Dihydro[1,4]oxazino[2,3,4-hi]indazole derivatives as 5-hydroxytryptamine-6 ligands

The present invention provides a compound of formula I and the use thereof for the treatment of a central nervous system disorder related to or affected by the 5-HT6 receptor.

1-SUBSTITUTED-3-(NAPHTHALEN-1-YLSULFONYL)-5-(PIPERAZIN-1-YL)-1H-INDAZOLE COMPOUNDS AS 5-HYDROXYTRYPTAMINE-6 LIGANDS

The disclosure is directed to compounds of Formula I: processes for their preparation, treatment of central nervous system (CNS) disorders and methods for the modulation of 5HT6 activity.

NEUROACTIVE STEROIDS, COMPOSITIONS, AND USES THEREOF

Described herein are steroids of Formula (I): 2. The method of claim 1 , wherein Ris methyl.3. The method of claim 1 , wherein both Rand Rare hydrogen.4. The method of claim 1 , wherein Ris C-Calkyl claim 1 , C-Calkenyl claim 1 , C-Calkynyl claim 1 , carbocyclyl claim 1 , heterocyclyl claim 1 , C(O)R claim 1 , —C(O)OR claim 1 , or —C(O)NRR.5. The method of claim 4 , wherein Ris —C(O)NRR.6. The method of claim 1 , wherein Ris hydrogen claim 1 , C-Calkyl claim 1 , or —OH.7. The method of claim 6 , wherein Ris hydrogen.8. The method of claim 1 , wherein both Rand Rare hydrogen claim 1 , the between —CRand —CRRis a single bond claim 1 , and both Rand Rare hydrogen.9. The method of claim 1 , wherein Z is —CH—.10. The method of claim 1 , wherein Ris hydrogen and Ris C-Calkyl.12. The method of claim 11 , wherein Ris methyl.13. The method of claim 11 , wherein Ris C-Calkyl claim 11 , C-Calkenyl claim 11 , C-Calkynyl claim 11 , carbocyclyl claim 11 , heterocyclyl claim 11 , —C(O)R claim 11 , —C(O)OR claim 11 , or —C(O)NRR.14. The method of claim 11 , wherein Ris C-Calkyl.15. The method of claim 11 , wherein Ris hydrogen.16. The method of claim 11 , wherein both Rand Rare hydrogen and both Rand Rare hydrogen.19. The method of claim 18 , wherein Ris methyl.20. The method of claim 18 , wherein Ris C-Calkyl claim 18 , C-Calkenyl claim 18 , C-Calkynyl claim 18 , carbocyclyl claim 18 , heterocyclyl claim 18 , —C(O)R claim 18 , —C(O)OR claim 18 , or —C(O)NRR.21. The method of claim 18 , wherein Ris C-Calkyl.22. The method of claim 20 , wherein Ris —C(O)NRR.23. The method of claim 18 , wherein Ris —OH.24. The method of claim 18 , wherein Ris hydrogen.25. The method of claim 18 , wherein both Rand Rare hydrogen and both Rand Rare hydrogen.27. The method of claim 1 , wherein the CNS-related disorder is a sleep disorder claim 1 , a mood disorder claim 1 , a schizophrenia spectrum disorder claim 1 , a convulsive disorder claim 1 , a disorder of memory and/or cognition claim 1 , a ...

Oxysterols and methods of use thereof

Compounds are provided according to Formula (I): ,R R2 R R' ' R Formula (I) and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R1, R2, R3, R6, R, R 8, and n are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.

Oxysterols and methods of use thereof

Compounds are provided according to Formula (A): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R1, R2, R3, R4, R5, R6, and RG are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.

Compositions and methods for treating CNS disorders

Described herein are neuroactive steroids of the Formula (II): or a pharmaceutically acceptable salt thereof; wherein A, R1, R2a, R2b, R3a, R3b, R4a, R4b, R5, R6and are as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. The present invention also provides pharmaceutical compositions comprising a compound of the present invention and methods of use and treatment, e.g., such for inducing sedation and/or anesthesia.

Sulfonyl-3-heterocyclylindazole derivatives as 5-hydroxytryptamine-6 ligands

The present invention provides a compound of formula I and the use thereof for the treatment of a central nervous system disorder related to or affected by the 5-HT6 receptor.

19-NOR neuroactive steroids and methods of use thereof

Provided herein are 3,3-disubstituted 19-nor-steroidal compounds according to Formula (I): and pharmaceutical compositions thereof. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, disorders of memory and/or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, tinnitus, and status epilepticus.

OXYSTEROLS AND METHODS OF USE THEREOF

Compounds are provided according to Formula (I): Formula (I) and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, wherein R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , and n are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.

OXYSTEROLS AND METHODS OF USE THEREOF

Compounds are provided according to Formula (I): 144-. (canceled)47. The method according to claim 46 , wherein the disorder is inflammatory bowel disease.48. The method according to claim 46 , wherein the disorder is diabetes.49. The method according to claim 46 , wherein the disorder is colitis.51. The method according to claim 50 , wherein the disorder is sterol synthesis disorder.52. The method according to claim 50 , wherein the disorder is a cognitive disorder.53. The method according to claim 50 , wherein the disorder is a mood disorder. This application is a Continuation Application of U.S. National Phase application Ser. No. 15/319,504 filed Dec. 16, 2016, which is a National Phase Application under 35 U.S.C. § 371 of International Application No. PCT/US2015/036510 filed Jun. 18, 2015, which claims priority to U.S. Provisional Application No. 62/014,014 filed Jun. 18, 2014, and U.S. Provisional Application No. 62/107,236 filed Jan. 23, 2015, the entire contents of which are incorporated herein by reference.NMDA receptors are heteromeric complexes comprised of NR1, NR2, and/or NR3 subunits and possess distinct recognition sites for exogenous and endogenous ligands. These recognition sites include binding sites for glycine, and glutamate agonists and modulators. NMDA receptors are expressed in the peripheral tissues and the CNS, where they are involved in excitatory synaptic transmission. Activating these receptors contributes to synaptic plasticity in some circumstances and excitotoxicity in others. These receptors are ligand-gated ion channels that admit Ca2+ after binding of the glutamate and glycine, and are fundamental to excitatory neurotransmission and normal CNS function. Positive modulators may be useful as therapeutic agents with potential clinical uses as cognitive enhancers and in the treatment of psychiatric disorders in which glutamatergic transmission is reduced or defective (see, e.g., Horak et al., J. of Neuroscience, 2004, 24(46), 10318- ...

19-NOR NEUROACTIVE STEROIDS AND METHODS OF USE THEREOF

Provided herein are 3,3-disubstituted 19-nor-steroidal compounds according to Formula (I): 3. (canceled)6. The method of claim 5 , wherein Ris substituted or unsubstituted hydrogen claim 5 , substituted or unsubstituted Calkyl claim 5 , —C(═O)R claim 5 , —C(═O)OR claim 5 , —C(═O)N(R) claim 5 , or —S(═O)R.9. The method of claim 1 , wherein e is 1.10. The method of claim 1 , wherein Ris substituted or unsubstituted Calkyl.11. The method of claim 1 , wherein Ris —CH.12. The method of claim 1 , wherein Ris ORwherein Ris hydrogen or substituted or unsubstituted Calkyl.13. The method of claim 1 , wherein Ris OH.14. The method of claim 1 , wherein Ris —S(═O)Rwherein Ris substituted or unsubstituted Calkyl.15. The method of claim 1 , wherein Ris —S(═O)CH.16. The method of claim 1 , wherein Ris —C(═O) Rwherein Ris substituted or unsubstituted Calkyl.17. The method of claim 1 , wherein Ris —C(═O)CH.18. The method of claim 1 , wherein Ris —C(═O)N(R)wherein Ris hydrogen or substituted or unsubstituted Calkyl.19. The method of claim 1 , wherein Ris —C(═O)NHCH.20. The method of claim 1 , wherein between C5 and C6 is a double bond and Ris absent.21. The method of claim 1 , wherein between C5 and C6 is a single bond.23. (canceled)24. (canceled)25. The method of claim 1 , wherein the CNS-related disorder is a sleep disorder claim 1 , a mood disorder claim 1 , a schizophrenia spectrum disorder claim 1 , a convulsive disorder claim 1 , a disorder of memory and/or cognition claim 1 , a movement disorder claim 1 , a personality disorder claim 1 , autism spectrum disorder claim 1 , pain claim 1 , traumatic brain injury claim 1 , a vascular disease claim 1 , a substance abuse disorder and/or withdrawal syndrome claim 1 , tinnitus claim 1 , or status epilepticus.26. The method of claim 1 , wherein the compound is administered orally claim 1 , subcutaneously claim 1 , intravenously claim 1 , or intramuscularly.27. The method of claim 1 , wherein the compound is administered chronically.28. ...

NEUROACTIVE STEROIDS, COMPOSITIONS, AND USES THEREOF

Described herein are neuroactive steroids of the Formula (I): or a pharmaceutically acceptable salt thereof; wherein -------, R, R, R, A and L are as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. The present invention also provides pharmaceutical compositions comprising a compound of the present invention and methods of use and treatment, e.g., such for inducing sedation and/or anesthesia. 213-. (canceled)15. (canceled)16. The compound of claim 14 , wherein n is 0.1722-. (canceled)23. The compound of claim 14 , wherein Ris C-Calkyl.2425-. (canceled)2829-. (canceled)32. The compound of claim 27 , wherein A is monocyclic.33. The compound of claim 27 , wherein A is bicyclic.3436-. (canceled)37. The compound of claim 27 , wherein A is a 5-membered or 6-membered heteroaryl or heterocyclyl comprising 1 claim 27 , 2 claim 27 , 3 claim 27 , or 4 nitrogen atoms.38. (canceled)39. The compound of claim 37 , wherein A is morpholine or piperazine.4041-. (canceled)42. The compound of claim 27 , wherein the heteroaryl is benzotriazole claim 27 , azabenzotriazole claim 27 , diazabenzotriazole claim 27 , benzopyrazole claim 27 , azabenzopyrazole claim 27 , or diazabenzopyrazole.4345-. (canceled)46. The compound of claim 37 , wherein A is pyrazole claim 37 , triazole claim 37 , or tetrazole.47. The compound of claim 27 , wherein Ris C-Calkyl claim 27 , C-Calkenyl claim 27 , C-Calkynyl claim 27 , carbocyclyl claim 27 , or heterocyclyl.48. (canceled)49. The compound of claim 47 , wherein Ris methyl claim 47 , ethyl claim 47 , or isopropyl.50. (canceled)51. The compound of claim 27 , wherein Ris methyl.52. The compound of claim 27 , wherein n is 0.53. The compound of claim 27 , wherein n is 1 or 2 claim 27 , and Ris cyano claim 27 , halo claim 27 , C-Calkyl claim 27 , C-Calkoxy claim 27 , —C(O)R claim 27 , or —S(O)R.5459-. (canceled)60. The compound of claim 53 , wherein Ris C-Calkyl.61. The compound of claim 60 , wherein Ris methyl ...

Compositions and methods for treating CNS disorders

Described herein are neuroactive steroids of the Formula (I): or a pharmaceutically acceptable said thereof; wherein, R1, R2a, R2b, R3and A are as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. The present invention also provides pharmaceutical compositions comprising a compound of the present invention and methods of use and treatment, e.g., such for inducing sedation and/or anesthesia.

NEUROACTIVE STEROIDS, COMPOSITIONS, AND USES THEREOF

... and wherein L1, L2, L3, X1, X2, Y, RZ4, RZ5, RZ6, n, R1, R2, R3a, R3b, R4a, R4b, R6a, R6b, R7a, R7b, R11a, R11b, R14, R17, R19, R20, R23a, R23b, and R24 are as defined herein, and pharmaceutical compositions thereof. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of CNS-related conditions in mammals.

OXYSTEROLS AND METHODS OF USE THEREOF

Compounds are provided according to Formula (I): Formula (I) and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R, R, R, R, R, R, and n are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions. 2. (canceled)3. The compound of claim 1 , wherein Ris methyl claim 1 , substituted alkyl selected from the group consisting of CHF claim 1 , —CF claim 1 , —CHOCH claim 1 , or —CHOCHCH claim 1 , ethyl claim 1 , or isopropyl.4. The compound of claim 3 , wherein Ris methyl or ethyl.5. The compound of claim 1 , wherein each of Rand Ris dependently hydrogen claim 1 , Calkyl claim 1 , or carbocyclyl claim 1 , or wherein Rand Rare taken together with the carbon atom to which they are attached form a 3-8 membered ring.6. The compound of claim 5 , wherein the 3-8 membered ring is a carbocyclyl ring (e.g. claim 5 , cyclopropyl).7. (canceled)8. The compound of claim 5 , wherein each of Rand Ris independently hydrogen claim 5 , substituted or unsubstituted methyl claim 5 , substituted or unsubstituted ethyl claim 5 , propyl claim 5 , isopropyl claim 5 , cyclopropyl claim 5 , or butyl.9. (canceled)10. (canceled)11. The compound of claim 5 , wherein Ris hydrogen and Ris Calkyl.12. The compound of claim 5 , wherein Ris Calkyl and Ris Calkyl.13. (canceled)14. The compound of claim 1 , wherein Rand Rare hydrogen.15. The compound of claim 1 , wherein n is 1.16. The compound of claim 1 , wherein n is 1 and Rand Rare hydrogen.1746-. (canceled)48. A pharmaceutical composition comprising a compound of claim 1 , or pharmaceutically acceptable salt thereof claim 1 , and a pharmaceutically acceptable carrier.49. A method of inducing sedation or anesthesia comprising administering to a subject an effective amount of a compound of claim 1 , or pharmaceutically acceptable salt thereof claim 1 , or pharmaceutical composition thereof.50. A method for treating or preventing a ...

NEUROACTIVE STEROIDS, COMPOSITIONS, AND USES THEREOF

Described herein are steroids of Formula (I): and pharmaceutically acceptable salts thereof; wherein R1, R2a, R2b, R3, R4, R5a, R5b, R6, and Z are as defined herein. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, convulsive disorders, disorders of memory and/or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, and tinnitus.

19-nor neuroactive steroids and methods of use thereof

Provided herein are 3,3-disubstituted 19-nor-steroidal compounds according to Formula (I): and pharmaceutical compositions thereof. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, disorders of memory and/or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, tinnitus, status epilepticus.

Amino-pyridines as inhibitors of -secretase

The present invention provides an amino-pyridine compound of formula I The present invention also provides methods for the use thereof to inhibit -secretase (BACE) and treat -amyloid deposits and neurofibrillary tangles.

COMPOSITIONS AND METHODS FOR TREATING CNS DISORDERS

Described herein are neuroactive steroids of the Formula (I): 173-. (canceled)75. A pharmaceutical composition comprising the compound of and a pharmaceutically acceptable excipient.77. A pharmaceutical composition comprising the compound of and a pharmaceutically acceptable excipient.79. A pharmaceutical composition comprising the compound of and a pharmaceutically acceptable excipient.80. A pharmaceutically acceptable salt of the compound according to claim 78 , claim 78 , or .81. A pharmaceutical composition comprising a pharmaceutically acceptable salt according to and a pharmaceutically acceptable excipient. This application is a continuation of U.S. Ser. No. 15/519,480 filed Apr. 14, 2017, which is a U.S. National Stage Application filed under 35 U.S.C. § 371 of International Patent Application No. PCT/US2015/056054, filed Oct. 16, 2015, which claims priority to U.S. Provisional Application No. 62/064,961, filed Oct. 16, 2014, the entire contents of which are incorporated herein by reference.Brain excitability is defined as the level of arousal of an animal, a continuum that ranges from coma to convulsions, and is regulated by various neurotransmitters. In general, neurotransmitters are responsible for regulating the conductance of ions across neuronal membranes. At rest, the neuronal membrane possesses a potential (or membrane voltage) of approximately −70 mV, the cell interior being negative with respect to the cell exterior. The potential (voltage) is the result of ion (K, Na, Cl, organic anions) balance across the neuronal semipermeable membrane. Neurotransmitters are stored in presynaptic vesicles and are released under the influence of neuronal action potentials. When released into the synaptic cleft, an excitatory chemical transmitter such as acetylcholine will cause membrane depolarization, e.g., a change of potential from −70 mV to −50 mV. This effect is mediated by postsynaptic nicotinic receptors which are stimulated by acetylcholine to increase ...

Dihydro[1,4]oxazino[2,3,4-hi]indazole derivatives as 5-hydroxytryptamine-6 ligands and use thereof in the treatment of attention deficit disorders

The present invention provides a compound of formula I and the use thereof for the treatment of a central nervous system disorder related to or affected by the 5-HT6 receptor ...

Compositions and methods for treating CNS disorders

Described herein are neuroactive steroids of the Formula (I):or a pharmaceutically acceptable salt thereof; wherein , A, R1, R2, and R3 are as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. The present invention also provides pharmaceutical compositions comprising a compound of the present invention and methods of use, e.g., for treating a subject suffering from a disease or disorder described herein.

19-NOR C3, 3-DISUBSTITUTED C21-N-PYRAZOLYL STEROIDS AND METHODS OF USE THEREOF

Provided herein are 19-nor C3,3-disubstituted C21-pyrazolyl steroids of Formula (I): 147-. (canceled)49. The method of claim 48 , wherein the compound is administered orally claim 48 , subcutaneously claim 48 , intravenously claim 48 , or intramuscularly.50. The method of claim 48 , wherein the compound is administered chronically.51. The method of claim 49 , wherein the compound is administered orally.52. The method of claim 49 , wherein the compound is administered intravenously.54. The method of claim 53 , wherein the compound is administered orally claim 53 , subcutaneously claim 53 , intravenously claim 53 , or intramuscularly.55. The method of claim 53 , wherein the compound is administered chronically.56. The method of claim 54 , wherein the compound is administered orally.57. The method of claim 54 , wherein the compound is administered intravenously.59. The method of claim 58 , wherein the pharmaceutical composition is administered orally claim 58 , subcutaneously claim 58 , intravenously claim 58 , or intramuscularly.60. The method of claim 58 , wherein the pharmaceutical composition is administered chronically.61. The method of claim 59 , wherein the pharmaceutical composition is administered orally.62. The method of claim 59 , wherein the pharmaceutical composition is administered intravenously. This application is a divisional of U.S. Ser. No. 16/020,641 filed Jun. 27, 2018, which is a divisional of U.S. Ser. No. 15/297,845 filed Oct. 19, 2016, which is a divisional of U.S. Ser. No. 14/785,171, which issued as U.S. Pat. No. 9,512,165, filed Oct. 16, 2015, which is a national stage application under U.S.C. § 371 of International Application No. PCT/CN2014/075594, filed Apr. 17, 2014, published as International Publication No. WO2014/169833 on Oct. 23, 2014, which claims priority to International Application No. PCT/CN2013/074323, filed Apr. 17, 2013, the contents of each of which is incorporated herein by reference in its entirety.Brain excitability is ...

