WO2014169832A1 - 19-nor neuroactive steroids and methods of use thereof - Google Patents

19-nor neuroactive steroids and methods of use thereof Download PDF

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Publication number
WO2014169832A1
WO2014169832A1 PCT/CN2014/075593 CN2014075593W WO2014169832A1 WO 2014169832 A1 WO2014169832 A1 WO 2014169832A1 CN 2014075593 W CN2014075593 W CN 2014075593W WO 2014169832 A1 WO2014169832 A1 WO 2014169832A1
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Prior art keywords
substituted
unsubstituted
compound
certain embodiments
alkyl
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PCT/CN2014/075593
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French (fr)
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WO2014169832A9 (en
Inventor
Gabriel Martinez Botella
Boyd L. Harrison
Albert Jean Robichaud
Francesco G. Salituro
Richard Thomas Beresis
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Sage Therapeutics, Inc.
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Priority to EP14786089.4A priority Critical patent/EP2986624B1/en
Priority to PL14786089T priority patent/PL2986624T3/en
Priority to RS20200756A priority patent/RS60420B1/en
Priority to AU2014256228A priority patent/AU2014256228C1/en
Priority to DK14786089.4T priority patent/DK2986624T3/en
Priority to CA2909546A priority patent/CA2909546C/en
Priority to RU2015149009A priority patent/RU2700264C2/en
Priority to CN202311040959.3A priority patent/CN117304245A/en
Priority to CN202010962164.8A priority patent/CN112110976B/en
Priority to ES14786089T priority patent/ES2807264T3/en
Priority to SI201431599T priority patent/SI2986624T1/en
Priority to JP2016507994A priority patent/JP6239091B2/en
Application filed by Sage Therapeutics, Inc. filed Critical Sage Therapeutics, Inc.
Priority to CN201480031474.0A priority patent/CN105246909B/en
Priority to EP20163073.8A priority patent/EP3719030A1/en
Priority to LTEP14786089.4T priority patent/LT2986624T/en
Priority to US14/785,192 priority patent/US9365611B2/en
Publication of WO2014169832A1 publication Critical patent/WO2014169832A1/en
Publication of WO2014169832A9 publication Critical patent/WO2014169832A9/en
Priority to US15/143,312 priority patent/US10377790B2/en
Priority to HK16109158.1A priority patent/HK1220979A1/en
Priority to AU2017203495A priority patent/AU2017203495B9/en
Priority to US16/440,527 priority patent/US11261211B2/en
Priority to AU2019213394A priority patent/AU2019213394B2/en
Priority to HRP20200995TT priority patent/HRP20200995T1/en
Priority to CY20201100581T priority patent/CY1124175T1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J13/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17
    • C07J13/007—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17 with double bond in position 17 (20)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
    • C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
    • C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
    • C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/0065—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by an OH group free esterified or etherified
    • C07J7/007—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by an OH group free esterified or etherified not substituted in position 17 alfa
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/008—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21
    • C07J7/0085—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21 by an halogen atom

Definitions

  • 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.
  • neurotransmitters are responsible for regulating the conductance of ions across neuronal membranes.
  • the neuronal membrane 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 + , CI " , organic anions) balance across the neuronal semipermeable membrane.
  • Neurotransmitters are stored in presynaptic vesicles and are released under the influence of neuronal action potentials.
  • an excitatory chemical transmitter such as acetylcholine will cause membrane depolarization (change of potential from - 70 mV to -50 mV).
  • 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.
  • GABA receptor complex 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 neurons by regulating the conductance of chloride ions across the neuronal membrane. GABA interacts with its recognition site on the GRC to facilitate the flow of chloride ions down an electrochemical gradient of the GRC into the cell. An intracellular increase in the levels of this anion causes hyperpolarization of the transmembrane potential, rendering the neuron less susceptible to excitatory inputs (i.e., reduced neuron excitability). In other words, the higher the chloride ion concentration in the neuron, the lower the brain excitability (the level of arousal).
  • GRC is responsible for the mediation of anxiety, seizure activity, and sedation.
  • GABA and drugs that act like GABA or facilitate the effects of GABA e.g., the therapeutically useful barbiturates and benzodiazepines (BZs), such as Valium ®
  • BZs benzodiazepines
  • Neuroactive steroids can occur endogenously.
  • the most potent endogenous neuroactive steroids are 3a-hydroxy-5-reduced pregnan-20-one and 3a-21-dihydroxy-5-reduced pregnan-20-one, metabolites of hormonal steroids progesterone and deoxycorticosterone, respectively.
  • the ability of these steroid metabolites to alter brain excitability was recognized in 1986 (Majewska, M. D. et al, Science 232: 1004-1007 (1986); Harrison, N. L. et al, J Pharmacol. Exp. Ther. 241 :346-353 (1987)).
  • the ovarian hormone progesterone and its metabolites have been demonstrated to have profound effects on brain excitability (Backstrom, T. et al, Acta Obstet. Gynecol. Scand. Suppl. 130: 19-24 (1985); Pfaff, D.W and McEwen, B. S., Science 219:808-814 (1983); Gyermek et al, J Med Chem. 11 : 117 (1968); Lambert, J. et al, Trends Pharmacol. Sci. 8:224-227 (1987)).
  • the levels of progesterone and its metabolites vary with the phases of the menstrual cycle. It has been well documented that the levels of progesterone and its metabolites decrease prior to the onset of menses.
  • PMS premenstrual syndrome
  • PND postnatal depression
  • progesterone levels decrease dramatically leading to the onset of PND.
  • the symptoms of PND range from mild depression to psychosis requiring hospitalization.
  • PND is also associated with severe anxiety and irritability.
  • PND-associated depression is not amenable to treatment by classic antidepressants, and women experiencing PND show an increased incidence of PMS
  • New and improved neuroactive steroids are needed that act as modulating agents for brain excitability, as well as agents for the prevention and treatment of CNS-related diseases.
  • the compounds, compositions, and methods described herein are directed toward this end.
  • the present invention is based, in part, on the desire to provide novel 19-nor (i.e., C19 desmethyl) compounds, e.g., related to progesterone, deoxycorticosterone, and their metabolites, with good potency, pharmacokinetic (PK) properties, oral bioavailability, formulatability, stability, safety, clearance and/or metabolism.
  • PK pharmacokinetic
  • One key feature of the compounds as described herein is disubstitution at the C3 position (e.g., with one substituent being a 3a hydroxy moiety.
  • the inventors envision disubstitution at C-3 will eliminate the potential for oxidation of the hydroxy moiety to the ketone, prevent further metabolism, and reduce the potential for secondary elimination pathways, such as glucuronidation.
  • the inventors further envision the overall effect of C3 disubstitution should be of improving the overall PK parameters and reducing potential toxicities and side effects, which may allow, in certain embodiments, administration orally and/or chronically.
  • Another key feature of the compounds as described herein is the presence of a hydrogen at the CI 9 position ("19-nor") rather than a methyl group.
  • the inventors envision futher enhancement of solubility, for example, when the AB ring system is in the cis configuration.
  • R is substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2 - 6 alkenyl, substituted or unsubstituted C 2- 6 alkynyl, or substituted or unsubstituted C3-6 carbocyclyl;
  • R 2 is hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2 -6 alkenyl, substituted or unsubstituted C 2 -6 alkynyl, or substituted or unsubstituted C3-6 carbocyclyl, or -OR A2 , wherein R A2 is hydrogen or substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2 -6 alkenyl, substituted or unsubstituted C 2 -6 alkynyl, or substituted or unsubstituted C3-6 carbocyclyl;
  • G 1 is N, NR N1 , O, S, C, or C-R G1 as valency permits;
  • G 3 is N, NR N3 , O, S, C, or C-R G3 as valency permits;
  • G 4 is N, NR N4 , C-R G4 , or C-(R G4 ) 2 as valency permits;
  • G 5 is N, NR N5 , C-R G5 , or C-(R G5 ) 2 as valency permits
  • G 6 is N, NR N6 , C-R G6 , or C-(R G6 ) 2 as valency permits
  • G 7 is N, NR N7 , C-R G7 , or C-(R G7 ) 2 as valency permits
  • R N1 , R N2 , R N3 , R N4 , R N5 , R N6 , and R N7 is independently hydrogen, substituted or unsubstituted Ci- 6 alkyl, or a nitrogen protecting group; and each instance of R GA is independently hydrogen, substituted or unsubstituted Ci -6 alkyl, substituted or unsubstituted C 2 - 6 alkenyl, substituted or unsubstituted C 2 - 6 alkynyl, substituted or unsubstituted C3-6 carbocylyl, substituted
  • G 4 is N or NR N4
  • G 5 is N or NR N5
  • G 6 is N or NR N6
  • G 7 is N or NR N7 .
  • a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient.
  • the compound of the present invention is provided in an effective amount in the pharmaceutical composition.
  • the compound of the present invention is provided in a therapeutically effective amount.
  • the compound of the present invention is provided in a prophylactically effective amount.
  • GABA modulators act, in certain embodiments, as GABA modulators, e.g., effecting the GABA A receptor in either a positive or negative manner.
  • modulators of the excitability of the central nervous system (CNS) as mediated by their ability to modulate GABA A receptor, such compounds are expected to have CNS-activity.
  • a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present invention.
  • the CNS-related disorder is selected from the group consisting of a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, and tinnitus.
  • the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered chronically.
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et ah, Enantiomers, Racemates and Resolutions (Wiley).
  • Ci_6 alkyl is intended to encompass, Ci, C 2 , C 3 , C 4 , C 5 , C 6 , Ci_ 6 , Ci_ 5 , Ci_ 4 , Ci_ 3 , Ci-2, C 2 -6, C2-5, C 2 -4, C 2 - 3 , C 3 _6, C 3 -5, C 3 - , C4-6, C4-5, and C5-6 alkyl.
  • an analogue means one analogue or more than one analogue.
  • Alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms ("Ci- 20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“Ci- 12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“Ci- 10 alkyl”).
  • an alkyl group has 1 to 9 carbon atoms ("C 1 -9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci_8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“Ci_7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“Ci_6 alkyl”, also referred to herein as "lower alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1 -5 alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1 -4 alkyl").
  • an alkyl group has 1 to 3 carbon atoms ("C 1 -3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1 - 2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2 -6 alkyl”).
  • Ci_ 6 alkyl groups include methyl (Ci), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), iso- butyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ), and n-hexyl (C 6 ).
  • alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 ) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted Ci- 10 alkyl ⁇ e.g., -CH 3 ). In certain embodiments, the alkyl group is substituted Ci- 10 alkyl.
  • alkylene As used herein, “alkylene,” “alkenylene,” and “alkynylene,” refer to a divalent radical of an alkyl, alkenyl, and alkynyl group, respectively. When a range or number of carbons is provided for a particular “alkylene,” “alkenylene,” and “alkynylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain.
  • Alkylene,” “alkenylene,” and “alkynylene” groups may be substituted or unsubstituted with one or more substituents as described herein.
  • Alkylene refers to an alkyl group wherein two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted.
  • Unsubstituted alkylene groups include, but are not limited to, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like.
  • substituted alkylene groups e.g., substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted methylene (-CH(CH 3 )-, (-C(CH 3 ) 2 -), substituted ethylene (-CH(CH 3 )CH2-,-CH 2 CH(CH3)-, -C(CH 3 )2CH2-,-CH 2 C(CH3)2-), substituted propylene (-CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH 2 CH(CH 3 )-, -C(CH 3 ) 2 CH 2 CH 2 -, - CH 2 C(CH 3 ) 2 CH 2 -, -CH 2 CH 2 C(CH 3 ) 2 -), and the like.
  • alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon- carbon triple bonds) ("C 2 - 20 alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C 2 - 10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2 -9 alkenyl").
  • an alkenyl group has 2 to 8 carbon atoms ("C 2 -8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2 _ 7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C 2 _6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2 -5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C 2 -4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2 - 3 alkenyl”).
  • an alkenyl group has 2 carbon atoms ("C 2 alkenyl").
  • the one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1- butenyl).
  • Examples of C 2 -4 alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • C 2 -6 alkenyl groups include the aforementioned C 2 - 4 alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like. Additional examples of alkenyl include heptenyl (C 7 ), octenyl (Cs), octatrienyl (C 8 ), and the like.
  • each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkenyl") or substituted (a "substituted alkenyl") with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3
  • the alkenyl group is unsubstituted C 2 - 10 alkenyl. In certain embodiments, the alkenyl group is substituted C 2 - 10 alkenyl.
  • Alkenylene refers to an alkenyl group wherein two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted.
  • substituted alkenylene groups e.g., substituted with one or more alkyl (methyl) groups
  • Alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) ("C 2 _ 2 o alkynyl"). In certain embodiments, alkynyl does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C 2 _io alkynyl"). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C 2 _9 alkynyl").
  • an alkynyl group has 2 to 8 carbon atoms ("C 2 _8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2 _ 7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C 2 _6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C 2 _5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2 _4 alkynyl").
  • an alkynyl group has 2 to 3 carbon atoms ("C 2 _3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms ("C 2 alkynyl”).
  • the one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1- butynyl).
  • Examples of C 2 _ 4 alkynyl groups include, without limitation, ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
  • C 2 _ 6 alkenyl groups include the aforementioned C 2 _ 4 alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like. Additional examples of alkynyl include heptynyl (C 7 ), octynyl (C 8 ), and the like.
  • each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the alkynyl group is unsubstituted C 2 _io alkynyl.
  • the alkynyl group is substituted C 2 _io alkynyl.
  • Alkynylene refers to a linear alkynyl group wherein two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted.
  • Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like.
  • heteroalkyl refers to an alkyl group, as defined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment.
  • a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroCi-io alkyl").
  • a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroCi-9 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroCi-8 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroCi-7 alkyl”). In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1 , 2, or 3 heteroatoms ("heteroCi-6 alkyl").
  • a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("heteroCi-5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and lor 2 heteroatoms ("heteroCi-4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroCi-3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“heteroCi_ 2 alkyl").
  • a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroCi alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms ("heteroC 2 -6 alkyl"). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroCi-10 alkyl.
  • heteroalkenyl refers to an alkenyl group, as defined herein, which further comprises one or more ⁇ e.g., 1, 2, 3, or 4) heteroatoms ⁇ e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment.
  • heteroatoms e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus
  • a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC2-io alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2 -9 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2 -8 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4
  • heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms ("heteroC 2 -6 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2 -5 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and lor 2 heteroatoms ("heteroC 2 - 4 alkenyl").
  • a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom (“heteroC 2 -3 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2 -6 alkenyl"). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an "unsubstituted heteroalkenyl") or substituted (a "substituted heteroalkenyl") with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC 2 -io alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2-io alkenyl.
  • heteroalkynyl refers to an alkynyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment.
  • one or more heteroatoms e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus
  • a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2 -io alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2 -9 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2 -8 alkynyl").
  • a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2 -7 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms ("heteroC 2 -6 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2 -5 alkynyl").
  • a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms ("heteroC 2 - 4 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom
  • heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2 -6 alkynyl").
  • heteroC 2 -6 alkynyl 1 or 2 heteroatoms
  • each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl") or substituted (a "substituted heteroalkynyl”) with one or more substituents.
  • the heteroalkynyl group is an unsubstituted heteroC 2 -io alkynyl.
  • the heteroalkynyl group is a substituted heteroC2-io alkynyl.
  • alkylene alkenylene
  • alkynylene alkynylene
  • heteroalkylene heteroalkenylene
  • heteroalkynylene refers to a divalent radical of an alkyl, alkenyl, alkynyl group, heteroalkyl, heteroalkenyl, and heteroalkynyl group respectively.
  • heteroalkenylene or “heteroalkynylene,” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain.
  • Alkylene alkenylene
  • alkynylene alkynylene
  • heteroalkenylene alkynylene
  • heteroalkenylene and “heteroalkynylene” groups may be substituted or unsubstituted with one or more substituents as described herein.
  • Aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C 6 -i 4 aryl”).
  • an aryl group has six ring carbon atoms ("Ce aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms ("Cio aryl”; e.g., naphthyl such as 1- naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms ("Ci 4 aryl”; e.g., anthracyl).
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene.
  • aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.
  • each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents.
  • the aryl group is unsubstituted C 6 -i4 aryl.
  • the aryl group is substituted C 6 -i4 aryl.
  • R and R may be hydrogen and at least one of R and R is each independently selected from Ci-Cs alkyl, Ci-Cs haloalkyl, 4-10 membered heterocyclyl, alkanoyl, Ci-Cs alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 , NR 58 SOR 59 NR 58 S0 2 R 59 , COOalkyl, COOaryl, CONR 58 R 59 , CONR 58 OR 59 , NR 58 R 59 , S0 2 NR 58 R 59 , S-alkyl, SOalkyl, S0 2 alkyl, Saryl, SOaryl, S0 2 aryl; or R 56 and R 57 may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O,
  • R 60 and R 61 are independently hydrogen, Ci-Cg alkyl, C1-C4 haloalkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -Cio aryl, substituted C 6 -Cio aryl, 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl .
  • aryl groups having a fused heterocyclyl group include the following wherein each W is selected from C(R ) 2 , NR , O, and S; and each Y is selected from carbonyl, NR 66 , O and S; and R 66 is independently hydrogen, Ci-Cs alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -Cio aryl, and 5-10 membered heteroaryl.
  • “Fused aryl” refers to an aryl having two of its ring carbon in common with a second aryl or heteroaryl ring or with a carbocyclyl or heterocyclyl ring.
  • Alkyl is a subset of alkyl and aryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group.
  • Heteroaryl refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 ⁇ electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl").
  • Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system.
  • Heteroaryl also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system.
  • Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5- indolyl).
  • a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl").
  • a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl").
  • a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl").
  • the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5- 6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl") with one or more substituents.
  • the heteroaryl group is unsubstituted 5-14 membered heteroaryl.
  • the heteroaryl group is substituted 5-14 membered heteroaryl.
  • Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
  • Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6- membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl.
  • Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • Exemplary 6,6- bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • heteroaryls examples include the following:
  • each Y is selected from carbonyl, N, NR , O, and S; and R is independently hydrogen, Ci-Cs alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -Cio aryl, and 5-10 membered heteroaryl.
  • “Heteroaralkyl” is a subset of alkyl and heteroaryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted heteroaryl group.
  • Carbocyclyl or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms ("C3-10 carbocyclyl") and zero heteroatoms in the non- aromatic ring system.
  • a carbocyclyl group has 3 to 8 ring carbon atoms ("C3-8 carbocyclyl”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms (“C3_6 carbocyclyl”).
  • a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5 -10 carbocyclyl").
  • Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
  • Exemplary C3-8 carbocyclyl groups include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1 ]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (Cs), and the like.
  • Exemplary C3-10 carbocyclyl groups include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C10), cyclodecenyl (C10), octahydro-lH-indenyl (C 9 ), decahydronaphthalenyl (Cio), spiro[4.5]decanyl (C 10 ), and the like.
  • the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated.
  • “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
  • each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl") with one or more substituents.
  • the carbocyclyl group is unsubstituted C3-10 carbocyclyl.
  • the carbocyclyl group is a substituted C3-10 carbocyclyl.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms ("C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3_ 6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C5-6 cycloalkyl").
  • a cycloalkyl group has 5 to 10 ring carbon atoms ("C5-10 cycloalkyl").
  • C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5).
  • C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C 4 ).
  • Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (Cs).
  • each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents.
  • the cycloalkyl group is unsubstituted C3-10 cycloalkyl.
  • the cycloalkyl group is substituted C3-10 cycloalkyl.
  • Heterocyclyl or “heterocyclic” refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3-10 membered heterocyclyl").
