propoxy, butoxy), spirooxirane, cyano, ═O, nitro, (C.sub.1-C.sub.4 alkyl)C(O) (e.g., CH.sub.3C(O), CH.sub.3CH.sub.2C(O), CH.sub.3CH.sub.2 CH.sub.2C(O), CH.sub.3CH.sub.2 CH.sub.2 CH.sub.2C(O)), and HO(C.sub.1-C.sub.4 alkyl)C(O) (e.g., HOCH.sub.2C(O), HOCH.sub.2CH.sub.2C(O), HOCH.sub.2CH.sub.2 CH.sub.2C(O), HOCH.sub.2CH.sub.2 CH.sub.2 CH.sub.2C(O)), with R.sub.1 preferably being in the beta position when other than ═O, and/or in one or more preferred embodiments C.sub.1-C.sub.4 alkyl being methyl, R.sub.1 therefore being is selected from methoxy, spirooxirane, cyano, ═O, nitro, CH.sub.3C(O)— and OHCH.sub.2C(O)—;

[0168] R.sub.2 is ═O, H, or OR.sub.a, where R.sub.a is selected from hydrogen, optionally substituted C.sub.1-C.sub.4 alkyl, or optionally substituted aryl, with the proviso that when R.sub.2 is ═O, R.sub.8 is not present;

[0169] R.sub.3 is hydrogen, optionally substituted C.sub.1-C.sub.4 alkyl, optionally substituted C.sub.2-C.sub.4 alkenyl, optionally substituted C.sub.2-C.sub.4 alkynyl, or optionally substituted aryl;

[0170] R.sub.4 is independently selected from hydrogen and unsubstituted C.sub.1-C.sub.4 alkyl;

[0171] R.sub.5 is substituted C.sub.1-C.sub.4 alkyl, optionally substituted C.sub.2-C.sub.4 alkenyl, or optionally substituted C.sub.2-C.sub.4 alkynyl (and in particular is alkoxy-substituted methyl, or even more particular is —CH.sub.2—OR.sub.b, where R.sub.b is C.sub.1-C.sub.4 alkyl, or even still more particularly is —CH.sub.2—OCH.sub.3);

[0172] R.sub.6 is hydrogen, optionally substituted C.sub.1-C.sub.4 alkyl, or optionally substituted C.sub.1-C.sub.4 alkoxy;

[0173] R.sub.7 is hydrogen, optionally substituted C.sub.1-C.sub.4 alkoxy, or an optionally substituted morpholinyl ring;

[0174] R.sub.8, when present, is hydrogen or optionally substituted C.sub.1-C.sub.4 alkyl; [0175] ——— denotes an optional, additional C—C bond, resulting in either a C═C bond between C.sub.4-0.sub.5 or C.sub.5-C.sub.6, with the proviso that when present, the R.sub.5-H substituent is not present; and, [0176] ——— denotes an optional, additional C—C bond, resulting in a C═C bond between C.sub.16-C.sub.17, with the proviso that when present, the R.sub.1 is not ═O.

[0177] As generally defined above, R.sub.1 is selected from (C.sub.1-C.sub.4 alkyl)-O, spirooxirane, cyano, ═O, nitro, (C.sub.1-C.sub.4 alkyl)C(O), and HO(C.sub.1-C.sub.4 alkyl)C(O). In certain embodiments, R.sub.1 is preferably in the beta position (when other than ═O, or when a C═C is not present between C.sub.16-C.sub.17). In certain embodiments, R.sub.1 is selected from (C.sub.1-C.sub.4 alkyl)-O (e.g., methoxy, ethoxy, propoxy, butoxy), spirooxirane, cyano, ═O, nitro, (C.sub.1-C.sub.4 alkyl)C(O) (e.g., CH.sub.3C(O), CH.sub.3CH.sub.2C(O), CH.sub.3CH.sub.2 CH.sub.2C(O), CH.sub.3CH.sub.2 CH.sub.2 CH.sub.2C(O)), and HO(C.sub.1-C.sub.4 alkyl)C(O) (e.g., HOCH.sub.2C(O), HOCH.sub.2CH.sub.2C(O), HOCH.sub.2CH.sub.2 CH.sub.2C(O), HOCH.sub.2CH.sub.2 CH.sub.2 CH.sub.2C(O)). In certain embodiments, C.sub.1-C.sub.4 alkyl is methyl, R.sub.1 therefore being is selected from methoxy, spirooxirane, cyano, ═O, nitro, CH.sub.3C(O)— and OHCH.sub.2C(O)—.

[0178] As generally defined above, R.sub.2 is ═O, hydrogen, or OR.sub.a, where R.sub.a is selected from hydrogen, optionally substituted C.sub.1-C.sub.4 alkyl, or optionally substituted aryl, with the proviso that when R.sub.2 is ═O, R.sub.8 is not present. In certain embodiments, R.sub.2 is ═O and R.sub.8 is not present. In certain embodiments, R.sub.2 is hydrogen. In certain embodiments, R.sub.2 is OR.sub.a. In certain embodiments, R.sub.2 is OR.sub.a and R.sub.a is optionally substituted C.sub.1, C.sub.2, C.sub.3, or C.sub.4 alkyl (e.g., methyl, ethyl), optionally substituted benzyl, or C.sub.1, C.sub.2, C.sub.3, or C.sub.4 alkyl substituted with O-aryl, such as O-benzyl. In certain embodiments, R.sub.2 is OR.sub.a and R.sub.a is optionally substituted aryl. In certain embodiments, R.sub.2 is OR.sub.a and R.sub.a is hydrogen.