AMINO-5-(6-MEMBERED)HETEROARYLIMIDAZOLONE COMPOUNDS AND THE USE THEREOF FOR BETA-SECRETASE MODULATION

The present invention provides a 2-amino-5-heteroaryl-5-phenylimidazolone compound of formula I The present invention also provides methods for the use thereof to inhibit β-secretase (BACE) and treat β-amyloid deposits and neurofibrillary tangles ...

Amino-5-[4-(difluoromethoxy)phenyl]-5-phenylimidazolone compounds for the inhibition of beta-secretase

The present invention provides a 2-amino-5-[4-(difluoromethoxy)phenyl]-5-phenylimidazolone compound of formula I The present invention also provides methods for the use thereof to inhibit beta-secretase (BACE) and treat beta-amyloid deposits and neurofibrillary tangles.

OXYSTEROLS AND METHODS OF USE THEREOF

Compounds are provided according to Formula (I): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, wherein R2, R3, R4, R5, and and R6are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.

NEUROACTIVE STEROID SOLUTIONS AND THEIR METHODS OF USE

Provided herein are pharmaceutically acceptable aqueous solution comprising a neuroactive steroid, a sulfobutyl ether beta cyclodextrin and a buffer; wherein: the solution is a stable solution between a pH of about 3 and about 9, e.g., at room temperature, for at least 1, 2, 3, 4 weeks; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months; 1, 2, 3 years or more; the buffer is present at a concentration of at least 0.1 mM; or the solution remains substantially free of impurities (e.g., the solution is substantially free of impurities at room temperature for at least 1, 2, 3, 4 weeks; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months; 1, 2, 3 years or more). 184-. (canceled)86. The method of claim 85 , wherein the assaying comprises analysis using HPLC.88. The method of claim 85 , wherein the composition further comprises a buffer.89. The method of claim 88 , wherein the buffer is a citrate buffer.90. The method of claim 88 , wherein the buffer in the composition is present at a concentration of from about 0.1 to about 20 mM.91. The method of claim 85 , wherein the composition comprises about 5 mg/mL of allopregnanolone.92. The method of claim 85 , wherein the composition comprises about 250 mg/mL of sulfo butyl ether beta cyclodextrin.93. The method of claim 85 , wherein the composition comprises about 5 mg/mL of allopregnanolone and about 250 mg/mL of sulfo butyl ether beta cyclodextrin. This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 62/181,550 filed Jun. 18, 2015, the entire contents of which are incorporated herein by reference.Homogeneous solutions (e.g., aqueous solutions) comprising a therapeutic agent, e.g., a neuroactive steroid described herein, enable administration to a human subject in need by various modes of administration (e.g., oral, parenteral (e.g., intravenous, intramuscular, subcutaneous) delivery). Neuroactive steroids are typically highly lipophilic compounds with low intrinsic water solubility. Particularly for ...

Amino-5-[4-(difluoromethoxy)phenyl]-5-phenylimidazolone Compounds For The Inhibition Of Beta-secretase

The present invention provides compounds and methods for the use thereof to inhibit -secretase (BACE) and treat -amyloid deposits and neurofibrillary tangles.

NEUROACTIVE 19-ALKOXY-17-SUBSTITUTED STEROIDS, PRODRUGS THEREOF, AND METHODS OF TREATMENT USING SAME

The present disclosure is generally directed to neuroactive 19-alkoxy-17-substituted steroids as referenced herein, and pharmaceutically acceptable salts thereof, for use as, for example, an anesthetic, and/or in the treatment of disorders relating to GABA function and activity. The present disclosure is further directed to pharmaceutical compositions comprising such compounds. 153-. (canceled)55. The compound of claim 54 , wherein the Rgroup is selected from the group consisting of H claim 54 , methyl claim 54 , and trifluoromethyl.56. The compound of claim 54 , wherein Ris selected from the group consisting of H claim 54 , methoxy claim 54 , ethoxy claim 54 , and an optionally substituted morpholinyl ring.57. The compound of claim 54 , wherein Ris H.58. The compound of claim 54 , wherein each instance of - - - between C-Cand C-Cis absent and C—H is in the alpha position.59. The compound of claim 54 , wherein each instance of - - - between C-Cand C-Cis absent and C—H is in the beta position.60. The compound of claim 54 , wherein each instance of - - - between C-Cis absent and Ris in the beta position.61. The compound of claim 54 , wherein Ris ═O claim 54 , methoxy or H.62. The compound of claim 54 , wherein Ris methyl.63. The compound of claim 54 , wherein Ris beta-methoxy.64. The compound of claim 54 , wherein Ris beta-spirooxirane.65. The compound of claim 54 , wherein Ris beta-cyano.66. The compound of claim 54 , wherein Ris ═O.67. The compound of claim 54 , wherein Ris beta-nitro.68. The compound of claim 54 , wherein Ris beta-CHC(O)—.69. The compound of claim 54 , wherein Ris beta-HOCHC(O)—.73. The method of claim 72 , wherein the disorder is selected from the group consisting of insomnia claim 72 , mood disorders claim 72 , convulsive disorders claim 72 , anxiety claim 72 , or symptoms of ethanol withdrawal. This application is a continuation application and claims priority to U.S. patent application Ser. No. 15/459,492, filed on Mar. 15, 2017, which claims ...

19-nor C3, 3-disubstituted C21-N-pyrazolyl steroids and methods of use thereof

Provided herein are 19-nor C3,3-disubstituted C21-pyrazolyl steroids of Formula (I): and pharmaceutically acceptable salts thereof; wherein , R1, R2, R3a, R3b, R4a, R4b, R5, R6, and R7are as defined herein. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, convulsive disorders, disorders of memory and/or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, and tinnitus.

Neuroactive steroids, compositions, and uses thereof

Described herein are steroids of Formula (I):and pharmaceutically acceptable salts thereof; wherein R1, R2a, R2b, R3, R4, R5a, R5b, R6 and Z are as defined herein. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, convulsive disorders, disorders of memory and/or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, and tinnitus.

OXYSTEROLS AND METHODS OF USE THEREOF

Compounds are provided according to Formula (I): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R2, R3, R4, R5, and R6 are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.

COMPOSITIONS AND METHODS FOR TREATING CNS DISORDERS

Provided herein is a compound of Formula (I) 2. The compound of claim 1 , wherein Ris C-Calkyl substituted with 0-7 independent occurrences of deuterium or X—OX claim 1 , wherein Xis C-Calkylene substituted with 0-7 independent occurrences of deuterium and Xis C-Calkylene substituted with 0-7 independent occurrences of deuterium.3. The compound of or claim 1 , wherein if Ris —CH claim 1 , then at least one of R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , and Ris deuterium claim 1 , or if all of R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , and Rare hydrogen claim 1 , then Ris a methyl group substituted with 1-3 independent occurrences of deuterium.4. The compound of claim 1 , wherein Ris selected from the group consisting of —CHand CD.5. The compound of or claim 1 , wherein Ris —CH.6. The compound of or claim 1 , wherein Ris —CD.7. The compound any one of - claim 1 , wherein at least one of R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , and Ris deuterium.8. The compound of claim any one of - claim 1 , wherein at least one of R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , and Ris deuterium.9. The compound of any one of - claim 1 , wherein Ris —CHand at least one of R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , and Ris deuterium.10. The compound of any one of - claim 1 , wherein Ris —CHand at least one of R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , and Ris deuterium.11. The compound of any one of - claim 1 , wherein Rand Rare hydrogen.12. ...

OXYSTEROLS AND METHODS OF USE THEREOF

Compounds are provided according to Formula (III) and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R, R, R, and n are as defined herein, and at least one hydrogen is replaced with a deuterium. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions. 2. The compound of claim 1 , wherein Ris hydrogen.3. The compound of claim 1 , wherein Ris deuterium.4. The compound of claim 1 , wherein Rand Rare deuterium.5. The compound of claim 1 , wherein one of Rand Ris deuterium and the other of Rand Ris Calkyl.6. The compound of claim 1 , wherein each of Rand Ris independently —Calkyl.7. The compound of claim 1 , wherein each of Rand Ris independently isopropyl claim 1 , —CH claim 1 , or —CF.8. The compound of claim 1 , wherein Ris hydrogen.911-. (canceled)1719-. (canceled)20. A method for treating or preventing a disorder claim 1 , the method comprising administering to a subject in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein the disorder is a gastrointestinal (GI) disorder claim 1 , irritable bowel syndrome (IBS) claim 1 , inflammatory bowel disease (IBD) claim 1 , structural disorders affecting the GI claim 1 , anal disorders claim 1 , colon polyps claim 1 , cancer claim 1 , or colitis.21. The method according to claim 20 , wherein the disorder is inflammatory bowel disease.22. The method according to claim 20 , wherein the disorder is cancer claim 20 , diabetes claim 20 , or a sterol synthesis disorder.23. A method for treating or preventing a CNS-related condition comprising administering to a subject in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.24. The method according to claim 23 , wherein the CNS-related condition is an adjustment disorder claim 23 , anxiety disorder claim 23 , cognitive disorder claim 23 , dissociative ...

3,3 DISUBSTITUTED 19-NOR PREGNANE COMPOUNDS, COMPOSITIONS, AND USES THEREOF

Provided herein are 3,3-disubstituted 19-nor-steroidal compounds according to Formula (I) and (III): 2. (canceled)3. The compound of claim 1 , wherein Ris hydrogen.4. The compound of claim 1 , wherein Ris —OR.56-. (canceled)824-. (canceled)26. (canceled)27. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 , or a pharmaceutically acceptable salt thereof. This application is a division of U.S. Ser. No. 15/681,983 filed Aug. 21, 2017, which is a continuation of U.S. Ser. No. 14/351,449 filed Apr. 11, 2014, which is a national stage application under 35 U.S.C. § 371 of International Application No. PCT/US2012/060136 filed Oct. 12, 2012, published as International Publication No. WO2013/056181 on Apr. 18, 2013, which claims priority under 35 U.S.C. § 119(e) to U.S. provisional patent applications, U.S. Ser. No. 61/547,291, filed Oct. 14, 2011 and U.S. Ser. No. 61/698,204, filed Sep. 7, 2012, each of which is incorporated herein by reference.Brain excitability is defined as the level of arousal of an animal, a continuum that ranges from coma to convulsions, and is regulated by various neurotransmitters. In general, neurotransmitters are responsible for regulating the conductance of ions across neuronal membranes. At rest, the neuronal membrane possesses a potential (or membrane voltage) of approximately −70 mV, the cell interior being negative with respect to the cell exterior. The potential (voltage) is the result of ion (K, Na, Cl, organic anions) balance across the neuronal semipermeable membrane. Neurotransmitters are stored in presynaptic vesicles and are released under the influence of neuronal action potentials. When released into the synaptic cleft, an excitatory chemical transmitter such as acetylcholine will cause membrane depolarization (change of potential from −70 mV to −50 mV). This effect is mediated by postsynaptic nicotinic receptors which are stimulated by acetylcholine to increase membrane ...

NEUROACTIVE STEROIDS, COMPOSITIONS, AND USES THEREOF

Described herein are steroids of Formula (I): and pharmaceutically acceptable salts thereof; wherein R 1 , R 2a , R 2b , R 3 , R 4 , R 5a , R 5b , R 6 , and Z are as defined herein. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, convulsive disorders, disorders of memory and/or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, and tinnitus.

NEUROACTIVE STEROIDS, COMPOSITIONS, AND USES THEREOF

Described herein are neuro-active steroids of the Formula (I): (I) or a pharmaceutically acceptable salt thereof; wherein R, R, R, G, X, Y, Z, and n are as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. Also provided are pharmaceutical compositions comprising a compound described herein and methods of use and treatment, e.g., such for inducing sedation and/or anesthesia. 166-. (canceled)68. The method of claim 67 , wherein Ris C-Calkyl.69. The method of claim 68 , wherein Ris —CH claim 68 , —CHCH claim 68 , or —CH(CH).70. The method of claim 67 , wherein Ris C-Calkyl.71. The method of claim 70 , wherein Ris —CH.72. The method of claim 67 , wherein each of Rand Ris independently —H or -D.73. The method of claim 67 , wherein each of Rand Ris independently —H.74. The method of claim 67 , wherein one of Rand Ris —H claim 67 , -D claim 67 , or C-Calkyl claim 67 , and the other of Rand Ris —H.76. The method of claim 75 , wherein X is N claim 75 , and Y and Z are CH.77. The method of claim 75 , wherein X and Z are N claim 75 , and Y is CH.78. The method of claim 75 , wherein X claim 75 , Y claim 75 , and Z are N.79. The method of claim 75 , wherein Ris C-Calkyl.80. The method of claim 75 , wherein Ris C-Calkyl.81. The method of claim 75 , wherein each of Rand Ris independently —H or -D.82. The method of claim 75 , wherein one of Rand Ris —H claim 75 , -D claim 75 , or C-Calkyl claim 75 , and the other of Rand Ris —H.83. The method of claim 75 , wherein one of Rand Ris -D or C-Calkyl claim 75 , and the other of Rand Ris —H.84. The method of claim 75 , wherein n is 1.85. The method of claim 75 , wherein Ris C-Calkyl or C-Calkoxy.86. The method of claim 75 , wherein Ris —S(O)R claim 75 , —NRR claim 75 , —C(O)R claim 75 , or —C(O)OR.87. The method of claim 75 , wherein Ris halogen.88. The method of claim 75 , wherein n is 1 or 2 claim 75 , and Ris cyano claim 75 , halogen claim 75 , nitro claim 75 , or C-Calkoxy.91. The ...

Oxysterols and methods of use thereof

Compounds are provided according to Formula (I) and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R1, R2, R3, R4, R5, and R8are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.

NEUROACTIVE STEROIDS, COMPOSITIONS, AND USES THEREOF

Provided herein are 19-nor C3, 3-disubstituted steroids of Formula (I): and pharmaceutically acceptable salts thereof; wherein R1, R2, R3, and R4are as defined herein, and A is a heteroaryl ring system comprising 3 or 4 nitrogens as defined herein. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, convulsive disorders, disorders of memory and/or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, and tinnitus.

DIHYDRO[1,4]OXAZINO[2,3,4-hi]INDAZOLE DERIVATIVES AS 5-HYDROXYTRYPTAMINE-6 LIGANDS

The present invention provides a compound of formula I and the use thereof for the treatment of a central nervous system disorder related to or affected by the 5-HT6 receptor.

Substituted-dihydro[1,4]oxazino[2,3,4-hi]indazole derivatives as 5-hydroxytryptamine-6 ligands

The present invention provides a compound of formula I and the use thereof for the treatment of a central nervous system disorder related to or affected by the 5-HT6 receptor.

C7 substituted oxysterols and methods of use thereof

Compounds are provided according to Formula (A): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R1A, R1b, n, R2A, R2b, R3, and R4 are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.

COMPOSITIONS AND METHODS FOR TREATING CNS DISORDERS

Provided herein is a compound of Formula (I-I), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I-I), and methods of using the compounds, e.g. in the treatment of CNS-related disorders. 3. The compound of or , wherein Rand Ris each independently hydrogen , halogen , cyano , hydroxyl , substituted or unsubstituted alkyl , substituted or unsubstituted alkenyl , substituted or unsubstituted heterocyclyl , or substituted or unsubstituted alkynyl , —OR , —OC(═O)R , —NH , —N(R) , or —NRC(═O)R , wherein each instance of Ris independently hydrogen , substituted or unsubstituted alkyl , substituted or unsubstituted alkenyl , substituted or unsubstituted alkynyl , substituted or unsubstituted carbocyclyl , substituted or unsubstituted heterocyclyl , substituted or unsubstituted aryl , or substituted or unsubstituted heteroaryl.4. The compound of any one of - , wherein Rand Ris each independently hydrogen , halogen , cyano , hydroxyl , substituted or unsubstituted alkyl , substituted or unsubstituted alkenyl , —OR , —OC(═O)R , —NH , or —N(R) , wherein each instance of Ris independently hydrogen , substituted or unsubstituted alkyl , substituted or unsubstituted carbocyclyl , substituted or unsubstituted heterocyclyl , substituted or unsubstituted aryl , or substituted or unsubstituted heteroaryl.5. The compound of any one of - , wherein Rand Ris each independently hydrogen , substituted or unsubstituted alkyl , —OR , —OC(═O)R , —NH , —N(R) , or —NRC(═O)R , wherein each instance of Ris independently hydrogen , substituted or unsubstituted alkyl , substituted or unsubstituted carbocyclyl , substituted or unsubstituted heterocyclyl , substituted or unsubstituted aryl , or substituted or unsubstituted heteroaryl.6. The compound of any one of - , wherein Rand Rare both hydrogen.7. The compound of any one of - , wherein Rand Ris each independently hydrogen ...

COMPOSITIONS AND METHODS FOR TREATING CNS DISORDERS

Described herein are deuterium-enriched neuroactive steroids of the Formula (II) or a pharmaceutically acceptable salt thereof; wherein R2a, R2b, R3, R4a, R4b, R5, R6a, R6b, R11a, R11b, R12a, R12b, R16a, R16b, R17, R19, Ra, and Rband subvariables thereof are as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. The present invention also provides pharmaceutical compositions comprising a compound of the present invention and methods of use and treatment.

NEUROACTIVE 19-ALKOXY-17-SUBSTITUTED STEROIDS, PRODRUGS THEREOF, AND METHODS OF TREATMENT USING SAME

The present disclosure is generally directed to neuroactive 19-alkoxy-17-substituted steroids as referenced herein, and pharmaceutically acceptable salts thereof, for use as, for example, an anesthetic, and/or in the treatment of disorders relating to GABA function and activity. The present disclosure is further directed to pharmaceutical compositions comprising such compounds. 2. The method of claim 1 , wherein the R3 group is selected from the group consisting of H claim 1 , methyl claim 1 , and trifluoromethyl.3. The method of claim 1 , wherein R7 is H.4. The method of claim 1 , wherein R5 is substituted methyl.5. The method of claim 1 , wherein the C5-H is in the alpha position.6. The method of claim 1 , wherein the C5-H is in the beta configuration and R5 group is in the beta configuration.7. The method of claim 1 , wherein R6 is H.8. The method of claim 1 , wherein R2 is ═O claim 1 , methoxy or H.9. The method of claim 1 , wherein R4 is methyl.11. The method of claim 10 , wherein Rb is methyl.12. The method of claim 10 , wherein R1 is beta-methoxy.13. The method of claim 10 , wherein R1 is beta-cyano.14. The method of claim 10 , wherein R1 is ═O.15. The method of claim 10 , wherein R1 is beta-CH3C(O)—.16. The method of claim 10 , wherein R1 is beta-HOCH2C(O)—.18. The method of claim 17 , wherein Rb is methyl.20. The method of claim 1 , wherein the disorder is selected from the group consisting of insomnia claim 1 , mood disorders claim 1 , convulsive disorders claim 1 , anxiety claim 1 , or symptoms of ethanol withdrawal. This application is a divisional of U.S. patent application Ser. No. 14/652,717, filed on Jun. 16, 2015, which is a U.S. National Stage Application based on International Patent Application No. PCT/US2013/076214, filed on Dec. 18, 2013, which claims priority benefit of U.S. Provisional Patent Application Ser. No. 61/738,822, filed on Dec. 18, 2012, the entire contents of which are incorporated herein by reference.The invention was made with ...