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic ("monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated.
  • Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
  • each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an
  • heterocyclyl or substituted (a "substituted heterocyclyl") with one or more substituents.
  • the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3-10 membered heterocyclyl.
  • a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10 membered heterocyclyl").
  • a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl").
  • a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1- 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl").
  • the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl.
  • Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
  • Exemplary 5- membered heterocyclyl groups containing one heteroatom include, without limitation,
  • Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.
  • Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl.
  • Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl.
  • Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8- membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary 5-membered heterocyclyl groups fused to a C 6 aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
  • Exemplary 6-membered heterocyclyl groups fused to an aryl ring include, without limitation, tetrahydroquinolinyl,
  • heterocyclyl groups are shown in the following illustrative examples:
  • each W is selected from CR , C(R b / )2, NR , O, and S; and each Y is selected from NR , O, and S; and R 67 is independently hydrogen, C -C» alkyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -Cio aryl, 5-10 membered heteroaryl.
  • heterocyclyl rings may be optionally substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (carbamoyl or amido), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, keto, nitro, thiol, -S-alkyl, -S-aryl, -S(0)-alkyl,- S(0)-aryl, -S(0)2-alkyl, and -S(0)2-aryl.
  • Substituting groups include carbonyl or thiocarbonyl which provide, for example, lactam and urea derivatives.
  • Hetero when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g,. heteroaryl, cycloalkenyl, e.g,. cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.
  • alkyl e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g,. heteroaryl, cycloalkenyl, e.g,. cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.
  • Acyl refers to a radical -C(0)R 20 , where R 20 is hydrogen, substituted or unsubstitued alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl, as defined herein.
  • “Alkanoyl” is an acyl group wherein R 20 is a group other than hydrogen.
  • R is Ci- C8 alkyl, substituted with halo or hydroxy; or C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C 6 - C10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
  • R 22 is an amino protecting group.
  • acylamino groups include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino and benzylcarbonylamino.
  • acylamino groups are -NR 24 C(0)-Ci-C 8 alkyl, -NR 24 C(O)-(CH 2 ) t (C 6 -Ci 0 aryl), -NR 24 C(0)- (CH 2 ) t (5-10 membered heteroaryl), -NR 24 C(0)-(CH 2 ) t (C 3 -Cio cycloalkyl), and -NR 24 C(0)- ( ⁇ 3 ⁇ 4 (4-10 member ed heterocyclyl), wherein t is an integer from 0 to 4, and each R independently represents H or C -C» alkyl.
  • R 25 is H, C -C» alkyl, substituted with halo or hydroxy; C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -Cio aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubsti
  • Acyloxy refers to a radical -OC(0)R 27 , where R 27 is hydrogen, substituted or unsubstitued alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl, as defined herein.
  • Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and benzylcarbonyl.
  • R 28 is C -C» alkyl, substituted with halo or hydroxy; C3- C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -Cio aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
  • Alkoxy refers to the group -OR 29 where R 29 is substituted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl.
  • Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.
  • Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.
  • R is a group that has 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino, C 6 -Cio aryl, aryloxy, carboxyl, cyano, C 3 -C 10 cycloalkyl, 4-10 member ed heterocyclyl, halogen, 5-10 member ed heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(0) 2 - and aryl-S(0) 2 -.
  • substituents for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino, C 6 -Cio aryl, aryloxy, carboxyl, cyano, C 3 -C
  • Exemplary 'substituted alkoxy' groups include, but are not limited to, -0-(C]3 ⁇ 4) t (C 6 -Cio aryl), -O-(CH 2 ) t (5-10 membered heteroaryl), -0-(CH 2 ) t (C 3 -Cio cycloalkyl), and -O-(CH 2 ) t (4-10 membered
  • heterocyclyl wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
  • Particular exemplary 'substituted alkoxy' groups are - OCF 3 , -OCH 2 CF 3 , -OCH 2 Ph, -OCH 2 -cyclopropyl, -OCH 2 CH 2 OH, and -OCH 2 CH 2 NMe 2 .
  • Amino refers to the radical -NH 2 .
  • Substituted amino refers to an amino group of the formula -N(R 38 ) 2 wherein R 38 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstitued heteroaryl, or an amino protecting group, wherein at least one of R 38 is not a hydrogen.
  • each R 38 is independently selected from hydrogen, Ci-Cs alkyl, C 3 -C 8 alkenyl, C 3 -C 8 alkynyl, C 6 -Cio aryl, 5- 10 membered heteroaryl, 4-10 membered heterocyclyl, or C 3 -C 10 cycloalkyl; or Ci-Cs alkyl, substituted with halo or hydroxy; C 3 -C 8 alkenyl, substituted with halo or hydroxy; C 3 -C 8 alkynyl, substituted with halo or hydroxy, or -(CH 2 ) t (C 6 -Cio aryl), -(CH 2 ) t (5-10 membered heteroaryl), - (CH 2 ) t (C 3 -Cio cycloalkyl), or -( ⁇ 3 ⁇ 4 (4-10 membered heterocyclyl), wherein t is an integer between 0 and 8, each of which is substituted by unsubsti
  • C 4 haloalkoxy or hydroxy; or both R groups are joined to form an alkylene group.
  • exemplary "substituted amino" groups include, but are not limited to, -NR 39 -Ci-Cs alkyl, -NR 39 - (CH 2 ) t (C 6 -Cio aryl), -NR 39 -(CH 2 ) t (5-10 membered heteroaryl), -NR 39 -(CH 2 ) t (C3-Ci 0 cycloalkyl), and -NR 39 -(CH 2 ) t (4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, for instance 1 or 2, each R 39 independently represents H or Ci-Cs alkyl; and any alkyl groups present, may themselves be substituted by halo, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl, or heterocyclyl groups present, may themselves be
  • substituted amino includes the groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino as defined below.
  • Substituted amino encompasses both monosubstituted amino and disubstituted amino groups.
  • Carbamoyl or “amido” refers to the radical -C(0)NH 2 .
  • Substituted carbamoyl or “substituted amido” refers to the radical -C(0)N(R 62 )2 wherein each R 62 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstitued heteroaryl, or an amino protecting group, wherein at least one of R 62 is not a hydrogen.
  • R 62 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
  • R 62 is selected from H, C ⁇ -C & alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -Cio aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or Ci-C» alkyl substituted with halo or hydroxy; or C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -Cio aryl, aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted Ci-C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted Ci-C 4 haloalkyl, unsubstituted Ci-C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy; provided that at least one R
  • substituted carbamoyl groups include, but are not limited to, -C(O) NR 64 -Ci-C 8 alkyl, -C(0)NR 64 -(CH 2 ) t (C 6 -Cio aryl), -C(O)N 64 -(CH 2 ) t (5-10 membered heteroaryl), -C(0)NR 64 - (CH 2 ) t (C 3 -Cio cycloalkyl), and -C(O)NR 64 -(CH 2 ) t (4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, each R 64 independently represents H or C -C» alkyl and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted Ci-C 4 alkoxy, unsubstituted C 1 -
  • Carboxy refers to the radical -C(0)OH.
  • Cyano refers to the radical -CN.
  • Halo or “halogen” refers to fluoro (F), chloro (CI), bromo (Br), and iodo (I). In certain embodiments, the halo group is either fluoro or chloro.
  • Haldroxy refers to the radical -OH.
  • Nonro refers to the radical -N0 2 .
  • Cycloalkylalkyl refers to an alkyl radical in which the alkyl group is substituted with a cycloalkyl group. Typical cycloalkylalkyl groups include, but are not limited to,
  • Heterocyclylalkyl refers to an alkyl radical in which the alkyl group is substituted with a heterocyclyl group. Typical heterocyclylalkyl groups include, but are not limited to,
  • Cycloalkenyl refers to substituted or unsubstituted carbocyclyl group having from 3 to 10 carbon atoms and having a single cyclic ring or multiple condensed rings, including fused and bridged ring systems and having at least one and particularly from 1 to 2 sites of olefinic unsaturation.
  • Such cycloalkenyl groups include, by way of example, single ring structures such as cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like.
  • Fused cycloalkenyl refers to a cycloalkenyl having two of its ring carbon atoms in common with a second aliphatic or aromatic ring and having its olefinic unsaturation located to impart aromaticity to the cycloalkenyl ring.
  • Ethylene refers to substituted or unsubstituted -(C-C)-.
  • Ethynyl refers to -(C ⁇ C)-.
  • Nonrogen-containing heterocyclyl group means a 4- to 7- membered non-aromatic cyclic group containing at least one nitrogen atom, for example, but without limitation, morpholine, piperidine (e.g. 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 2-pyrrolidinyl and 3- pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl piperazine. Particular examples include azetidine, piperidone and piperazone.
  • Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted (e.g., "substituted” or “unsubstituted” alkyl, "substituted” or
  • substituted means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a permissible substituent e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
  • substituted is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
  • R cc is, independently, selected from hydrogen, Ci-10 alkyl, Ci-10 perhaloalkyl, C 2 _ 10 alkenyl, C 2 _io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6 -i4 aryl, and 5-14 membered heteroaryl, or two R cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; each instance of R dd is, independently, selected from halogen, -CN, -N0 2 , -N3, -S0 2 H, -SO 3 H, - OH, -OR ee ,
  • a “counterion” or “anionic counterion” is a negatively charged group associated with a cationic quaternary amino group in order to maintain electronic neutrality.
  • exemplary counterions include halide ions (e.g., F “ , CI “ , Br “ , ⁇ ), N0 3 " , C10 4 “ , OH “ , H 2 P0 4 “ , HS0 4 “ , S0 4 “2 sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-1 -sulfonic acid-5-sulfonate, ethan-1 -sulfonic acid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate
  • Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al, describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19.
  • Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate
  • Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (Ci- 4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • a "subject" to which administration is contemplated includes, but is not limited to, humans ⁇ i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • the terms "human,” “patient,” and “subject” are used interchangeably herein.
  • treat contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition ("therapeutic treatment"), and also
  • prophylactic treatment contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition ("prophylactic treatment").
  • the "effective amount" of a compound refers to an amount sufficient to elicit the desired biological response.
  • the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject An effective amount encompasses therapeutic and prophylactic treatment.
  • a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition.
  • the term "therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.
  • a prophylactically effective amount of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder or condition.
  • the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • FIGS. 1-13 depict representative 1 H NMR spectrum of exemplary compounds described herein.
  • the present invention provides 3,3-disubstituted 19-nor neuroactive steroids of Formula (I): harmaceutically acceptable salts thereof; wherein:
  • G 1 is N, NR N1 , O, S, C, or C-R G1 as valency permits
  • G 3 is N, NR N3 , O, S, C, or C-R G3 as valency permits
  • G 4 is N, NR N4 , C-R G4 , or C-(R G4 ) 2 as valency permits
  • G 5 is N, NR N5 , C-R G5 , or C-(R G5 ) 2 as valency permits
  • G 6 is N, NR N6 , C-R G6 , or C-(R G6 ) 2 as valency permits
  • G 7 is N, NR N7 , C-R G7 , or C-(R G7 ) 2 as valency permits; each instance of R G1 , R G2 , R G3 ,
  • R 1 is substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C 2 - 6 alkenyl, substituted or unsubstituted C 2 - 6 alkynyl, or substituted or unsubstituted C3-6 carbocylyl;
  • R 2 is hydrogen, halogen, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C 2 - 6 alkenyl, substituted or unsubstituted C 2 - 6 alkynyl, or substituted or unsubstituted C3-6 carbocylyl, or -OR A2 , wherein R A2 is hydrogen or substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C 2 - 6 alkenyl, substituted or unsubstituted C 2- 6 alkynyl, or substituted or unsubstituted C3-6 carbocylyl;
  • G 4 is N or NR N4
  • G 5 is N or NR N5
  • G 6 is N or NR N6
  • G 7 is N or NR N7 .
  • compounds of Formula (I) encompass 3,3-disubstituted 19-nor neuroactive steroids wherein the A/B ring system of the compound is cis (as provided in Formula (I-A), wherein the A/B ring system of the compound is trans (as provided in Formula (I-B), wherein the B ring of the compound comprises a C5-C6 double bond (as provided in Formula (I-C)), and wherein the A ring of the compound comprises a C4-C5 double bond (as provided in Formula (I-D)),
  • R 1 is substituted or unsubstituted C 1-6 alkyl, substituted or
  • R 1 is substituted or unsubstituted C 1-6 alkyl, e.g., substituted or unsubstituted Ci_ 2 alkyl, substituted or unsubstituted C 2 - 3 alkyl, substituted or unsubstituted C3- 4 alkyl, substituted or unsubstituted C 4 _ 5 alkyl, or substituted or unsubstituted Cs-ealkyl.
  • Ci_ 6 alkyl groups include, but are not limited to, substituted or unsubstituted methyl (Ci), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), iso-butyl (C 4 ), n- pentyl (C 5 ), 3-pentanyl (C 5 ), amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ), n-hexyl (C 6 ), Ci_ 6 alkyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more fluoro groups ⁇ e.g.
  • R 1 is substituted Ci-6 alkyl, e.g., R 1 is haloalkyl, alkoxyalkyl, or aminoalkyl.
  • R 1 is Me, Et, n-Pr, n-Bu, i-Bu, fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, difluoroethyl, 2,2,2-trifluoro- 1,1 -dimethyl-ethyl, methoxymethyl, methoxyethyl, or ethoxymethyl.
  • R 1 is unsubstituted C 1 -3 alkyl, e.g., R 1 is -CH 3 , -CH 2 CH 3 , or - CH 2 CH 2 CH 3 .
  • R is C 1-6 alkyl substituted with one or more fluorine atoms; e.g., R is - CH 2 F, -CHF 2 , or -CF 3 .
  • R is C 1-6 alkyl substituted with one or more -OR groups, wherein R is hydrogen or substituted or unsubstitued alkyl.
  • R 1 is -CH 2 OR A1 , e.g., wherein R A1 is hydrogen, -CH 3 , -CH 2 CH 3 , or -CH 2 CH 2 CH 3 , e.g., to provide a group R 1 of formula -CH 2 OH, -CH 2 OCH 3 , -CH 2 OCH 2 CH 3 , or -CH 2 OCH 2 CH 2 CH 3 .
  • R 1 is substituted or unsubstituted C 2- 6 alkenyl, e.g., substituted or unsubstituted C 2 _ 3 alkenyl, substituted or unsubstituted C 3 _ 4 alkenyl, substituted or unsubstituted C 4 _ 5 alkenyl, or substituted or unsubstituted Cs-ealkenyl.
  • R 1 is ethenyl (C 2 ), propenyl (C 3 ), or butenyl (C 4 ), unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, alkoxyalkyl, or hydroxyl.
  • R 1 is ethenyl, propenyl, or butenyl, unsubstituted or substituted with alkyl, halo, haloalkyl, alkoxyalkyl, or hydroxy. In certain embodiments, R 1 is ethenyl.
  • R 1 is substituted or unsubstituted C 2 - 6 alkynyl, e.g., substituted or unsubstituted C 2 _ 3 alkynyl, substituted or unsubstituted C 3 _ 4 alkynyl, substituted or unsubstituted C 4 _ 5 alkynyl, or substituted or unsubstituted Cs-ealkynyl.
  • R 1 is ethynyl, propynyl, or butynyl, unsubstituted or substituted with alkyl, halo, haloalkyl (e.g., CF 3 ), alkoxyalkyl, cycloalkyl (e.g., cyclopropyl or cyclobutyl), or hydroxyl.
  • R 1 is selected from the group consisting of trifluoroethynyl, cyclopropylethynyl, cyclobutylethynyl, and propynyl, fluoropropynyl, and chloroethynyl.
  • R 1 is ethynyl (C 2 ), propynyl (C 3 ), or butynyl (C 4 ), unsubstituted or substituted with one or more substituents selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl.
  • R 1 is ethynyl (C 2 ), propynyl (C 3 ), or butynyl (C 4 ) substituted with substituted phenyl.
  • the phenyl substituent is further substituted with one or more substituents selected from the group consisting of halo, alkyl, trifluoroalkyl, alkoxy, acyl, amino or amido.
  • R 1 is ethynyl (C 2 ), propynyl (C 3 ), or butynyl (C 4 ) substituted with substituted or unsubstituted pyrrolyl, imidazolyl, pyrazolyl, oxazoyl, thiazolyl, isoxazoyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl.
  • R is ethynyl, propynyl, or butynyl, unsubstituted or substituted with alkyl, halo, haloalkyl, alkoxyalkyl, or hydroxyl.
  • R 1 is ethynyl or propynyl, substituted with substituted or unsubstituted aryl.
  • R 1 is ethynyl or propynyl, substituted with phenyl unsubstituted or substituted with halo, alkyl, alkoxy, haloalkyl, trihaloalkyl, or acyl.
  • R 1 is ethynyl or propynyl, substituted with
  • R 3a is ethynyl or propynyl, substituted with substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 1 is ethynyl or propynyl, substituted with substituted or unsubstituted heteroaryl.
  • R 1 is ethynyl or propynyl, substituted with substituted or unsubstituted pyridinyl, or pyrimidinyl.
  • R 1 is ethynyl or propynyl, substituted with substituted or unsubstituted pyrrolyl, imidazolyl, pyrazolyl, oxazoyl, thiazolyl, isoxazoyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl.
  • R 1 is ethynyl or propynyl, substituted with substituted or unsubstituted heterocyclyl. In certain embodiments, R 1 is ethynyl or propynyl, substituted with substituted or unsubstituted pyrrolidinyl, piperidinyl, piperazinyl, or mopholinyl. In certain embodiments, R 1 is propynyl or butynyl, substituted with hydroxyl or alkoxy. In certain embodiments, R 1 is propynyl or butynyl, substituted with methoxy or ethoxy. In certain embodiments, R 1 is ethynyl or propynyl, substituted with chloro. In certain embodiments, R 1 is ethynyl or propynyl, substituted with trifluoromethyl.
  • R 1 is substituted or unsubstituted C3-6 carbocyclyl, e.g., substituted or unsubstituted C3_ 4 carbocyclyl, substituted or unsubstituted C 4 _ 5 carbocyclyl, or substituted or unsubstituted C5-6 carbocyclyl. In certain embodiments, R 1 is substituted or unsubstituted cyclopropyl or substituted or unsubstituted cyclobutyl.
  • R 2 is hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-6 carbocyclyl, or -OR A2 , wherein R A2 is hydrogen, substituted or unsubstituted 6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-6 carbocyclyl. In certain embodiments, R 2 is hydrogen.
  • R 2 is halogen, e.g., fluoro, chloro, bromo, or iodo. In certain embodiments, R 2 is fluoro or chloro. In certain embodiments, R 2 is substituted or unsubstituted Ci_ 6 alkyl, e.g., substituted or unsubstituted Ci_ 2 alkyl, substituted or unsubstituted C 2 - 3 alkyl, substituted or unsubstituted C 3 _ 4 alkyl, substituted or unsubstituted C 4 _ 5 alkyl, or substituted or unsubstituted Cs-ealkyl.
  • Ci_ 6 alkyl e.g., substituted or unsubstituted Ci_ 2 alkyl, substituted or unsubstituted C 2 - 3 alkyl, substituted or unsubstituted C 3 _ 4 alkyl, substituted or unsubstituted C 4 _ 5 alkyl, or substituted or unsub
  • R is substituted or unsubstituted C 2- 6 alkenyl
  • R 2 is substituted or unsubstituted C 2- 6 alkynyl, e.g., substituted or unsubstituted C 2 - 3 alkynyl, substituted or unsubstituted C 3 _ 4 alkynyl, substituted or unsubstituted C 4 _ 5 alkynyl, or substituted or unsubstituted Cs-ealkynyl.