[0179] As generally defined above, R.sub.3 is hydrogen, optionally substituted C.sub.1-C.sub.4 alkyl, optionally substituted C.sub.2-C.sub.4 alkenyl, optionally substituted C.sub.2-C.sub.4 alkynyl, or optionally substituted aryl. In certain embodiments, R.sub.3 is hydrogen. In certain embodiments, R.sub.3 is optionally substituted C.sub.1, C.sub.2, C.sub.3 or C.sub.4 alkyl (e.g., methyl, ethyl, trifluoromethyl, difluoromethyl). In certain embodiments, R.sub.3 is methyl. In certain embodiments, R.sub.3 is trifluoromethyl. In certain embodiments, R.sub.3 is optionally substituted C.sub.2, C.sub.3 or C.sub.4 alkenyl (e.g., optionally substituted allyl). In certain embodiments, R.sub.3 is optionally substituted C.sub.2, C.sub.3, or C.sub.4 alkynyl (e.g., optionally substituted acetylene or optionally substituted propargyl). In certain embodiments, R.sub.3 is optionally substituted aryl (e.g., optionally substituted phenyl, such as phenyl substituted with OH, methyl, or COR.sub.c, where R.sub.c is optionally substituted C.sub.1-C.sub.22 alkyl or optionally substituted C.sub.2-C.sub.22 alkenyl, including for example optionally substituted C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7, C.sub.8, C.sub.9, C.sub.10, C.sub.11, C.sub.12, C.sub.13, C.sub.14, C.sub.15, C.sub.16, C.sub.17, C.sub.18, C.sub.19, C.sub.20, C.sub.21, or C.sub.22 alkyl or C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7, C.sub.S, C.sub.9, C.sub.10, C.sub.11, C.sub.12, C.sub.13, C.sub.14, C.sub.15, C.sub.16, C.sub.17, C.sub.18, C.sub.19, C.sub.20, C.sub.21, or C.sub.22 alkenyl).

As generally defined above, R.sub.4 is hydrogen or unsubstituted C.sub.1-C.sub.4 alkyl. In certain embodiments, R.sub.4 is hydrogen. In certain embodiments, R.sub.4 is unsubstituted C.sub.1, C.sub.2, C.sub.3 or C.sub.4 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, or n-butyl).

[0180] As generally defined above, R.sub.5 is substituted C.sub.1-C.sub.4 alkyl, optionally substituted C.sub.2-C.sub.4 alkenyl, or optionally substituted C.sub.2-C.sub.4 alkynyl. In certain embodiments, R.sub.5 is substituted C.sub.1-C.sub.4 alkyl, and in particular is alkoxy-substituted C.sub.1-C.sub.4 alkyl. In other particular embodiments, R.sub.5 is substituted methyl, and more particularly is alkoxy-substituted methyl (or even more particularly is —CH.sub.2—OR.sub.b, where R.sub.b is C.sub.1-C.sub.4 alkyl, or even still more particularly is —CH.sub.2—OCH.sub.3). In other embodiments, R.sub.5 is optionally substituted C.sub.2-C.sub.4 alkenyl. In other embodiments, R.sub.5 is optionally substituted C.sub.2-C.sub.4 alkynyl.

[0181] As generally defined above, R.sub.6 is hydrogen, optionally substituted C.sub.1-C.sub.4 alkyl, or optionally substituted C.sub.1-C.sub.4 alkoxy. In certain embodiments, R.sub.6 is hydrogen. In certain embodiments, R.sub.6 is optionally substituted C.sub.1, C.sub.2, C.sub.3, or C.sub.4 alkyl (e.g., methyl). In certain embodiments, R.sub.6 is optionally substituted C.sub.1, C.sub.2, C.sub.3 or C.sub.4 alkoxy (e.g., methoxy, ethoxy, n-propyloxy, isopropyloxy, or n-butoxy). In certain embodiments, when R.sub.6 is a non-hydrogen group, R.sub.6 is in the alpha (down) position. In certain preferred embodiments, however, when R.sub.6 is a non-hydrogen group, R.sub.6 is in the beta (up) position.

[0182] As generally defined above, R.sub.7 is hydrogen, optionally substituted C.sub.1-C.sub.4 alkoxy, or an optionally substituted morpholinyl ring. In certain embodiments, R.sub.7 is hydrogen. In certain embodiments, R.sub.7 is optionally substituted C.sub.1, C.sub.2, C.sub.3 or C.sub.4 alkoxy (e.g., methoxy, ethoxy, n-propyloxy, isopropyloxy, or n-butoxy). In certain embodiments, R.sub.7 is an optionally substituted morpholinyl ring. In certain embodiments, when R.sub.7 is a non-hydrogen group, R.sub.7 is in the alpha (down) position. In certain preferred embodiments, however, when R.sub.7 is a non-hydrogen group, R.sub.7 is in the beta (up) position.

As generally defined above, R.sub.8, when present, is hydrogen or optionally substituted C.sub.1-C.sub.4 alkyl. In certain embodiments, R.sub.8 is hydrogen. In certain embodiments, R.sub.8 is C.sub.1, C.sub.2, C.sub.3 or C.sub.4 optionally substituted alkyl (e.g., methyl). In certain embodiments, when R.sub.8 is optionally substituted C.sub.1-C.sub.4 alkyl, R.sub.8 is in the alpha (down) position. In certain embodiments, when R.sub.8 is optionally substituted C.sub.1-C.sub.4 alkyl, R.sub.8 is in the beta (up) position.

[0183] In certain embodiments, R.sub.2 and R.sub.8 are both hydrogen. In certain embodiments, R.sub.2 is OR.sub.a and R.sub.8 is hydrogen.

[0184] As generally defined above, ——— denotes an optional, additional C—C bond, resulting in either a C═C bond between C.sub.4-0.sub.5 or C.sub.s-C.sub.6, with the proviso that when present, the C.sub.5—H substituent is not present. In certain embodiments, the additional C—C bond is absent, and the hydrogen at C.sub.5 is in the alpha or beta position. In certain embodiments, the additional C—C bond is absent, and the hydrogen at C.sub.5 is in the alpha (down) position. In certain embodiments, the additional C—C bond is absent, and the hydrogen at C.sub.5 is in the beta (up) position. In certain embodiments, ——— denotes an additional C—C bond, resulting in a C═C bond between C.sub.4-0.sub.5. In certain embodiments, ——— denotes an additional C—C bond, resulting in a C═C bond between C.sub.5-C.sub.6.

[0185] As generally defined above, ——— denotes an optional, additional C—C bond, resulting in a C═C bond, between C.sub.16-C.sub.17, with the proviso that when present, the R.sub.1 is other than ═O. In certain embodiments, the additional C—C bond is absent (i.e., there is not C═C bond), and therefore R.sub.1 may be in the alpha or beta position. In certain embodiments, the additional C—C bond is absent, and the R.sub.1 is in the alpha (down) position. In certain embodiments, the additional C—C bond is absent, and the R.sub.1 is in the beta (up) position.