OXYSTEROLS AND METHODS OF USE THEREOF

Compounds are provided according to Formula (I) and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R, R, R, R, R, and Rare as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions. 3. The compound of claim 1 , wherein Rand Rare not both hydrogen.4. (canceled)5. (canceled)6. The compound of claim 1 , wherein each of Rand Ris independently hydrogen claim 1 , —P(O)(R) claim 1 , —S(O)R claim 1 , —C(O)R claim 1 , —C(O)OR claim 1 , —C(O)N(R) claim 1 , —(CH)C(O)N(R) claim 1 , —(CH)OP(O)(R) claim 1 , —(CH)OS(O)R claim 1 , —(CH)OC(O)R claim 1 , or —(CH)C(O)OR;{'sup': a', 'b', 'd, 'each of Rand Ris independently selected from —ORor alkyl;'}{'sup': 'c', 'sub': 2', '2', '2', '2', '2', '3', '2', '2', '2', '2', '3', '2, 'each Ris independently alkyl (e.g., —CHNH, —CHCHCOH, —CH(CH(CH))NH, —CHCHC(O)OH, or —CH(CH)NH);'}{'sup': 'd', 'each Ris independently hydrogen or alkyl;'}each x is independently 1 or 2; andeach of n, m, p is independently 1, 2, 3, or 4.7. (canceled)8. The compound of claim 1 , wherein Ris Calkyl (e.g. claim 1 , substituted or unsubstituted Calkyl).9. (canceled)10. The compound of claim 8 , wherein Ris hydrogen claim 8 , methyl (e.g. claim 8 , —CH claim 8 , —CFor —CHOCH) claim 8 , ethyl claim 8 , or isopropyl.11. (canceled)12. The compound of claim 1 , wherein each of Rand Ris independently hydrogen claim 1 , methyl (e.g. claim 1 , —CH claim 1 , —CF) claim 1 , ethyl claim 1 , isopropyl claim 1 , cyclopropyl claim 1 , or butyl.13. The compound of claim 1 , wherein Ris a moiety cleavable under biological conditions and Ris hydrogen.14. The compound of claim 1 , wherein Ris hydrogen and Ris a moiety cleavable under biological conditions.15. The compound of claim 1 , wherein each of Rand Ris a moiety cleavable under biological conditions.16. (canceled)17. The compound of claim 16 , wherein when Ris hydrogen and Ris —S(O)Rand x is 2 claim 16 , ...

COMPOSITIONS AND METHODS FOR TREATING CNS DISORDERS

Provided herein is a deuterated compound of Formula (I) Formula (I) or a pharmaceutically acceptable salt thereof, wherein R, R, R, R, R, R, Rb, R, R, R, R, R, R, R, R, R, R, R, R2, R, R, and Rare defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I) and methods of using the compounds, e.g., in the treatment of CNS-related disorders.

OXYSTEROLS AND METHODS OF USE THEREOF

Compounds are provided according to Formula (I), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein A, R, and Rare as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions. 4. The compound of claim 2 , wherein p is an integer selected from 0 claim 2 , 1 claim 2 , or 2.5. The compound of claim 2 , wherein p is 0.6. The compound of claim 2 , wherein p is 1.7. The compound of claim 2 , wherein p is 1 and X is halogen.9. The compound of claim 2 , wherein Ris Calkyl.10. The compound of claim 9 , wherein Ris methyl or ethyl.11. (canceled)14. The compound of claim 2 , wherein Z is —C(R)— claim 2 , —O— claim 2 , or —NR—.15. The compound of claim 2 , wherein Ris halogen.16. The compound of claim 2 , wherein Z is —CH— claim 2 , —CF— claim 2 , or —C(CH)—.17. The compound of claim 2 , wherein Z is —O— or —NR—.18. The compound of claim 2 , wherein Z is —NH— claim 2 , —NMe- claim 2 , or —NAc—.19. The compound of claim 2 , wherein Z is —CH—.20. The compound of claim 2 , wherein Z is —C(CH)—.21. The compound of claim 2 , wherein Z is —CF—.22. The compound of claim 2 , wherein m is 1 claim 2 , n is 2 claim 2 , and Z is —O—.23. The compound of claim 2 , wherein m is 2 and n is 2.24. The compound of claim 2 , wherein m is 3 and n is 1.25. The compound of claim 2 , wherein m is 3 claim 2 , n is 1 claim 2 , and Z is —O—.26. The compound of claim 2 , wherein m is 2 claim 2 , n is 2 claim 2 , and Z is —O— or —NR—.29. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutically acceptable carrier.30. A method of inducing sedation or anesthesia comprising administering to a subject an effective amount of a compound according to or pharmaceutical composition thereof.31. A method for treating or preventing a disorder described herein claim 1 , comprising administering to a subject in need thereof an effective amount of a compound ...

AZACYCLYLBENZAMIDE DERIVATIVES AS HISTAMINE-3 ANTAGONISTS

The present invention provides a compound of formula I and the use thereof for the treatment of a central nervous system disorder related to or affected by the histamine-3 receptor

Oxysterols and methods of use thereof

Compounds are provided according to Formula (III): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R2, R3, R5, and n are as defined herein, and at least one hydrogen is replaced with a deuterium. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.

COMPOSITIONS AND METHODS FOR TREATING CNS DISORDERS

Provided herein is a compound of Formula (I-I) or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I-I), and methods of using the compounds, e.g., in the treatment of CNS-related disorders.

NEUROACTIVE STERIODS, COMPOSITIONS, AND USES THEREOF

Provided herein are 19-nor C3,3-disubstituted steroids of Formula (I): 134-. (canceled) This application is a continuation of U.S. Ser. No. 15/314,565 filed Nov. 29, 2016, which is a national stage application under 35 U.S.C. § 371 of International Application No. PCT/CN2015/080216, filed May 29, 2015, published as International Publication No. WO2015/180679 on Dec. 3, 2015, which claims priority to international application No. PCT/CN2014/078820, filed May 29, 2014, the entire contents of each of which are incorporated herein by reference in their entirety.Brain excitability is defined as the level of arousal of an animal, a continuum that ranges from coma to convulsions, and is regulated by various neurotransmitters. In general, neurotransmitters are responsible for regulating the conductance of ions across neuronal membranes. At rest, the neuronal membrane possesses a potential (or membrane voltage) of approximately −70 mV, the cell interior being negative with respect to the cell exterior. The potential (voltage) is the result of ion (K, Na, Cl, organic anions) balance across the neuronal semipermeable membrane. Neurotransmitters are stored in presynaptic vesicles and are released under the influence of neuronal action potentials. When released into the synaptic cleft, an excitatory chemical transmitter such as acetylcholine will cause membrane depolarization (change of potential from −70 mV to −50 mV). This effect is mediated by postsynaptic nicotinic receptors which are stimulated by acetylcholine to increase membrane permeability to Na ions. The reduced membrane potential stimulates neuronal excitability in the form of a postsynaptic action potential.In the case of the GABA receptor complex (GRC), the effect on brain excitability is mediated by GABA, a neurotransmitter. GABA has a profound influence on overall brain excitability because up to 40% of the neurons in the brain utilize GABA as a neurotransmitter. GABA regulates the excitability of individual ...

19-nor C3, 3-disubstituted C21-N-pyrazolyl steroids and methods of use thereof

Provided herein are 19-nor C3,3-disubstituted C21-pyrazolyl steroids of Formula (I), and pharmaceutically acceptable salts thereof; wherein, R1, R2, R3a, R3b, R4a, R4b, R5, R6, and R7are as defined herein. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, convulsive disorders, disorders of memory and/or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, and tinnitus.

COMPOSITIONS AND METHODS FOR TREATING CNS DISORDERS

Described herein are neuroactive steroids of the Formula (II): or a pharmaceutically acceptable salt thereof; wherein A, R, R, R, R, R, R, R, R, Rand are as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. The present invention also provides pharmaceutical compositions comprising a compound of the present invention and methods of use and treatment, e. g., such for inducing sedation and/or anesthesia. 164-. (canceled)74. The method of claim 66 , wherein A is a 5-10-membered ring.75. The compound of claim 74 , wherein A is phenyl claim 74 , naphthyl claim 74 , furan claim 74 , thiophene claim 74 , thiazole claim 74 , pyrrole claim 74 , imidazole claim 74 , pyrazole claim 74 , or triazole.77. The method of claim 65 , wherein the CNS-related disorder is a sleep disorder claim 65 , a mood disorder claim 65 , a schizophrenia spectrum disorder claim 65 , a convulsive disorder claim 65 , a disorder of memory claim 65 , a disorder of cognition claim 65 , a movement disorder claim 65 , a personality disorder claim 65 , autism spectrum disorder claim 65 , pain claim 65 , traumatic brain injury claim 65 , a vascular disease claim 65 , a substance abuse disorder claim 65 , a substance abuse withdrawal syndrome claim 65 , a neurodegenerative disorder claim 65 , or tinnitus.78. The method of claim 77 , wherein the CNS-related disorder is tremor.79. The method of claim 78 , wherein the tremor is essential tremor.80. The method of claim 66 , wherein the CNS-related disorder is a sleep disorder claim 66 , a mood disorder claim 66 , a schizophrenia spectrum disorder claim 66 , a convulsive disorder claim 66 , a disorder of memory claim 66 , a disorder of cognition claim 66 , a movement disorder claim 66 , a personality disorder claim 66 , autism spectrum disorder claim 66 , pain claim 66 , traumatic brain injury claim 66 , a vascular disease claim 66 , a substance abuse disorder claim 66 , a substance abuse withdrawal syndrome claim ...

AZACYCLYLISOQUINOLINONE AND ISOINDOLINONE DERIVATIVES AS HISTAMINE-3 ANTAGONISTS

The present invention provides a compound of formula I and the use thereof for the treatment of a central nervous system disorder related to or affected by the histamine-3 receptor.

OXYSTEROLS AND METHODS OF USE THEREOF

Compounds are provided according to Formula (I): Formula (I) and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, wherein R1, R2, R3, R6, R7, R8, and n are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.

N-substituted-azacyclylamines as histamine-3 antagonists

The present invention provides a compound of formula I and the use thereof for the treatment of a central nervous system disorder related to or affected by the histamine-3 receptor.

COMPOSITIONS AND METHODS FOR TREATING CNS DISORDERS

Described herein are neuroactive steroids of the Formula (I): or a pharmaceutically acceptable salt thereof, wherein , A, R 1 , R 2 , R 3a , R 4a , R 4b , R 5 , R 7a , and R 7b are as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. The present invention also provides pharmaceutical compositions comprising a compound of the present invention and methods of use and treatment, e.g., such for inducing sedation and/or anesthesia.

19-nor C3, 3-disubstituted C21-C-bound heteroaryl steroids and methods of use thereof

Provided herein are 19-nor C3,3-disubstituted steroids of Formula (I): and pharmaceutically acceptable salts thereof; wherein, , R1, R2, R3a, R3b, R4a, and R4bare as defined herein, and A is a carbon bound substituted or unsubstituted 5-to6-membered heteroaryl ring as defined herein. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, convulsive disorders, disorders of memory and/or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, and tinnitus.

19-NOR NEUROACTIVE STEROIDS AND METHODS OF USE THEREOF

Provided herein are 3,3-disubstituted 19-nor-steroidal compounds according to Formula (1): and pharmaceutical compositions thereof. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, disorders of memory and/or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, tinnitus, and status epilepticus. 237-. (canceled)39. The method of claim 38 , wherein the CNS-related disorder is a sleep disorder claim 38 , a mood disorder claim 38 , a schizophrenia spectrum disorder claim 38 , a convulsive disorder claim 38 , a disorder of memory and/or cognition claim 38 , a movement disorder claim 38 , a personality disorder claim 38 , autism spectrum disorder claim 38 , pain claim 38 , traumatic brain injury claim 38 , a vascular disease claim 38 , a substance abuse disorder and/or withdrawal syndrome claim 38 , tinnitus claim 38 , or status epilepticus.40. The method of or wherein the compound is administered orally claim 38 , subcutaneously claim 38 , intravenously claim 38 , or intramuscularly.41. The method of or wherein the compound is administered chronically. Brain excitability is defined as the level of arousal of an animal, a continuum that ranges from coma to convulsions, and is regulated by various neurotransmitters. In general, neurotransmitters are responsible for regulating the conductance of ions across neuronal membranes. At rest, the neuronal membrane possesses a potential (or membrane voltage) of approximately −70 mV, the cell interior being negative with respect to the cell exterior. The potential (voltage) is the result of ion (K, Na, Cl, organic anions) balance across the neuronal semipermeable membrane.Neurotransmitters are stored in presynaptic vesicles and are released under the ...

Oxysterols and methods of use thereof

Compounds are provided according to Formula (I): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein X, Y, R1, R2a, R2b, R4a, R4b, R5a, R5b, R6a, R6b, R7, and R8are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.

ISOQUINOLINYL AND ISOINDOLINYL DERIVATIVES AS HISTAMINE-3 ANTAGONISTS

The present invention provides a compound of formula I and the use thereof for the treatment of a central nervous system disorder related to or affected by the histamine-3 receptor.

19-NOR NEUROACTIVE STEROIDS AND METHODS OF USE THEREOF

Provided herein are 3,3-disubstituted 19-nor-steroidal compounds according to Formula (1): and pharmaceutical compositions thereof. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, disorders of memory and/or cognition, movement disorders, personality disorders, autism spectrum disorders, pain,traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, tinnitus, and status epilepticus. 141-. (canceled)60. The method of claim 42 , wherein the method is a method of treating a sleep disorder.61. The method of claim 60 , wherein the sleep disorder is insomnia.62. The method of claim 42 , wherein the method is a method of treating a mood disorder.63. The method of claim 42 , wherein the mood disorder is depression.64. The method of claim 63 , wherein the depression is postnatal depression.65. The method of claim 64 , wherein the compound or pharmaceutical composition is administered orally. Brain excitability is defined as the level of arousal of an animal, a continuum that ranges from coma to convulsions, and is regulated by various neurotransmitters. In general, neurotransmitters are responsible for regulating the conductance of ions across neuronal membranes. At rest, the neuronal membrane possesses a potential (or membrane voltage) of approximately −70 mV, the cell interior being negative with respect to the cell exterior. The potential (voltage) is the result of ion (K, Na, organic anions) balance across the neuronal semipermeable membrane. Neurotransmitters are stored in presynaptic vesicles and are released under the influence of neuronal action potentials. When released into the synaptic cleft, an excitatory chemical transmitter such as acetylcholine will cause membrane depolarization (change of potential from −70 mV to −50 mV). This effect is mediated by postsynaptic ...

Neuroactive steroids and methods of use thereof

Compounds are provided according to Formula (I):and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R1, R2, R3a, R3b, R4, R5a, R5b, R6a, and R6b are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of CNS-related conditions.

C7 substituted oxysterols and methods of use thereof

Compounds are provided according to Formula (A): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R1A, R1B, n, R2A, R2B, R3, and R4are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.

19-NOR NEUROACTIVE STEROIDS AND METHODS OF USE THEREOF

Provided herein are 3,3-disubstituted 19-nor-steroidal compounds according to Formula (I): and pharmaceutical compositions thereof. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, disorders of memory and/or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, tinnitus, and status epilepticus. 2. (canceled)2434-. (canceled)37. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.38. A method for treating a CNS-related disorder in a subject in need thereof claim 1 , comprising administering to the subject an effective amount of a compound claim 1 , or a pharmaceutically acceptable salt thereof.39. The method of claim 38 , wherein the CNS-related disorder is a sleep disorder claim 38 , a mood disorder claim 38 , a schizophrenia spectrum disorder claim 38 , a convulsive disorder claim 38 , a disorder of memory and/or cognition claim 38 , a movement disorder claim 38 , a personality disorder claim 38 , autism spectrum disorder claim 38 , pain claim 38 , traumatic brain injury claim 38 , a vascular disease claim 38 , a substance abuse disorder and/or withdrawal syndrome claim 38 , tinnitus claim 38 , or status epilepticus.4041-. (canceled) Brain excitability is defined as the level of arousal of an animal, a continuum that ranges from coma to convulsions, and is regulated by various neurotransmitters. In general, neurotransmitters are responsible for regulating the conductance of ions across neuronal membranes. At rest, the neuronal membrane possesses a potential (or membrane voltage) of approximately −70 mV, the cell interior being negative with respect to the cell exterior. The potential ( ...

C7, C12, AND C16 SUBSTITUTED NEUROACTIVE STEROIDS AND THEIR METHODS OF USE

Described herein are neuroactive steroids of Formula (I), Formula (V), or Formula (IX) or a pharmaceutically acceptable salt thereof; wherein each instance of R, R, R, R, R, R, R, R, R, R, R, R, and are as herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. Also provided are pharmaceutical compositions comprising a compound described herein and methods of use and treatment, e.g., such as for inducing sedation and/or anesthesia. 25-. (canceled)62. The compound of claim , wherein Ris C-Calkyl.7. (canceled)9. (canceled)10. The compound of claim 8 , wherein Ris —CH claim 8 , —CHCH claim 8 , —OH claim 8 , —OCH claim 8 , or —CHOCH.11. The compound of claim 8 , wherein Ris —OCH claim 8 , —CN claim 8 , or —C(O)CH.12. (canceled)13. The compound of claim 8 , wherein Ris —C(O)CHR.1417-. (canceled)1931-. (canceled)3335-. (canceled)36. The compound of wherein Ris C-Calkyl.37. (canceled)39. (canceled)40. The compound of claim 38 , wherein Ris —CH claim 38 , —CHCH claim 38 , —OH claim 38 , —OCH claim 38 , or —CHOCH.41. The compound of claim 38 , wherein Ris —OCH claim 38 , —CN claim 38 , or —C(O)CH.42. (canceled)43. The compound of claim 38 , wherein Ris —C(O)CHR.4447-. (canceled)4957-. (canceled)59. (canceled)60. (canceled)61. The compound of claim 58 , wherein Ris C-Calkyl.62. (canceled)64. (canceled)65. The compound of claim 63 , wherein Ris —CH claim 63 , —CHCH claim 63 , —OH claim 63 , —OCH claim 63 , or —CHOCH.66. The compound of claim 63 , wherein Ris —OCH claim 63 , —CN claim 63 , or —C(O)CH.67. (canceled)68. The compound of claim 63 , wherein Ris —C(O)CHR.6972-. (canceled)7481-. (canceled)84. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable excipient.8599-. (canceled)100. A composition for use in treating disorders related to GABA function in a subject in need thereof claim 1 , comprising a therapeutically effective amount of a compound of .101. A method of treating a CNS-related disorder in a ...