  • R 2 is substituted or unsubstituted C 3 -6 carbocyclyl, e.g.
  • R is substituted or unsubstituted cyclopropyl or substituted or unsubstituted cyclobutyl.
  • R is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , or substituted or unsubstituted cyclopropyl.
  • R 2 is -OR A2 .
  • R A2 is hydrogen.
  • R A2 is substituted or unsubstituted alkyl, e.g., substituted or unsubstituted Ci_ 6 alkyl, substituted or unsubstituted Ci_ 2 alkyl, substituted or unsubstituted C 2 - 3 alkyl, substituted or unsubstituted C 3 _ 4 alkyl, substituted or unsubstituted C 4 _ 5 alkyl, or substituted or unsubstituted Cs-ealkyl.
  • alkyl e.g., substituted or unsubstituted Ci_ 6 alkyl, substituted or unsubstituted Ci_ 2 alkyl, substituted or unsubstituted C 2 - 3 alkyl, substituted or unsubstituted C 3 _ 4 alkyl, substituted or unsubstituted C 4 _ 5 alkyl, or substituted or unsubstituted Cs-ealkyl.
  • R A2 is hydrogen, -CH 3 , - CH 2 CH 3 , or -CH 2 CH 2 CH 3 , i.e., to provide a group R 2 of formula -OH, -OCH 3 , -OCH 2 CH 3 , or - OCH 2 CH 2 CH 3 .
  • R 2 is a non-hydrogen substituent in the alpha
  • R 2 is a non-hydrogen substituent in the beta configuration.
  • R 3a is -OR A3 and R 3 is hydrogen. In certain embodiments, wherein R 3a is -OR A3 , R 3a is in the alpha or beta configuration ⁇ e.g., R or S configuration). In certain
  • R 3a is -OR A3 , R 3a is in the alpha configuration. In certain embodiments, wherein R 3a is -OR A3 , R 3a is in the beta configuration. In certain embodiments, R A3 is hydrogen. In certain embodiments, R is substituted or unsubstituted C 1-6 alkyl, e.g., substituted or unsubstituted C h alky 1, substituted or unsubstituted C h alky 1, substituted or unsubstituted C3- 4 alkyl, substituted or unsubstituted C 4 _ 5 alkyl, or substituted or unsubstituted Cs-ealkyl.
  • R A3 is hydrogen, -CH 3 , -CH 2 CH 3 , or -CH 2 CH 2 CH 3 , i.e., to provide a group R 3a of formula -OH, -OCH 3 , -OCH 2 CH 3 , or -OCH 2 CH 2 CH 3 .
  • R 4a and R 4 is substituted or unsubstituted C 1-6 alkyl, e.g., substituted or unsubstituted Ci_ 2 alkyl, substituted or unsubstituted C 2 _ 3 alkyl, substituted or unsubstituted C 3 _ 4 alkyl, substituted or unsubstituted C 4 _ 5 alkyl, or substituted or unsubstituted C5_ 6 alkyl.
  • both of R 4a and R 4 are hydrogen.
  • both of R 4a and R 4 are independently substituted or unsubstituted C 1-6 alkyl, e.g., substituted or unsubstituted Ci_ 2 alkyl, substituted or unsubstituted C 2 _ 3 alkyl, substituted or unsubstituted C 3 _ 4 alkyl, substituted or unsubstituted C 4 _ 5 alkyl, or substituted or unsubstituted Cs-ealkyl.
  • R 4a is hydrogen.
  • R 4a is substituted or unsubstituted C 1-6 alkyl, e.g., substituted or unsubstituted Ci_ 2 alkyl, substituted or unsubstituted C 2 _ 3 alkyl, substituted or unsubstituted C 3 _ 4 alkyl, substituted or unsubstituted C 4 _5alkyl, or substituted or unsubstituted Cs-ealkyl.
  • R 4a is Ci alkyl, e.g., -CH 3 or -CF 3 .
  • R 4a is halogen, e.g., fluoro.
  • A is of Formula (A-1) or Formula (A-2)
  • the point of attachment is at Gi or G 2 in Formula (A-1) and the point of attachment is at G 2 or G3 in Formula (A-2);
  • G 1 is N, NR N1 , O, S, C, or C-R G1 as valency permits;
  • G 3 is N, NR N3 , O, S, C, or C-R G3 as valency permits;
  • G 4 is N, NR N4 , C-R G4 , or C-(R G4 ) 2 as valency permits
  • G 5 is N, NR N5 , C-R G5 , or C-(R G5 ) 2 as valency permits
  • G 6 is N, NR N6 , C-R G6 , or C-(R G6 ) 2 as valency permits;
  • G 4 is N or NR N4
  • G 5 is N or NR N5
  • G 6 is N or NR N6
  • A is of Formula (A-1)
  • A is of Formula (A-2) (A-2), wh r in the oint of attachment is at G 2 or G 3 .
  • A is of Formula (A-2) wherein the point of attachment is at G 2 .
  • A is of Formula (A-2) (A-2), wherein the point of attachment is at G .
  • A is one of the following formulae:
  • A is one of the following formulae:
  • bond s is a double bond. In certain embodiments, bond s is a single bond. In certain embodiments, bond t is a double bond. In certain embodiments, bond t is a single bond.
  • A is one of the following formulae:
  • R G1 is hydrogen. In some embodiments, R G1 is halogen. In certain embodiments, R G1 is F. In certain embodiments, R G1 is CI. In certain embodiments, R G1 is Br. In certain embodiments, R G1 is I. In certain embodiments, R G1 is substituted or unsubstituted Ci-6 alkyl. In certain embodiments, R G1 is substituted Ci-6 alkyl. In certain embodiments, R G1 is -CH 2 F, -CHF 2 , or -CF 3 . In certain embodiments, R is unsubstituted C 1-6 alkyl.
  • R is methyl, ethyl, propyl, butyl, pentyl, or hexyl.
  • R G1 is -CN.
  • R G1 is -N0 2 .
  • R G1 is substituted or unsubstituted carbocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl.
  • R Gl is cyclopropyl or cyclobutyl.
  • R G1 is -NHR GA . In certain embodiments, R is -NH 2 . In certain embodiments, R is -NHR , wherein R is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R is -NHR , wherein R is
  • R is -N(R ) 2 , wherein each R is
  • R G1 is - N(CH 3 )R GA , wherein each R GA is independently unsubstituted C 1-6 alkyl.
  • R is -N(CH 2 CH 3 )R , wherein each R is independently substituted or unsubstituted C 1-6 alkyl.
  • certai ⁇ n embodi ⁇ ments R Gl is -OH.
  • R is -OR , wherein R is substituted or unsubstituted C 1-6 alkyl.
  • R G 1 is -O-methyl, -O-ethyl, or -O-propyl.
  • R G 1 is -OR G A , wherein R GA is substituted or unsubstituted aryl.
  • R G1 is -O-phenyl.
  • R is CI. In certain embodiments, R is Br. In certain embodiments, R is I. In certain embodiments, R G2 is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R G2 is substituted C 1-6 alkyl. In certain embodiments, R G2 is -CH 2 F, -CHF 2 , or -CF3. In certain embodiments, R G2 is unsubstituted C 1-6 alkyl. In certain embodiments, R G2 is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R is -CN. In some embodiments, R is -N0 2 .
  • R G2 is substituted or unsubstituted carbocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl.
  • R is cyclopropyl or cyclobutyl.
  • R G2 is -NHR GA .
  • R is -NH 2 . In certain embodiments, R is -NHR , wherein R is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R is -NHR , wherein R is methyl, ethyl, or propyl. In certain embodiments, R is -N(R ) 2 , wherein each R is
  • R G2 is - N(CH 3 )R GA , wherein each R GA is independently unsubstituted C 1-6 alkyl.
  • R is -N(CH 2 CI3 ⁇ 4)R , wherein each R is independently substituted or unsubstituted C 1-6 alkyl.
  • R is -OR .
  • R is -OH.
  • R is -OR , wherein R is substituted or unsubstituted C 1-6 alkyl.
  • R is -O-methyl, -O-ethyl, or -O-propyl.
  • R is -OR , wherein R GA is substituted or unsubstituted aryl.
  • R G2 is -O-phenyl.
  • R G3 is hydrogen. In some embodiments, R G3 is halogen. In certain embodiments, R G3 is F. In certain embodiments, R G3 is CI. In certain embodiments, R G3 is Br. In certain embodiments, R G3 is I. In certain embodiments, R G3 is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R G3 is substituted C 1-6 alkyl. In certain embodiments, R G3 is -CH 2 F, -CHF 2 , or -CF 3 . In certain embodiments, R G3 is unsubstituted C 1-6 alkyl.
  • R G3 is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R G3 is -CN. In some embodiments, R G3 is -N0 2 . In some embodiments, R is substituted or unsubstituted carbocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. In some embodiments, R is cyclopropyl or cyclobutyl.
  • R G3 is -NHR GA .
  • R is -NH 2 .
  • R is -NHR , wherein R is substituted or unsubstituted C 1-6 alkyl.
  • R is -NHR , wherein R is methyl, ethyl, or propyl.
  • R is -N(R ) 2 , wherein each R is
  • R G3 is -
  • each R GA is independently unsubstituted C 1-6 alkyl.
  • R is -N(CH 2 CI3 ⁇ 4)R , wherein each R is independently substituted or unsubstituted C 1-6 alkyl.
  • R is -OR .
  • R is -OH.
  • R is -OR , wherein R is substituted or unsubstituted C 1-6 alkyl.
  • R G3 is -O-methyl, -O-ethyl, or -O-propyl.
  • R G3 is -OR GA , wherein R GA is substituted or unsubstituted aryl.
  • R G3 is -O-phenyl.
  • R G4 is hydrogen. In some embodiments, R G4 is halogen. In certain embodiments, R G4 is F. In certain embodiments, R is CI. In certain embodiments, R is Br. In certain embodiments, R is I. In certain embodiments, R G4 is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R G4 is substituted C 1-6 alkyl. In certain embodiments, R 5 is -CH 2 F, -CHF 2 , or -CF 3 . In certain embodiments, R G4 is unsubstituted C 1-6 alkyl.
  • R G4 is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R G4 is -CN. In some embodiments, R G4 is -N0 2 . In some embodiments, R G4 is substituted or unsubstituted carbocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. In
  • R is cyclopropyl or cyclobutyl.
  • R G4 is -NHR GA .
  • R is -NH 2 . In certain embodiments, R is -NHR , wherein R is
  • R is -NHR , wherein R is
  • R is -N(R ) 2 , wherein each R is
  • R G4 is - N(CH 3 )R GA , wherein each R GA is independently unsubstituted C 1-6 alkyl. In certain embodiments,
  • R is -N(CH 2 CI3 ⁇ 4)R , wherein each R is independently substituted or unsubstituted C 1-6 alkyl.
  • R G4 is -OH.
  • R is -OR , wherein R is substituted or unsubstituted C 1-6 alkyl.
  • R is -O-methyl, -O-ethyl, or -O-propyl.
  • R is -OR , wherein R GA is substituted or unsubstituted aryl.
  • R G4 is -O-phenyl.
  • R G5 is hydrogen. In some embodiments, R G5 is halogen. In certain embodiments, R G5 is F. In certain embodiments, R G5 is CI. In certain embodiments, R G5 is Br. In certain embodiments, R G5 is I. In certain embodiments, R G5 is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R G5 is substituted C 1-6 alkyl. In certain embodiments, R 5 is -CH 2 F, -CHF 2 , or -CF3. In certain embodiments, R G5 is unsubstituted C 1-6 alkyl.
  • R G5 is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R G5 is -CN. In some embodiments, R G5 is -N0 2 . In some embodiments, R G5 is substituted or unsubstituted carbocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. In some embodiments, R is cyclopropyl or cyclobutyl.
  • R G5 is -NHR GA . In certain embodiments, R G5 i *s -NH 2 . In certai *n embodi *ments, R G5 i *s -NHR GA , wherei ⁇ n R GA is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R is -NHR , wherein R is methyl, ethyl, or propyl. In certain embodiments, R is -N(R ) 2 , wherein each R is
  • R G5 is - N(CH 3 )R GA , wherein each R GA is independently unsubstituted C 1-6 alkyl. In certain embodiments, R is -N(CH 2 CH 3 )R , wherein each R is independently substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R G5 i *s -OR GA . In certai ⁇ n embodi ⁇ ments, R G5 is -OH. In certain
  • R is -OR , wherein R is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R is -O-methyl, -O-ethyl, or -O-propyl. In certain embodiments, R is -OR , wherein R GA is substituted or unsubstituted aryl. In certain embodiments, R G5 is -O-phenyl.
  • R G6 is hydrogen. In some embodiments, R G6 is halogen. In certain embodiments, R G6 is F. In certain embodiments, R G6 is CI. In certain embodiments, R G6 is Br. In certain embodiments, R G6 is I. In certain embodiments, R G6 is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R G6 is substituted C 1-6 alkyl. In certain embodiments, R 5 is -CH 2 F, -CHF 2 , or -CF 3 . In certain embodiments, R G6 is unsubstituted C 1-6 alkyl.
  • R G6 is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R G6 is -CN. In some embodiments, R G6 is -N0 2 . In some embodiments, R G6 is substituted or unsubstituted carbocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. In some embodiments, R is cyclopropyl or cyclobutyl.
  • R G6 is -NHR GA .
  • R is -NH 2 .
  • R is -NHR , wherein R is
  • R is -NHR , wherein R is methyl, ethyl, or propyl. In certain embodiments, R is -N(R ) 2 , wherein each R is
  • R G6 is - N(CH 3 )R GA , wherein each R GA is independently unsubstituted C 1-6 alkyl.
  • R is -N(CH 2 CI3 ⁇ 4)R , wherein each R is independently substituted or unsubstituted C 1-6 alkyl.
  • R is -OR .
  • R is -OH.
  • R is -OR , wherein R is substituted or unsubstituted C 1-6 alkyl.
  • R G6 is -O-methyl, -O-ethyl, or -O-propyl.
  • R G6 is -OR GA , wherein R GA is substituted or unsubstituted aryl.
  • R G6 is -O-phenyl.
  • R G7 is hydrogen. In some embodiments, R G7 is halogen. In certain embodiments, R G7 is F. In certain embodiments, R is CI. In certain embodiments, R is Br. In certain embodiments, R is I. In certain embodiments, R G7 is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R G7 is substituted C 1-6 alkyl. In certain embodiments, R 5 is -CH 2 F, -CHF 2 , or -CF 3 . In certain embodiments, R G7 is unsubstituted C 1-6 alkyl.
  • R G7 is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R G7 is -CN. In some embodiments, R G7 is -N0 2 . In some embodiments, R G7 is substituted or unsubstituted carbocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. In some embodiments, R is cyclopropyl or cyclobutyl.
  • R G7 is -NHR GA . In certain embodiments, R is -NH 2 . In certain embodiments, R is -NHR , wherein R is substituted or unsubstituted Ci_6 alkyl. In certain embodiments, R is -NHR , wherein R is
  • R is -N(R ) 2 , wherein each R is independently substituted or unsubstituted Ci -6 alkyl.
  • R G7 is - N(CH 3 )R GA , wherein each R GA is independently unsubstituted Ci_6 alkyl.
  • R is -N(CH 2 CI3 ⁇ 4)R , wherein each R is independently substituted or unsubstituted Ci_6 alkyl.
  • R is -OR .
  • R is -OH.
  • R is -OR , wherein R is substituted or unsubstituted Ci_6 alkyl.
  • R is -O-methyl, -O-ethyl, or -O-propyl.
  • R is -OR , wherein R GA is substituted or unsubstituted aryl.
  • R G7 is -O-phenyl.
  • each instance of R N1 is independently hydrogen, substituted or unsubstituted Ci_6 alkyl, or a nitrogen protecting group.
  • R N2 is hydrogen.
  • R N2 is substituted Ci -6 alkyl.
  • R N2 is unsubstituted Ci -6 alkyl.
  • R N2 is methyl.
  • R N2 is ethyl.
  • R N2 is propyl.
  • R N2 is a nitrogen protecting group.
  • R N2 is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts.
  • each instance of R N2 is independently hydrogen, substituted or unsubstituted Ci -6 alkyl, or a nitrogen protecting group.
  • R N2 is hydrogen.
  • R N2 is substituted Ci_6 alkyl.
  • R N2 is unsubstituted Ci_6 alkyl.
  • R N2 is methyl.
  • R N2 is ethyl.
  • R N2 is propyl.
  • R N2 is a nitrogen protecting group.
  • R N2 is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts.
  • each instance of R N3 is independently hydrogen, substituted or unsubstituted Ci_6 alkyl, or a nitrogen protecting group.
  • R N2 is hydrogen.
  • R N2 is substituted Ci_6 alkyl.
  • R N2 is unsubstituted Ci_6 alkyl.
  • R N2 is methyl.
  • R N2 is ethyl.
  • R N2 is propyl.
  • R N2 is a nitrogen protecting group.
  • R N2 is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts.
  • each instance of R is independently hydrogen, substituted or unsubstituted Ci- 6 alkyl, or a nitrogen protecting group.
  • R N4 is hydrogen. In some embodiments, R N4 is substituted C 1-6 alkyl. In some embodiments, R N4 is unsubstituted C 1-6 alkyl. In certain embodiments, R N4 is methyl. In certain embodiments, R N4 is ethyl. In certain embodiments, R N4 is propyl. In certain embodiments, R N4 is a nitrogen protecting group. In certain embodiments, R N4 is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts.
  • each instance of R N5 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group.
  • R N5 is hydrogen.
  • R N5 is substituted C 1-6 alkyl.
  • R N5 is unsubstituted C 1-6 alkyl.
  • R N5 is methyl.
  • R N5 is ethyl.
  • R N5 is propyl.
  • R N5 is a nitrogen protecting group.
  • R N5 is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts.
  • each instance of R N6 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group.
  • R N6 is hydrogen.
  • R N6 is substituted C 1-6 alkyl.
  • R N6 is unsubstituted C 1-6 alkyl.
  • R N6 is methyl.
  • R N6 is ethyl.
  • R N6 is propyl.
  • R N6 is a nitrogen protecting group.
  • R N6 is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts.
  • each instance of R N7 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group.
  • R N7 is hydrogen.
  • R N7 is substituted C 1-6 alkyl.
  • R N7 is unsubstituted C 1-6 alkyl.
  • R N7 is methyl.
  • R N7 is ethyl.
  • R N7 is propyl.
  • R N7 is a nitrogen protecting group.
  • R N7 is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts.
  • each instance of R GA is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2- 6 alkynyl, substituted or unsubstituted C3-6 carbocylyl, substituted or unsubstituted 3- to 6- membered heterocylyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, or two R GA groups are taken with the intervening atoms to form a substituted or unsubstituted heterocylyl or heteroaryl ring.
  • R is hydrogen.
  • R GA is substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2 - 6 alkenyl, substituted or unsubstituted C 2- 6 alkynyl, or substituted or unsubstituted C3-6 carbocyclyl.
  • R GA is substituted or unsubstituted C 1-6 alkyl.
  • R GA is unsubstituted C 1-6 alkyl.
  • R GA is methyl, ethyl, propyl, butyl, pentyl, or hexyl.
  • R GA is substituted or unsubstituted heterocyclyl.