[0186] It is to be noted that the present disclosure contemplates and is intended to encompass all of the various combinations and permutations (i.e., combinations of substituent options, locations and stereochemical configurations) possible here.

[0187] For example, in various embodiments, compounds of the present disclosure may be selected from among those encompassed by the structure of Formula (VI), wherein R.sub.2 is ═O; alternatively, R.sub.2 may be hydrogen and R.sub.8 is hydrogen (e.g., C.sub.11 thus having two hydrogen atoms bound thereto as substituents). In certain embodiments, R.sub.2 may be OR.sub.a, wherein R.sub.a is methyl, optionally substituted benzyl, or C.sub.1-C.sub.4 alkyl substituted with O-aryl, such as O-benzyl. In certain embodiments, R.sub.3 may be hydrogen, methyl, trifluoromethyl, or substituted aryl (e.g., substituted phenyl, which in turn may be optionally substituted such as, for example, with OH, methyl, or COR.sub.c, where R.sub.c═C.sub.1-C.sub.4 alkyl); further, when R.sub.3 is something other than hydrogen, R.sub.3 is preferably in the β-position. In certain embodiments, each of R.sub.4 and R.sub.6 are independently selected from hydrogen and methyl, R.sub.5 being in the β-configuration and R.sub.6 optionally being in the a-configuration or β-configuration (e.g., when R.sub.6 is methyl), which the β-configuration being preferred. In certain embodiments, R.sub.7 is selected from hydrogen, methoxy, ethoxy, and an optionally substituted morpholinyl ring; further, when R.sub.7 is something other than hydrogen, R.sub.7 is preferably in the β-position. In certain embodiments, R.sub.8, when present, is selected from hydrogen or optionally substituted C.sub.1-C.sub.4 alkyl. In certain embodiments, R.sub.8 is methyl (e.g., methyl in the alpha-configuration).

[0188] In certain embodiments, the C.sub.5—H is in the alpha configuration and the R.sub.5 is, for example, a substituted methyl group (e.g., alkoxy-substituted methyl, or in particular a methoxy-substituted methyl) in the beta configuration. In certain embodiments, the C5—H is in the beta configuration and R.sub.5 is, for example, a substituted methyl (e.g., a methoxy-substituted methyl) group in the beta configuration. In certain embodiments, R.sub.6 is hydrogen. In certain embodiments, R.sub.4 is methyl. In certain embodiments, R.sub.2 is ═O or methoxy.

[0189] Accordingly, as noted, the steroid of Formula (VI) may encompass a number of various structures in accordance with the present disclosure.

[0190] In certain embodiments, wherein R.sub.1 is as defined above, R.sub.3 is in the beta position, R.sub.4 is methyl, R.sub.5 is substituted methyl in the beta position, and R.sub.6 is hydrogen, provided is a compound of Formula (VI-a):

##STR00035##

or a pharmaceutically acceptable salt thereof, wherein ———, R.sub.2, R.sub.3, R.sub.7 and R.sub.8 are as defined herein, and further wherein R.sub.b is optionally substituted C.sub.1-C.sub.4 alkyl. In certain embodiments, each instance of ——— between C.sub.5-C.sub.6 and C.sub.6-C.sub.7 is absent and C.sub.5—H is in the alpha position. In certain embodiments, each instance of ——— between C.sub.5-C.sub.6 and C.sub.6-C.sub.7 is absent and C.sub.5—H is in the beta position. In certain embodiments, each instance of ——— between C.sub.16-C.sub.17 is absent and R.sub.1 is in the beta position.

[0191] In certain embodiments of Formula (VI), wherein R.sub.2 is ═O and R.sub.8 is absent, provided is a compound of Formula (VI-b):

##STR00036##

or a pharmaceutically acceptable salt thereof, wherein ———, R.sub.3 and R.sub.7 are as defined herein, and further wherein R.sub.b is optionally substituted C.sub.1-C.sub.4 alkyl. In certain embodiments, each instance of ——— between C.sub.5-C.sub.6 and C.sub.6-C.sub.7 is absent and C.sub.5—H is in the alpha position. In certain embodiments, each instance of ——— between C.sub.5-C.sub.6 and C.sub.6-C.sub.7 is absent and C.sub.5—H is in the beta position. In certain embodiments, each instance of ——— between C.sub.16-C.sub.17 is absent and R.sub.1 is in the beta position.

[0192] In certain embodiments of Formula (VI), wherein R.sub.2 and R.sub.8 are hydrogen, provided is a compound of Formula (VI-c):

##STR00037##

or a pharmaceutically acceptable salt thereof, wherein ———, R.sub.2, R.sub.3, and R.sub.7 are as defined herein, and further wherein R.sub.b is optionally substituted C.sub.1-C.sub.4 alkyl. In certain embodiments, each instance of ——— between C.sub.5-C.sub.6 and C.sub.6-C.sub.7 is absent and C.sub.5—H is in the alpha position. In certain embodiments, each instance of ——— between C.sub.5-C.sub.6 and C.sub.6-C.sub.7 is absent and C.sub.5—H is in the beta position. In certain embodiments, each instance of ——— between C.sub.16-C.sub.17 is absent and R.sub.1 is in the beta position.

[0193] In certain embodiments of Formula (VI), wherein R.sub.2 is OR.sub.a and R.sub.8 is hydrogen, provided is a compound of Formula (VI-d):

##STR00038##

or a pharmaceutically acceptable salt thereof, wherein ———, R.sub.3, R.sub.7, and R.sub.a are as defined herein, and further wherein R.sub.b is optionally substituted C.sub.1-C.sub.4 alkyl. In certain embodiments, each instance of ——— between C.sub.5-C.sub.6 and C.sub.6-C.sub.7 is absent and C.sub.5—H is in the alpha position. In certain embodiments, each instance of ——— between C.sub.5-C.sub.6 and C.sub.6-C.sub.7 is absent and C.sub.5—H is in the beta position. In certain embodiments, each instance of ——— between C.sub.16-C.sub.17 is absent and R.sub.1 is in the beta position.