NEUROACTIVE STEROIDS, COMPOSITIONS, AND USES THEREOF

Described herein are neuroactive steroids of the Formula (I): or a pharmaceutically acceptable salt thereof; wherein R 1 , R 2 , R a , G, X, Y, Z, and n are as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. Also provided are pharmaceutical compositions comprising a compound described herein and methods of use and treatment, e.g., such for inducing sedation and/or anesthesia.

AMINOALKYLAZOLE DERIVATIVES AS HISTAMINE-3 ANTAGONISTS

The present invention provides a compound of formula I: and the use thereof for the treatment of a central nervous system disorder related to or affected by the histamine-3 receptor.

N-substituted-azacyclylamines as histamine-3 antagonists

The present invention provides a compound of formula I and the use thereof for the treatment of a central nervous system disorder related to or affected by the histamine-3 receptor.

NEUROACTIVE STEROIDS AND METHODS OF USE THEREOF

Compounds are provided according to Formula (I): 2. The compound of claim 1 , wherein Ris unsubstituted Calkyl.3. The compound of claim 2 , wherein Ris —CH claim 2 , —CHCH claim 2 , or —CHCHCH.4. The compound of claim 1 , wherein Ris hydrogen.5. The compound of claim 1 , wherein Rand Rare both hydrogen.6. The compound of claim 1 , wherein Ris hydrogen.7. The compound of claim 1 , wherein Rand Rare both hydrogen.8. The compound of claim 1 , wherein at least one of Rand Ris fluorine.9. The compound of claim 1 , wherein Ris a non-hydrogen group substituted with fluorine.10. The compound of claim 1 , wherein Ris a non-hydrogen group substituted with one or more —ORgroups claim 1 , wherein Ris hydrogen or substituted or unsubstituted alkyl.11. The compound of claim 1 , wherein Ris a substituted or unsubstituted Calkyl claim 1 , substituted or unsubstituted Calkenyl claim 1 , substituted or unsubstituted Calkynyl claim 1 , or substituted or unsubstituted Ccarbocyclyl.12. The compound of claim 1 , wherein Ris hydrogen.13. The compound of claim 1 , wherein Ris —CHor —CF.14. The compound of claim 1 , wherein Ris —CFand Ris hydrogen or Calkyl.15. The compound of claim 1 , wherein Ris a non-hydrogen group substituted with fluorine claim 1 , and Ris —CH.16. The compound of claim 15 , wherein Ris substituted with one or more —ORgroups claim 15 , wherein Ris hydrogen or substituted or unsubstituted alkyl.17. The compound of claim 1 , wherein Ris a substituted or unsubstituted Calkyl claim 1 , substituted or unsubstituted Calkenyl claim 1 , substituted or unsubstituted Calkynyl claim 1 , or substituted or unsubstituted Ccarbocyclyl claim 1 , and Ris —CH.18. The compound of claim 1 , wherein Ris Calkyl claim 1 , Ris a non-hydrogen group substituted with fluorine claim 1 , and Ris —CH.19. The compound of claim 1 , wherein Ris Calkyl claim 1 , Ris a non-hydrogen group substituted with fluorine claim 1 , and Ris hydrogen.20. The compound of claim 1 , wherein Ris Calkyl claim 1 , Ris a ...

N-substituted-azacyclylamines as histamine-3 antagonists

The present invention provides a compound of formula I and the use thereof for the treatment of a central nervous system disorder related to or affected by the histamine-3 receptor: wherein the variables are described in the specification.

N-SUBSTITUTED-AZACYCLYLAMINES AS HISTAMINE-3 ANTAGONISTS

The present invention provides a compound of formula I and the use thereof for the treatment of a central nervous system disorder related to or affected by the histamine-3 receptor: wherein the variables are described in the specification.

SUBSTITUTED-DIHYDRO[1,4]OXAZINO[2,3,4-hi]INDAZOLE DERIVATIVES AS 5-HYDROXYTRYPTAMINE-6 LIGANDS

The present invention provides a compound of formula I and the use thereof for the treatment of a central nervous system disorder related to or affected by the 5-HT6 receptor.

19-nor C3, 3-disubstituted C21-C-bound heteroaryl steroids and methods of use thereof

Provided herein are 19-nor C3,3-disubstituted steroids of Formula (I): and pharmaceutically acceptable salts thereof; wherein , R1, R2, R3a, R3b, R4a, and R4bare as defined herein, and A is a carbon bound substituted or unsubstituted 5- to 6-membered heteroaryl ring as defined herein. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, convulsive disorders, disorders of memory and/or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, and tinnitus.

COMPOSITIONS AND METHODS FOR TREATING CNS DISORDERS

Described herein are neuroactive steroids of the Formula (I); or a pharmaceutically acceptable salt thereof, wherein, R, R, R, Rand A are as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. The present invention also provides pharmaceutical compositions comprising a compound of the present invention and methods of use and treatment, e.g., such for inducing sedation and/or anesthesia. 151-. (canceled)53. The process of claim 52 , wherein the process is performed in a solvent.54. The process of claim 52 , wherein the solvent is tetrahydrofuran.55. The process of claim 52 , wherein the process occurs at room temperature. This application claims priority to Provisional Application No. 62/064,957, filed Oct. 16, 2014, the entire contents of which are incorporated herein by reference.Brain excitability is defined as the level of arousal of an animal, a continuum that ranges from coma to convulsions, and is regulated by various neurotransmitters. In general, neurotransmitters are responsible for regulating the conductance of ions across neuronal membranes. At rest, the neuronal membrane possesses a potential (or membrane voltage) of approximately −70 mV, the cell interior being negative with respect to the cell exterior. The potential (voltage) is the result of ion (K, Na, Cl, organic anions) balance across the neuronal semipermeable membrane. Neurotransmitters are stored in presynaptic vesicles and are released under the influence of neuronal action potentials. When released into the synaptic cleft, an excitatory chemical transmitter such as acetylcholine will cause membrane depolarization, e.g., a change of potential from −70 mV to −50 mV. This effect is mediated by postsynaptic nicotinic receptors which are stimulated by acetylcholine to increase membrane permeability to Na ions. The reduced membrane potential stimulates neuronal excitability in the form of a postsynaptic action potential.In the case of the GABA ...

Heterocyclyl-3-sulfonylindazoles as 5-hydroxytryptamine-6 ligands

The present invention provides a compound of formula I and the use thereof in the therapeutic treatment of disorders related to or affected by the 5-HT6 receptor ...

Aminoalkylazole derivatives as histamine-3 antagonists

The present invention provides a compound of formula Ia: and the use thereof for the treatment of a central nervous system disorder related to or affected by the histamine-3 receptor.

19-nor neuroactive steroids and methods of use thereof

Provided herein are 3,3-disubstituted 19-nor-steroidal compounds according to Formula (I): and pharmaceutical compositions thereof. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, disorders of memory and/or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, tinnitus, status epilepticus.

NEUROACTIVE STEROIDS, COMPOSITIONS, AND USES THEREOF

Described herein are neuroactive steroids of the Formula (I): or a pharmaceutically acceptable salt thereof; wherein -------, R, R, R, A and L are as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. The present invention also provides pharmaceutical compositions comprising a compound of the present invention and methods of use and treatment, e.g., such for inducing sedation and/or anesthesia. 190-. (canceled)92. The compound of claim 91 , wherein each is a single bond and Ris hydrogen.93. The compound of claim 92 , wherein Ris methyl claim 92 , ethyl claim 92 , or isopropyl claim 92 , each of which is unsubstituted.94. The compound of claim 93 , wherein Ris unsubstituted methyl or unsubstituted ethyl.95. The compound of claim 91 , wherein Ris unsubstituted Calkyl.96. The compound of claim 91 , wherein Ris methyl or —CF.99. The compound of claim 91 , wherein ring A is an optionally substituted 5-membered or 6-membered monocyclic heteroaryl claim 91 , wherein the heteroaryl of ring A comprises 2 claim 91 , 3 claim 91 , or 4 nitrogen atoms and wherein the heteroaryl of ring A is linked through a nitrogen atom.103. The compound of claim 100 , wherein n is 1 or 2 claim 100 , and each Ris independently cyano claim 100 , halo claim 100 , Calkyl claim 100 , Calkoxy claim 100 , —C(O)R claim 100 , or —S(O)R.104. The compound of claim 103 , wherein n is 1 claim 103 , and Ris —C(O)CH claim 103 , —S(O)CH claim 103 , cyano claim 103 , halo claim 103 , or Calkyl.108. The compound of claim 105 , wherein n is 1 or 2 claim 105 , and each Ris independently cyano claim 105 , halo claim 105 , Calkyl claim 105 , Calkoxy claim 105 , —C(O)R claim 105 , or —S(O)R.109. The compound of claim 108 , wherein n is 1 claim 108 , and Ris —C(O)CH claim 108 , —S(O)CH claim 108 , cyano claim 108 , halo claim 108 , or Calkyl.113. The compound of claim 110 , wherein n is 1 or 2 claim 110 , and each Ris independently cyano claim 110 , halo claim 110 , ...

NEUROACTIVE STEROIDS, COMPOSITIONS, AND USES THEREOF

Provided herein are 19-nor C3,3-disubstituted steroids of Formula (I): and pharmaceutically acceptable salts thereof; wherein R 1 , R 2 , R 3 , and R 4 are as defined herein, and A is a heteroaryl ring system comprising 3 or 4 nitrogens as defined herein. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, convulsive disorders, disorders of memory and/or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, and tinnitus.

Substituted-3-sulfonylindazole derivatives as 5-hydroxytryptamine-6 ligands

The present invention provides a compound of formula I and the use thereof for the treatment of a central nervous system disorder related to or affected by the 5-HT6 receptor.

1-(arylsulfonyl)-4-(piperazin-1-yl)-1H-benzimidazoles as 5-hydroxytryptamine-6 ligands

The invention relates to 1-(arylsulfonyl)-4-(piperazin-1-yl)-1H-benzimidazole compounds of the Formula I: or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein the constituent variables are as defined herein, compositions comprising the compounds, and methods for making and using the compounds.

NEUROACTIVE STEROIDS, COMPOSITIONS, AND USES THEREOF

Compounds are provided according to Formula (I): 2. The process of claim 1 , wherein the reducing agent is NaBH.3. The process of claim 2 , wherein a catalyst is used with the reducing agent claim 2 , and wherein the catalyst is CeCl.4. The process of claim 1 , wherein the coupling agent is methyl propiolate.5. The process of claim 4 , wherein the coupling agent is used with a catalyst claim 4 , and the catalyst is N-methylmorpholine. This application is a continuation of U.S. Ser. No. 14/343,603, filed Nov. 25, 2014, which is a national stage application under U.S.C. § 371 of International Application No. PCT/US2012/054261, filed Sep. 7, 2012, which claims priority under 35 U.S.C. § 119(e) to U.S. provisional patent application, U.S. Ser. No. 61/532,427, filed Sep. 8, 2011, the contents of each of which is incorporated herein by reference.Brain excitability is defined as the level of arousal of an animal, a continuum that ranges from coma to convulsions, and is regulated by various neurotransmitters. In general, neurotransmitters are responsible for regulating the conductance of ions across neuronal membranes. At rest, the neuronal membrane possesses a potential (or membrane voltage) of approximately −70 mV, the cell interior being negative with respect to the cell exterior. The potential (voltage) is the result of ion (K, Na, Cl, organic anions) balance across the neuronal semipermeable membrane. Neurotransmitters are stored in presynaptic vesicles and are released as a result of of neuronal action potentials. When released into the synaptic cleft, an excitatory chemical transmitter such as acetylcholine will cause membrane depolarization (change of potential from −70 mV to −50 mV). This effect is mediated by postsynaptic nicotinic receptors which are stimulated by acetylcholine to increase the membrane permeability of Na ions. The reduced membrane potential stimulates neuronal excitability in the form of a postsynaptic action potential.NMDA receptors are highly ...

19-nor C3, 3-disubstituted C21-N-pyrazolyl steroids and methods of use thereof

Provided herein are 19-nor C3,3-disubstituted C21-pyrazolyl steroids of Formula (I): and pharmaceutically acceptable salts thereof; wherein , R1, R2, R3a, R3b, R4a, R4b, R5, R6, and R7are as defined herein. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, convulsive disorders, disorders of memory and/or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, and tinnitus.

COMPOSITIONS AND METHODS FOR TREATING CNS DISORDERS

Described herein are neuroactive steroids of the Formula (I): 173-. (canceled)75. The compound of claim 74 , wherein is a single bond.76. The compound of claim 74 , wherein Ris substituted Calkyl claim 74 , unsubstituted Calkyl claim 74 , or alkoxyalkyl.77. The compound of claim 76 , wherein Ris substituted Calkyl or unsubstituted Calkyl.78. The compound of claim 76 , wherein Ris methyl claim 76 , ethyl claim 76 , propyl claim 76 , or methoxymethyl.79. The compound of claim 78 , wherein Ris methyl.80. The compound of claim 74 , wherein Ris hydrogen claim 74 , —OR claim 74 , wherein Ris hydrogen claim 74 , or substituted or unsubstituted Calkyl.81. The compound of claim 74 , wherein Ris —OR claim 74 , wherein Ris hydrogen claim 74 , or substituted or unsubstituted Calkyl (e.g. claim 74 , methyl).82. The compound of claim 74 , wherein Ris hydrogen claim 74 , substituted Calkyl claim 74 , or unsubstituted Calkyl.83. The compound of claim 74 , wherein Ris hydrogen claim 74 , substituted Calkyl claim 74 , or unsubstituted Calkyl.84. The compound of claim 74 , wherein Ris hydrogen claim 74 , and Ris substituted Calkyl or unsubstituted Calkyl.85. The compound of claim 74 , wherein each of Rand Ris independently unsubstituted Calkyl.86. The compound of claim 74 , wherein each of Rand Ris hydrogen.87. The compound of claim 74 , wherein Ris hydrogen.88. The compound of claim 74 , wherein n is 1 and Ris substituted or unsubstituted Calkyl claim 74 , Chaloalkyl claim 74 , halogen claim 74 , cyano claim 74 , —OR claim 74 , —C(═O)OR claim 74 , —SR claim 74 , —S(═O)R claim 74 , or S(═O)R claim 74 , wherein Ris hydrogen claim 74 , substituted or unsubstituted Calkyl claim 74 , or Chaloalkyl claim 74 , and Ris substituted or unsubstituted Calkyl.89. The compound of claim 88 , wherein n is 1 and Ris halogen or cyano.90. The compound of claim 88 , wherein n is 1 and Ris substituted or unsubstituted Calkyl.91. The compound of claim 90 , wherein n is 1 and Ris methyl.92. The compound of ...

NEUROACTIVE 19-ALKOXY-17-SUBSTITUTED STEROIDS, PRODRUGS THEREOF, AND METHODS OF TREATMENT USING SAME

The present disclosure is generally directed to neuroactive 19-alkoxy-17-substituted steroids as referenced herein, and pharmaceutically acceptable salts thereof, for use as, for example, an anesthetic, and/or in the treatment of disorders relating to GABA function and activity. The present disclosure is further directed to pharmaceutical compositions comprising such compounds. 2. The compound of claim 1 , wherein one or both of Ror R claim 1 , when present and other than H claim 1 , are in the beta configuration.3. The compound of or claim 1 , wherein the Rgroup is selected from the group consisting of H claim 1 , methyl claim 1 , and trifluoromethyl.4. The compound of one of the preceding claims claim 1 , wherein Ris selected from the group consisting of H claim 1 , methoxy claim 1 , ethoxy claim 1 , and an optionally substituted morpholinyl ring.5. The compound of one of the preceding claims claim 1 , wherein Ris H.6. The compound of one of the preceding claims claim 1 , wherein Ris substituted methyl.7. The compound of one of the preceding claims claim 1 , wherein the C—H is in the alpha position.8. The compound of one of preceding - claim 1 , wherein the C—H is in the beta configuration and Rgroup is in the beta configuration.9. The compound of one of the preceding claims claim 1 , wherein Ris H.10. The compound of one of the preceding claims claim 1 , wherein Ris ═O claim 1 , methoxy or H.11. The compound of one of the preceding claims claim 1 , wherein Ris methyl.13. The compound of wherein Ris methyl.14. The compound of or claim 12 , wherein Ris beta-methoxy.15. The compound of or claim 12 , wherein Ris beta-spirooxirane.16. The compound of or claim 12 , wherein Ris beta-cyano.17. The compound of or claim 12 , wherein Ris ═O.18. The compound of or claim 12 , wherein Ris beta-nitro.19. The compound of or claim 12 , wherein Ris beta-CHC(O)—.20. The compound of or claim 12 , wherein Ris beta-HOCHC(O)—.22. The compound of claim 21 , wherein Ris methyl.23. A ...

Amino-5-(6-membered)heteroarylimidazolone compounds and the use thereof for beta-secretase modulation

The present invention provides a 2-amino-5-heteroaryl-5-phenylimidazolone compound of formula I The present invention also provides methods for the use thereof to inhibit beta-secretase (BACE) and treat beta-amyloid deposits and neurofibrillary tangles.

HETEROCYCLYL-3-SULFONYLINDAZOLES AS 5-HYDROXYTRYPTAMINE-6 LIGANDS

The present invention provides a compound of formula I and the use thereof in the therapeutic treatment of disorders related to or affected by the 5-HT6 receptor.

19-NOR NEUROACTIVE STEROIDS AND METHODS OF USE THEREOF

Provided herein are 3,3-disubstituted 19-nor-steroidal compounds according to Formula (I): 6. The compound of claim 5 , wherein Ris substituted or unsubstituted hydrogen claim 5 , substituted or unsubstituted Calkyl claim 5 , —C(═O)R claim 5 , —C(═O)OR claim 5 , —C(═O)N(R) claim 5 , or —S(═O)R.9. The compound of any one of preceding claims claim 5 , wherein e is 1.10. The compound of any one of preceding claims claim 5 , wherein Ris substituted or unsubstituted Calkyl.11. The compound of any one of preceding claims claim 5 , wherein Ris —CH.12. The compound of any one of - claim 5 , wherein Ris ORwherein Ris hydrogen or substituted or unsubstituted Calkyl.13. The compound of any one of - claim 5 , wherein Ris OH.14. The compound of any one of - claim 5 , wherein Ris —S(═O)Rwherein Ris substituted or unsubstituted Calkyl.15. The compound of any one of - claim 5 , wherein Ris —S(═O)CH.16. The compound of any one of - claim 5 , wherein Ris —C(═O)Rwherein Ris substituted or unsubstituted Calkyl.17. The compound of any one of - claim 5 , wherein Ris —C(═O)CH.18. The compound of any one of - claim 5 , wherein Ris —C(═O)N(R)wherein Ris hydrogen or substituted or unsubstituted Calkyl.19. The compound of any one of - claim 5 , wherein Ris —C(═O)NHCH.20. The compound of any one of preceding claims claim 5 , wherein between C5 and C6 is a double bond and Ris absent.21. The compound of any one of preceding claims claim 5 , wherein between C5 and C6 is a single bond.23. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of any one of the proceeding claims claim 5 , or a pharmaceutically acceptable salt thereof.24. A method for treating a CNS-related disorder in a subject in need thereof claim 5 , comprising administering to the subject an effective amount of a compound of any one of to claim 5 , or a pharmaceutically acceptable salt thereof.25. The method of claim 24 , wherein the CNS-related disorder is a sleep disorder claim 24 , a ...