  • R GA is substituted or unsubstituted aryl. In certain embodiments, R GA is substituted or unsubstituted phenyl. In certain embodiments, R GA is a nitrogen protecting group. In certain embodiments, R GA is an oxygen protecting group. In certain embodiments, the compound of Formula (I) is of Formula (II),
  • the point of attachment in Formula (II) is at the nitrogen at the Gl position. In certain embodiments, the point of attachment in Formula (II) is at the nitrogen at the G2 position. In certain embodiments, the compound of Formula (I) is of
  • the point of attachment ' Formula (Il-a) is at the nitrogen at the Gl position. In certain embodiments, the point of attachment in Formula (Il-a) is at the nitrogen at the G2 position.
  • the compound of Formula (I) is of one of the following formulae:
  • the point of attachment in any one of Formulae (II-al)-(II-a5) is at the nitrogen at the Gl position. In certain embodiments, the point of attachment in any one of Formulae (II-al)-(II-a5) is at the nitrogen at the G2 position.
  • the compound of Formula (I) is of one of the following formulae:
  • the compound of Formula (I) is of Formula (H-b):
  • the point of attachment in any one of Formula (Il-b) is at the nitrogen at the Gl position. In certain embodiments, the point of attachment in any one of Formula (Il-b) is at the nitrogen at the G2 position. In certain embodiments, the compound of Formula (I) is of one of the following formulae:
  • the point of attachment in any one of Formulae (II-bl)-(II-b5) is at the nitrogen at the Gl position. In certain embodiments, the point of attachment in any one of Formulae (II-bl)-(II-b5) is at the nitrogen at the G2 position. In certain embodiments, the compound of Formula (I) is of one of the following formulae:
  • the compound of Formula (I) is of Formula (III):
  • the compound of Formula (I) is of Formula (Ill-a):
  • the compound of Formula (I) is of Formula (III-bl):
  • the compound of Formula (I) is of Formula (IV): or a pharmaceutically acceptable salt thereof.
  • the point of attachment in Formula (IV) is at the nitrogen at the Gl position. In certain embodiments, the point of attachment in Formula (IV) is at the nitrogen at the G2 position. In certain embodiments, the compound of Formula (I) is of Formula (IV-a):
  • the point of attachment in Formula (IV-a) is at the nitrogen at the Gl position. In certain embodiments, the point of attachment in Formula (IV-a) is at the nitrogen at the G2 position.
  • the compound of Formula (I) is of Formula (IV-al):
  • the point of attachment in Formula (IV-al) is at the nitrogen at the Gl position. In certain embodiments, the point of attachment in Formula (IV-al) is at the nitrogen at the G2 position.
  • the compound of Formula (I) is of one of the following formulae:
  • the compound of Formula (I) is of one of the following formulae:
  • R is hydrogen or a non-hydrogen alpha substituent
  • R is hydrogen or a non-hydrogen alpha substituent
  • R 1 is -CH 3 -CH 2 CH 3 , - CH 2 F, -CHF 2 , -CF 3 , -CH 2 OCH 3 , or substituted or unsubstituted cyclopropyl.
  • R 2 is -OH, -OCH3, -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , substituted or unsubstituted cyclopropyl, fluoro, or chloro.
  • R 3a and R 3 are both hydrogen.
  • R 4a is hydrogen, fluoro, -CH 3 , or - CF 3 .
  • both of R 4a and R 4 are hydrogen.
  • both of R 4a and R 4 are -CH 3 or -CF 3 .
  • both of R 4a and R 4 are fluoro.
  • R 4a is a non-hydrogen substituent and R 4 is hydrogen.
  • R 2 is hydrogen or a non-hydrogen beta substituent, provided is a compound of Formula (I-A2), (I-B2), (I-C2), or (I-D2):
  • R 1 is -CH 3 -CH 2 CH 3 , - CH 2 F, -CHF 2 , -CF 3 , -CH 2 OCH 3 , or substituted or unsubstituted cyclopropyl.
  • R 2 is -OH, -OCH3, -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , substituted or unsubstituted cyclopropyl, fluoro, or chloro.
  • R 3a and R 3 are both hydrogen.
  • R 4a is hydrogen, fluoro, -CH 3 , or - CF 3 .
  • both of R 4a and R 4 are hydrogen.
  • both of R 4a and R 4 are -CH 3 or -CF 3 .
  • both of R 4a and R 4 are fluoro.
  • Ring B does not comprises a C5-C6 double bond
  • R 4a is a non-hydrogen substituent and R 4 is hydrogen.
  • R 3a is hydrogen or a non-hydrogen alpha substituent, and R 3 is hydrogen, provided is a compound of Formula (I- A3), (I-B3), (I-C3), or (I-D3):
  • R 1 is -CH 3 -CH 2 CH 3 , - CH 2 F, -CHF 2 , -CF 3 , -CH 2 OCH 3 , or substituted or unsubstituted cyclopropyl.
  • R 2 is -OH, -OCH3, -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , substituted or unsubstituted cyclopropyl, fluoro, or chloro.
  • R 2 is a non- hydrogen substituent in the alpha configuration.
  • R is a non-hydrogen substituent in the beta configuration.
  • R 4a is hydrogen, fluoro, -CH 3 , or -CF 3 .
  • both of R 4a and R 4 are hydrogen.
  • both of R 4a and R 4 are -CH 3 or -CF 3 .
  • Ring B does not comprises a C5-C6 double bond, both of R 4a and
  • R 4b are fluoro. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond,
  • R 4a is a non-hydrogen substituent and R 4 is hydrogen.
  • R 3a is hydrogen or a non-hydrogen beta substituent, and R 3 is hydrogen, provided is a compound of Formula (I-A4), (I-B4), (I-C4), or (I-D4):
  • R 1 is -CH 3 -CH 2 CH 3 , - CH 2 F, -CHF 2 , -CF 3 , -CH 2 OCH 3 , or substituted or unsubstituted cyclopropyl.
  • R 2 is -OH, -OCH3, -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , substituted or unsubstituted cyclopropyl, fluoro, or chloro.
  • R 2 is a non- hydrogen substituent in the alpha configuration.
  • R is a non-hydrogen substituent in the beta configuration.
  • R 4a is hydrogen, fluoro, -CH 3 , or -CF 3 .
  • both of R 4a and R 4 are hydrogen.
  • both of R 4a and R 4 are -CH 3 or -CF 3 .
  • Ring B does not comprises a C5-C6 double bond, both of R 4a and
  • R 4b are fluoro. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond,
  • R 4a is a non-hydrogen substituent and R 4 is hydrogen.
  • R 3a and R 3 are joined to form an oxo group, provided is a compound of Formula (I-A5), (I-B5), (I-C5), (I-D5):
  • R 1 is -C3 ⁇ 4 -CH 2 CH 3 , - CH 2 F, -CHF 2 , -CF 3 , -CH 2 OCH 3 , or substituted or unsubstituted cyclopropyl.
  • R 2 is -OH, -OCH3, -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , substituted or unsubstituted cyclopropyl, fluoro, or chloro.
  • R is a non- hydrogen substituent in the alpha configuration.
  • R is a non-hydrogen substituent in the beta configuration.
  • R 4a is hydrogen, fluoro, -CH 3 , or -CF 3 .
  • both of R 4a and R 4 are hydrogen.
  • both of R 4a and R 4 are -CH 3 or -CF 3 .
  • Ring B does not comprises a C5-C6 double bond, both of R 4a and
  • R 4b are fluoro. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond,
  • R 4a is a non-hydrogen substituent and R 4 is hydrogen.
  • R 4a is a non-hydrogen substituent, provided is a compound of Formula (I-A6) or (I-B6):
  • R 1 is -C3 ⁇ 4 -CH 2 CH 3 , - CH 2 F, -CHF 2 , -CF 3 , -CH 2 OCH 3 , or substituted or unsubstituted cyclopropyl.
  • R 2 is -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 substituted or unsubstituted cyclopropyl, fluoro, or chloro.
  • R 2 is a non- hydrogen substituent in the alpha configuration.
  • R 2 is a non-hydrogen substituent in the beta configuration.
  • R 3a and R 3 are both hydrogen.
  • R 4a is fluoro, -CH 3 , or -CF 3 and R 4 is hydrogen.
  • R 4 is fluoro, -C3 ⁇ 4, or -CF 3 and R 4a is hydrogen.
  • both of R 4a and R 4 are -CH 3 or -CF 3 .
  • both of R 4a and R 4 are fluoro.
  • a compound of Formula (I) is selected from the group consisting of
  • a compound of Formula (I) is selected from the group consisting of:
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention (also referred to as the "active ingredient") and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises an effective amount of the active ingredient.
  • the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient.
  • the pharmaceutical composition comprises a prophylactically effective amount of the active ingredient.
  • compositions provided herein can be administered by a variety of routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration.
  • the compounds provided herein are administered in an effective amount.
  • the amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of
  • the compounds provided herein When used to prevent the onset of a CNS-disorder, the compounds provided herein will be administered to a subject at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above.
  • Subjects at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.
  • the pharmaceutical compositions provided herein can also be administered chronically ("chronic administration").
  • Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc, or may be continued indefinitely, for example, for the rest of the subject's life.
  • the chronic administration is intended to provide a constant level of the compound in the blood, e.g., within the therapeutic window over the extended period of time.
  • the pharmaceutical composition may be given as a bolus, e.g., in order to raise the concentration of the compound in the blood to an effective level.
  • the placement of the bolus dose depends on the systemic levels of the active ingredient desired throughout the body, e.g., an intramuscular or subcutaneous bolus dose allows a slow release of the active ingredient, while a bolus delivered directly to the veins (e.g., through an IV drip) allows a much faster delivery which quickly raises the concentration of the active ingredient in the blood to an effective level.
  • the pharmaceutical composition may be given as a bolus, e.g., in order to raise the concentration of the compound in the blood to an effective level.
  • the placement of the bolus dose depends on the systemic levels of the active ingredient desired throughout the body, e.g., an intramuscular or subcutaneous bolus dose allows a slow release of the active ingredient, while a bolus delivered directly to the veins (e.g., through an IV drip) allows a much faster delivery
  • composition may be administered as a continuous infusion, e.g., by IV drip, to provide
  • the pharmaceutical composition may be administered as first as a bolus dose, followed by continuous infusion.
  • compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • the compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or excipients and processing aids helpful for forming the desired dosing form.
  • a minor component from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight
  • the remainder being various vehicles or excipients and processing aids helpful for forming the desired dosing form.
  • oral dosing one to five and especially two to four and typically three oral doses per day are representative regimens. Using these dosing patterns, each dose provides from about 0.01 to about 20 mg/kg of the compound provided herein, with preferred doses each providing from about 0.1 to about 10 mg/kg, and especially about 1 to about 5 mg/kg.
  • Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses, generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • Injection dose levels range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours.
  • a preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels.
  • the maximum total dose is not expected to exceed about 2 g/day for a 40 to 80 kg human patient.
  • Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like.
  • Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s).
  • the active ingredients When formulated as a ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base.
  • Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or Formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.
  • transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
  • transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
  • the above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington 's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.
  • the compounds of the present invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.
  • the present invention also relates to the pharmaceutically acceptable formulations of a compound of the present invention.
  • the formulation comprises water.
  • the formulation comprises a cyclodextrin derivative. The most common
  • cyclodextrins are ⁇ -, ⁇ - and ⁇ - cyclodextrins consisting of 6, 7 and 8 a-1 ,4-linked glucose units, respectively, optionally comprising one or more substituents on the linked sugar moieties, which include, but are not limited to, methylated, hydroxyalkylated, acylated, and sulfoalkylether substitution.
  • the cyclodextrin is a sulfoalkyl ether ⁇ -cyclodextrin, e.g., for example, sulfobutyl ether ⁇ -cyclodextrin, also known as Captisol . See, e.g., U.S. 5,376,645.
  • the formulation comprises hexapropyl-P-cyclodextrin (e.g., 10-50% in water).
  • the present invention also relates to the pharmaceutically acceptable acid addition salt of a compound of the present invention.
  • the acid which may be used to prepare the pharmaceutically acceptable salt is that which forms a non-toxic acid addition salt, i.e., a salt containing
  • pharmacologically acceptable anions such as the hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like.
  • the following formulation examples illustrate representative pharmaceutical compositions that may be prepared in accordance with this invention. The present invention, however, is not limited to the following pharmaceutical compositions.
  • a compound of the present invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 2 - Capsules A compound of the present invention may be admixed as a dry powder with a starch diluent in an approximate 1 : 1 weight ratio. The mixture is filled into 250 mg capsules (125 mg of active compound per capsule).
  • Exemplary Formulation 3 - Liquid A compound of the present invention (125 mg) may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11 :89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color are diluted with water and added with stirring. Sufficient water may then be added to produce a total volume of 5 mL.
  • a compound of the present invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 450-900 mg tablets (150- 300 mg of active compound) in a tablet press.
  • a compound of the present invention may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/mL.
  • a compound of the present invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 90-150 mg tablets (30-50 mg of active compound per tablet) in a tablet press.
  • a compound of the present invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 30-90 mg tablets (10-30 mg of active compound per tablet) in a tablet press.
  • a compound of the present invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 0.3-30 mg tablets (0.1-10 mg of active compound per tablet) in a tablet press.
  • a compound of the present invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 150-240 mg tablets (50-80 mg of active compound per tablet) in a tablet press.
  • a compound of the present invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 270-450 mg tablets (90- 150 mg of active compound per tablet) in a tablet press.
  • the present invention is directed to C21 -substituted neuroactive steroids designed, for example, to act as GABA modulators.
  • such compounds are envisioned to be useful as therapeutic agents for the inducement of anesthesia and/or sedation in a subject.
  • such compounds are envisioned to be useful as therapeutic agents for treating a CNS-related disorder (e.g., sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, or tinnitus) in a subject in need (e.g., a subject with Rett syndrome, Fragile X syndrome, or Angelman syndrome).
  • a CNS-related disorder e.g., sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, or tinnitus
  • the present invention provides a method of inducing sedation and/or anesthesia in a subject, comprising administering to the subject an effective amount of a compound of the present invention or a composition thereof.
  • the compound is administered by intravenous administration.
  • Compounds of the present invention are generally designed to modulate GABA function, and therefore to act as neuroactive steroids for the treatment and prevention of CNS-r elated conditions in a subject.
  • Modulation refers to the inhibition or potentiation of GABA receptor function.
  • the compounds and pharmaceutical compositions provided herein find use as therapeutics for preventing and/or treating CNS conditions in mammals including humans and non-human mammals.
  • the present invention includes within its scope, and extends to, the recited methods of treatment, as well as to the compounds for such methods, and to the use of such compounds for the preparation of medicaments useful for such methods.
  • Exemplary CNS conditions related to GABA-modulation include, but are not limited to, sleep disorders [e.g., insomnia], mood disorders [e.g., depression, dysthymic disorder ⁇ e.g., mild depression), bipolar disorder ⁇ e.g., I and/or II), anxiety disorders ⁇ e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), compulsive disorders ⁇ e.g., obsessive compulsive disorder (OCD))], schizophrenia spectrum disorders [e.g., schizophrenia, schizoaffective disorder], convulsive disorders [e.g., epilepsy (e.g., status epilepticus (SE)), seizures], disorders of memory and/or cognition [e.g., attention disorders (e.g., attention deficit hyperactivity disorder (ADHD)), dementia (e.g., Alzheimer's type dementia, Lewis body type dementia, vascular type dementia], movement disorders [e.g., Huntington's disease, Parkinson's disease],
  • a combination of a compound of the present invention and another pharmacologically active agent is provided.
  • the compounds provided herein can be administered as the sole active agent or they can be administered in combination with other agents. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent and alternating administration.
  • a method of treating or preventing brain excitability in a subject susceptible to or afflicted with a condition associated with brain excitability comprising administering to the subject an effective amount of a compound of the present invention to the subject.
  • a method of treating or preventing stress or anxiety in a subject comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention, or a composition thereof.
  • a method of alleviating or preventing seizure activity in a subject comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention.
  • a method of inducing sleep and maintaining substantially the level of REM sleep that is found in normal sleep, wherein substantial rebound insomnia is not induced comprising administering an effective amount of a compound of the present invention.
  • a method of alleviating or preventing PMS or PND in a subject comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention.
  • the mood disorder is depression.
  • a method of inducing anesthesia in a subject comprising administering to the subject an effective amount of a compound of the present invention.
  • a method of cognition enhancement or treating memory disorder by administering to the subject a therapeutically effective amount of a compound of the present invention.
  • the disorder is Alzheimer's disease.
  • the disorder is Rett syndrome.
  • a method of treating attention disorders by administering to the subject a therapeutically effective amount of a compound of the present invention.
  • the attention disorder is ADHD.
  • the compound is administered to the subject chronically. In certain embodiments, the compound is administered to the subject orally, subcutaneously, intramuscularly, or intravenously.
  • Anesthesia is a pharmacologically induced and reversible state of amnesia, analgesia, loss of responsiveness, loss of skeletal muscle reflexes, decreased stress response, or all of these simultaneously. These effects can be obtained from a single drug which alone provides the correct combination of effects, or occasionally with a combination of drugs ⁇ e.g., hypnotics, sedatives, paralytics, analgesics) to achieve very specific combinations of results. Anesthesia allows patients to undergo surgery and other procedures without the distress and pain they would otherwise experience.
  • Sedation is the reduction of irritability or agitation by administration of a pharmacological agent, generally to facilitate a medical procedure or diagnostic procedure.
  • Sedation and analgesia include a continuum of states of consciousness ranging from minimal sedation (anxiolysis) to general anesthesia.
  • Minimal sedation is also known as anxiolysis. Minimal sedation is a drug-induced state during which the patient responds normally to verbal commands. Cognitive function and coordination may be impaired. Ventilatory and cardiovascular functions are typically unaffected.
  • Moderate sedation/analgesia is a drug-induced depression of consciousness during which the patient responds purposefully to verbal command, either alone or accompanied by light tactile stimulation. No interventions are usually necessary to maintain a patent airway. Spontaneous ventilation is typically adequate. Cardiovascular function is usually maintained.
  • Deep sedation/analgesia is a drug-induced depression of consciousness during which the patient cannot be easily aroused, but responds purposefully (not a reflex withdrawal from a painful stimulus) following repeated or painful stimulation. Independent ventilatory function may be impaired and the patient may require assistance to maintain a patent
  • General anesthesia is a drug-induced loss of consciousness during which the patient is not arousable, even to painful stimuli.
  • the ability to maintain independent ventilatory function is often impaired and assistance is often required to maintain a patent airway.
  • Positive pressure ventilation may be required due to depressed spontaneous ventilation or drug-induced depression of neuromuscular function.
  • Cardiovascular function may be impaired.
  • Sedation in the intensive care unit allows the depression of patients' awareness of the environment and reduction of their response to external stimulation. It can play a role in the care of the critically ill patient, and encompasses a wide spectrum of symptom control that will vary between patients, and among individuals throughout the course of their illnesses. Heavy sedation in critical care has been used to facilitate endotracheal tube tolerance and ventilator
  • sedation e.g., long-term sedation, continuous sedation
  • a prolonged period of time e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 week, 3 weeks, 1 month, 2 months.
  • Long-term sedation agents may have long duration of action. Sedation agents in the ICU may have short elimination half-life.
  • Procedural sedation and analgesia is a technique of administering sedatives or dissociative agents with or without analgesics to induce a state that allows a subject to tolerate unpleasant procedures while maintaining cardiorespiratory function.
  • Anxiety disorder is a blanket term covering several different forms of abnormal and pathological fear and anxiety.
  • Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders.
  • Generalized anxiety disorder is a common chronic disorder characterized by long-lasting anxiety that is not focused on any one object or situation. Those suffering from generalized anxiety experience non-specific persistent fear and worry and become overly concerned with everyday matters. Generalized anxiety disorder is the most common anxiety disorder to affect older adults.