[0194] In certain embodiments of Formula (VI), wherein R.sub.7 is hydrogen, provided is a compound of Formula (VI-e):

##STR00039##

or a pharmaceutically acceptable salt thereof, wherein ———, R.sub.2, R.sub.3, and R.sub.8 are as defined herein, and further wherein R.sub.b is optionally substituted C.sub.1-C.sub.4 alkyl. In certain embodiments, each instance of ——— between C.sub.5-C.sub.6 and C.sub.6-C.sub.7 is absent and C.sub.5—H is in the alpha position. In certain embodiments, each instance of ——— between C.sub.5-C.sub.6 and C.sub.6-C.sub.7 is absent and C.sub.5—H is in the beta position. In certain embodiments, each instance of ——— between C.sub.16-C.sub.17 is absent and R.sub.1 is in the beta position.

[0195] In certain embodiments of Formula (VI), wherein each instance of ——— is absent and C.sub.5—H is in the alpha position, provided is a compound of Formula (VI-f):

##STR00040##

or a pharmaceutically acceptable salt thereof, wherein R.sub.2, R.sub.3, R.sub.7 and R.sub.8 are as defined herein, and further wherein R.sub.b is optionally substituted C.sub.1-C.sub.4 alkyl. In certain embodiments, each instance of ——— between C.sub.16-C.sub.17 is absent and R.sub.1 is in the beta position.

[0196] In certain embodiments of Formula (VI), wherein R.sub.7 is hydrogen, provided is a compound of Formula (VI-g):

##STR00041##

or a pharmaceutically acceptable salt thereof, wherein R.sub.2, R.sub.3, and R.sub.8 are as defined herein, and further wherein R.sub.b is optionally substituted C.sub.1-C.sub.4 alkyl. In certain embodiments, each instance of ——— between C.sub.16-C.sub.17 is absent and R.sub.1 is in the beta position.

[0197] In certain embodiments of Formula (VI), wherein R.sub.2 is ═O, provided is a compound of Formula (VI-h):

##STR00042##

or a pharmaceutically acceptable salt thereof, wherein R.sub.3 and R.sub.7 are as defined herein, and further wherein R.sub.b is optionally substituted C.sub.1-C.sub.4 alkyl. In certain embodiments, each instance of ——— between C.sub.16-C.sub.17 is absent and R.sub.1 is in the beta position.

[0198] In certain embodiments of Formula (VI), wherein R.sub.2 is OR.sub.a, provided is a compound of Formula (VI-i):

##STR00043##

or a pharmaceutically acceptable salt thereof, wherein R.sub.a, R.sub.3, and R.sub.7 are as defined herein, and further wherein R.sub.b is optionally substituted C.sub.1-C.sub.4 alkyl. In certain embodiments, each instance of ——— between C.sub.16-C.sub.17 is absent and R.sub.1 is in the beta position.
In certain embodiments of Formula (VI), wherein ——— represents an additional C—C bond, resulting in a C═C bond between C.sub.4-0.sub.5 provided is a compound of Formula (VI-j):

##STR00044##

##STR00045##

or a pharmaceutically acceptable salt thereof, wherein R.sub.3, R.sub.2, R.sub.7 and R.sub.8 are as defined herein, and further wherein R.sub.b is optionally substituted C.sub.1-C.sub.4 alkyl. In certain embodiments, each instance of ——— between C.sub.16-C.sub.17 is absent and R.sub.1 is in the beta position.
It is to be noted that, in one or more of the preferred embodiments detailed above, R.sub.1 may, in particular, be selected from methoxy (or more generally lower alkoxy, e.g., —O-(C.sub.1-C.sub.4)), or alternatively selected from CH.sub.3C(O)— or HOCH.sub.2C(O)— (or more generally substituted or unsubstituted lower alkyl-carbonyl, e.g., (C.sub.1-C.sub.4)C(O)—, wherein one or more of the carbon atoms is optionally substituted, such as for example by a hydroxyl group). Alternatively, R.sub.1 may be selected from nitro or cyano, with an optional C═C being present between C.sub.16-C.sub.17. In yet another alternative embodiment, C.sub.17 may be a carbonyl carbon (i.e., R.sub.1 is ═O), or it may be part of a oxirane ring fused with the D-ring (i.e., R.sub.1 being a spirooxirane substituent, wherein C.sub.17 is the carbon atom common to both rings).

[0199] Exemplary compounds of Formula (VI) include, but are not limited to, the following:

##STR00046## ##STR00047##

and pharmaceutically acceptable salts thereof, wherein in one preferred embodiment R.sub.b is CH.sub.3. In certain embodiments, the steroid of Formula (VI) is selected from the group consisting of:

##STR00048## ##STR00049##

and pharmaceutically acceptable salts thereof, wherein R.sub.3 is as defined above, and in one particular embodiment is hydrogen, and further wherein in this or another preferred embodiment R.sub.b is CH.sub.3.

[0200] In certain embodiments, the steroid of Formula (VI) is selected from the group consisting of:

##STR00050##

[0201] In certain embodiments, the steroid of Formula (VI) is selected from the group consisting of:

##STR00051##

and a pharmaceutically acceptable salt thereof, wherein R.sub.3 and/or R.sub.1 are as defined above, and in one particular embodiment R.sub.3 is hydrogen and R.sub.1 is methoxy, and further wherein in these or other preferred embodiments R.sub.b is CH.sub.3.

[0202] In certain embodiments, the steroid of Formula (VI) is selected from the group consisting of:

##STR00052##

and a pharmaceutically acceptable salt thereof, wherein R.sub.3 is as defined above, and in one particular embodiment is hydrogen, and further wherein in this or another preferred embodiment R.sub.b is CH.sub.3.