OXYSTEROLS AND METHODS OF USE THEREOF

Compounds are provided according to Formula (I): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R1, R2, R3and R6, R11a, and R11bare as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.

NEUROACTIVE STEROIDS, COMPOSITIONS, AND USES THEREOF

Described herein are neuroactive steroids of the Formula (I): or a pharmaceutically acceptable salt thereof; wherein R1, R2, RaG, X, Y, Z, and n are as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. Also provided are pharmaceutical compositions comprising a compound described herein and methods of use and treatment, e.g., such for inducing sedation and/or anesthesia.

Neuroactive 19-alkoxy-17-substituted steroids, prodrugs thereof, and methods of treatment using same

The present disclosure is generally directed to neuroactive 19-alkoxy-17-substituted steroids as referenced herein, and pharmaceutically acceptable salts thereof, for use as, for example, an anesthetic, and/or in the treatment of disorders relating to GABA function and activity. The present disclosure is further directed to pharmaceutical compositions comprising such compounds.

AMINO-5-[4-(DIFLUOROMETHOXY)PHENYL]-5-PHENYLIMIDAZOLONE COMPOUNDS FOR THE INHIBITION OF BETA-SECRETASE

The present invention provides compounds and methods for the use thereof to inhibit β-secretase (BACE) and treat β-amyloid deposits and neurofibrillary tangles.

19-NOR neuroactive steroids and methods of use thereof

Provided herein are 3,3-disubstituted 19-nor-steroidal compounds according to Formula (1): and pharmaceutical compositions thereof. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, disorders of memory and/or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, tinnitus, and status epilepticus.

Oxysterols and methods of use thereof

Compounds are provided according to Formula (I) and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein X, Y, R1, R2a, R2b, R4a, R4b, R5a, R5b, R6a, R6b, R7, and R8are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.

Heterocyclyl-3-sulfonylindazoles as 5-hydroxytryptamine-6 ligands

The present invention provides a compound of formula I and the use thereof in the therapeutic treatment of disorders related to or affected by the 5-HT6 receptor.

OXYSTEROLS AND METHODS OF USE THEREOF

Compounds are provided according to Formula (A): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R, R, R, R, R, R, and Rare as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions. 2. The compound of claim 1 , wherein Ris alkyl.36-. (canceled)7. The compound of claim 1 , wherein Ris hydrogen or alkyl.8. The compound of claim 1 , wherein Ris unsubstituted C-Calkyl or C-Chaloalkyl.912-. (canceled)13. The compound of claim 1 , wherein wherein Ris unsubstituted C-Calkyl claim 1 , C-Chaloalkyl claim 1 , carbocyclyl claim 1 , carbocyclylalkyl claim 1 , aralkyl claim 1 , or heterocyclylalkyl.1426-. (canceled)27. The compound of claim 1 , wherein Ris aryl or heteroaryl and Ris hydrogen.28. The compound of claim 1 , wherein Ris carbocyclyl or heterocyclyl and Ris hydrogen.2930-. (canceled)31. The compound of claim 1 , wherein Rand R claim 1 , together with the carbon atom to which they are attached form a 3-8 membered carbocyclic or heterocyclic ring.3233-. (canceled)3540-. (canceled)4247-. (canceled)4836. The compound of claim claim 1 , wherein each of Rand Ris independently hydrogen or alkyl.49. The compound of claim 1 , wherein each of Rand Ris independently hydrogen or C-Chaloalkyl.5059-. (canceled)6162-. (canceled)64. A pharmaceutical composition comprising a compound of claim 1 , or pharmaceutically acceptable salt thereof claim 1 , and a pharmaceutically acceptable carrier.65. A method for treating or preventing a disorder described herein claim 1 , comprising administering to a subject in need thereof an effective amount of a compound of claim 1 , or pharmaceutically acceptable salt thereof claim 1 , or pharmaceutical composition thereof.66. The method according to claim 65 , wherein the disorder is a gastrointestinal (GI) disorder claim 65 , structural disorders affecting the GI claim 65 , anal disorders claim 65 , colon polyps claim 65 , ...

Oxysterols and methods of use thereof

Compounds are provided according to Formula (I), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein A, R1, and R5are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.

NEUROACTIVE STEROIDS, COMPOSITIONS, AND USES THEREOF

Described herein are neuroactive steroids of the Formula (I): (Formula (I)) or a pharmaceutically acceptable salt thereof; wherein Rand Rare as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. The present invention also provides pharmaceutical compositions comprising a compound of the present invention and methods of use and treatment, e.g., such for inducing sedation and/or anesthesia. 3. The compound of claim 1 , wherein one of Ror Ris hydroxy claim 1 , alkyl claim 1 , or alkoxy.4. The compound of claim 3 , wherein one of Ror Ris hydroxy.5. The compound of claim 3 , wherein one of Ror Ris alkoxy.6. The compound of claim 5 , wherein Ris methoxy.10. The compound of claim 8 , wherein Ror Ris alkyl claim 8 , methoxy claim 8 , substituted ethoxy claim 8 , or C-Calkoxy.11. The compound of claim 10 , wherein Ris alkyl claim 10 , methoxy claim 10 , substituted ethoxy claim 10 , or C-Calkoxy.12. The compound of claim 9 , wherein Ris hydrogen.16. The compound of claim 14 , wherein Rand Rare taken together with the carbon to which they are attached to form C(═O).17. The compound of claim 14 , wherein Ror Ris hydroxy claim 14 , alkyl claim 14 , or alkoxy.18. (canceled)19. The compound of claim 14 , wherein Ror Ris hydroxy claim 14 , alkyl claim 14 , or alkoxy.2024-. (canceled)25. The compound of claim 14 , wherein Ris alkyl.2739-. (canceled)40. A pharmaceutical composition comprising a compound of Formula (I) claim 14 , (Ib) claim 14 , (II) claim 14 , (IIb) claim 14 , (III) claim 14 , or (IIIb) claim 14 , and a pharmaceutically acceptable excipient.4152-. (canceled) The present application claims priority under 35 U.S.C. §119(e) to U.S. provisional patent application, U.S. Ser. No. 61/856,592, filed Jul. 19, 2013, which is incorporated herein by reference.Brain excitability is defined as the level of arousal of an animal, a continuum that ranges from coma to convulsions, and is regulated by various neurotransmitters. In ...

Oxysterols and methods of use thereof

Compounds are provided according to Formula (I) and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R1, R2, and R3 are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.

C7, c12, and c16 substituted neuroactive steroids and their methods of use

Described herein are neuroactive steroids of Formula (I), Formula (V), or Formula (IX) or a pharmaceutically acceptable salt thereof; wherein each instance of R2, R3, R4, R5, R6, R7, R11a, R11b, R12, R16, R17, R19, and are as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. Also provided are pharmaceutical compositions comprising a compound described herein and methods of use and treatment, e.g., such as for inducing sedation and/or anesthesia.

OXYSTEROLS AND METHODS OF USE THEREOF

Compounds are provided according to Formula (I): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R, R, R, and R, R, and Rare as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions. 2. The compound of claim 1 , wherein Ris Calkyl.3. The compound of claim 1 , wherein Ris hydrogen claim 1 , methyl or ethyl claim 1 , —CHF claim 1 , —CF claim 1 , —CHOCH claim 1 , or —CHOCHCH.4. The compound of claim 1 , wherein Ris unsubstituted Calkyl.5. The compound of wherein Ris hydrogen.6. The compound of claim 1 , wherein Ris —CH.7. The compound of claim 1 , wherein Ris —CHCH.8. The compound of claim 1 , wherein each of Rand Ris independently hydrogen claim 1 , methyl claim 1 , ethyl claim 1 , propyl claim 1 , isopropyl claim 1 , cyclopropyl claim 1 , butyl claim 1 , —CF claim 1 , or —CHCF.9. The compound of claim 8 , wherein each of Rand Ris independently methyl claim 8 , isopropyl claim 8 , or tert-butyl.10. The compound of claim 8 , wherein Ris hydrogen claim 8 , methyl claim 8 , ethyl claim 8 , or —CF.11. The compound of claim 1 , wherein Ris methyl claim 1 , ethyl claim 1 , propyl claim 1 , isopropyl claim 1 , cyclopropyl claim 1 , butyl claim 1 , —CF claim 1 , or —CHCF.12. The compound of claim 1 , wherein Ris hydrogen and Ris —OH.13. The compound of claim 1 , wherein Ris C-Calkyl and Ris —OH.14. The compound of claim 1 , wherein Rand Rare joined together to form oxo.1617-. (canceled)1923-. (canceled)2733-. (canceled)34. A pharmaceutical composition comprising a compound of claim 1 , or pharmaceutically acceptable salt thereof claim 1 , and a pharmaceutically acceptable carrier.35. A method of inducing sedation or anesthesia comprising administering to a subject an effective amount of a compound of claim 1 , or pharmaceutically acceptable salt thereof.36. A method for treating or preventing a disorder selected from the group consisting of ...

NEUROACTIVE STEROID SOLUTIONS AND THEIR METHODS OF USE

Provided herein are pharmaceutically acceptable aqueous solution comprising a neuroactive steroid, a sulfobutyl ether beta cyclodextrin and a buffer; wherein: the solution is a stable solution between a pH of about 3 and about 9, e.g., at room temperature, for at least 1, 2, 3, 4 weeks; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months; 1, 2, 3 years or more; the buffer is present at a concentration of at least 0.1 mM; or the solution remains substantially free of impurities (e.g., the solution is substantially free of impurities at room temperature for at least 1, 2, 3, 4 weeks; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months; 1, 2, 3 years or more). 1. A pharmaceutically acceptable aqueous solution comprising (e.g. , consisting essentially of , consisting of) a neuroactive steroid , a sulfobutyl ether beta cyclodextrin and a buffer; wherein:the solution is a stable solution between a pH of about 3 and about 9, for at least 2 weeks; orthe buffer is present at a concentration of at least 0.1 mM; orthe solution remains substantially free of impurities for at least 2 weeks.2. The solution of claim 1 , wherein the solution is a stable solution between a pH of about 3 and about 9 claim 1 , for at least 2 weeks at a temperature from about 2° C. to about 8° C.3. The solution of claim 1 , wherein the solution is a stable solution between a pH of about 3 and about 9 claim 1 , for at least 2 weeks at a temperature from about 0° C. to about 45° C.4. The solution of claim 1 , wherein the solution remains substantially free of impurities for at least 2 weeks at a temperature from about 2° C. to about 8° C.5. The solution of claim 1 , wherein the solution remains substantially free of impurities for at least 2 weeks at a temperature from about 15° C. to about 25° C.6. The aqueous solution of claim 1 , wherein the buffer in the solution is present at a concentration of from about 5 to 100 mM.7. The aqueous solution of claim 1 , wherein the buffer in the solution is present at a ...

OXYSTEROLS AND METHODS OF USE THEREOF

Compounds are provided according to Formula (A): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R, R, R, R, R, R, and Rare as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions. 140-. (canceled)4243-. (canceled)44. The pharmaceutical composition of claim 41 , wherein Ris substituted or unsubstituted C-Calkyl.45. The pharmaceutical composition of claim 41 , wherein Ris —CH claim 41 , —CF claim 41 , —CHCH claim 41 , or —CHOR claim 41 , wherein Ris substituted or unsubstituted C-Calkyl.4647-. (canceled)48. The pharmaceutical composition of claim 41 , wherein each of Rand Ris independently hydrogen or substituted or unsubstituted alkyl.49. (canceled)50. The pharmaceutical composition of claim 41 , wherein each of Rand Ris independently hydrogen claim 41 , —CF claim 41 , or —CH.51. (canceled)52. The pharmaceutical composition of claim 41 , wherein Rand R claim 41 , together with the carbon atom to which they are attached form an oxo group.5354-. (canceled)55. The pharmaceutical composition of claim 41 , wherein Rand Rare hydrogen.56. The pharmaceutical composition of claim 41 , wherein Ris substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl and Ris hydrogen.57. The pharmaceutical composition of claim 41 , wherein Ris substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl and Ris hydrogen.5859-. (canceled)6193-. (canceled)95. The pharmaceutical composition of claim 94 , wherein Ris substituted or unsubstituted C-Calkyl.96. The pharmaceutical composition of claim 94 , wherein Ris —CH claim 94 , —CF claim 94 , —CHCH claim 94 , or —CHOR claim 94 , wherein Ris substituted or unsubstituted C-Calkyl.97. The pharmaceutical composition of claim 94 , wherein each of Rand Ris independently hydrogen or substituted or unsubstituted alkyl.98. The pharmaceutical composition of claim 94 , wherein each ...

19-NOR C3, 3-DISUBSTITUTED C21-C-BOUND HETEROARYL STEROIDS AND METHODS OF USE THEREOF

Provided herein are 19-nor C3,3-disubstituted steroids of Formula (I): 127-. (canceled)30. The method of claim 28 , wherein Ris —CH claim 28 , —CHCH claim 28 , —CHF claim 28 , —CHF claim 28 , —CF claim 28 , —CHOCH claim 28 , or substituted or unsubstituted cyclopropyl.31. The method of claim 30 , wherein Ris —CH.32. The method of claim 28 , wherein Ris hydrogen.33. The method of claim 28 , wherein Rand Rare both hydrogen.34. The method of claim 28 , wherein represents a single bond claim 28 , and both of Rand Rare hydrogen.35. The method of claim 28 , wherein represents a single bond claim 28 , and both of Rand Rare fluoro.36. The method of claim 28 , wherein at least one of R claim 28 , R claim 28 , R claim 28 , R claim 28 , and Ris substituted or unsubstituted Calkyl claim 28 , —COR claim 28 , —C(═O)R claim 28 , —CN claim 28 , —NO claim 28 , or halogen claim 28 , wherein Ris substituted or unsubstituted Calkyl.37. The method of claim 36 , wherein at least one of R claim 36 , R claim 36 , R claim 36 , R claim 36 , and Ris substituted or unsubstituted —CH.38. The method of claim 28 , wherein R claim 28 , R claim 28 , R claim 28 , R claim 28 , and Rare hydrogen.42. The method of claim 28 , wherein the human subject has a CNS-related disorder.43. The method of claim 42 , wherein the CNS-related disorder is a sleep disorder claim 42 , a mood disorder claim 42 , a schizophrenia spectrum disorder claim 42 , a convulsive disorder claim 42 , a disorder of memory and/or cognition claim 42 , a movement disorder claim 42 , a personality disorder claim 42 , autism spectrum disorder claim 42 , pain claim 42 , traumatic brain injury claim 42 , a vascular disease claim 42 , a substance abuse disorder and/or withdrawal syndrome claim 42 , or tinnitus.44. The method of claim 43 , wherein the mood disorder is depression.45. The method of claim 44 , wherein the depression is postnatal depression.46. The method of claim 43 , wherein the sleep disorder is insomnia.47. The method of ...

NEUROACTIVE STEROIDS, COMPOSITIONS, AND USES THEREOF

Described herein are neuroactive steroids of the Formula (I): 17-. (canceled)10. The compound of claim 8 , wherein Rand Rare taken together with the carbon to which they are attached to form C(═O).11. The compound of claim 8 , wherein Ror Ris hydroxy claim 8 , alkyl claim 8 , or alkoxy.12. The compound of claim 8 , wherein Rand Rare taken together with the carbon to which they are attached to form C(═O) and Ror Ris hydroxy claim 8 , alkyl claim 8 , or alkoxy.13. The compound of claim 8 , wherein Ror Ris hydroxy claim 8 , alkyl claim 8 , or alkoxy.14. The compound of claim 13 , wherein Ris hydroxy.15. The compound of claim 13 , wherein Ris alkoxy.16. The compound of claim 8 , wherein Ror Ris hydroxy claim 8 , alkyl claim 8 , or alkoxy and Ror Ris hydroxy claim 8 , alkyl claim 8 , or alkoxy.17. The compound of claim 11 , wherein Ris alkyl.18. The compound of claim 11 , wherein Ris alkoxy.19. The compound of claim 8 , wherein Ris C-Calkyl.2133-. (canceled)34. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable excipient.3546-. (canceled) This application is a divisional of U.S. Ser. No. 15/698,151 filed Sep. 7, 2017, which is a continuation of U.S. Ser. No. 14/906,043 filed Jan. 19, 2016, which is a national stage application under 35 U.S.C. § 371 of International Application No. PCT/US2014/047246 filed Jul. 18, 2014, which claims priority under 35 U.S.C. § 119(e) to U.S. provisional patent application, U.S. Ser. No. 61/856,592, filed Jul. 19, 2013, the contents of each of which are incorporated herein by reference.Brain excitability is defined as the level of arousal of an animal, a continuum that ranges from coma to convulsions, and is regulated by various neurotransmitters. In general, neurotransmitters are responsible for regulating the conductance of ions across neuronal membranes. At rest, the neuronal membrane possesses a potential (or membrane voltage) of approximately −70 mV, the cell interior being negative with respect to ...