  • panic disorder a person suffers from brief attacks of intense terror and apprehension, often marked by trembling, shaking, confusion, dizziness, nausea, difficulty breathing.
  • panic attacks defined by the APA as fear or discomfort that abruptly arises and peaks in less than ten minutes, can last for several hours and can be triggered by stress, fear, or even exercise; although the specific cause is not always apparent.
  • a diagnosis of panic disorder also requires that said attacks have chronic consequences: either worry over the attacks' potential implications, persistent fear of future attacks, or significant changes in behavior related to the attacks. Accordingly, those suffering from panic disorder experience symptoms even outside of specific panic episodes.
  • Obsessive compulsive disorder is a type of anxiety disorder primarily characterized by repetitive obsessions (distressing, persistent, and intrusive thoughts or images) and compulsions (urges to perform specific acts or rituals).
  • the OCD thought pattern may be likened to superstitions insofar as it involves a belief in a causative relationship where, in reality, one does not exist.
  • the process is entirely illogical; for example, the compulsion of walking in a certain pattern may be employed to alleviate the obsession of impending harm. And in many cases, the compulsion is entirely inexplicable, simply an urge to complete a ritual triggered by nervousness.
  • sufferers of OCD may only experience obsessions, with no overt compulsions; a much smaller number of sufferers experience only compulsions.
  • the single largest category of anxiety disorders is that of Phobia, which includes all cases in which fear and anxiety is triggered by a specific stimulus or situation.
  • Sufferers typically anticipate cosmic consequences from encountering the object of their fear, which can be anything from an animal to a location to a bodily fluid.
  • Post-traumatic stress disorder or PTSD is an anxiety disorder which results from a traumatic experience.
  • Post-traumatic stress can result from an extreme situation, such as combat, rape, hostage situations, or even serious accident. It can also result from long term (chronic) exposure to a severe stressor, for example soldiers who endure individual battles but cannot cope with continuous combat. Common symptoms include flashbacks, avoidant behaviors, and depression.
  • neurodegenerative disease includes diseases and disorders that are associated with the progressive loss of structure or function of neurons, or death of neurons.
  • Neurodegenerative diseases and disorders include, but are not limited to, Alzheimer's disease (including the associated symptoms of mild, moderate, or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic injuries; ataxia and convulsion (including for the treatment and prevention and prevention of seizures that are caused by schizoaffective disorder or by drugs used to treat schizophrenia); benign forgetfulness; brain edema; cerebellar ataxia including McLeod neuroacanthocytosis syndrome (MLS); closed head injury; coma; contusive injuries (e.g., spinal cord injury and head injury); dementias including multi-infarct dementia and senile dementia; disturbances of consciousness; Down syndrome; drug-induced or medication-induced Parkinsonism (such as neuroleptic- induced acute akathisia, acute dystonia, Parkinsonism, or tardive dyskinesia, neuroleptic mal
  • neuronal damage including ocular damage, retinopathy or macular degeneration of the eye; neurotoxic injury which follows cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest;
  • Neurodegenerative diseases also include, but are not limited to, neurotoxic injury which follows cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest.
  • Methods of treating or preventing a neurodegenerative disease also include treating or preventing loss of neuronal function characteristic of neurodegenerative disorder.
  • Epilepsy is a brain disorder characterized by repeated seizures over time.
  • Types of epilepsy can include, but are not limited to generalized epilepsy, e.g., childhood absence epilepsy, juvenile nyoclonic epilepsy, epilepsy with grand-mal seizures on awakening, West syndrome, Lennox-
  • Gastaut syndrome partial epilepsy, e.g., temporal lobe epilepsy, frontal lobe epilepsy, benign focal epilepsy of childhood.
  • Status epilepticus can include, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non- convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges.
  • convulsive status epilepticus e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus
  • non- convulsive status epilepticus e.g., generalized status epilepticus, complex partial status epilepticus
  • generalized periodic epileptiform discharges e.g., periodic epileptiform discharges.
  • Convulsive status epilepticus is characterized by the presence of convulsive status epileptic seizures, and can include early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus.
  • Early status epilepticus is treated with a first line therapy.
  • Established status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line therapy, and a second line therapy is administered.
  • Refractory status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line and a second line therapy, and a general anesthetic is generally administered.
  • Super refractory status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line therapy, a second line therapy, and a general anesthetic for 24 hours or more.
  • Non-convulsive status epilepticus can include, e.g., focal non-convulsive status epilepticus, e.g., complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, subtle non-convulsive status epilepticus; generalized non-convulsive status epilepticus, e.g., late onset absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus.
  • focal non-convulsive status epilepticus e.g., complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, subtle non-convulsive status epilepticus
  • generalized non-convulsive status epilepticus e.g., late onset absence non-convulsive status epilepticus, atypical absence non-convulsive
  • compositions described herein can also be administered as a prophylactic to a subject having a CNS disorder e.g., a traumatic brain injury, status epilepticus, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super- refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges; prior to the onset of a seizure.
  • a CNS disorder e.g., a traumatic brain injury
  • status epilepticus e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super- refractory status epileptic
  • a seizure is the physical findings or changes in behavior that occur after an episode of abnormal electrical activity in the brain.
  • the term "seizure" is often used interchangeably with
  • Convulsions are when a person's body shakes rapidly and uncontrollably. During convulsions, the person's muscles contract and relax repeatedly.
  • seizures are divided into two broad categories: generalized and partial (also called local or focal). Classifying the type of seizure helps doctors diagnose whether or not a patient has epilepsy.
  • Generalized seizures are produced by electrical impulses from throughout the entire brain, whereas partial seizures are produced (at least initially) by electrical impulses in a relatively small part of the brain.
  • the part of the brain generating the seizures is sometimes called the focus.
  • Absence seizures cause a short loss of consciousness (just a few seconds) with few or no symptoms.
  • the patient most often a child, typically interrupts an activity and stares blankly. These seizures begin and end abruptly and may occur several times a day. Patients are usually not aware that they are having a seizure, except that they may be aware of "losing time.”
  • Myoclonic seizures consist of sporadic jerks, usually on both sides of the body. Patients sometimes describe the jerks as brief electrical shocks. When violent, these seizures may result in dropping or involuntarily throwing objects.
  • Clonic seizures are repetitive, rhythmic jerks that involve both sides of the body at the same time. Tonic seizures are characterized by stiffening of the muscles.
  • Atonic seizures consist of a sudden and general loss of muscle tone, particularly in the arms and legs, which often results in a fall.
  • Seizures described herein can include epileptic seizures; acute repetitive seizures; cluster seizures; continuous seizures; unremitting seizures; prolonged seizures; recurrent seizures; status epilepticus seizures, e.g., refractory convulsive status epilepticus, non-convulsive status epilepticus seizures; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondarily generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign Rolandic seizures; febrile seizures; emotional seizures; focal seizures; gelastic seizures; generalized onset seizures; infantile spasms; Jacksonian seizures; massive bilateral myoclonus seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post traumatic seizures; subtle seizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures.
  • status epilepticus seizures e.g., refractory convulsive status epilepticus, non
  • Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • the choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.
  • the compounds provided herein may be isolated and purified by known standard procedures.
  • Exemplary chiral columns available for use in the separation/purification of the enantiomers/diastereomers provided herein include, but are not limited to, CfflRALPAK® AD- 10, CfflRALCEL® OB, CfflRALCEL® OB- H, CfflRALCEL® OD, CfflRALCEL® OD-H, CfflRALCEL® OF, CfflRALCEL® OG, CfflRALCEL® OJ and CfflRALCEL® OK.
  • SFC purification was carried out using a Thar 200 preparative SFC instrument equipped with a ChiralPak AD- 10 ⁇ , 200x50 mm ID. The compounds were separated eluting with mixtures of carbon dioxide and methanol or ethanol (e.g., 20-35% methanol or ethanol and 0.1% ammonium hydroxide) at a flow rate of 55- 200 mL/min and monitored at 220 nm wavelength.
  • 1 H-NMR reported herein may be a partial representation of the full NMR spectrum of a compound, e.g., a compound described herein. For example, the reported 1 H NMR may exclude the region between ⁇ (ppm) of about 1 to about 2.5 ppm.
  • the compounds of the invention can be prepared in accordance with methods described in the art (Upasani e/ a/., J. Med. Chem. 1997, 40:73-84; and Hogenkamp et ah, J. Med. Chem. 1997, 40:61- 72) and using the appropriate reagents, starting materials, and purification methods known to those skilled in the art.
  • compounds described herein can be prepared using methods shown in general Schemes 1-4, comprising a nucleophilic substitution of 19-nor pregnane bromide with a neucleophile.
  • the nucleophile reacts with the 19-nor pregnane bromide in the presence of K 2 CO 3 in THF.
  • SA-73 1H NMR (500 MHz, CDC1 3 ) ⁇ (ppm): 7.63 (IH, d), 7.23 (IH, t), 6.76 (IH, d), 5.59 (IH, AB), 5.58 (IH, AB), 3.89 (IH , s), 2.67 (IH , t0.73 (3H, s).
  • SA-C (3.23 g, 9.6 mmol) was added to the mixture, stirred at 60 °C for 15 h.
  • the residue mixture was purified by reverse-phase prep-HPLC to afford SA-120 as a white solid (6.0mg, 6.2%) and SA-121 as a white solid (8.6mg, 8.9%) and SA-122 as a white solid (12.6mg, 13.0%).
  • SA-123 1H NMR: (500 MHz, CDC13), ⁇ (ppm), 9.47 (s, 1H), 8.56 (d, 1H), 7.29 (dd, 1H), 5.48 (AB, 1H), 5.40 (AB, 1H), 3.42 (AB, 1H), 3.40 (s, 3H), 3.39 (AB, 1H), 2.74 (t, 1H), 0.71 (s, 3H).
  • SG-21 IH NMR (500 MHz, CDC1 3 ) ⁇ (ppm): 7.73 (d), 7.08-7.05 (m, 2H), 5.50 (AB), 5.43 (AB,), 4.17 (d), 3.88 (3H, s), 2.65 (t,), 0.75 (s, 3H).
  • SG-24 1H NMR (400 MHz, CDC1 3 ), ⁇ (ppm), 7.85 (IH, dd), 7.46 (IH, dd), 7.19 (IH, td), 5.50 (IH, AB), 5.48 (IH, AB), 4.17 (2H, d), 2.66 (IH, t), 0.73 (3H, s).

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Abstract

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.

Description

19-NOR NEURO ACTIVE STEROIDS AND METHODS OF USE THEREOF
Background of the Invention
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+, CI", 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 neurons by regulating the conductance of chloride ions across the neuronal membrane. GABA interacts with its recognition site on the GRC to facilitate the flow of chloride ions down an electrochemical gradient of the GRC into the cell. An intracellular increase in the levels of this anion causes hyperpolarization of the transmembrane potential, rendering the neuron less susceptible to excitatory inputs (i.e., reduced neuron excitability). In other words, the higher the chloride ion concentration in the neuron, the lower the brain excitability (the level of arousal).
It is well-documented that the GRC is responsible for the mediation of anxiety, seizure activity, and sedation. Thus, GABA and drugs that act like GABA or facilitate the effects of GABA (e.g., the therapeutically useful barbiturates and benzodiazepines (BZs), such as Valium®) produce their therapeutically useful effects by interacting with specific regulatory sites on the GRC.
Accumulated evidence has now indicated that in addition to the benzodiazepine and barbiturate binding site, the GRC contains a distinct site for neuroactive steroids (Lan, N. C. et al,
Neurochem. Res. 16:347-356 (1991)).
Neuroactive steroids can occur endogenously. The most potent endogenous neuroactive steroids are 3a-hydroxy-5-reduced pregnan-20-one and 3a-21-dihydroxy-5-reduced pregnan-20-one, metabolites of hormonal steroids progesterone and deoxycorticosterone, respectively. The ability of these steroid metabolites to alter brain excitability was recognized in 1986 (Majewska, M. D. et al, Science 232: 1004-1007 (1986); Harrison, N. L. et al, J Pharmacol. Exp. Ther. 241 :346-353 (1987)).
The ovarian hormone progesterone and its metabolites have been demonstrated to have profound effects on brain excitability (Backstrom, T. et al, Acta Obstet. Gynecol. Scand. Suppl. 130: 19-24 (1985); Pfaff, D.W and McEwen, B. S., Science 219:808-814 (1983); Gyermek et al, J Med Chem. 11 : 117 (1968); Lambert, J. et al, Trends Pharmacol. Sci. 8:224-227 (1987)). The levels of progesterone and its metabolites vary with the phases of the menstrual cycle. It has been well documented that the levels of progesterone and its metabolites decrease prior to the onset of menses. The monthly recurrence of certain physical symptoms prior to the onset of menses has also been well documented. These symptoms, which have become associated with premenstrual syndrome (PMS), include stress, anxiety, and migraine headaches (Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook, Chicago (1984)). Subjects with PMS have a monthly recurrence of symptoms that are present in premenses and absent in postmenses.
In a similar fashion, a reduction in progesterone has also been temporally correlated with an increase in seizure frequency in female epileptics, i.e., catamenial epilepsy (Laidlaw, J., Lancet, 1235-1237 (1956)). A more direct correlation has been observed with a reduction in progesterone metabolites (Rosciszewska et al, J. Neurol. Neurosurg. Psych. 49:47-51 (1986)). In addition, for subjects with primary generalized petit mal epilepsy, the temporal incidence of seizures has been correlated with the incidence of the symptoms of premenstrual syndrome (Backstrom, T. et al, J. Psychosom. Obstet. Gynaecol. 2:8-20 (1983)). The steroid deoxycorticosterone has been found to be effective in treating subjects with epileptic spells correlated with their menstrual cycles (Aird, R.B. and Gordan, G, J. Amer. Med. Soc. 145:715-719 (1951)). A syndrome also related to low progesterone levels is postnatal depression (PND). Immediately after birth, progesterone levels decrease dramatically leading to the onset of PND. The symptoms of PND range from mild depression to psychosis requiring hospitalization. PND is also associated with severe anxiety and irritability. PND-associated depression is not amenable to treatment by classic antidepressants, and women experiencing PND show an increased incidence of PMS
(Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook, Chicago (1984)).
Collectively, these observations imply a crucial role for progesterone and deoxycorticosterone and more specifically their metabolites in the homeostatic regulation of brain excitability, which is manifested as an increase in seizure activity or symptoms associated with catamenial epilepsy, PMS, and PND. The correlation between reduced levels of progesterone and the symptoms associated with PMS, PND, and catamenial epilepsy (Backstrom, T. et al, J Psychosom.Obstet. Gynaecol. 2:8-20 (1983)); Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook, Chicago (1984)) has prompted the use of progesterone in their treatment (Mattson et ah, "Medroxyprogesterone therapy of catamenial epilepsy," in Advances in Epileptology: XVth Epilepsy International Symposium, Raven Press, New York (1984), pp. 279- 282, and Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook, Chicago (1984)). However, progesterone is not consistently effective in the treatment of the aforementioned syndromes. For example, no dose-response relationship exists for progesterone in the treatment of PMS (Maddocks et al., Obstet. Gynecol. 154:573-581 (1986); Dennerstein et ah, Brit. Med J 290: 16-17 (1986)).
New and improved neuroactive steroids are needed that act as modulating agents for brain excitability, as well as agents for the prevention and treatment of CNS-related diseases. The compounds, compositions, and methods described herein are directed toward this end.
Summary of the Invention The present invention is based, in part, on the desire to provide novel 19-nor (i.e., C19 desmethyl) compounds, e.g., related to progesterone, deoxycorticosterone, and their metabolites, with good potency, pharmacokinetic (PK) properties, oral bioavailability, formulatability, stability, safety, clearance and/or metabolism. One key feature of the compounds as described herein is disubstitution at the C3 position (e.g., with one substituent being a 3a hydroxy moiety. The inventors envision disubstitution at C-3 will eliminate the potential for oxidation of the hydroxy moiety to the ketone, prevent further metabolism, and reduce the potential for secondary elimination pathways, such as glucuronidation. The inventors further envision the overall effect of C3 disubstitution should be of improving the overall PK parameters and reducing potential toxicities and side effects, which may allow, in certain embodiments, administration orally and/or chronically. Another key feature of the compounds as described herein is the presence of a hydrogen at the CI 9 position ("19-nor") rather than a methyl group. The inventors envision 19- nor compounds, as compared to their C19-methyl counterparts, will have improved physical properties, such as improved solubility. The inventors envision futher enhancement of solubility, for example, when the AB ring system is in the cis configuration.
Thus, in one aspect, provided herein are compounds of Formula (I):
Figure imgf000006_0001
harmaceutically acceptable salts thereof; wherein:
= represents a single or double bond;
R is substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-6 carbocyclyl; R2 is hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-6 carbocyclyl, or -ORA2, wherein RA2 is hydrogen or substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-6 carbocyclyl;
R3a is hydrogen or -ORA3, wherein RA3 is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-6 carbocyclyl, and R3 is hydrogen; or R3a and R3b are joined to form an oxo (=0) group; each instance of R4a and R4 is independently hydrogen, substituted or unsubstituted C1-6 alkyl, or halogen; provided if bond p is a double bond, then bond q is a single bond, provided if bond q is a double bond, then bond p is a single bond and R4 is absent; and provided if both bonds p and q are single bonds, then the hydrogen at C5 is in the alpha or beta configuration; of Formula (A-1) or Formula (A-2):
Figure imgf000007_0001
(A-2), wherein the point of attachment is
1 2 2 3
at G or G in Formula (A-1) and the point of attachment is at G or G in Formula (A-2)
G1 is N, NRN1, O, S, C, or C-RG1 as valency permits;
G2 is N, NRN2, O, S, C, -C=N-, or C-RG2 as valency permits;
G3 is N, NRN3, O, S, C, or C-RG3 as valency permits;
G4 is N, NRN4, C-RG4, or C-(RG4)2 as valency permits;
G5 is N, NRN5, C-RG5, or C-(RG5)2 as valency permits; G6 is N, NRN6, C-RG6, or C-(RG6)2 as valency permits; and G7 is N, NRN7, C-RG7, or C-(RG7)2 as valency permits; each instance of RG1, RG2, RG3, RG4, RG5, RG6, and RG7 is, independently, hydrogen, halogen, -N02, -CN, -ORGA, -N(RGA)2, -C(=0)RGA, -C(=0)ORGA, -OC(=0)RGA, - OC(=0)ORGA, -C(=0)N(RGA)2, -N(RGA)C(=0)RGA, -OC(=0)N(RGA)2, -
N(RGA)C(=0)ORGA, -S(=0)2RGA, -S(=0)2ORGA, -OS(=0)2RGA, -S(=0)2N(RGA)2, - N(RGA)S(=0)2RGA, -S(=0)RGA, -S(=0)ORGA, -OS(=0)RGA, -S(=0)N(RGA)2, - N(RGA)S(=0)RGA, substituted or unsubstituted Ci.6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocylyl, substituted or unsubstituted 3- to 6- membered heterocylyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each instance of RN1, RN2, RN3, RN4, RN5, RN6, and RN7 is independently hydrogen, substituted or unsubstituted Ci-6 alkyl, or a nitrogen protecting group; and each instance of RGA is independently hydrogen, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocylyl, substituted or unsubstituted 3- to 6- membered heterocylyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, or two RGA groups are taken with the intervening atoms to form a substituted or unsubstituted carbocyclic or heterocylic ring.
In certain embodiments, G4 is N or NRN4, and/or G5 is N or NRN5, and/or G6 is N or NRN6, and/or G7 is N or NRN7.