[0203] In certain embodiments, the steroid of Formula (VI) is selected from the group consisting of:

##STR00053##

##STR00054##

or a pharmaceutically acceptable salt thereof, wherein: each of R.sup.2, R.sup.4, R.sup.6, R.sup.7, R.sup.11a and R.sup.11b is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —OR.sup.A1, —SR.sup.A1, —N(R.sup.A1).sub.2, —NHC(═O)R.sup.A1, —S(═O)R.sup.A2, —SO.sub.2R.sup.A2, or —S(═O).sub.2OR.sup.A1, wherein each instance of R.sup.A1 is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R.sup.A1 groups are joined to form an heterocyclic or heteroaryl ring; and R.sup.A2 is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R.sup.11a and R.sup.11b together with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl, or —C(═O)—; R.sup.3 is hydrogen, alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; each of R.sup.17a and R.sup.17b is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —OR.sup.A1, —SR.sup.A1, —N(R.sup.A1).sub.2,—NHC(═O)R.sup.A1—S(═O)R.sup.A2, —SO.sub.2R.sup.A2, or —S(═O).sub.2OR.sup.A1, wherein at least one of R.sup.17a and R.sup.17b is not hydrogen; R.sup.19 is hydrogen or alkyl (e.g., unsubstituted alkyl or substituted alkyl (e.g., —C(R.sup.C).sub.2OR.sup.A1, wherein R.sup.C is hydrogen or alkyl)); R.sup.5 is absent or hydrogen; and custom-character represents a single or double bond, wherein when oneis a double bond, the otheris a single bond and R.sup.5 is absent.

[0205] In some embodiments, R.sup.19 is hydrogen or alkyl. In some embodiments, R.sup.19 is unsubstituted alkyl. In some embodiments, R.sup.19 is substituted alkyl. In some embodiments, R.sup.19 is —CH.sub.2OH, —CH.sub.2OCH.sub.3, —CH.sub.2OCH.sub.2CH.sub.3, or —CH.sub.2OCH(CH.sub.3).sub.2.

[0206] In some embodiments, R.sup.2 is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —OR.sup.A1, —SR.sup.A1, or —N(R.sup.A1).sub.2. In some embodiments, R.sup.2 is hydrogen, halogen, alkyl, or —OR.sup.A1. In some embodiments, R.sup.2 is hydrogen.

[0207] In some embodiments, R.sup.3 is alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl.

[0208] In some embodiments, R.sup.3 is alkyl (e.g., substituted or unsubstituted alkyl). In some embodiments, R.sup.3 is methyl and ethyl (e.g., substituted or unsubstituted alkyl).

[0209] In some embodiments, R.sup.4 is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —OR.sup.A1, —SR.sup.A1, or —N(R.sup.A1).sub.2. In some embodiments, R.sup.4 is hydrogen, halogen, alkyl, or —OR.sup.A1. In some embodiments, R.sup.4 is hydrogen.

[0210] In some embodiments, custom-character represents a single bond and R.sup.5 is hydrogen. In some embodiments, R.sup.5 is absent, and represents a single or double bond, wherein when one is a double bond, the other is a single bond.

[0211] In some embodiments, R.sup.6 is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —OR.sup.A1, —SR.sup.A1, or —N(R.sup.A1).sub.2. In some embodiments, R.sup.6 is hydrogen, halogen, alkyl, or —OR.sup.A1. In some embodiments, R.sup.6 is hydrogen.

[0212] In some embodiments, R.sup.7 is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —OR.sup.A1, —SR.sup.A1, or —N(R.sup.A1).sub.2. In some embodiments, R.sup.7 is hydrogen, halogen, alkyl, or —OR.sup.A1. In some embodiments, R.sup.7 is hydrogen.

[0213] In some embodiments, R.sup.11a is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —OR.sup.A1, —SR.sup.A1, —N(R.sup.A1).sub.2, or R.sup.11a and R.sup.11b together with the carbon atom to which they are attached form C(═O). In some embodiments, R.sup.11a is hydrogen, halogen, alkyl, or —OR.sup.A1. In some embodiments, R.sup.11a and R.sup.11b together with the carbon atom to which they are attached form —C(═O)—. In some embodiments, R.sup.11a and R.sup.11b are hydrogen.

[0214] In some embodiments, each of R.sup.2, R.sup.4, R.sup.6, R.sup.7, R.sup.11a, and R.sup.11b is independently hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —OR.sup.A1, —SR.sup.A1, or —N(R.sup.A1).sub.2. In some embodiments, each of R.sup.2, R.sup.4, R.sup.6, R.sup.7, R.sup.11a and R.sup.11b is independently hydrogen, halogen, alkyl, or —OR.sup.A1. In some embodiments, R.sup.2, R.sup.4, R.sup.6, R.sup.7, R.sup.11a, and R.sup.11b are hydrogen.

[0215] In some embodiments, each of R.sup.17a and R.sup.17b is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, —SR.sup.A1, —N(R.sup.A1).sub.2,—NHC(═O)R.sup.A1—S(═O)R.sup.A2, —SO.sub.2R.sup.A2, or —S(═O).sub.2OR.sup.A1. In some embodiments, each of R.sup.17a and R.sup.17b is independently hydrogen, halogen, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, —SR.sup.A1, —N(R.sup.A1).sub.2,—NHC(═O)R.sup.A1—S(═O)R.sup.A2, —SO.sub.2R.sup.A2, or —S(═O).sub.2OR.sup.A1.

[0216] In some embodiments, R.sup.17a is halogen, cyano, nitro, alkyl, carbocyclyl, heterocyclyl, —OR.sup.A1, —SR.sup.A1, —N(R.sup.A1).sub.2, —NHC(═O)R.sup.A1, —S(═O)R.sup.A2, or —SO.sub.2R.sup.A2. In some embodiments, R.sup.17a is halogen, cyano, nitro, alkyl,—OR.sup.A1, —SR.sup.A1, or —N(R.sup.A1).sub.2. In some embodiments, R.sup.17a is halogen, nitro, alkyl, carbocyclyl, heterocyclyl, —OR.sup.A1, —SR.sup.A1, —N(R.sup.A1).sub.2, —NHC(═O)R.sup.A1, —S(═O)R.sup.A2, or —SO.sub.2R.sup.A2, wherein at least one of R.sup.17a and R.sup.17b is not hydrogen.

[0217] In some embodiments, the compound is:

##STR00055##

or a pharmaceutically acceptable salt thereof.

Methods of Use and Treatment

[0218] The compounds described herein can be used, for example, to treat an injury or disorder in a subject who has been exposed to a chemical warfare agent. In some embodiments, the chemical warfare agent is a nerve agent or toxin. In some embodiments, the injury or disorder is a seizure.