C7 SUBSTITUTED OXYSTEROLS AND METHODS OF USE THEREOF

Compounds are provided according to Formula (A): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R, R, n, R, R, R, and Rare as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions. 2. The compound of claim 1 , where n is 1.3. The compound of claim 1 , where n is 2.4. The compound of claim 1 , that when R claim 1 , R claim 1 , and Rare hydrogen and Ris unsubstituted isopropyl claim 1 , then Rand R claim 1 , together with the carbon atom to which they are attached do not form an oxo group; and{'sup': 4', '3', '1A', '1B', '2A', '2B, 'sub': 3', '3, 'when Ris absent, Ris hydrogen, and Rand Rare —CH, then Ris not —CHand Ris not —OH.'}5. The compound of claim 1 , that when Ris absent claim 1 , Ris —OH claim 1 , Ris hydrogen or —CF claim 1 , and Rand Rare —CH claim 1 , then Ris not hydrogen; and{'sup': 1A', '1B', '3', '2A', '2B, 'sub': '3', 'when Rand Rare —CHand Ris hydrogen, then Rand R, together with the carbon atom to which they are attached do not form an oxo group.'}612-. (canceled)13. The compound of claim 1 , wherein Ris absent claim 1 , one of Rand Ris —OH claim 1 , and Ris not hydrogen.14. The compound of claim 1 , wherein each of Rand Ris independently unsubstituted or substituted alkyl.15. The compound of claim 14 , wherein each of Rand Ris independently selected from the group consisting of haloalkyl claim 14 , alkoxyalkyl claim 14 , —CH claim 14 , —CHCH claim 14 , —CH(CH) claim 14 , —CFand —CHOCH.1620-. (canceled)21. The compound of claim 1 , wherein Rand R claim 1 , together with the carbon atom to which they are attached form a 3-8 membered ring.22. The compound of claim 1 , wherein Ris hydrogen and Ris alkyl claim 1 , carbocyclyl claim 1 , heterocyclyl claim 1 , aryl claim 1 , or heteroaryl.23. (canceled)24. The compound of claim 1 , wherein each of Rand Ris independently substituted or unsubstituted alkyl.2527-. (canceled)28. ...

OXYSTEROLS AND METHODS OF USE THEREOF

Compounds are provided according to Formula (I) and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R, R, and Rare as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions. 2. (canceled)3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris substituted Calkyl.4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris unsubstituted Calkyl.5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris —CH claim 1 , —CF claim 1 , —CHOCH claim 1 , —CH(CH)(CF) claim 1 , —CHCH claim 1 , or —CH(CH).6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris —CHor —CHCH.7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris unsubstituted Calkyl.8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris substituted or unsubstituted ethyl claim 1 , substituted or unsubstituted isopropyl claim 1 , or substituted or unsubstituted tert-butyl.911-. (canceled)12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein represents a single bond.1617-. (canceled)2021-. (canceled)23. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable carrier.24. A method of inducing sedation or anesthesia comprising administering to a subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , or a pharmaceutical composition thereof.25. A method for treating a disorder claim 1 , comprising administering to a subject in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , or a pharmaceutical composition thereof; wherein the disorder is a gastrointestinal (GI) disorder ...

19-NOR NEUROACTIVE STEROIDS AND METHODS OF USE THEREOF

Provided herein are 3,3-disubstituted 19-nor-steroidal compounds according to Formula (1): and pharmaceutical compositions thereof. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, disorders of memory and/or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, tinnitus, and status epilepticus. 237-. (canceled)39. The method of claim 38 , wherein the CNS-related disorder is a sleep disorder claim 38 , a mood disorder claim 38 , a schizophrenia spectrum disorder claim 38 , a convulsive disorder claim 38 , a disorder of memory and/or cognition claim 38 , a movement disorder claim 38 , a personality disorder claim 38 , autism spectrum disorder claim 38 , pain claim 38 , traumatic brain injury claim 38 , a vascular disease claim 38 , a substance abuse disorder and/or withdrawal syndrome claim 38 , tinnitus claim 38 , or status epilepticus.40. The method of or wherein the compound is administered orally claim 38 , subcutaneously claim 38 , intravenously claim 38 , or intramuscularly.41. The method of or wherein the compound is administered chronically. Brain excitability is defined as the level of arousal of an animal, a continuum that ranges from coma to convulsions, and is regulated by various neurotransmitters. In general, neurotransmitters are responsible for regulating the conductance of ions across neuronal membranes. At rest, the neuronal membrane possesses a potential (or membrane voltage) of approximately −70 mV, the cell interior being negative with respect to the cell exterior. The potential (voltage) is the result of ion (K, Na, Cl, organic anions) balance across the neuronal semipermeable membrane.Neurotransmitters are stored in presynaptic vesicles and are released under the ...

NEUROACTIVE STEROIDS, COMPOSITIONS, AND USES THEREOF

Provided herein are 19-nor C3,3-disubstituted steroids of Formula (I): 134-. (canceled)36. The method of claim 35 , wherein step (a) is performed at a temperature of about 60° C.38. The method of any one of - claim 35 , wherein the solvent of step (a) is THF.41. The method of claim 39 , wherein the solvent system comprises CHClsaturated with water.42. The method of or claim 39 , wherein the reaction of step (d) is performed under stirring conditions.44. The method of claim 43 , wherein the solvent of step (e) is DMSO.45. The method of or claim 43 , wherein step (e) is performed under stirring conditions at room temperature.47. The method of claim 46 , wherein the HCl of step (f) is reacted at a concentration of 2M.48. The method of or claim 46 , wherein step (f) is performed under stirring conditions for about 12 hours.49. The method of any one of - claim 46 , wherein step (f) is performed at room temperature.51. The method of claim 50 , wherein step (g) is performed in the presence of NaOH.52. The method of claim 51 , wherein the NaOH is provided as about 10% aqueous NaOH.53. The method of or claim 51 , wherein step (g) is performed in the presence of HO.54. The method of claim 53 , wherein the HOis provided as an about 30% aqueous solution of HO.56. The method of claim 55 , wherein step (a) is performed at a temperature of about 60° C.; and the solvent of step (a) is THF. This application is a continuation of U.S. Ser. No. 15/314,565 filed Nov. 29, 2016, which is a national stage application under 35 U.S.C. § 371 of International Application No. PCT/CN2015/080216, filed May 29, 2015, published as International Publication No. WO2015/180679 on Dec. 3, 2015, which claims priority to international application No. PCT/CN2014/078820, filed May 29, 2014, the entire contents of each of which are incorporated herein by reference in their entirety.Brain excitability is defined as the level of arousal of an animal, a continuum that ranges from coma to convulsions, and is ...

C7 SUBSTITUTED OXYSTEROLS AND METHODS OF USE THEREOF

Compounds are provided according to Formula (A): 167.-. (canceled)69. (canceled)7176.-. (canceled)78174.-. (canceled)175. The method according to any one of , or , wherein n is 1.176. The method according to any one of , or , where n is 2.177. The method according to any one of , or , wherein each of Rand Ris independently unsubstituted or substituted alkyl.178. The method according to any one of , or , wherein each of Rand Ris independently selected from the group consisting of haloalkyl , alkoxyalkyl , —CH , CHCH , —CH(CH) , —CFand —CHOCH.179. The method according to any one of , or , wherein Rand R , together with the carbon atom to which they are attached form a 3-8 membered ring.180. The method according to any one of , or , wherein Ris hydrogen and Ris alkyl , carbocyclyl , heterocyclyl , aryl , or heteroaryl.181. The method according to any one of , or , wherein each of Rand Ris independently substituted or unsubstituted alkyl.182. The method according to any one of , or , wherein Ris substituted or unsubstituted alkyl. This application is a divisional of U.S. patent application Ser. No. 16/338,315, filed Mar. 29, 2019, which is a U.S. National Phase Application under 35 U.S.C. § 371 of International Application PCT/US2017/054657, filed Sep. 30, 2017, which claims priority to and the benefit of U.S. Provisional Application No. 62/402,789, filed Sep. 30, 2016, and U.S. Provisional Application No. 62/402,797, filed Sep. 30, 2016. The disclosures of each of the foregoing applications are incorporated herein by reference in their entirety.NMDA receptors are heteromeric complexes comprised of NR1, NR2, and/or NR3 subunits and possess distinct recognition sites for exogenous and endogenous ligands. These recognition sites include binding sites for glycine, and glutamate agonists and modulators. NMDA receptors are expressed in the peripheral tissues and the CNS, where they are involved in excitatory synaptic transmission. Activating these receptors contributes to ...

19-NOR NEUROACTIVE STEROIDS AND METHODS OF USE THEREOF

Provided herein are 3,3-disubstituted 19-nor-steroidal compounds according to Formula (I): and pharmaceutical compositions thereof. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, disorders of memory and/or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, tinnitus, status epilepticus. 6. The compound of claim 5 , wherein Ris substituted or unsubstituted hydrogen claim 5 , substituted or unsubstituted Calkyl claim 5 , —C(═O)R claim 5 , —C(═O)OR claim 5 , —C(═O)N(R) claim 5 , or —S(═O)R.9. The compound of claim 1 , wherein e is 1.10. The compound of claim 1 , wherein Ris substituted or unsubstituted Calkyl.11. The compound of claim 1 , wherein Ris —CH.12. The compound of claim 1 , wherein Ris ORwherein Ris hydrogen or substituted or unsubstituted Calkyl.13. The compound of claim 1 , wherein Ris OH.14. The compound of claim 1 , wherein Ris —S(═O)Rwherein Ris substituted or unsubstituted Calkyl.15. The compound of claim 1 , wherein Ris —S(═O)CH.16. The compound of claim 1 , wherein Ris —C(═O)Rwherein Ris substituted or unsubstituted Calkyl.17. The compound of claim 1 , wherein Ris —C(═O)CH.18. The compound of claim 1 , wherein Ris —C(═O)N(R)wherein Ris hydrogen or substituted or unsubstituted Calkyl.19. The compound of claim 1 , wherein Ris —C(═O)NHCH.20. The compound of claim 1 , wherein between C5 and C6 is a double bond and Ris absent.21. The compound of claim 1 , wherein between C5 and C6 is a single bond.23. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.24. A method for treating a CNS-related disorder in a subject in need thereof claim 1 , comprising administering to the ...

19-nor c3, 3-disubstituted c21-c-bound heteroaryl steroids and methods of use thereof

Provided herein are 19-nor C3,3-disubstituted steroids of Formula (I): and pharmaceutically acceptable salts thereof; wherein, , R 1 , R 2 , R 3a , R 3b , R 4a , and R 4b are as defined herein, and A is a carbon bound substituted or unsubstituted 5- to 6-membered heteroaryl ring as defined herein. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, convulsive disorders, disorders of memory and/or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, and tinnitus.

COMPOSITIONS AND METHODS FOR TREATING CNS DISORDERS

Described herein are neuroactive steroids of the Formula (I): 2. The compound of claim 1 , wherein Ris substituted or unsubstituted Calkyl (e.g. claim 1 , haloalkyl).3. The compound of any one of the preceding claims claim 1 , wherein Ris methyl or CF.4. The compound of any one of the preceding claims claim 1 , wherein Ris methyl.5. The compound of any one of the preceding claims claim 1 , wherein Ris hydrogen.6. The compound of any one of the preceding claims claim 1 , wherein Ris methyl and Ris hydrogen.7. The compound of any one of the preceding claims claim 1 , wherein represents a single bond.11. The compound of any one of the preceding claims claim 1 , wherein A is heterocyclyl or heteroaryl (e.g. claim 1 , nitrogen-containing heterocyclyl or a nitrogen-containing heteroaryl).12. The compound of any one of the preceding claims claim 1 , wherein A is monocyclic or bicyclic.13. The compound of any one of the preceding claims claim 1 , wherein A is substituted with at least one R claim 1 , wherein Ris Calkyl claim 1 , Calkenyl claim 1 , Calkynyl claim 1 , Ccarbocyclyl claim 1 , Chaloalkyl claim 1 , halogen claim 1 , cyano claim 1 , —OR claim 1 , —C(═O)OR claim 1 , —SR claim 1 , —S(═O)R claim 1 , or S(═O)R claim 1 , wherein Ris hydrogen or Calkyl claim 1 , Calkenyl claim 1 , Calkynyl claim 1 , Ccarbocyclyl claim 1 , or Chaloalkyl claim 1 , and Ris Calkyl or Ccarbocyclyl.14. The compound of claim 13 , wherein Ris Calkyl claim 13 , halogen claim 13 , or cyano.15. The compound of any one of - claim 13 , wherein A is substituted with 1-3 instances of R.17. The compound of claim 16 , wherein Ris substituted or unsubstituted Calkyl (e.g. claim 16 , haloalkyl).18. The compound of any one of - claim 16 , wherein Ris methyl or CF.19. The compound of any one of - claim 16 , wherein Ris methyl.20. The compound of any one of - claim 16 , wherein Ris hydrogen.21. The compound of any one of - claim 16 , wherein Ris methyl and Ris hydrogen.22. The compound of any one of - claim ...

NEUROACTIVE STEROIDS, COMPOSITIONS, AND USES THEREOF

Described herein are steroids of Formula (I): 2. The method of claim 1 , wherein Ris methyl.3. The method of claim 1 , wherein both Rand Rare hydrogen.4. The method of claim 1 , wherein Ris C-Calkyl claim 1 , C-Calkenyl claim 1 , C-Calkynyl claim 1 , carbocyclyl claim 1 , heterocyclyl claim 1 , C(O)R claim 1 , —C(O)OR claim 1 , or —C(O)NRR.5. The method of claim 4 , wherein Ris —C(O)NRR.6. The method of claim 1 , wherein Ris hydrogen claim 1 , C-Calkyl claim 1 , or —OH.7. The method of claim 6 , wherein Ris hydrogen.8. The method of claim 1 , wherein both Rand Rare hydrogen claim 1 , the between —CRand —CRRis a single bond claim 1 , and both Rand Rare hydrogen.9. The method of claim 1 , wherein Z is —CH—.10. The method of claim 1 , wherein Ris hydrogen and Ris C-Calkyl.12. The method of claim 11 , wherein Ris methyl.13. The method of claim 11 , wherein Ris C-Calkyl claim 11 , C-Calkenyl claim 11 , C-Calkynyl claim 11 , carbocyclyl claim 11 , heterocyclyl claim 11 , —C(I)R claim 11 , —C(O)OR claim 11 , or —C(O)NRR.14. The method of claim 11 , wherein Ris C-Calkyl.15. The method of claim 11 , wherein Ris hydrogen.16. The method of claim 11 , wherein both Rand Rare hydrogen and both Rand Rare hydrogen.19. The method of claim 18 , wherein Ris methyl.20. The method of claim 18 , wherein Ris C-Calkyl claim 18 , C-Calkenyl claim 18 , C-Calkynyl claim 18 , carbocyclyl claim 18 , heterocyclyl claim 18 , —C(O)R claim 18 , —C(O)OR claim 18 , or —C(O)NRR.21. The method of claim 18 , wherein Ris C-Calkyl.22. The method of claim 20 , wherein Ris —C(O)NRR.23. The method of claim 18 , wherein Ris —OH.24. The method of claim 18 , wherein Ris hydrogen.25. The method of claim 18 , wherein both Rand Rare hydrogen and both Rand Rare hydrogen.27. (canceled)28. (canceled)29. (canceled)30. The method of claim 1 , wherein the CNS-related disorder is a major depressive disorder.31. The method of claim 1 , wherein the CNS-related disorder is tremor.32. The method of claim 31 , wherein the ...

OXYSTEROLS AND METHODS OF USE THEREOF

Compounds are provided according to Formula (I) and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R, R, R, R, R, and Rare as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions. 1. (canceled)3. The compound or pharmaceutically acceptable salt thereof claim 2 , of claim 2 , wherein Rand Rare not both hydrogen.45.-. (canceled)6. The compound or pharmaceutically acceptable salt thereof claim 2 , of claim 2 , wherein each of Rand Ris independently hydrogen claim 2 , —P(O)(R) claim 2 , —S(O)R claim 2 , —C(O)R claim 2 , —C(O)OR claim 2 , —C(O)N(R) claim 2 , —(CH)C(O)N(R) claim 2 , —(CH)OP(O)(R) claim 2 , —(CH)OS(O)R claim 2 , —(CH)OC(O)R claim 2 , or —(CH)C(O)OR;{'sup': a', 'b', 'd, 'each of Rand Ris independently selected from —ORor substituted or unsubstituted alkyl;'}{'sup': 'c', 'each Ris independently substituted or unsubstituted alkyl;'}{'sup': 'd', 'each Ris independently hydrogen or substituted or unsubstituted alkyl;'}each x is independently 1 or 2; andeach of n, m, p is independently 1, 2, 3, or 4.7. (canceled)8. The compound or pharmaceutically acceptable salt thereof claim 2 , of claim 2 , wherein Ris substituted or unsubstituted Calkyl.9. The compound or pharmaceutically acceptable salt thereof claim 2 , of claim 2 , wherein Ris hydrogen.1011.-. (canceled)12. The compound or pharmaceutically acceptable salt thereof claim 2 , of claim 2 , wherein each of Rand Ris independently hydrogen claim 2 , methyl claim 2 , —CF claim 2 , ethyl claim 2 , isopropyl claim 2 , cyclopropyl claim 2 , or butyl.13. The compound or pharmaceutically acceptable salt thereof claim 2 , of claim 2 , wherein Ris a moiety cleavable under biological conditions and Ris hydrogen.14. The compound or pharmaceutically acceptable salt thereof claim 2 , of claim 2 , wherein Ris hydrogen and Ris a moiety cleavable under biological conditions.15. The compound or ...

COMPOSITIONS AND METHODS FOR TREATING CNS DISORDERS

Provided herein are compounds of Formula (I-I): and pharmaceutically acceptable alts thereof; wherein p, R, R, R, R, R, R, and Rare defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I-X) and methods of using the compounds, e.g., in the treatment of CNS-related disorders. 2. The compound of claim 1 , wherein Ris hydrogen.3. The compound of claim 1 , wherein Ris methyl.4. The compound of any one of - claim 1 , wherein le is substituted or unsubstitued alkyl.5. The compound of any one of - claim 1 , wherein le is substituted or unsubstitued heteroaryl.6. The compound of any one of - claim 1 , wherein le is substituted or unsubstitued heteroaryl claim 1 , wherein the heteroaryl contains at least one nitrogen atom.7. The compound of any one of - claim 1 , wherein le is substituted or unsubstitued heteroaryl claim 1 , wherein the heteroaryl is a bicyclic.9. The compound of any one of - claim 1 , wherein Ris Calkyl optionally substituted with alkoxy or one to two halo groups (e.g. claim 1 , fluoro) claim 1 , and at least one of R claim 1 , R claim 1 , and Ris halogen (e.g. claim 1 , —F claim 1 , —Cl claim 1 , —Br) claim 1 , —NO claim 1 , —CN claim 1 , —OR claim 1 , —N(R) claim 1 , —C(═O)R claim 1 , —C(═O)OR claim 1 , —SR claim 1 , —S(O)R claim 1 , e.g. claim 1 , —S(═O)R claim 1 , —S(═O)R claim 1 , —SOS(═O)R. —S(═O)N(R) claim 1 , substituted or unsubstituted Calkyl (e.g. claim 1 , —CH claim 1 , —CHCH claim 1 , haloalkyl claim 1 , e.g. claim 1 , —CF) claim 1 , wherein Ris substituted or unsubstituted Calkyl.12. The compound of any one of - claim 1 , wherein Ris unsubstituted Calkyl.13. The compound of any one of - claim 1 , wherein Ris a Calkyl optionally substituted with alkoxy.14. The compound of any one of - claim 1 , wherein Ris a Calkyl optionally substituted with one or two halo (e.g. claim 1 , fluoro).15. The compound of any one of - claim 1 , wherein Ris —CH claim 1 , —CHCH claim 1 , —CHF claim 1 , —CHF claim 1 , — ...