Compounds of Formula (I), sub-genera thereof, and pharmaceutically acceptable salts thereof are collectively referred to herein as "compounds of the present invention." In another aspect, provided is a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient. In certain embodiments, the compound of the present invention is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the compound of the present invention is provided in a therapeutically effective amount. In certain embodiments, the compound of the present invention is provided in a prophylactically effective amount.
Compounds of the present invention as described herein, act, in certain embodiments, as GABA modulators, e.g., effecting the GABAA receptor in either a positive or negative manner. As modulators of the excitability of the central nervous system (CNS), as mediated by their ability to modulate GABAA receptor, such compounds are expected to have CNS-activity.
Thus, in another aspect, provided are methods of treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present invention. In certain embodiments, the CNS-related disorder is selected from the group consisting of a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, and tinnitus. In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered chronically.
Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing Detailed Description, Examples, and Claims.
Definitions Chemical Definitions
Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March 's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock,
Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3r Edition, Cambridge University Press, Cambridge, 1987.
Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et ah, Enantiomers, Racemates and Resolutions (Wiley
Interscience, New York, 1981); Wilen et ah, Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example "Ci_6 alkyl" is intended to encompass, Ci, C2, C3, C4, C5, C6, Ci_6, Ci_5, Ci_4, Ci_3, Ci-2, C2-6, C2-5, C2-4, C2-3, C3_6, C3-5, C3- , C4-6, C4-5, and C5-6 alkyl.
The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention. When describing the invention, which may include compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term "substituted" is to be defined as set out below. It should be further understood that the terms "groups" and "radicals" can be considered interchangeable when used herein. The articles "a" and "an" may be used herein to refer to one or to more than one {i.e. at least one) of the grammatical objects of the article. By way of example "an analogue" means one analogue or more than one analogue. "Alkyl" refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms ("Ci-20 alkyl"). In some embodiments, an alkyl group has 1 to 12 carbon atoms ("Ci-12 alkyl"). In some embodiments, an alkyl group has 1 to 10 carbon atoms ("Ci-10 alkyl"). In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C1-9 alkyl"). In some embodiments, an alkyl group has 1 to 8 carbon atoms ("Ci_8 alkyl"). In some embodiments, an alkyl group has 1 to 7 carbon atoms ("Ci_7 alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("Ci_6 alkyl", also referred to herein as "lower alkyl"). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C1-5 alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C1-4 alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C1-2 alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("Ci alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C2-6 alkyl"). Examples of Ci_6 alkyl groups include methyl (Ci), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso- butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted Ci-10 alkyl {e.g., -CH3). In certain embodiments, the alkyl group is substituted Ci-10 alkyl. Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3), lPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (- CH2CH2CH2CH3), or l-Bu (-CH2CH(CH3)2).
As used herein, "alkylene," "alkenylene," and "alkynylene," refer to a divalent radical of an alkyl, alkenyl, and alkynyl group, respectively. When a range or number of carbons is provided for a particular "alkylene," "alkenylene," and "alkynylene" group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. "Alkylene," "alkenylene," and "alkynylene" groups may be substituted or unsubstituted with one or more substituents as described herein.
"Alkylene" refers to an alkyl group wherein two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylene groups, e.g., substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-,-CH2CH(CH3)-, -C(CH3)2CH2-,-CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, - CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.
"Alkenyl" refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon- carbon triple bonds) ("C2-20 alkenyl"). In certain embodiments, alkenyl does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C2-10 alkenyl"). In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C2-9 alkenyl"). In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C2-8 alkenyl"). In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C2_7 alkenyl"). In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C2_6 alkenyl"). In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C2-5 alkenyl"). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C2-4 alkenyl"). In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C2-3 alkenyl"). In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1- butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkenyl") or substituted (a "substituted alkenyl") with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3
substituents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C2-10 alkenyl. In certain embodiments, the alkenyl group is substituted C2-10 alkenyl.
"Alkenylene" refers to an alkenyl group wherein two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted. Exemplary unsubstituted divalent alkenylene groups include, but are not limited to, ethenylene (-CH=CH-) and propenylene (e.g., - CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenylene groups, e.g., substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted ethylene (- C(CH3)=CH-, -CH=C(CH3)-), substituted propylene (e.g., -C(CH3)=CHCH2-, -CH=C(CH3)CH2-, - CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-,-C(CH3)2-CH=CH-, -CH2- C(CH3)=CH-, -CH2-CH=C(CH3)-), and the like.
"Alkynyl" refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) ("C2_2o alkynyl"). In certain embodiments, alkynyl does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms ("C2_io alkynyl"). In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C2_9 alkynyl"). In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C2_8 alkynyl"). In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C2_7 alkynyl"). In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C2_6 alkynyl"). In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C2_5 alkynyl"). In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C2_4 alkynyl"). In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C2_3 alkynyl"). In some embodiments, an alkynyl group has 2 carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1- butynyl). Examples of C2_4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2_6 alkenyl groups include the aforementioned C2_4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkynyl group is unsubstituted C2_io alkynyl. In certain embodiments, the alkynyl group is substituted C2_io alkynyl.
"Alkynylene" refers to a linear alkynyl group wherein two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted. Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like. The term "heteroalkyl," as used herein, refers to an alkyl group, as defined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroCi-io alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroCi-9 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroCi-8 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroCi-7 alkyl"). In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1 , 2, or 3 heteroatoms ("heteroCi-6 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("heteroCi-5 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and lor 2 heteroatoms ("heteroCi-4 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom ("heteroCi-3 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom ("heteroCi_2 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroCi alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms ("heteroC2-6 alkyl"). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "substituted heteroalkyl") with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroCi-10 alkyl.
The term "heteroalkenyl," as used herein, refers to an alkenyl group, as defined herein, which further comprises one or more {e.g., 1, 2, 3, or 4) heteroatoms {e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC2-io alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC2-9 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC2-8 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4
heteroatoms ("heteroC2_7 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms ("heteroC2-6 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC2-5 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and lor 2 heteroatoms ("heteroC2-4 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom ("heteroC2-3 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC2-6 alkenyl"). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an "unsubstituted heteroalkenyl") or substituted (a "substituted heteroalkenyl") with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC2-io alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2-io alkenyl.
The term "heteroalkynyl," as used herein, refers to an alkynyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC2-io alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC2-9 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC2-8 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC2-7 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms ("heteroC2-6 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC2-5 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms ("heteroC2-4 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom
("heteroC2-3 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC2-6 alkynyl"). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an "unsubstituted heteroalkynyl") or substituted (a "substituted heteroalkynyl") with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC2-io alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2-io alkynyl. As used herein, "alkylene," "alkenylene," "alkynylene," "heteroalkylene," "heteroalkenylene," and "heteroalkynylene," refer to a divalent radical of an alkyl, alkenyl, alkynyl group, heteroalkyl, heteroalkenyl, and heteroalkynyl group respectively. When a range or number of carbons is provided for a particular "alkylene," "alkenylene," "alkynylene," "heteroalkylene,"
"heteroalkenylene," or "heteroalkynylene," group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. "Alkylene," "alkenylene," "alkynylene," "heteroalkylene," "heteroalkenylene," and "heteroalkynylene" groups may be substituted or unsubstituted with one or more substituents as described herein.
"Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C6-i4 aryl"). In some embodiments, an aryl group has six ring carbon atoms ("Ce aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("Cio aryl"; e.g., naphthyl such as 1- naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms ("Ci4 aryl"; e.g., anthracyl). "Aryl" also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. In certain embodiments, the aryl group is unsubstituted C6-i4 aryl. In certain embodiments, the aryl group is substituted C6-i4 aryl.
In certain embodiments, an aryl group substituted with one or more of groups selected from halo, C1-C8 alkyl, Ci-Cs haloalkyl, cyano, hydroxy, Ci-Cs alkoxy, and amino.
Examples of representative substituted aryls include the following
Figure imgf000017_0001
wherein one of R and R may be hydrogen and at least one of R and R is each independently selected from Ci-Cs alkyl, Ci-Cs haloalkyl, 4-10 membered heterocyclyl, alkanoyl, Ci-Cs alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR58COR59, NR58SOR59 NR58S02R59, COOalkyl, COOaryl, CONR58R59, CONR58OR59, NR58R59, S02NR58R59, S-alkyl, SOalkyl, S02alkyl, Saryl, SOaryl, S02aryl; or R56 and R57 may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O, or S. R60 and R61 are independently hydrogen, Ci-Cg alkyl, C1-C4 haloalkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-Cio aryl, substituted C6-Cio aryl, 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl .
Other representative aryl groups having a fused heterocyclyl group include the following
Figure imgf000017_0002
wherein each W is selected from C(R )2, NR , O, and S; and each Y is selected from carbonyl, NR66, O and S; and R66 is independently hydrogen, Ci-Cs alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-Cio aryl, and 5-10 membered heteroaryl. "Fused aryl" refers to an aryl having two of its ring carbon in common with a second aryl or heteroaryl ring or with a carbocyclyl or heterocyclyl ring.
"Aralkyl" is a subset of alkyl and aryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group. "Heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5- indolyl).
In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- 6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl") with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl. Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6- membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6- bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
Examples of representative heteroaryls include the following:
Figure imgf000020_0001
Figure imgf000020_0002
wherein each Y is selected from carbonyl, N, NR , O, and S; and R is independently hydrogen, Ci-Cs alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-Cio aryl, and 5-10 membered heteroaryl. "Heteroaralkyl" is a subset of alkyl and heteroaryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted heteroaryl group.
"Carbocyclyl" or "carbocyclic" refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms ("C3-10 carbocyclyl") and zero heteroatoms in the non- aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C3-8 carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C3-6 carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C3_6 carbocyclyl"). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C5-10 carbocyclyl"). Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like.
Exemplary C3-8 carbocyclyl groups include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1 ]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), and the like. Exemplary C3-10 carbocyclyl groups include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-lH-indenyl (C9), decahydronaphthalenyl (Cio), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or contain a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic carbocyclyl") and can be saturated or can be partially unsaturated. "Carbocyclyl" also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl") with one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C3-10 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-10 carbocyclyl.
In some embodiments, "carbocyclyl" is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms ("C3-10 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C3-8 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3_6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C5-6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C5-10 cycloalkyl"). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (Cs). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C3-10 cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C3-10 cycloalkyl. "Heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3-10 membered heterocyclyl"). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic heterocyclyl"), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an
"unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3-10 membered heterocyclyl.
In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1- 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.
Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5- membered heterocyclyl groups containing one heteroatom include, without limitation,
tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8- membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6- bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, and the like.
Particular examples of heterocyclyl groups are shown in the following illustrative examples:
Figure imgf000023_0001
wherein each W is selected from CR , C(Rb /)2, NR , O, and S; and each Y is selected from NR , O, and S; and R67 is independently hydrogen, C -C» alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-Cio aryl, 5-10 membered heteroaryl. These heterocyclyl rings may be optionally substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (carbamoyl or amido), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, keto, nitro, thiol, -S-alkyl, -S-aryl, -S(0)-alkyl,- S(0)-aryl, -S(0)2-alkyl, and -S(0)2-aryl. Substituting groups include carbonyl or thiocarbonyl which provide, for example, lactam and urea derivatives.
"Hetero" when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g,. heteroaryl, cycloalkenyl, e.g,. cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.
"Acyl" refers to a radical -C(0)R20, where R20 is hydrogen, substituted or unsubstitued alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl, as defined herein. "Alkanoyl" is an acyl group wherein R20 is a group other than hydrogen. Representative acyl groups include, but are not limited to, formyl (-CHO), acetyl (-C(=0)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (- C(=0)Ph), benzylcarbonyl (-C(=0)CH2Ph),— C(0)-Ci-C8 alkyl, -C(0)-(CH2)t(C6-Cio aryl), - C(O)-(CH2)t(5-10 membered heteroaryl), -C(0)-(CH2)t(C3-Cio cycloalkyl), and -C(0)-(CH2)t(4-
21
10 membered heterocyclyl), wherein t is an integer from 0 to 4. In certain embodiments, R is Ci- C8 alkyl, substituted with halo or hydroxy; or C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6- C10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
22 23 22
"Acylamino" refers to a radical -NR C(0)R , where each instance of R and R23 is
independently hydrogen, substituted or unsubstitued alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl,, as defined herein, or R22 is an amino protecting group. Exemplary "acylamino" groups include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino and benzylcarbonylamino. Particular exemplary "acylamino" groups are -NR24C(0)-Ci-C8 alkyl, -NR24C(O)-(CH2)t(C6-Ci0 aryl), -NR24C(0)- (CH2)t(5-10 membered heteroaryl), -NR24C(0)-(CH2)t(C3-Cio cycloalkyl), and -NR24C(0)- (Ο¾ (4-10 member ed heterocyclyl), wherein t is an integer from 0 to 4, and each R independently represents H or C -C» alkyl.In certain embodiments, R25 is H, C -C» alkyl, substituted with halo or hydroxy; C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-Cio aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; and R26 is H, C\- alkyl, substituted with halo or hydroxy; C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-Cio aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted Ci-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxyl; provided at least one of R25 and R26 is other than H.
"Acyloxy" refers to a radical -OC(0)R27, where R27 is hydrogen, substituted or unsubstitued alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl, as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and benzylcarbonyl. In certain embodiments, R28 is C -C» alkyl, substituted with halo or hydroxy; C3- C10 cycloalkyl, 4-10 membered heterocyclyl, C6-Cio aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
"Alkoxy" refers to the group -OR29 where R29 is substituted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.
In certain embodiments, R is a group that has 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino, C6-Cio aryl, aryloxy, carboxyl, cyano, C3-C10 cycloalkyl, 4-10 member ed heterocyclyl, halogen, 5-10 member ed heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(0)2- and aryl-S(0)2-. Exemplary 'substituted alkoxy' groups include, but are not limited to, -0-(C]¾)t(C6-Cio aryl), -O-(CH2)t(5-10 membered heteroaryl), -0-(CH2)t(C3-Cio cycloalkyl), and -O-(CH2)t(4-10 membered
heterocyclyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Particular exemplary 'substituted alkoxy' groups are - OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.
"Amino" refers to the radical -NH2.
"Substituted amino" refers to an amino group of the formula -N(R38)2 wherein R38 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstitued heteroaryl, or an amino protecting group, wherein at least one of R38 is not a hydrogen. In certain embodiments, each R38 is independently selected from hydrogen, Ci-Cs alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C6-Cio aryl, 5- 10 membered heteroaryl, 4-10 membered heterocyclyl, or C3-C10 cycloalkyl; or Ci-Cs alkyl, substituted with halo or hydroxy; C3-C8 alkenyl, substituted with halo or hydroxy; C3-C8 alkynyl, substituted with halo or hydroxy, or -(CH2)t(C6-Cio aryl), -(CH2)t(5-10 membered heteroaryl), - (CH2)t(C3-Cio cycloalkyl), or -(Ο¾ (4-10 membered heterocyclyl), wherein t is an integer between 0 and 8, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted Ci- C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted Ci-
38
C4 haloalkoxy or hydroxy; or both R groups are joined to form an alkylene group. Exemplary "substituted amino" groups include, but are not limited to, -NR39-Ci-Cs alkyl, -NR39- (CH2)t(C6-Cio aryl), -NR39-(CH2)t(5-10 membered heteroaryl), -NR39-(CH2)t(C3-Ci0 cycloalkyl), and -NR39-(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, for instance 1 or 2, each R39 independently represents H or Ci-Cs alkyl; and any alkyl groups present, may themselves be substituted by halo, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl, or heterocyclyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. For the avoidance of doubt the term 'substituted amino' includes the groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino as defined below. Substituted amino encompasses both monosubstituted amino and disubstituted amino groups.
"Azido" refers to the radical -N3.
"Carbamoyl" or "amido" refers to the radical -C(0)NH2.
"Substituted carbamoyl" or "substituted amido" refers to the radical -C(0)N(R62)2 wherein each R62 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstitued heteroaryl, or an amino protecting group, wherein at least one of R62 is not a hydrogen. In certain
embodiments, R62 is selected from H, C\-C& alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-Cio aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or Ci-C» alkyl substituted with halo or hydroxy; or C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-Cio aryl, aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted Ci-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted Ci-C4 haloalkyl, unsubstituted Ci-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; provided that at least one R62 is other than H. Exemplary "substituted carbamoyl" groups include, but are not limited to, -C(O) NR64-Ci-C8 alkyl, -C(0)NR64-(CH2)t(C6-Cio aryl), -C(O)N64-(CH2)t(5-10 membered heteroaryl), -C(0)NR64- (CH2)t(C3-Cio cycloalkyl), and -C(O)NR64-(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, each R64 independently represents H or C -C» alkyl and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted Ci-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
"Carboxy" refers to the radical -C(0)OH.
"Cyano" refers to the radical -CN. "Halo" or "halogen" refers to fluoro (F), chloro (CI), bromo (Br), and iodo (I). In certain embodiments, the halo group is either fluoro or chloro.
"Hydroxy" refers to the radical -OH.
"Nitro" refers to the radical -N02. "Cycloalkylalkyl" refers to an alkyl radical in which the alkyl group is substituted with a cycloalkyl group. Typical cycloalkylalkyl groups include, but are not limited to,
cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl, and the like. "Heterocyclylalkyl" refers to an alkyl radical in which the alkyl group is substituted with a heterocyclyl group. Typical heterocyclylalkyl groups include, but are not limited to,
pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and the like.
"Cycloalkenyl" refers to substituted or unsubstituted carbocyclyl group having from 3 to 10 carbon atoms and having a single cyclic ring or multiple condensed rings, including fused and bridged ring systems and having at least one and particularly from 1 to 2 sites of olefinic unsaturation. Such cycloalkenyl groups include, by way of example, single ring structures such as cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like.
"Fused cycloalkenyl" refers to a cycloalkenyl having two of its ring carbon atoms in common with a second aliphatic or aromatic ring and having its olefinic unsaturation located to impart aromaticity to the cycloalkenyl ring.
"Ethylene" refers to substituted or unsubstituted -(C-C)-.
"Ethenyl" refers to substituted or unsubstituted -(C=C)-.
"Ethynyl" refers to -(C≡C)-. "Nitrogen-containing heterocyclyl" group means a 4- to 7- membered non-aromatic cyclic group containing at least one nitrogen atom, for example, but without limitation, morpholine, piperidine (e.g. 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 2-pyrrolidinyl and 3- pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl piperazine. Particular examples include azetidine, piperidone and piperazone. "Thioketo" refers to the group =S.
Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted (e.g., "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 group). In general, the term "substituted", whether preceded by the term "optionally" or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term "substituted" is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -N02, -N3, - S02H, -S03H, -OH, -ORaa, -ON(R )2, -N(R )2, -N(R )3 +X", -N(ORcc)R , -SH, -SRaa, - SSRCC, -C(=0)Raa, -C02H, -CHO, -C(ORcc)2, -C02Raa, -OC(=0)Raa, -OC02Raa, -C(=0)N(R )2, -OC(=0)N(R )2, -NR C(=0)Raa, -NR C02Raa, -NR C(=0)N(R )2, -C(=NR )Raa, - C(=NR )ORaa, -OC(=NR )Raa, -OC(=NR )ORaa, -C(=NR )N(R )2, -OC(=NR )N(R )2, - NR C(=NR )N(R )2, -C(=0)NR S02Raa, -NR S02Raa, -S02N(R )2, -S02Raa, -S02ORaa, - OS02Raa, -S(=0)Raa, -OS(=0)Raa, -Si(Raa)3, -OSi(Raa)3 -C(=S)N(R )2, -C(=0)SRaa, - C(=S)SRaa, -SC(=S)SRaa, -SC(=0)SRaa, -OC(=0)SRaa, -SC(=0)ORaa, -SC(=0)Raa, -P(=0)2Raa, -OP(=0)2Raa, -P(=0)(Raa)2, -OP(=0)(Raa)2, -OP(=0)(ORcc)2, -P(=0)2N(Rbb)2, -OP(=0)2N(Rbb)2, -P(=0)(NR )2, -OP(=0)(NR )2, -NR P(=0)(ORcc)2, -NR P(=0)(NR )2, -P(RCC)2, -P(RCC)3, - OP(Rcc)2, -OP(Rcc)3, -B(Raa)2, -B(ORcc)2, -BRaa(ORcc), Ci_io alkyl, Ci_io perhaloalkyl, C2_i0 alkenyl, C2_io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-i4 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(R )2, =NNR C(=0)Raa, =NNR C(=0)ORaa, =NNR S(=0)2Raa, =NR , or =NORcc; each instance of Raa is, independently, selected from Ci-10 alkyl, Ci-10 perhaloalkyl, C2_io alkenyl, C2_io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-i4 aryl, and 5-14 membered heteroaryl, or two Raa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; each instance of R is, independently, selected from hydrogen, -OH, -ORaa, -N(RCC)2, -CN, - C(=0)Raa, -C(=0)N(Rcc)2, -C02Raa, -S02Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -S02N(Rcc)2, - S02Rcc, -S02ORcc, -SORaa, -C(=S)N(RCC)2, -C(=0)SRcc, -C(=S)SRCC, -P(=0)2Raa, -P(=0)(Raa)2, -P(=0)2N(Rcc)2, -P(=0)(NRcc)2, Ci_io alkyl, d_10 perhaloalkyl, C2_10 alkenyl, C2_10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-i4 aryl, and 5-14 membered heteroaryl, or two R groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; each instance of Rcc is, independently, selected from hydrogen, Ci-10 alkyl, Ci-10 perhaloalkyl, C2_ 10 alkenyl, C2_io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-i4 aryl, and 5-14 membered heteroaryl, or two Rcc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; each instance of Rdd is, independently, selected from halogen, -CN, -N02, -N3, -S02H, -SO3H, - OH, -ORee, -ON(Rff)2, -N(Rff)2, -NCR^+X", -N(ORee)Rff, -SH, -SRee, -SSRee, -C(=0)Ree, - C02H, -C02Ree, -OC(=0)Ree, -OC02Ree, -C(=0)N(Rff)2, -OC(=0)N(Rff)2, -NRffC(=0)Ree, - NRttC02Ree, -NRiiC(=0)N(Rfl)2, -C(=NRfl)ORee, -OC(=NRfl)Ree, -OC(=NRtt)ORee, - C(=NRff)N(Rff)2, -OC(=NRff)N(Rff)2, -NRffC(=NRff)N(Rff)2,-NRffS02Ree, -S02N(Rff)2, -S02Ree, -S02ORee, -OS02Ree, -S(=0)Ree, -Si(Ree)3, -OSi(Ree)3, -C(=S)N(Rff)2, -C(=0)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=0)2Ree, -P(=0)(Ree)2, -OP(=0)(Ree)2, -OP(=0)(ORee)2, Ci_6 alkyl, Ci_6 perhaloalkyl, C2_6 alkenyl, C2_6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-io aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups, or two geminal Rdd substituents can be joined to form =0 or =S; each instance of Ree is, independently, selected from Ci_6 alkyl, Ci_6 perhaloalkyl, C2_6 alkenyl, C2_6 alkynyl, C3-10 carbocyclyl, C6-io aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups; each instance of Rff is, independently, selected from hydrogen, Ci_6 alkyl, Ci_6 perhaloalkyl, C2_6 alkenyl, C2_6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-io aryl and 5-10 membered heteroaryl, or two Rff groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups; and each instance of Rgg is, independently, halogen, -CN, -N02, -N3, -S02H, -SO3H, -OH, -OCi_6 alkyl, -ON(Ci_6 alkyl)2, -N(Ci_6 alkyl)2, -N(Ci_6 alkyl^+X", -NH(Ci_6 alkyl^+X", -NH2(Ci_6 alkyl) -NHs+X", -N(OCi_6 alkyl)(Ci_6 alkyl), -N(OH)(Ci_6 alkyl), -NH(OH), -SH, -SCi_6 alkyl, -SS(Ci_6 alkyl), -C(=0)(Ci_6 alkyl), -C02H, -C02(Ci_6 alkyl), -OC(=0)(Ci_6 alkyl), - OC02(Ci_6 alkyl), -C(=0)NH2, -C(=0)N(Ci_6 alkyl)2, -OC(=0)NH(Ci_6 alkyl), -NHC(=0)( Ci_6 alkyl), -N(Ci_6 alkyl)C(=0)( Ci_6 alkyl), -NHC02(Ci_6 alkyl), -NHC(=0)N(Ci_6 alkyl)2, - NHC(=0)NH(Ci_6 alkyl), -NHC(=0)NH2, -C(=NH)0(Ci_6 alkyl) ,-OC(=NH)(Ci_6 alkyl), - OC(=NH)OCi_6 alkyl, -C(=NH)N(Ci_6 alkyl)2, -C(=NH)NH(Ci_6 alkyl), -C(=NH)NH2, - OC(=NH)N(Ci_6 alkyl)2, -OC(NH)NH(Ci_6 alkyl), -OC(NH)NH2, -NHC(NH)N(Ci_6 alkyl)2, - NHC(=NH)NH2, -NHS02(Ci_6 alkyl), -S02N(Ci_6 alkyl)2, -S02NH(Ci_6 alkyl), -S02NH2 ,- S02Ci_6 alkyl, -S02OCi_6 alkyl, -OS02Ci_6 alkyl, -SOCi_6 alkyl, -Si(Ci_6 alkyl)3, -OSi(Ci_6 alkyl)3 -C(=S)N(Ci_6 alkyl)2, C(=S)NH(Ci_6 alkyl), C(=S)NH2, -C(=0)S(Ci_6 alkyl), -C(=S)SCi_6 alkyl, -SC(=S)SCi_6 alkyl, -P(=0)2(Ci_6 alkyl), -P(=0)(Ci_6 alkyl)2, -OP(=0)(Ci_6 alkyl)2, - OP(=0)(OCi_6 alkyl)2, Ci_6 alkyl, Ci_6 perhaloalkyl, C2-6 alkenyl, C2_6 alkynyl, C3-10 carbocyclyl, C6-io aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rgg substituents can be joined to form =0 or =S; wherein X~ is a counterion.
A "counterion" or "anionic counterion" is a negatively charged group associated with a cationic quaternary amino group in order to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F", CI", Br", Γ), N03 ", C104 ", OH", H2P04 ", HS04 ", S04 "2sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-1 -sulfonic acid-5-sulfonate, ethan-1 -sulfonic acid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, gly cerate, lactate, tartrate, glycolate, and the like).
Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -ORaa, -N(RCC)2, -CN, -C(=0)Raa, -C(=0)N(Rcc)2, - C02Raa, -S02Raa, -C(=NR )Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -S02N(Rcc)2, -S02Rcc, - S02ORcc, -SORaa, -C(=S)N(RCC)2, -C(=0)SRcc, -C(=S)SRCC, -P(=0)2Raa, -P(=0)(Raa)2, -
P(=0)2N(Rcc)2, -P(=0)(NRcc)2, Ci_io alkyl, Ci-10 perhaloalkyl, C2_i0 alkenyl, C2_i0 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-i4 aryl, and 5-14 membered heteroaryl, or two Rcc groups attached to a nitrogen atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups, and wherein Raa, R , Rcc and Rdd are as defined above.
These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents.
Other definitions
The term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al, describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
A "subject" to which administration is contemplated includes, but is not limited to, humans {i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.
Disease, disorder, and condition are used interchangeably herein. As used herein, and unless otherwise specified, the terms "treat," "treating" and "treatment" contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition ("therapeutic treatment"), and also
contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition ("prophylactic treatment").
In general, the "effective amount" of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject An effective amount encompasses therapeutic and prophylactic treatment.
As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.
As used herein, and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder or condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. Brief Description of the Drawings
FIGS. 1-13 depict representative 1H NMR spectrum of exemplary compounds described herein.
Detailed Description of Certain Embodiments of the Invention
As described herein, the present invention provides 3,3-disubstituted 19-nor neuroactive steroids of Formula (I):
Figure imgf000035_0001
harmaceutically acceptable salts thereof; wherein:
=== represents a single or double bond as valency permits; of Formula (A-l) or Formula (A-2):
Figure imgf000035_0002
(A-l), or (A-2), wherein the point of attachment is
1 2 2 3
at G or G in Formula (A-l) and the point of attachment is at G or G in Formula (A-2);
G1 is N, NRN1, O, S, C, or C-RG1 as valency permits; G2 is N, NRN2, O, S, C, -C=N-, or C-RG2 as valency permits; G3 is N, NRN3, O, S, C, or C-RG3 as valency permits; G4 is N, NRN4, C-RG4, or C-(RG4)2 as valency permits; G5 is N, NRN5, C-RG5, or C-(RG5)2 as valency permits; G6 is N, NRN6, C-RG6, or C-(RG6)2 as valency permits; and G7 is N, NRN7, C-RG7, or C-(RG7)2 as valency permits; each instance of RG1, RG2, RG3, RG4, RG5, RG6, and RG7 is, independently, hydrogen, halogen, -N02, -CN, -ORGA, -N(RGA)2, -C(=0)RGA, -C(=0)ORGA, -OC(=0)RGA, -OC(=0)ORGA, -C(=0)N(RGA)2, -N(RGA)C(=0)RGA, -OC(=0)N(RGA)2, -N(RGA)C(=0)ORGA, -S(=0)2RGA, -S(=0)2ORGA, - OS(=0)2RGA, -S(=0)2N(RGA)2, -N(RGA)S(=0)2RGA, -S(=0)RGA, -S(=0)ORGA, -OS(=0)RGA, - S(=0)N(RGA)2, -N(RGA)S(=0)RGA, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocylyl, substituted or unsubstituted 3- to 6- membered heterocylyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each instance of RGA is independently hydrogen, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocylyl, substituted or unsubstituted 3- to 6- membered heterocylyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, or two RGA groups are taken with the intervening atoms to form a substituted or unsubstituted carbocyclic or heterocylic ring;
R1 is substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-6 carbocylyl;
R2 is hydrogen, halogen, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-6 carbocylyl, or -ORA2, wherein RA2 is hydrogen or substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-6 carbocylyl;
R3a is hydrogen or -ORA3, wherein RA3 is hydrogen, or substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-6 carbocylyl, and R3 is hydrogen; or R3a and R3 are joined to form an oxo (=0) group; each of R4a or R4 is independently hydrogen, substituted or unsubstituted C1-6 alkyl, or halogen; and provided if bond p is a double bond, then bond q is a single bond, provided if bond q is a double bond, then bond p is a single bond and R4 is absent; and provided if both bonds q and p are single bonds, then the hydrogen at C5 is in the alpha or beta configuration.
In certain embodiments, G4 is N or NRN4, and/or G5 is N or NRN5, and/or G6 is N or NRN6, and/or G7 is N or NRN7.
It is understood, based on the aforementioned description, that compounds of Formula (I) encompass 3,3-disubstituted 19-nor neuroactive steroids wherein the A/B ring system of the compound is cis (as provided in Formula (I-A), wherein the A/B ring system of the compound is trans (as provided in Formula (I-B), wherein the B ring of the compound comprises a C5-C6 double bond (as provided in Formula (I-C)), and wherein the A ring of the compound comprises a C4-C5 double bond (as provided in Formula (I-D)),
Figure imgf000037_0001
Figure imgf000038_0001
Group R As generally defined herein, R1 is substituted or unsubstituted C1-6 alkyl, substituted or
unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-6 carbocyclyl.
In certain embodiments, R1 is substituted or unsubstituted C1-6 alkyl, e.g., substituted or unsubstituted Ci_2alkyl, substituted or unsubstituted C2-3alkyl, substituted or unsubstituted C3- 4alkyl, substituted or unsubstituted C4_5alkyl, or substituted or unsubstituted Cs-ealkyl. Exemplary R1 Ci_6alkyl groups include, but are not limited to, substituted or unsubstituted methyl (Ci), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n- pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), n-hexyl (C6), Ci_6 alkyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more fluoro groups {e.g. , -CF3, -CH2F, -CHF2, difluoroethyl, and 2,2,2-trifluoro-l , 1 -dimethyl-ethyl), Ci_6 alkyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more chloro groups {e.g., -CH2C1, -CHC12), and Ci_6 alkyl substituted with alkoxy groups {e.g., -CH2OCH3 and -CH2OCH2CH3). In certain embodiments, R1 is substituted Ci-6 alkyl, e.g., R1 is haloalkyl, alkoxyalkyl, or aminoalkyl. In certain embodiments, R1 is Me, Et, n-Pr, n-Bu, i-Bu, fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, difluoroethyl, 2,2,2-trifluoro- 1,1 -dimethyl-ethyl, methoxymethyl, methoxyethyl, or ethoxymethyl.
In certain embodiments, R1 is unsubstituted C1-3 alkyl, e.g., R1 is -CH3, -CH2CH3, or - CH2 CH2 CH3. In certain embodiments, R is C1-6 alkyl substituted with one or more fluorine atoms; e.g., R is - CH2F, -CHF2, or -CF3.
In certain embodiments, R is C1-6 alkyl substituted with one or more -OR groups, wherein R is hydrogen or substituted or unsubstitued alkyl. In certain embodiments, R1 is -CH2ORA1, e.g., wherein RA1 is hydrogen, -CH3, -CH2CH3, or -CH2CH2CH3, e.g., to provide a group R1 of formula -CH2OH, -CH2OCH3, -CH2OCH2CH3, or -CH2OCH2CH2CH3.
In certain embodiments, R1 is substituted or unsubstituted C2-6 alkenyl, e.g., substituted or unsubstituted C2_3alkenyl, substituted or unsubstituted C3_4alkenyl, substituted or unsubstituted C4_ 5alkenyl, or substituted or unsubstituted Cs-ealkenyl. In certain embodiments, R1 is ethenyl (C2), propenyl (C3), or butenyl (C4), unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, alkoxyalkyl, or hydroxyl. In certain
embodiments, R1 is ethenyl, propenyl, or butenyl, unsubstituted or substituted with alkyl, halo, haloalkyl, alkoxyalkyl, or hydroxy. In certain embodiments, R1 is ethenyl.
In certain embodiments, R1 is substituted or unsubstituted C2-6 alkynyl, e.g., substituted or unsubstituted C2_3alkynyl, substituted or unsubstituted C3_4alkynyl, substituted or unsubstituted C4_5alkynyl, or substituted or unsubstituted Cs-ealkynyl. In certain embodiments, R1 is ethynyl, propynyl, or butynyl, unsubstituted or substituted with alkyl, halo, haloalkyl (e.g., CF3), alkoxyalkyl, cycloalkyl (e.g., cyclopropyl or cyclobutyl), or hydroxyl. In certain embodiments, R1 is selected from the group consisting of trifluoroethynyl, cyclopropylethynyl, cyclobutylethynyl, and propynyl, fluoropropynyl, and chloroethynyl. In certain embodiments, R1 is ethynyl (C2), propynyl (C3), or butynyl (C4), unsubstituted or substituted with one or more substituents selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl. In certain embodiments, R1 is ethynyl (C2), propynyl (C3), or butynyl (C4) substituted with substituted phenyl. In certain embodiments, the phenyl substituent is further substituted with one or more substituents selected from the group consisting of halo, alkyl, trifluoroalkyl, alkoxy, acyl, amino or amido. In certain embodiments, R1 is ethynyl (C2), propynyl (C3), or butynyl (C4) substituted with substituted or unsubstituted pyrrolyl, imidazolyl, pyrazolyl, oxazoyl, thiazolyl, isoxazoyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl. In certain embodiments, R is ethynyl, propynyl, or butynyl, unsubstituted or substituted with alkyl, halo, haloalkyl, alkoxyalkyl, or hydroxyl. In certain embodiments, R1 is ethynyl or propynyl, substituted with substituted or unsubstituted aryl. In certain embodiments, R1 is ethynyl or propynyl, substituted with phenyl unsubstituted or substituted with halo, alkyl, alkoxy, haloalkyl, trihaloalkyl, or acyl. In certain embodiments, R1 is ethynyl or propynyl, substituted with
substituted or unsubstituted carbocyclyl. In certain embodiments, R3a is ethynyl or propynyl, substituted with substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, R1 is ethynyl or propynyl, substituted with substituted or unsubstituted heteroaryl. In certain embodiments, R1 is ethynyl or propynyl, substituted with substituted or unsubstituted pyridinyl, or pyrimidinyl. In certain embodiments, R1 is ethynyl or propynyl, substituted with substituted or unsubstituted pyrrolyl, imidazolyl, pyrazolyl, oxazoyl, thiazolyl, isoxazoyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl. In certain
embodiments, R1 is ethynyl or propynyl, substituted with substituted or unsubstituted heterocyclyl. In certain embodiments, R1 is ethynyl or propynyl, substituted with substituted or unsubstituted pyrrolidinyl, piperidinyl, piperazinyl, or mopholinyl. In certain embodiments, R1 is propynyl or butynyl, substituted with hydroxyl or alkoxy. In certain embodiments, R1 is propynyl or butynyl, substituted with methoxy or ethoxy. In certain embodiments, R1 is ethynyl or propynyl, substituted with chloro. In certain embodiments, R1 is ethynyl or propynyl, substituted with trifluoromethyl.
In certain embodiments, R1 is substituted or unsubstituted C3-6 carbocyclyl, e.g., substituted or unsubstituted C3_4carbocyclyl, substituted or unsubstituted C4_5 carbocyclyl, or substituted or unsubstituted C5-6 carbocyclyl. In certain embodiments, R1 is substituted or unsubstituted cyclopropyl or substituted or unsubstituted cyclobutyl.
Groups = , R2, R3a, R3b, R4a, and R4"
As generally defined herein, R2 is hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-6 carbocyclyl, or -ORA2, wherein RA2 is hydrogen, substituted or unsubstituted
Figure imgf000040_0001
6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-6 carbocyclyl. In certain embodiments, R2 is hydrogen. In certain embodiments, R2 is halogen, e.g., fluoro, chloro, bromo, or iodo. In certain embodiments, R2 is fluoro or chloro. In certain embodiments, R2 is substituted or unsubstituted Ci_6alkyl, e.g., substituted or unsubstituted Ci_2alkyl, substituted or unsubstituted C2-3alkyl, substituted or unsubstituted C3_4alkyl, substituted or unsubstituted C4_ 5alkyl, or substituted or unsubstituted Cs-ealkyl. In certain embodiments, R is substituted or unsubstituted C2-6 alkenyl, In certain embodiments, R2 is substituted or unsubstituted C2-6 alkynyl, e.g., substituted or unsubstituted C2-3alkynyl, substituted or unsubstituted C3_4alkynyl, substituted or unsubstituted C4_5alkynyl, or substituted or unsubstituted Cs-ealkynyl. In certain embodiments, R2 is substituted or unsubstituted C3-6 carbocyclyl, e.g. , substituted or unsubstituted C3- 4carbocyclyl, substituted or unsubstituted C4_5 carbocyclyl, or substituted or unsubstituted C5-6 carbocyclyl. In certain embodiments, R is substituted or unsubstituted cyclopropyl or substituted or unsubstituted cyclobutyl. In certain embodiments, R is -CH3, -CH2CH3, -CH2CH2CH3, or substituted or unsubstituted cyclopropyl. In certain embodiments, R2 is -ORA2. In certain embodiments, RA2 is hydrogen. In certain embodiments, RA2 is substituted or unsubstituted alkyl, e.g., substituted or unsubstituted Ci_6alkyl, substituted or unsubstituted Ci_2alkyl, substituted or unsubstituted C2-3alkyl, substituted or unsubstituted C3_4alkyl, substituted or unsubstituted C4_ 5alkyl, or substituted or unsubstituted Cs-ealkyl. In certain embodiments, RA2 is hydrogen, -CH3, - CH2CH3, or -CH2CH2CH3, i.e., to provide a group R2 of formula -OH, -OCH3, -OCH2CH3, or - OCH2CH2CH3. In certain embodiments, R2 is a non-hydrogen substituent in the alpha
configuration. In certain embodiments, R2 is a non-hydrogen substituent in the beta configuration.