[0219] In an aspect, provided is a method of alleviating or preventing seizure activity in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention. In some embodiments, the method alleviates or prevents epileptogenesis.

[0220] In some embodiments, such compounds are envisioned to be useful as therapeutic agents for treating a CNS-related disorder (e.g., sleep disorder, a mood disorder such as depression, a schizophrenia spectrum disorder, a convulsive disorder, epileptogenesis, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, or tinnitus) in a subject in need (e.g., a subject with Rett syndrome, Fragile X syndrome, or Angelman syndrome). Exemplary CNS conditions related to GABA-modulation include, but are not limited to, sleep disorders [e.g., insomnia], mood disorders [e.g., depression, dysthymic disorder (e.g., mild depression), bipolar disorder (e.g., I and/or II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), compulsive disorders (e.g., obsessive compulsive disorder (OCD))], schizophrenia spectrum disorders [e.g., schizophrenia, schizoaffective disorder], convulsive disorders [e.g., epilepsy (e.g., status epilepticus (SE)), seizures], disorders of memory and/or cognition [e.g., attention disorders (e.g., attention deficit hyperactivity disorder (ADHD)), dementia (e.g., Alzheimer's type dementia, Lewis body type dementia, vascular type dementia], movement disorders [e.g., Huntington's disease, Parkinson's disease], personality disorders [e.g., anti-social personality disorder, obsessive compulsive personality disorder], autism spectrum disorders (ASD) [e.g., autism, monogenetic causes of autism such as synaptophathy's, e.g., Rett syndrome, Fragile X syndrome, Angelman syndrome], pain [e.g., neuropathic pain, injury related pain syndromes, acute pain, chronic pain], traumatic brain injury (TBI), vascular diseases [e.g., stroke, ischemia, vascular malformations], substance abuse disorders and/or withdrawal syndromes [e.g., addition to opiates, cocaine, and/or alcohol], and tinnitus.

[0221] In yet another aspect, provided is a combination of a compound of the present invention and another pharmacologically active agent. The compounds provided herein can be administered as the sole active agent or they can be administered in combination with other agents. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent and alternating administration.

[0222] In another aspect, provided is a method of treating or preventing brain excitability in a subject susceptible to or afflicted with a condition associated with brain excitability, comprising administering to the subject an effective amount of a compound of the present invention to the subject.

[0223] In yet another aspect, provided is a method of treating or preventing stress or anxiety in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention, or a composition thereof.

[0224] In yet another aspect, provided is a method of alleviating or preventing insomnia in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention, or a composition thereof.

[0225] In yet another aspect, provided is a method of inducing sleep and maintaining substantially the level of REM sleep that is found in normal sleep, wherein substantial rebound insomnia is not induced, comprising administering an effective amount of a compound of the present invention.

[0226] In yet another aspect, provided is a method of alleviating or preventing PMS or PND in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention.

[0227] In yet another aspect, provided is a method of treating or preventing mood disorders in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention. In certain embodiments the mood disorder is depression.

[0228] In yet another aspect, provided is a method of cognition enhancement or treating memory disorder by administering to the subject a therapeutically effective amount of a compound of the present invention. In certain embodiments, the disorder is Alzheimer's disease. In certain embodiments, the disorder is Rett syndrome.

[0229] In yet another aspect, provided is a method of treating attention disorders by administering to the subject a therapeutically effective amount of a compound of the present invention. In certain embodiments, the attention disorder is ADHD.

[0230] In certain embodiments, the compound is administered to the subject chronically. In certain embodiments, the compound is administered to the subject orally, subcutaneously, intramuscularly, or intravenously.

Seizure

[0231] The compounds and methods described herein can be used, for example, to treat an injury or disorder in a subject who has been exposed to a chemical warfare agent. In some embodiments, the chemical warfare agent is a nerve agent or toxin. In some embodiments, the injury or disorder is a seizure.

[0232] A seizure is the physical findings or changes in behavior that occur after an episode of abnormal electrical activity in the brain. The term “seizure” is often used interchangeably with “convulsion.” Convulsions are when a person's body shakes rapidly and uncontrollably. During convulsions, the person's muscles contract and relax repeatedly.

[0233] Based on the type of behavior and brain activity, seizures are divided into two broad categories: generalized and partial (also called local or focal). Classifying the type of seizure helps doctors diagnose whether or not a patient has epilepsy.

[0234] Generalized seizures are produced by electrical impulses from throughout the entire brain, whereas partial seizures are produced (at least initially) by electrical impulses in a relatively small part of the brain. The part of the brain generating the seizures is sometimes called the focus.

[0235] There are six types of generalized seizures. The most common and dramatic, and therefore the most well known, is the generalized convulsion, also called the grand-mal seizure. In this type of seizure, the patient loses consciousness and usually collapses. The loss of consciousness is followed by generalized body stiffening (called the “tonic” phase of the seizure) for 30 to 60 seconds, then by violent jerking (the “clonic” phase) for 30 to 60 seconds, after which the patient goes into a deep sleep (the “postictal” or after-seizure phase). During grand-mal seizures, injuries and accidents may occur, such as tongue biting and urinary incontinence.

[0236] Absence seizures cause a short loss of consciousness (just a few seconds) with few or no symptoms. The patient, most often a child, typically interrupts an activity and stares blankly. These seizures begin and end abruptly and may occur several times a day. Patients are usually not aware that they are having a seizure, except that they may be aware of “losing time.”

[0237] Myoclonic seizures consist of sporadic jerks, usually on both sides of the body. Patients sometimes describe the jerks as brief electrical shocks. When violent, these seizures may result in dropping or involuntarily throwing objects.

[0238] Clonic seizures are repetitive, rhythmic jerks that involve both sides of the body at the same time.

[0239] Tonic seizures are characterized by stiffening of the muscles.

[0240] Atonic seizures consist of a sudden and general loss of muscle tone, particularly in the arms and legs, which often results in a fall.