19-NOR C3, 3-DISUBSTITUTED C21-N-PYRAZOLYL STEROIDS AND METHODS OF USE THEREOF

Provided herein are 19-nor C3,3-disubstituted C21-pyrazolyl steroids of Formula (I), and pharmaceutically acceptable salts thereof; wherein-, R, R, R, R, R, R, R, R, and Rare as defined herein. Such compounds are contemplated useful NI for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, convulsive disorders, disorders of memory and/or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, and tinnitus. 2. The compound of Formula (I) of claim 1 , wherein Ris Calkyl optionally substituted with alkoxy or one to two halo groups claim 1 , and at least one of R claim 1 , R claim 1 , and Ris halogen claim 1 , —NO claim 1 , —CN claim 1 , —OR claim 1 , —N(R) claim 1 , —C(═O)R claim 1 , —C(═O)OR claim 1 , SR claim 1 , —S(O)R claim 1 , e.g. claim 1 , —S(═O)R claim 1 , —S(═O)R claim 1 , —S(═O)OR claim 1 , —OS(═O)R claim 1 , —S(═O)N(R) claim 1 , substituted or unsubstituted Calkyl claim 1 , wherein Ris substituted or unsubstituted Calkyl.5. The compound of claim 1 , wherein Ris unsubstituted Calkyl.6. The compound of claim 1 , wherein Ris a Calkyl optionally substituted with alkoxy.7. The compound of claim 1 , wherein Ris a Calkyl optionally substituted with one or two halo.8. The compound of claim 1 , wherein Ris —CH claim 1 , —CHCH claim 1 , —CHF claim 1 , —CHF claim 1 , —CHO CHCH claim 1 , or —CHOCH.9. The compound of claim 8 , wherein Ris —CH.10. The compound of claim 1 , wherein Ris —OH claim 1 , —OCH claim 1 , —OCHCH claim 1 , —OCHCHCH claim 1 , —CH claim 1 , —CHCH claim 1 , —CHCHCH claim 1 , substituted or unsubstituted cyclopropyl claim 1 , fluoro claim 1 , or chloro.11. The compound of claim 10 , wherein Ris —CHor —OCH.12. The compound of claim 11 , wherein Ris —OCH.13. The compound of claim 1 , wherein Ris hydrogen.14. The ...

19-NOR NEUROACTIVE STEROIDS AND METHODS OF USE THEREOF

Provided herein are 3,3-disubstituted 19-nor-steroidal compounds according to Formula (I): 12-. (canceled)48-. (canceled)9. The compound or pharmaceutically acceptable salt of claim 3 , wherein e is 1.10. The compound or pharmaceutically acceptable salt of claim 9 , wherein Ris substituted or unsubstituted Calkyl.11. The compound or pharmaceutically acceptable salt of claim 10 , wherein Ris —CH.12. The compound or pharmaceutically acceptable salt of claim 9 , wherein Ris —ORwherein Ris hydrogen or substituted or unsubstituted Calkyl.13. The compound or pharmaceutically acceptable salt of claim 12 , wherein Ris —OH.14. The compound or pharmaceutically acceptable salt of claim 9 , wherein Ris —S(═O)Rwherein Ris substituted or unsubstituted Calkyl.15. The compound or pharmaceutically acceptable salt of claim 14 , wherein Ris —S(═O)CH.16. The compound or pharmaceutically acceptable salt of claim 9 , wherein Ris —C(═O)Rwherein Ris substituted or unsubstituted Calkyl.17. The compound or pharmaceutically acceptable salt of claim 16 , wherein Ris —C(═O)CH.18. The compound or pharmaceutically acceptable salt of claim 9 , wherein Ris —C(═O)N(R)wherein Ris hydrogen or substituted or unsubstituted Calkyl.19. The compound or pharmaceutically acceptable salt of claim 18 , wherein Ris —C(═O)NHCH.20. (canceled)21. The compound or pharmaceutically acceptable salt of claim 3 , wherein between C5 and C6 is a single bond.23. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 3 , or a pharmaceutically acceptable salt thereof.2427-. (canceled)28. A method for positively modulating a GABA receptor in a subject in need thereof claim 3 , comprising administering to the subject an effective amount of a compound of or a pharmaceutically acceptable salt thereof.29. The method of claim 28 , wherein the subject has a CNS-related disorder.30. The method of claim 29 , wherein the CNS-related disorder is a sleep disorder claim 29 , a mood disorder ...

OXYSTEROLS AND METHODS OF USE THEREOF

Compounds are provided according to Formula (III): 2. The pharmaceutical composition of claim 1 , wherein Ris hydrogen.3. The pharmaceutical composition of claim 1 , wherein Ris deuterium.4. The pharmaceutical composition of claim 1 , wherein Rand Rare deuterium.5. The pharmaceutical composition of claim 1 , wherein one of Rand Ris deuterium and the other of Rand Ris Calkyl.6. The pharmaceutical composition of claim 1 , wherein each of Rand Ris independently —Calkyl.7. The pharmaceutical composition of claim 1 , wherein each of Rand Ris independently isopropyl claim 1 , —CH claim 1 , or —CF.8. The pharmaceutical composition of claim 1 , wherein Ris hydrogen.9. The pharmaceutical composition of claim 1 , wherein n is 1.10. The pharmaceutical composition of claim 1 , wherein n is 2.11. The pharmaceutical composition of claim 1 , wherein represents a single bond.17. (canceled)18. A method of inducing sedation or anesthesia comprising administering to a subject an effective amount of the pharmaceutical composition of .19. A method for treating or preventing a disorder described herein claim 1 , comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of .20. The method according to claim 19 , wherein the disorder is a gastrointestinal (GI) disorder claim 19 , irritable bowel syndrome (IBS) claim 19 , inflammatory bowel disease (IBD) claim 19 , structural disorders affecting the GI claim 19 , anal disorders claim 19 , colon polyps claim 19 , cancer claim 19 , or colitis.21. The method according to claim 19 , wherein the disorder is inflammatory bowel disease.22. The method according to claim 19 , wherein the disorder is cancer claim 19 , diabetes claim 19 , or a sterol synthesis disorder.23. A method for treating or preventing a CNS-related condition comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of .24. The method according to claim 23 , wherein the CNS- ...

NEUROACTIVE 19-ALKOXY-17-SUBSTITUTED STEROIDS, PRODRUGS THEREOF, AND METHODS OF TREATMENT USING SAME

The present disclosure is generally directed to neuroactive 19-alkoxy-17-substituted steroids as referenced herein, and pharmaceutically acceptable salts thereof, for use as, for example, an anesthetic, and/or in the treatment of disorders relating to GABA function and activity. The present disclosure is further directed to pharmaceutical compositions comprising such compounds. 2. (canceled)3. The compound of claim 1 , wherein the Rgroup is selected from the group consisting of H claim 1 , methyl claim 1 , and trifluoromethyl.4. (canceled)5. The compound of claim 1 , wherein Ris H.6. The compound of claim 1 , wherein Ris substituted methyl.7. The compound of claim 1 , wherein the C—H is in the alpha position.8. The compound of claim 1 , wherein the C—H is in the beta configuration and Rgroup is in the beta configuration.9. The compound of claim 1 , wherein Ris H.10. The compound of claim 1 , wherein Ris ═O claim 1 , methoxy or H.11. The compound of claim 1 , wherein Ris methyl.13. The compound of wherein Ris methyl.14. The compound of claim 12 , wherein Ris beta-methoxy.15. (canceled)16. The compound of claim 12 , wherein Ris beta-cyano.17. The compound of claim 12 , wherein Ris ═O.18. (canceled)19. The compound of claim 12 , wherein Ris beta-CHC(O)—.20. The compound of claim 12 , wherein Ris beta-HOCHC(O)—.22. The compound of claim 21 , wherein Ris methyl.2350-. (canceled)53. (canceled) This application claims priority benefit of U.S. Provisional Patent Application Ser. No. 61/738,822, filed on Dec. 18, 2012, the entire content of which is incorporated herein by reference.The claimed subject matter was developed with Government support under NIH Grant #GM47969, awarded by the National Institute of Health. Accordingly, the Government has certain rights in the claimed subject matter.The present disclosure is generally directed to novel compounds having utility as an anesthetic and/or in the treatment of disorders relating to GABA function and activity. More ...

NEUROACTIVE 19-ALKOXY-17-SUBSTITUTED STEROIDS, PRODRUGS THEREOF, AND METHODS OF TREATMENT USING SAME

The present disclosure is generally directed to neuroactive 19-alkoxy-17-substituted steroids as referenced herein, and pharmaceutically acceptable salts thereof, for use as, for example, an anesthetic, and/or in the treatment of disorders relating to GABA function and activity. The present disclosure is further directed to pharmaceutical compositions comprising such compounds. 2. The compound of claim 1 , wherein one or both of Ror R claim 1 , when present and other than H claim 1 , are in the beta configuration.3. The compound of claim 1 , wherein the Rgroup is selected from the group consisting of H claim 1 , methyl claim 1 , and trifluoromethyl.4. The compound of claim 1 , wherein Ris selected from the group consisting of H claim 1 , methoxy claim 1 , ethoxy claim 1 , and an optionally substituted morpholinyl ring.5. The compound of claim 1 , wherein Ris H.6. The compound of claim 1 , wherein Ris substituted methyl.7. The compound of claim 1 , wherein the C—H is in the alpha position.8. The compound of claim 1 , wherein the C—H is in the beta configuration and Rgroup is in the beta configuration.9. The compound of claim 1 , wherein Ris H.10. The compound of claim 1 , wherein Ris ═O claim 1 , methoxy or H.11. The compound of claim 1 , wherein Ris methyl.13. The compound of wherein Ris methyl.14. The compound of claim 12 , wherein Ris beta-methoxy.15. The compound of claim 12 , wherein Ris beta-spirooxirane.16. The compound of claim 12 , wherein Ris beta-cyano.17. The compound of claim 12 , wherein Ris ═O.18. The compound of claim 12 , wherein Ris beta-nitro.19. The compound of claim 12 , wherein Ris beta-CHC(O)—.20. The compound of claim 12 , wherein Ris beta-HOCHC(O)—.22. The compound of claim 21 , wherein Ris methyl.2324-. (canceled)26. The compound of claim 25 , wherein Ris OH in the beta configuration.27. The compound of claim 25 , wherein Ris ═O.28. The compound of claim 25 , wherein Ris selected from the group consisting of H claim 25 , methoxy claim 25 , ...

NEUROACTIVE STEROIDS, COMPOSITIONS, AND USES THEREOF

Described herein are neuroactive steroids of the Formula (1) or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, and/or isotopic variant thereof. Such compounds are envisioned, in certain embodiments, to behave as soft drugs and, in certain embodiments, as GABA modulators. The present invention also provides pharmaceutical compositions comprising a compound of the present invention and methods of use and treatment, e.g., such for inducing sedation and/or anesthesia. 14. The compound of claim 1 , wherein only one of R claim 1 , R claim 1 , R claim 1 , and X is a group of the formula —OC(═O)R.15. The compound of claim 14 , wherein Ris a group of the formula —OC(═O)R.16. The compound of claim 14 , wherein Ris a group of the formula —OC(═O)R.17. The compound of claim 14 , wherein Ris a group of the formula —OC(═O)R.18. The compound of claim 14 , wherein X is a group of the formula —OC(═O)R.19. The compound of claim 1 , wherein at least two of R claim 1 , R claim 1 , R claim 1 , and X is claim 1 , independently claim 1 , a group of the formula —OC(═O)R.20. The compound of claim 1 , wherein Ris —CH claim 1 , —CHCN claim 1 , or phenyl.21. The compound of claim 20 , wherein Ris —CH.23. The compound of claim 22 , wherein Zand Zare joined to form an alkenyl group ═CH(CN) claim 22 , wherein CN is in the Z configuration;24. The compound of claim 22 , wherein R claim 22 , R claim 22 , R claim 22 , and Rare each H.25. The compound of claim 22 , wherein Ris —CH claim 22 , —CHCN claim 22 , or phenyl.26. The compound of claim 25 , wherein Ris —CH.27. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable excipient.28. A method of inducing sedation and/or anesthesia in a subject claim 1 , comprising administering to the subject an effective amount of a compound of .29. The method of claim 28 , wherein the compound is administered by intravenous administration.30. The method of claim 28 , wherein the compound is metabolized in vivo ...

NEUROACTIVE STEROIDS, COMPOSITIONS, AND USES THEREOF

Provided herein are 19-nor C3, 3-disubstituted steroids of Formula (I): and pharmaceutically acceptable salts thereof; wherein R, R, R, and Rare as defined herein, and A is a heteroaryl ring system comprising 3 or 4 nitrogens as defined herein. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, convulsive disorders, disorders of memory and/or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, and tinnitus. 2. The compound of claim 1 , wherein n is 0 or 1.3. The compound of claim 1 , wherein n is 0.4. The compound of claim 1 , wherein n is 1.8. The compound of claim 1 , wherein Ris C-Calkyl.9. The compound of claim 1 , wherein Ris —CH.10. The compound of claim 1 , wherein Rand Rare H.11. The compound of claim 1 , wherein n is 1 and Ris halo claim 1 , cyano claim 1 , —S(O)R claim 1 , or C-Calkyl.12. The compound of claim 11 , wherein Ris —CH.13. The compound of claim 1 , wherein Ris —C(O)OR.14. The compound of claim 1 , wherein Ris —C(O)NRR.15. The compound of claim 13 , wherein Ris H or C-Calkyl.16. The compound of claim 14 , wherein Rand Rare H.17. The compound of claim 1 , wherein Ris cyano.18. The compound of claim 11 , wherein Ris —S(O)CH.21. A pharmaceutical composition comprising the compound of or a pharmaceutically acceptable salt thereof claim 1 , and a pharmaceutically acceptable excipient.22. A method for treating a CNS-related disorder in a subject in need thereof claim 1 , comprising administering to the subject an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.23. The method of claim 22 , wherein the CNS-related disorder is a sleep disorder claim 22 , an eating disorder claim 22 , a mood disorder claim 22 , a schizophrenia ...

OXYSTEROLS AND METHODS OF USE THEREOF

Compounds are provided according to Formula (I) and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R, R, and Rare as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions. 2. The compound of claim 1 , wherein Ris Calkyl.3. The compound of claim 2 , wherein Ris substituted Calkyl.4. The compound of claim 2 , wherein Ris unsubstituted Calkyl.5. (canceled)6. The compound of claim 1 , wherein Ris methyl or ethyl.7. The compound of claim 1 , wherein Ris Calkyl or carbocyclyl.8. (canceled)9. The compound of claim 1 , wherein Ris carbocyclyl or heterocyclyl.10. The compound of claim 9 , wherein Ris cyclopropyl claim 9 , cyclobutyl claim 9 , cyclopentyl claim 9 , cyclohexyl.11. (canceled)12. (canceled)23. A pharmaceutical composition comprising a compound of claim 1 , or pharmaceutically acceptable salt thereof claim 1 , and a pharmaceutically acceptable carrier.24. A method of inducing sedation or anesthesia comprising administering to a subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , or pharmaceutical composition thereof.25. A method for treating or preventing a disorder described herein claim 1 , comprising administering to a subject in need thereof an effective amount of a compound claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , or pharmaceutical composition thereof.26. The method according to claim 25 , wherein the disorder is a gastrointestinal (GI) disorder irritable bowel syndrome (IBS) claim 25 , inflammatory bowel disease (IBD) claim 25 , structural disorders affecting the GI claim 25 , anal disorders claim 25 , colon polyps claim 25 , cancer claim 25 , colitis.27. (canceled)28. The method according to claim 26 , wherein the disorder is inflammatory bowel disease claim 26 , cancer claim 26 , diabetes claim 26 , or a sterol synthesis disorder.29. A method for ...

19-nor c3, 3-disubstituted c21-n-pyrazolyl steroids and methods of use thereof

Provided herein are 19-nor C3,3-disubstituted C21-pyrazolyl steroids of Formula (I): and pharmaceutically acceptable salts thereof; wherein , R 1 , R 2 , R 3a , R 3b , R 4a , R 4b , R 5 , R 6 , and R 7 are as defined herein. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, convulsive disorders, disorders of memory and/or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, and tinnitus.

OXYSTEROLS AND METHODS OF USE THEREOF

Compounds are provided according to Formula (I) and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein X, Y, R, R, R, R, R, R, R, R, R, R, and Rare as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions. 2. The compound of claim 1 , wherein Ris unsubstituted Calkyl.3. The compound of claim 2 , wherein Ris —CH claim 2 , —CHCH claim 2 , or —CHCHCH.4. The compound of claim 1 , wherein Ris substituted Calkyl.5. The compound of claim 1 , wherein Ris haloalkyl or —CHOCH.6. The compound of claim 1 , wherein Ror Ris hydrogen.7. The compound of claim 1 , wherein Rand Ris hydrogen.8. The compound of claim 1 , wherein Ris hydrogen.9. The compound of claim 1 , wherein X is —CH—.10. The compound of claim 1 , wherein Ris substituted or unsubstituted Calkyl.11. The compound of claim 10 , wherein Ris —CH.15. The compound of claim 1 , wherein Ror Ris hydrogen.16. The compound of claim 1 , wherein Rand Rare both hydrogen.17. The compound of claim 1 , wherein Ris a substituted or unsubstituted Calkyl.18. The compound of claim 17 , wherein Ris —CHor —CHCH.19. The compound of claim 1 , wherein Ris a substituted or unsubstituted Calkyl claim 1 , substituted or unsubstituted Calkenyl claim 1 , substituted or unsubstituted Calkynyl claim 1 , or substituted or unsubstituted carbocyclyl.20. The compound of claim 1 , wherein Ris substituted or unsubstituted Calkyl.21. The compound of claim 20 , wherein Ris —CHor —CHCH.22. The compound of wherein Ris hydrogen.23. The compound of claim 20 , wherein Ris —CHor —CF.24. The compound of claim 1 , wherein Rand Rare both —CH.25. The compound of claim 1 , wherein Rand R claim 1 , taken together with the atom to which they are attached claim 1 , form a ring.26. The compound of claim 25 , wherein the ring is a 3-membered ring.27. The compound of claim 1 , wherein Ris hydrogen or Calkyl claim 1 , Ris substituted or unsubstituted ...