[0241] Seizures described herein can include epileptic seizures; acute repetitive seizures; cluster seizures; continuous seizures; unremitting seizures; prolonged seizures; recurrent seizures; status epilepticus seizures, e.g., refractory convulsive status epilepticus, non-convulsive status epilepticus seizures; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondarily generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign Rolandic seizures; febrile seizures; emotional seizures; focal seizures; gelastic seizures; generalized onset seizures; infantile spasms; Jacksonian seizures; massive bilateral myoclonus seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post traumatic seizures; subtle seizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures.

[0242] In some embodiments, the seizure is induced by a warfare agent (e.g., a chemical warfare agent). For example, in some embodiments, the seizure is induced by a nerve agent or toxin.

Epilepsy

[0243] Epilepsy is a brain disorder characterized by repeated seizures over time. Types of epilepsy can include, but are not limited to generalized epilepsy, e.g., childhood absence epilepsy, juvenile nyoclonic epilepsy, epilepsy with grand-mal seizures on awakening, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, e.g., temporal lobe epilepsy, frontal lobe epilepsy, benign focal epilepsy of childhood.

Status Epilepticus (SE)

[0244] Status epilepticus (SE) can include, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epileptic seizures, and can include early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus. Early status epilepticus is treated with a first line therapy. Established status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line therapy, and a second line therapy is administered. Refractory status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line and a second line therapy, and a general anesthetic is generally administered. Super refractory status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line therapy, a second line therapy, and a general anesthetic for 24 hours or more.

[0245] Non-convulsive status epilepticus can include, e.g., focal non-convulsive status epilepticus, e.g., complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, subtle non-convulsive status epilepticus; generalized non-convulsive status epilepticus, e.g., late onset absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus.

[0246] Compositions described herein can also be administered as a prophylactic to a subject having a CNS disorder e.g., a traumatic brain injury, status epilepticus, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges; prior to the onset of a seizure.

Epileptogenesis

[0247] The compounds and methods described herein can be used to treat or prevent epileptogenesis. Epileptogenesis is a gradual process by which a normal brain develops epilepsy (a chronic condition in which seizures occur). Epileptogenesis results from neuronal damage precipitated by the initial insult (e.g., status epilepticus).

Anxiety Disorders

[0248] Anxiety disorder is a blanket term covering several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders.

[0249] Generalized anxiety disorder is a common chronic disorder characterized by long-lasting anxiety that is not focused on any one object or situation. Those suffering from generalized anxiety experience non-specific persistent fear and worry and become overly concerned with everyday matters. Generalized anxiety disorder is the most common anxiety disorder to affect older adults.

[0250] In panic disorder, a person suffers from brief attacks of intense terror and apprehension, often marked by trembling, shaking, confusion, dizziness, nausea, difficulty breathing. These panic attacks, defined by the APA as fear or discomfort that abruptly arises and peaks in less than ten minutes, can last for several hours and can be triggered by stress, fear, or even exercise; although the specific cause is not always apparent. In addition to recurrent unexpected panic attacks, a diagnosis of panic disorder also requires that said attacks have chronic consequences: either worry over the attacks' potential implications, persistent fear of future attacks, or significant changes in behavior related to the attacks. Accordingly, those suffering from panic disorder experience symptoms even outside of specific panic episodes. Often, normal changes in heartbeat are noticed by a panic sufferer, leading them to think something is wrong with their heart or they are about to have another panic attack. In some cases, a heightened awareness (hypervigilance) of body functioning occurs during panic attacks, wherein any perceived physiological change is interpreted as a possible life threatening illness (i.e. extreme hypochondriasis).

[0251] Obsessive compulsive disorder is a type of anxiety disorder primarily characterized by repetitive obsessions (distressing, persistent, and intrusive thoughts or images) and compulsions (urges to perform specific acts or rituals). The OCD thought pattern may be likened to superstitions insofar as it involves a belief in a causative relationship where, in reality, one does not exist. Often the process is entirely illogical; for example, the compulsion of walking in a certain pattern may be employed to alleviate the obsession of impending harm. And in many cases, the compulsion is entirely inexplicable, simply an urge to complete a ritual triggered by nervousness. In a minority of cases, sufferers of OCD may only experience obsessions, with no overt compulsions; a much smaller number of sufferers experience only compulsions.

[0252] The single largest category of anxiety disorders is that of Phobia, which includes all cases in which fear and anxiety is triggered by a specific stimulus or situation. Sufferers typically anticipate terrifying consequences from encountering the object of their fear, which can be anything from an animal to a location to a bodily fluid.

[0253] Post-traumatic stress disorder or PTSD is an anxiety disorder which results from a traumatic experience. Post-traumatic stress can result from an extreme situation, such as combat, rape, hostage situations, or even serious accident. It can also result from long term (chronic) exposure to a severe stressor, for example soldiers who endure individual battles but cannot cope with continuous combat. Common symptoms include flashbacks, avoidant behaviors, and depression.

Neurodegenerative Diseases and Disorders

[0254] The term “neurodegenerative disease” includes diseases and disorders that are associated with the progressive loss of structure or function of neurons, or death of neurons. Neurodegenerative diseases and disorders include, but are not limited to, Alzheimer's disease (including the associated symptoms of mild, moderate, or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic injuries; ataxia and convulsion (including for the treatment and prevention and prevention of seizures that are caused by schizoaffective disorder or by drugs used to treat schizophrenia); benign forgetfulness; brain edema; cerebellar ataxia including McLeod neuroacanthocytosis syndrome (MLS); closed head injury; coma; contusive injuries (e.g., spinal cord injury and head injury); dementias including multi-infarct dementia and senile dementia; disturbances of consciousness; Down syndrome; drug-induced or medication-induced Parkinsonism (such as neuroleptic-induced acute akathisia, acute dystonia, Parkinsonism, or tardive dyskinesia, neuroleptic malignant syndrome, or medication-induced postural tremor); epilepsy; fragile X syndrome; Gilles de la Tourette's syndrome; head trauma; hearing impairment and loss; Huntington's disease; Lennox syndrome; levodopa-induced dyskinesia; mental retardation; movement disorders including akinesias and akinetic (rigid) syndromes (including basal ganglia calcification, corticobasal degeneration, multiple system atrophy, Parkinsonism-ALS dementia complex, Parkinson's disease, postencephalitic parkinsonism, and progressively supranuclear palsy); muscular spasms and disorders associated with muscular spasticity or weakness including chorea (such as benign hereditary chorea, drug-induced chorea, hemiballism, Huntington's disease, neuroacanthocytosis, Sydenham's chorea, and symptomatic chorea), dyskinesia (including tics such as complex tics, simple tics, and symptomatic tics), myoclonus (including generalized myoclonus and focal cyloclonus), tremor (such as rest tremor, postural tremor, and intention tremor) and dystonia (including axial dystonia, dystonic writer's cramp, hemiplegic dystonia, paroxysmal dystonia, and focal dystonia such as blepharospasm, oromandibular dystonia, and spasmodic dysphonia and torticollis); neuronal damage including ocular damage, retinopathy or macular degeneration of the eye; neurotoxic injury which follows cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest; Parkinson's disease; seizure; status epilecticus; stroke; tinnitus; tubular sclerosis, and viral infection induced neurodegeneration (e.g., caused by acquired immunodeficiency syndrome (AIDS) and encephalopathies). Neurodegenerative diseases also include, but are not limited to, neurotoxic injury which follows cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest. Methods of treating or preventing a neurodegenerative disease also include treating or preventing loss of neuronal function characteristic of neurodegenerative disorder.

Pharmaceutical Compositions

[0255] In one aspect, the invention provides a pharmaceutical composition comprising a compound of the present invention (also referred to as the “active ingredient”) and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of the active ingredient.

[0256] The pharmaceutical compositions provided herein can be administered by a variety of routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration.

[0257] Generally, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0258] When used to prevent the onset of a CNS-disorder, the compounds provided herein will be administered to a subject at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Subjects at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.

[0259] The pharmaceutical compositions provided herein can also be administered chronically (“chronic administration”). Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc, or may be continued indefinitely, for example, for the rest of the subject's life. In certain embodiments, the chronic administration is intended to provide a constant level of the compound in the blood, e.g., within the therapeutic window over the extended period of time.

[0260] The pharmaceutical compositions of the present invention may be further delivered using a variety of dosing methods. For example, in certain embodiments, the pharmaceutical composition may be given as a bolus, e.g., in order to raise the concentration of the compound in the blood to an effective level. The placement of the bolus dose depends on the systemic levels of the active ingredient desired throughout the body, e.g., an intramuscular or subcutaneous bolus dose allows a slow release of the active ingredient, while a bolus delivered directly to the veins (e.g., through an IV drip) allows a much faster delivery which quickly raises the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, e.g., by IV drip, to provide maintenance of a steady-state concentration of the active ingredient in the subject's body. Furthermore, in still yet other embodiments, the pharmaceutical composition may be administered as first as a bolus dose, followed by continuous infusion.

[0261] The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or excipients and processing aids helpful for forming the desired dosing form.

[0262] With oral dosing, one to five and especially two to four and typically three oral doses per day are representative regimens. Using these dosing patterns, each dose provides from about 0.01 to about 20 mg/kg of the compound provided herein, with preferred doses each providing from about 0.1 to about 10 mg/kg, and especially about 1 to about 5 mg/kg.

[0263] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses, generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.

[0264] Injection dose levels range from about 0.1 mg/kg/hour to at least 20 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 5 g/day for a 40 to 80 kg human patient.

[0265] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0266] Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable excipients known in the art. As before, the active compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable excipient and the like.

[0267] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s). When formulated as a ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or Formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.

[0268] The compounds provided herein can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

[0269] The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pa., which is incorporated herein by reference.

[0270] The compounds of the present invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0271] The present invention also relates to the pharmaceutically acceptable acid addition salt of a compound of the present invention. The acid which may be used to prepare the pharmaceutically acceptable salt is that which forms a non-toxic acid addition salt, i.e., a salt containing pharmacologically acceptable anions such as the hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like.

[0272] In another aspect, the invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, e.g., a composition suitable for injection, such as for intravenous (IV) administration.

[0273] Pharmaceutically acceptable excipients include any and all diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, preservatives, lubricants and the like, as suited to the particular dosage form desired, e.g., injection. General considerations in the formulation and/or manufacture of pharmaceutical compositions agents can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21.sup.st Edition (Lippincott Williams & Wilkins, 2005).

[0274] For example, injectable preparations, such as sterile injectable aqueous suspensions, can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. Exemplary excipients that can be employed include, but are not limited to, water, sterile saline or phosphate-buffered saline, or Ringer's solution.

[0275] In certain embodiments, the pharmaceutical composition further comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β- and γ-cyclodextrins consisting of 6, 7 and 8 α-1 ,4linked glucose units, respectively, optionally comprising one or more substituents on the linked sugar moieties, which include, but are not limited to, substituted or unsubstituted methylated, hydroxyalkylated, acylated, and sulfoalkylether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, e.g., for example, sulfobutyl ether β-cyclodextrin, also known as Captisol®. See, e.g., U.S. Pat. No. 5,376,645. In certain embodiments, the composition comprises hexapropyl-β-cyclodextrin. In a more particular embodiment, the composition comprises hexapropyl-β-cyclodextrin (10-50% in water).

[0276] The injectable composition can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0277] Generally, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, response of the individual patient, the severity of the patient's symptoms, and the like.

[0278] The compositions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions. In such compositions, the compound is usually a minor component (from about 0.1% to about 50% by weight or preferably from about 1% to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.

[0279] The compounds provided herein can be administered as the sole active agent, or they can be administered in combination with other active agents. In one aspect, the present invention provides a combination of a compound of the present invention and another pharmacologically active agent. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent, and alternating administration.

[0280] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation. General considerations in the formulation and/or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21.sup.st ed., Lippincott Williams & Wilkins, 2005.

Equivalents and Scope

[0281] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0282] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0283] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0284] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

COMPOUNDS AND METHODS OF THEIR USE

Inventors

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A61P25/08

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A61K9/0019

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A61K31/57

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A61K31/569

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A61P25/28

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A61P25/22

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A61K31/5685

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A61K31/568

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A61K31/573

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A61K31/58

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A61K31/569

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A61K31/568

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A61K31/5685

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A61K31/573

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A61K31/58

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A61K9/00

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A61P25/08

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A61P25/22

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A61P25/28

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Abstract

Claims

Description