NEUROACTIVE 19-ALKOXY-17-SUBSTITUTED STEROIDS, PRODRUGS THEREOF, AND METHODS OF TREATMENT USING SAME

The present disclosure is generally directed to neuroactive 19-alkoxy-17-substituted steroids as referenced herein, and pharmaceutically acceptable salts thereof, for use as, for example, an anesthetic, and/or in the treatment of disorders relating to GABA function and activity. The present disclosure is further directed to pharmaceutical compositions comprising such compounds. 2. The method of claim 1 , wherein the Rgroup is selected from the group consisting of H claim 1 , methyl claim 1 , and trifluoromethyl.3. The method of claim 1 , wherein Ris ═O claim 1 , methoxy or H.4. The method of claim 1 , wherein Ris beta-cyano.6. The method of claim 1 , wherein{'sub': 1', '1', '4', '1', '4', '1', '4, 'Ris selected from (C-Calkyl)-O, spirooxirane, cyano, ═O, (C-Calkyl)C(O), and HO(C-Calkyl)C(O).'}7. The method of claim 1 , wherein the mood disorder is selected from the group consisting of depression claim 1 , dysthymic disorder claim 1 , and bipolar disorder. This application is divisional of U.S. patent application Ser. No. 15/586,853 filed on May 4, 2017, which is a divisional of U.S. patent application Ser. No. 14/652,717 filed on Jun. 16, 2015 (now U.S. Pat. No. 9,676,812), which is a U.S. National Stage Application based on International Patent Application No. PCT/US2013/076214 filed on Dec. 18, 2013, which claims priority benefit of U.S. Provisional Patent Application Ser. No. 61/738,822 filed on Dec. 18, 2012, the entire contents of which are incorporated herein by reference.The invention was made with government support under GM047969, awarded by the National Institutes of Health. The government has certain rights in the invention.The present disclosure is generally directed to novel compounds having utility as an anesthetic and/or in the treatment of disorders relating to GABA function and activity. More specifically, the present disclosure is directed to steroids having a 19-alkoxy-17-substituted tetracyclic structure that are neuroactive and suitable for use ...

OXYSTEROLS AND METHODS OF USE THEREOF

Compounds are provided according to Formula (I): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R, R, R, R, and and Rare as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions. 2. The compound of claim 1 , wherein Ris hydrogen or substituted or unsubstituted C-Calkyl.3. The compound of claim 1 , wherein Ris C-Chaloalkyl.46-. (canceled)7. The compound of claim 1 , wherein each of Rand Ris independently hydrogen claim 1 , carbocyclyl claim 1 , or heterocyclyl.89-. (canceled)10. The compound of claim 1 , wherein at least one of Rand Ris C-Calkyl claim 1 , carbocyclyl claim 1 , or heterocyclyl; or Rand R claim 1 , together with the carbon atom to which they are attached form a 3-8 membered ring.1128-. (canceled)29. The compound of claim 1 , wherein Rand R claim 1 , together with the carbon atom to which they are attached form a 5-membered ring.3031-. (canceled)32. The compound of claim 1 , wherein Rand R claim 1 , together with the carbon atom to which they are attached form a 6-membered ring.3337-. (canceled)38. The compound of claim 1 , wherein Rand R claim 1 , together with the carbon atom to which they are attached form a 3-8 membered carbocyclic or heterocyclic ring.39. The compound of claim 38 , wherein the carbocyclic or heterocyclic ring is substituted with 1 or 2 halo or alkyl groups.4053-. (canceled)55. A pharmaceutical composition comprising a compound of claim 1 , or pharmaceutically acceptable salt thereof claim 1 , and a pharmaceutically acceptable carrier.56. A method for treating or preventing a disorder described herein claim 1 , comprising administering to a subject in need thereof an effective amount of a compound of claim 1 , or pharmaceutically acceptable salt thereof claim 1 , or pharmaceutical composition thereof claim 1 , wherein the disorder is a gastrointestinal (GI) disorder claim 1 , constipation claim 1 , ...

C17, C20, AND C21 SUBSTITUTED NEUROACTIVE STEROIDS AND THEIR METHODS OF USE

Described herein are neuroactive steroids or a pharmaceutically acceptable salt thereof. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. Also provided are pharmaceutical compositions comprising a compound described herein and methods of use and treatment, e.g., such as for inducing sedation and/or anesthesia. 310-. (canceled)12. The compound of claim 11 , wherein each instance of Ris independently hydrogen claim 11 , —CH claim 11 , —CN claim 11 , or —F.13. (canceled)14. The compound of claim 11 , wherein Ris hydrogen.1518-. (canceled)21. The compound of claim 20 , wherein Ris hydrogen claim 20 , —CH claim 20 , or —CHCH claim 20 , —CH(CH) claim 20 , or cycloalkyl.22. (canceled)23. The compound of claim 20 , wherein Ris heterocyclyl claim 20 , aryl claim 20 , or heteroaryl.24. (canceled)25. (canceled)2729-. (canceled)33. The compound of claim 32 , wherein Ris —NRR claim 32 , —N(R1)C(O)R claim 32 , —N(R1)SOR.34. The compound of claim 32 , wherein Ris aryl claim 32 , heteroaryl claim 32 , cycloalkyl claim 32 , or heterocyclyl.3538-. (canceled)4245-. (canceled)48. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable excipient.4964-. (canceled)65. A composition for use in treating a CNS-related disorder in a subject in need thereof claim 1 , comprising an effective amount of a compound of .66. The method of claim 65 , wherein the CNS-related disorder is a sleep disorder claim 65 , a mood disorder claim 65 , a schizophrenia spectrum disorder claim 65 , a convulsive disorder claim 65 , a disorder of memory and/or cognition claim 65 , a movement disorder claim 65 , a personality disorder claim 65 , autism spectrum disorder claim 65 , pain claim 65 , traumatic brain injury claim 65 , a vascular disease claim 65 , a substance abuse disorder and/or withdrawal syndrome claim 65 , or tinnitus.67. (canceled)68. A kit comprising a solid composition comprising a compound of and a sterile diluent.69. A ...

Compositions and methods for treating cns disorders

Described herein are neuroactive steroids of the Formula (I): or a pharmaceutically acceptable salt thereof; wherein , A, R 1 , R 2 , and R 3 are as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. The present invention also provides pharmaceutical compositions comprising a compound of the present invention and methods of use, e.g., for treating a subject suffering from a disease or disorder described herein.

NEUROACTIVE 19-ALKOXY-17-SUBSTITUTED STEROIDS, PRODRUGS THEREOF, AND METHODS OF TREATMENT USING SAME

The present disclosure is generally directed to neuroactive 19-alkoxy-17-substituted steroids as referenced herein, and pharmaceutically acceptable salts thereof, for use as, for example, an anesthetic, and/or in the treatment of disorders relating to GABA function and activity. The present disclosure is further directed to pharmaceutical compositions comprising such compounds. 2. (canceled)3. The compound of claim 1 , wherein the Rgroup is selected from the group consisting of H claim 1 , methyl claim 1 , and trifluoromethyl.4. (canceled)5. The compound of claim 1 , wherein Ris H.6. The compound of claim 1 , wherein Ris substituted methyl.7. The compound of claim 1 , wherein the C—H is in the alpha position.8. The compound of claim 1 , wherein the C—H is in the beta configuration and Rgroup is in the beta configuration.9. The compound of claim 1 , wherein Ris H.10. The compound of claim 1 , wherein Ris ═O claim 1 , methoxy or H.11. The compound of claim 1 , wherein Ris methyl.13. The compound of wherein Ris methyl.14. The compound of claim 12 , wherein Ris beta-methoxy.15. (canceled)16. The compound of claim 12 , wherein Ris beta-cyano.17. The compound of claim 12 , wherein Ris ═O.18. (canceled)19. The compound of claim 12 , wherein Ris beta-CHC(O)—.20. The compound of claim 12 , wherein Ris beta-HOCHC(O)—.22. The compound of claim 21 , wherein Ris methyl.2350-. (canceled)53. (canceled) This application claims priority benefit of U.S. Provisional Patent Application Ser. No. 61/738,822, filed on Dec. 18, 2012, the entire content of which is incorporated herein by reference.The claimed subject matter was developed with Government support under NIH Grant #GM47969, awarded by the National Institute of Health. Accordingly, the Government has certain rights in the claimed subject matter.The present disclosure is generally directed to novel compounds having utility as an anesthetic and/or in the treatment of disorders relating to GABA function and activity. More ...

COMPOSITIONS AND METHODS FOR TREATING CNS DISORDERS

Described herein are deuterium-enriched neuroactive steroids of the Formula (II) or a pharmaceutically acceptable salt thereof; wherein R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, and Rand subvariables thereof are as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. The present invention also provides pharmaceutical compositions comprising a compound of the present invention and methods of use and treatment. 2. The method of claim 1 , wherein the mood disorder is depression.3. The method of claim 2 , wherein the depression is postpartum depression.4. The method of claim 1 , wherein the administering is performed orally.5. The method of claim 1 , wherein the administering is performed parenterally.6. The method of claim 1 , wherein the administering is performed intravenously.7. The method of claim 6 , wherein the administering occurs by continuous intravenous infusion.8. The method of claim 1 , wherein the subject is a mammal.9. The method of claim 1 , wherein the subject is a human.10. The method of claim 8 , wherein the subject is a female.11. The method of claim 8 , wherein the subject is an adult.12. The method of claim 9 , wherein the subject is from 18 to 45 years of age.13. The method of claim 1 , wherein the subject is suffering from or has been diagnosed with postpartum depression or severe postpartum depression.14. The method of claim 1 , wherein the subject has experienced a Major Depressive Episode in the postpartum period.15. The method of claim 14 , wherein the period begins within the first 4 weeks following delivery of a baby.16. (canceled)18. The method of claim 17 , wherein the subject experiences sedation and/or anesthesia within one hour of administration.19. The method of claim 17 , wherein the subject experiences sedation and/or anesthesia instantaneously.20. The method of claim 17 , wherein the compound is administered by intravenous administration.21. The method of claim 17 , wherein ...

19-NOR C3, 3-DISUBSTITUTED C21-N-PYRAZOLYL STEROIDS AND METHODS OF USE THEREOF

Provided herein are 19-nor C3,3-disubstituted C21-pyrazolyl steroids of Formula (I): 147-. (canceled)49. The method of claim 48 , wherein the CNS-related disorder is a sleep disorder.50. The method of claim 49 , wherein the sleep disorder is insomnia.51. The method of claim 48 , wherein the CNS-related disorder is a mood disorder.52. The method of claim 51 , wherein the mood disorder is depression.53. The method of claim 48 , wherein the compound is administered orally.55. The method of claim 54 , wherein the CNS-related disorder is a sleep disorder.56. The method of claim 55 , wherein the sleep disorder is insomnia.57. The method of claim 54 , wherein the CNS-related disorder is a mood disorder.58. The method of claim 57 , wherein the mood disorder is depression.59. The method of claim 54 , wherein the pharmaceutical composition is administered orally. This application is a continuation of U.S. Ser. No. 14/785,171 filed Apr. 17, 2014, which is a national stage application under U.S.C. § 371 of International Application No. PCT/CN2014/075594, filed Apr. 17, 2014, published as International Publication No. WO2014/169833 on Oct. 23, 2014, which claims priority to International Application No. PCT/CN2013/074323, filed Apr. 17, 2013, the contents of each of which is incorporated herein by reference in its entirety.Brain excitability is defined as the level of arousal of an animal, a continuum that ranges from coma to convulsions, and is regulated by various neurotransmitters. In general, neurotransmitters are responsible for regulating the conductance of ions across neuronal membranes. At rest, the neuronal membrane possesses a potential (or membrane voltage) of approximately −70 mV, the cell interior being negative with respect to the cell exterior. The potential (voltage) is the result of ion (K, Na, Cl, organic anions) balance across the neuronal semipermeable membrane.Neurotransmitters are stored in presynaptic vesicles and are released under the influence of ...

Oxysterols and methods of use thereof

Compounds are provided according to Formula (I), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein A, R 1 , and R 5 are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.

19-nor neuroactive steroids and methods of use thereof

Provided herein are 3,3-disubstituted19-nor-steroidal compounds according to Formula(I): and pharmaceutical compositions thereof. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions,for example, treatment of sleep disorders, mood disorders,schizophrenia spectrum disorders, disorders of memory and/or cognition, movement disorders,personality disorders,autism spectrum disorders, pain,traumatic brain injury, vascular diseases,substance abuse disorders and/or withdrawal syndromes, tinnitus, status epilepticus.

Oxysterols and methods for use thereof

【課題】ＮＭＤＡ媒介性障害を含む障害の予防および／または処置に有用な置換オキシステロールを提供する。【解決手段】式（Ｉ）の化合物およびその薬学的に受容可能な塩ならびにその薬学的組成物が提供される。TIFF2022120062000111.tif3076（Ｒ１：Ｃ１～６アルキル。Ｒ２、Ｒ３：Ｈ、Ｃ１～６アルキル、カルボシクリルなど。Ｒ６：存在しない、またはＨ。Ｒ７、Ｒ８：Ｈ，ハロゲン、Ｃ１～６アルキル、カルボシクリルなど。ｎ：１、２、３）【選択図】なし

Neuroactive steroids, compositions, and uses thereof

19-nor C3,3-disubstituted C21-N-pyrazolyl steroids and methods of use thereof

Provided herein are 19-nor C3,3-disubstituted C2l-pyrazolyl steroids of Formula (SA-4), and pharmaceutically acceptable salts thereof. The use of the compound in the manufacture of medicaments for the treatment of mood disorders including depression, postnatal depression, generalized anxiety disorder, bipolar disorder, major depressive disorder, and tremor is claimed. r, bipolar disorder, major depressive disorder, and tremor is claimed.

Neuroactive steroids, compositions, and uses thereof

Neuroactive steroids, compositions, and uses thereof

Described herein are neuroactive steroids of the Formula (I): (Formula (I)) or a pharmaceutically acceptable salt thereof; wherein R1a and R1b are as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. The present invention also provides pharmaceutical compositions comprising a compound of the present invention and methods of use and treatment, e.g., such for inducing sedation and/or anesthesia.

Heterocyclyl-3-sulfonylindazoles as 5-hydroxytryptamine-6 ligands

The invention provides compounds of formula (I) and the use thereof in the therapeutic treatment of disorders related to or affected by the 5-HT6 receptor.

Neuroactive steroids, compositions, and uses thereof

Described herein are neuroactive steroids of the Formula (I): (A L CH3 RO H ON H HOW R2 R5 (I), or a pharmaceutically acceptable salt thereof; wherein R, R2, R, A and L are as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. The present invention also provides pharmaceutical compositions comprising a compound of the present invention and methods of use and treatment, e.g., such for inducing sedation and/or anesthesia.

Neuroactive steroid solutions and their methods of use

Provided herein are pharmaceutically acceptable aqueous solution comprising a neuroactive steroid, a sulfobutyl ether beta cyclodextrin and a buffer; wherein: the solution is a stable solution between a pH of about 3 and about 9, e.g., at room temperature, for at least 1, 2, 3, 4 weeks; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months; 1, 2, 3 years or more; the buffer is present at a concentration of at least 0.1 mM; or the solution remains substantially free of impurities (e.g., the solution is substantially free of impurities at room temperature for at least 1, 2, 3, 4 weeks; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months; 1, 2, 3 years or more).

Neuroactive steroids, compositions, and uses thereof

Oxysterols and methods of use thereof

Compounds are provided according to Formula (I): Formula (I) and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R1, R2, R3, R6, R7, R8, and n are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.

11-SUBSTITUTED 24-HYDROXYSTEROLS FOR USE IN THE TREATMENT OF NMDA-RELATED CONDITIONS

Oxysterols and methods of use thereof

Oxysterols and methods of use thereof

Compounds are provided according to Formula (I), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein A, R

C17, C20, and C21 substituted neuroactive steroids and their methods of use

Described herein are neuroactive steroids or a pharmaceutically acceptable salt thereof. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. Also provided are pharmaceutical compositions comprising a compound described herein and methods of use and treatment, e.g., such as for inducing sedation and/or anesthesia.

Compositions and methods for treating cns disorders

Substituted-3-sulfonylindazole derivatives as 5-hydroxytryptamine-6 ligands

The present invention provides a compound of formula (I) and the use thereof for the treatment of a central nervous system disorder related to or affected by the 5-HT6 receptor.

N-substituted-azacyclylamines as histamine-3 antagonists

The present invention provides a compound of formula (I) and the use thereof for the treatment of a central nervous system disorder related to or affected by the histamine-3 receptor.

19-nor c3,3-disubstituted c21-n-pyrazolyl steroid for use in therapy

compound; method for treating a central nervous system disorder related to or affected by the 5-ht6 receptor in a patient in need; pharmaceutical composition; and process for the preparation of the compound

COMPOSTO; MéTODO PARA TRATAMENTO DE UM TRANSTORNO DO SISTEMA NERVOSO CENTRAL RELACIONADO A OU AFETADO PELO RECEPTOR 5-HT6 EM UM PACIENTE NECESSITADO; COMPOSIçAO FARMACEUTICA; E PROCESSO PARA A PREPARAçAO DO COMPOSTO. A presente invenção apresenta um composto de fórmula I e seu uso para o tratamento de um transtorno do sistema nervoso central relacionado a ou afetado pelo receptor 5-HT6. COMPOUND; METHOD FOR TREATING A CENTRAL NERVOUS SYSTEM DISORDER RELATED TO OR AFFECTED BY THE 5-HT6 RECEPTOR IN A NEEDED PATIENT; PHARMACEUTICAL COMPOSITION; AND PROCESS FOR THE PREPARATION OF COMPOUND. The present invention features a compound of formula I and its use for the treatment of a disorder of the central nervous system related to or affected by the 5-HT6 receptor.

Dihydro[1,4]oxazino[2,3,4-hi]indazole derivatives as 5-hydroxytryptamine-6 ligands

The present invention provides a compound of formula (I) and the use thereof for the treatment of a central nervous system disorder related to or affected by the 5-HT6 receptor.

Neuroactive 19-alkoxy-17-substituted steroids, useful in methods of treatment

Neuroactive steroids, compositions and uses thereof

Compositions and methods for treating CNS disorders

Described herein are neuroactive steroids of the Formula (I): A R4 R3 a H R 2 R1 HO' R 5 R 7a R 7b or a pharmaceutically acceptable salt thereof; wherein ---- , A, R, R2, R3a, R 4a, R4b, R, R7 7a, and R 7b are as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. The present invention also provides pharmaceutical compositions comprising a compound of the present invention and methods of use and treatment, e.g., such for inducing sedation and/or anesthesia.

Amino-5-[substituted-4-(difluoromethoxy)phenyl]-5- phenylimidazolone compounds as ã¿-secretase inhibitors.

La presente invención proporciona un compuesto 2-amino-5-[-4-(difluorometoxi)fenil sustituido]-5-fenilimidazolona de la Fórmula I (ver fórmula (I)) La presente invención también proporciona métodos para el uso de estos para inhibir ß-secretasa (BACE) y tratar depósitos ß-amiloides y ovillos neurofibrilares.