As generally defined herein, R3a is hydrogen or -ORA3, wherein RA3 is hydrogen or substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-6 carbocylyl, and R3 is hydrogen; or R3a and R3 are joined to form an oxo (=0) group. In certain embodiments, both R3a and R3 are both hydrogen.
In certain embodiments, R3a and R3 are joined to form an oxo (=0) group.
In certain embodiments, R3a is -ORA3 and R3 is hydrogen. In certain embodiments, wherein R3a is -ORA3, R3a is in the alpha or beta configuration {e.g., R or S configuration). In certain
embodiments, wherein R3a is -ORA3, R3a is in the alpha configuration. In certain embodiments, wherein R3a is -ORA3, R3a is in the beta configuration. In certain embodiments, RA3 is hydrogen. In certain embodiments, R is substituted or unsubstituted C1-6 alkyl, e.g., substituted or unsubstituted Chalky 1, substituted or unsubstituted Chalky 1, substituted or unsubstituted C3- 4alkyl, substituted or unsubstituted C4_5alkyl, or substituted or unsubstituted Cs-ealkyl. In certain embodiments, RA3 is hydrogen, -CH3, -CH2CH3, or -CH2CH2CH3, i.e., to provide a group R3a of formula -OH, -OCH3, -OCH2CH3, or -OCH2CH2CH3.
As generally defined herein, each instance of R4a and R4 is independently hydrogen, substituted or unsubstituted C1-6 alkyl, or halogen, provided if the ===== between C5 and C6 are single bonds, then the hydrogen at C5 and R4a are each independently provided in the alpha or beta configuration, and R4 is absent. In certain embodiments, == is a single bond, at least one of R4a and R4 is hydrogen. In certain embodiments, ===== is a single bond, at least one of R4a and R4 is substituted or unsubstituted C1-6 alkyl, e.g., substituted or unsubstituted Ci_2alkyl, substituted or unsubstituted C2_3alkyl, substituted or unsubstituted C3_4alkyl, substituted or unsubstituted C4_5alkyl, or substituted or unsubstituted C5_6alkyl. In certain embodiments, == is a single bond, at least one of R4a and R4 is Ci alkyl, e.g., -CH3 or -CF3. In certain embodiments, is a single bond, at least one of R4a and R4 is halogen, e.g., fluoro.
In certain embodiments, == is a sins le bond, and both of R4a and R4 are hydrogen. In certain embodiments, == is a sins le bond, and both of R4a and R4 are independently substituted or unsubstituted C1-6 alkyl, e.g., substituted or unsubstituted Ci_2alkyl, substituted or unsubstituted C2_3alkyl, substituted or unsubstituted C3_4alkyl, substituted or unsubstituted C4_5alkyl, or substituted or unsubstituted Cs-ealkyl. In certain embodiments, == is a single bond, and both of R4a and R4 are independently Ci alkyl, e.g., -CH3 or -CF3. In certain embodiments, == is a single bond, and both of R4a and R4 are halogen, e.g., fluoro.
In certain embodiments, wherein == represents a sing le bond, R4a is a non-hydrogen substituent in the alpha configuration. In certain embodiments, wherein ===== represents a sing le bond, R4a is a non-hydrogen substituent in the beta configuration.
In certain embodiments, == is a double bond, and R4a is hydrogen. In certain embodiments, == is a double bond, and R4a is substituted or unsubstituted C1-6 alkyl, e.g., substituted or unsubstituted Ci_2alkyl, substituted or unsubstituted C2_3alkyl, substituted or unsubstituted C3_4alkyl, substituted or unsubstituted C4_5alkyl, or substituted or unsubstituted Cs-ealkyl. In certain embodiments, is a double bond, and R4a is Ci alkyl, e.g., -CH3 or -CF3. In certain embodiments, = is a double bond, and R4a is halogen, e.g., fluoro.
Groups A
As generally defined herein, A is of Formula (A-1) or Formula (A-2)
Figure imgf000043_0001
wherein: the point of attachment is at Gi or G2 in Formula (A-1) and the point of attachment is at G2 or G3 in Formula (A-2);
G1 is N, NRN1, O, S, C, or C-RG1 as valency permits;
G2 is N, NRN2, O, S, C, -C=N-, or C-RG2 as valency permits;
G3 is N, NRN3, O, S, C, or C-RG3 as valency permits;
G4 is N, NRN4, C-RG4, or C-(RG4)2 as valency permits; G5 is N, NRN5, C-RG5, or C-(RG5)2 as valency permits;
G6 is N, NRN6, C-RG6, or C-(RG6)2 as valency permits; and
G7 is N, NRN7, C-RG7, or C-(RG7)2 as valency permits; each instance of RG1, RG2, RG3, RG4, RG5, RG6, and RG7 is, independently, hydrogen, halogen, -N02, -CN, -ORGA, -N(RGA)2, -C(=0)RGA, -C(=0)ORGA, -OC(=0)RGA, -OC(=0)ORGA, -C(=0)N(RGA)2, -N(RGA)C(=0)RGA, -OC(=0)N(RGA)2, -N(RGA)C(=0)ORGA, -S(=0)2RGA, -S(=0)2ORGA, -
OS(=0)2RGA, -S(=0)2N(RGA)2, -N(RGA)S(=0)2RGA, -S(=0)RGA, -S(=0)ORGA, -OS(=0)RGA, - S(=0)N(RUA)2, -N(RUA)S(=0)R , substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocylyl, substituted or unsubstituted 3- to 6- membered heterocylyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each instance of RN2, RN4, RN5, RN6, and RN7 is independently hydrogen, substituted or unsubstituted Ci-6 alkyl, or a nitrogen protecting group; and each instance of RGA is independently hydrogen, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocylyl, substituted or unsubstituted 3- to 6- membered heterocylyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, or two RGA groups are taken with the intervening atoms to form a substituted or unsubstituted carbocyclic or heterocylic ring.
In certain embodiments G4 is N or NRN4, and/or G5 is N or NRN5, and/or G6 is N or NRN6, and/or
Figure imgf000044_0001
1), wherein the point of attachment is at G1. In certain embodiments, A is of Formula (A-1)
Figure imgf000044_0002
. In certain embodiments, A is of Formula (A-2)
Figure imgf000045_0001
(A-2), wh r in the oint of attachment is at G2 or G3. In certain
embodiments, A is of Formula (A-2) wherein the point of attachment is at G2. In
certain embodiments, A is of Formula
Figure imgf000045_0002
(A-2) (A-2), wherein the point of attachment is at G . In certain embodiments, A is one of the following formulae:
Figure imgf000045_0003
. In certain embodiments, A is one of the following formulae:
Figure imgf000045_0004
Figure imgf000046_0001
As used herein, = represents a single or double bond as valency permits. In certain embodiments, bond s is a double bond. In certain embodiments, bond s is a single bond. In certain embodiments, bond t is a double bond. In certain embodiments, bond t is a single bond.
In certain embodiments, A is one of the following formulae:
Figure imgf000046_0002
As generally defined herein, each instance of RG1 is, independently, hydrogen, halogen, -N02, -CN, -ORGA, -N(RGA)2, -C(=0)RGA, -C(=0)ORGA, -OC(=0)RGA, -OC(=0)ORGA, -C(=0)N(RGA)2, - N(RGA)C(=0)RGA, -OC(=0)N(RGA)2, -N(RGA)C(=0)ORGA, -S(=0)2RGA, -S(=0)2ORGA, - OS(=0)2RGA, -S(=0)2N(RGA)2, -N(RGA)S(=0)2RGA, -S(=0)RGA, -S(=0)ORGA, -OS(=0)RGA, - S(=0)N(RGA)2, -N(RGA)S(=0)RGA, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocylyl, substituted or unsubstituted 3- to 6- membered heterocylyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, RG1 is hydrogen. In some embodiments, RG1 is halogen. In certain embodiments, RG1 is F. In certain embodiments, RG1 is CI. In certain embodiments, RG1 is Br. In certain embodiments, RG1 is I. In certain embodiments, RG1 is substituted or unsubstituted Ci-6 alkyl. In certain embodiments, RG1 is substituted Ci-6 alkyl. In certain embodiments, RG1 is -CH2F, -CHF2, or -CF3. In certain embodiments, R is unsubstituted C1-6 alkyl. In certain embodiments, R is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, RG1 is -CN. In some embodiments, RG1 is -N02. In some embodiments, RG1 is substituted or unsubstituted carbocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. In some embodiments, R Gl is cyclopropyl or cyclobutyl. In certain embodiments, R Gl is -OR GA , - N(RGA)2, -C(=0)RGA, -C(=0)ORGA, -OC(=0)RGA, -OC(=0)ORGA, -C(=0)N(RGA)2, - N(RGA)C(=0)RGA, -OC(=0)N(RGA)2, -N(RGA)C(=0)ORGA, -S(=0)2RGA, -S(=0)2ORGA, - OS(=0)2RGA, -S(=0)2N(RGA)2, or -N(RGA)S(=0)2RGA. In certain embodiments, RG1 is -NHRGA. In certain embodiments, R is -NH2. In certain embodiments, R is -NHR , wherein R is substituted or unsubstituted C1-6 alkyl. In certain embodiments, R is -NHR , wherein R is
Gl GA GA
methyl, ethyl, or propyl. In certain embodiments, R is -N(R )2, wherein each R is
independently substituted or unsubstituted C1-6 alkyl. In certain embodiments, RG1 is - N(CH3)RGA, wherein each RGA is independently unsubstituted C1-6 alkyl. In certain embodiments, R is -N(CH2CH3)R , wherein each R is independently substituted or unsubstituted C1-6 alkyl. In certain embodiments, R Gl i *s -OR GA . In certai ·n embodi ·ments, R Gl is -OH. In certain
Gl GA GA
embodiments, R is -OR , wherein R is substituted or unsubstituted C1-6 alkyl. In certain embodiments, R G 1 is -O-methyl, -O-ethyl, or -O-propyl. In certain embodiments, R G 1 is -OR G A , wherein RGA is substituted or unsubstituted aryl. In certain embodiments, RG1 is -O-phenyl.
As generally defined herein, each instance of RG2 is, independently, hydrogen, halogen, -N02, -CN, -ORGA, -N(RGA)2, -C(=0)RGA, -C(=0)ORGA, -OC(=0)RGA, -OC(=0)ORGA, -C(=0)N(RGA)2, - N(RGA)C(=0)RGA, -OC(=0)N(RGA)2, -N(RGA)C(=0)ORGA, -S(=0)2RGA, -S(=0)2ORGA, - OS(=0)2RGA, -S(=0)2N(RGA)2, -N(RGA)S(=0)2RGA, -S(=0)RGA, -S(=0)ORGA, -OS(=0)RGA, - S(=0)N(RGA)2, -N(RGA)S(=0)RGA, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocylyl, substituted or unsubstituted 3- to 6- membered heterocylyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, RG2 is hydrogen. In some embodiments, RG2 is halogen. In certain embodiments, RG2 is F. In certain
G2 G2 G2 embodiments, R is CI. In certain embodiments, R is Br. In certain embodiments, R is I. In certain embodiments, RG2 is substituted or unsubstituted C1-6 alkyl. In certain embodiments, RG2 is substituted C1-6 alkyl. In certain embodiments, RG2 is -CH2F, -CHF2, or -CF3. In certain embodiments, RG2 is unsubstituted C1-6 alkyl. In certain embodiments, RG2 is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R is -CN. In some embodiments, R is -N02. In some embodiments, RG2 is substituted or unsubstituted carbocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. In some embodiments, R is cyclopropyl or cyclobutyl. In certain embodiments, R is -OR , - N(RGA)2, -C(=0)RGA, -C(=0)ORGA, -OC(=0)RGA, -OC(=0)ORGA, -C(=0)N(RGA)2, - N(RGA)C(=0)RGA, -OC(=0)N(RGA)2, -N(RGA)C(=0)ORGA, -S(=0)2RGA, -S(=0)2ORGA, - OS(=0)2RGA, -S(=0)2N(RGA)2, or -N(RGA)S(=0)2RGA. In certain embodiments, RG2 is -NHRGA.
In certain embodiments, R is -NH2. In certain embodiments, R is -NHR , wherein R is substituted or unsubstituted C1-6 alkyl. In certain embodiments, R is -NHR , wherein R is methyl, ethyl, or propyl. In certain embodiments, R is -N(R )2, wherein each R is
independently substituted or unsubstituted C1-6 alkyl. In certain embodiments, RG2 is - N(CH3)RGA, wherein each RGA is independently unsubstituted C1-6 alkyl. In certain embodiments, R is -N(CH2CI¾)R , wherein each R is independently substituted or unsubstituted C1-6 alkyl. In certain embodiments, R is -OR . In certain embodiments, R is -OH. In certain
G2 GA GA
embodiments, R is -OR , wherein R is substituted or unsubstituted C1-6 alkyl. In certain
G2 G2 GA embodiments, R is -O-methyl, -O-ethyl, or -O-propyl. In certain embodiments, R is -OR , wherein RGA is substituted or unsubstituted aryl. In certain embodiments, RG2 is -O-phenyl.
As generally defined herein, each instance of RG3 is, independently, hydrogen, halogen, -N02, -CN, -ORGA, -N(RGA)2, -C(=0)RGA, -C(=0)ORGA, -OC(=0)RGA, -OC(=0)ORGA, -C(=0)N(RGA)2, - N(RGA)C(=0)RGA, -OC(=0)N(RGA)2, -N(RGA)C(=0)ORGA, -S(=0)2RGA, -S(=0)2ORGA, -
OS(=0)2RGA, -S(=0)2N(RGA)2, -N(RGA)S(=0)2RGA, -S(=0)RGA, -S(=0)ORGA, -OS(=0)RGA, - S(=0)N(RGA)2, -N(RGA)S(=0)RGA, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocylyl, substituted or unsubstituted 3- to 6- membered heterocylyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, RG3 is hydrogen. In some embodiments, RG3 is halogen. In certain embodiments, RG3 is F. In certain embodiments, R G3 is CI. In certain embodiments, R G3 is Br. In certain embodiments, R G3 is I. In certain embodiments, RG3 is substituted or unsubstituted C1-6 alkyl. In certain embodiments, RG3 is substituted C1-6 alkyl. In certain embodiments, RG3 is -CH2F, -CHF2, or -CF3. In certain embodiments, RG3 is unsubstituted C1-6 alkyl. In certain embodiments, RG3 is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, RG3 is -CN. In some embodiments, RG3 is -N02. In some embodiments, R is substituted or unsubstituted carbocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. In some embodiments, R is cyclopropyl or cyclobutyl. In certain embodiments, R is -OR , - N(RGA)2, -C(=0)RGA, -C(=0)ORGA, -OC(=0)RGA, -OC(=0)ORGA, -C(=0)N(RGA)2, - N(RGA)C(=0)RGA, -OC(=0)N(RGA)2, -N(RGA)C(=0)ORGA, -S(=0)2RGA, -S(=0)2ORGA, -
OS(=0)2RGA, -S(=0)2N(RGA)2, or -N(RGA)S(=0)2RGA. In certain embodiments, RG3 is -NHRGA. In certain embodiments, R is -NH2. In certain embodiments, R is -NHR , wherein R is substituted or unsubstituted C1-6 alkyl. In certain embodiments, R is -NHR , wherein R is methyl, ethyl, or propyl. In certain embodiments, R is -N(R )2, wherein each R is
independently substituted or unsubstituted C1-6 alkyl. In certain embodiments, RG3 is -
N(CH3)RGA, wherein each RGA is independently unsubstituted C1-6 alkyl. In certain embodiments,
G3 GA GA
R is -N(CH2CI¾)R , wherein each R is independently substituted or unsubstituted C1-6 alkyl. In certain embodiments, R is -OR . In certain embodiments, R is -OH. In certain embodiments, R is -OR , wherein R is substituted or unsubstituted C1-6 alkyl. In certain embodiments, R G3 is -O-methyl, -O-ethyl, or -O-propyl. In certain embodiments, R G3 is -OR GA , wherein RGA is substituted or unsubstituted aryl. In certain embodiments, RG3 is -O-phenyl.
As generally defined herein, each instance of RG4 is, independently, hydrogen, halogen, -N02, -CN, -ORGA, -N(RGA)2, -C(=0)RGA, -C(=0)ORGA, -OC(=0)RGA, -OC(=0)ORGA, -C(=0)N(RGA)2, - N(RGA)C(=0)RGA, -OC(=0)N(RGA)2, -N(RGA)C(=0)ORGA, -S(=0)2RGA, -S(=0)2ORGA, - OS(=0)2RGA, -S(=0)2N(RGA)2, -N(RGA)S(=0)2RGA, -S(=0)RGA, -S(=0)ORGA, -OS(=0)RGA, - S(=0)N(RGA)2, -N(RGA)S(=0)RGA, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocylyl, substituted or unsubstituted 3- to 6- membered heterocylyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, RG4 is hydrogen. In some embodiments, RG4 is halogen. In certain embodiments, RG4 is F. In certain embodiments, R is CI. In certain embodiments, R is Br. In certain embodiments, R is I. In certain embodiments, RG4 is substituted or unsubstituted C1-6 alkyl. In certain embodiments, RG4 is substituted C1-6 alkyl. In certain embodiments, R5 is -CH2F, -CHF2, or -CF3. In certain embodiments, RG4 is unsubstituted C1-6 alkyl. In certain embodiments, RG4 is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, RG4 is -CN. In some embodiments, RG4 is -N02. In some embodiments, RG4 is substituted or unsubstituted carbocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. In
ί"1 some embodiments, R is cyclopropyl or cyclobutyl. In certain embodiments, R is -OR , - N(RGA)2, -C(=0)RGA, -C(=0)ORGA, -OC(=0)RGA, -OC(=0)ORGA, -C(=0)N(RGA)2, - N(RGA)C(=0)RGA, -OC(=0)N(RGA)2, -N(RGA)C(=0)ORGA, -S(=0)2RGA, -S(=0)2ORGA, - OS(=0)2RGA, -S(=0)2N(RGA)2, or -N(RGA)S(=0)2RGA. In certain embodiments, RG4 is -NHRGA.
ί"1 · ί"1
In certain embodiments, R is -NH2. In certain embodiments, R is -NHR , wherein R is
ί"1 ί"1 substituted or unsubstituted C1-6 alkyl. In certain embodiments, R is -NHR , wherein R is
ί"1 ί"1
methyl, ethyl, or propyl. In certain embodiments, R is -N(R )2, wherein each R is
independently substituted or unsubstituted C1-6 alkyl. In certain embodiments, RG4 is - N(CH3)RGA, wherein each RGA is independently unsubstituted C1-6 alkyl. In certain embodiments,
G4 GA GA
R is -N(CH2CI¾)R , wherein each R is independently substituted or unsubstituted C1-6 alkyl. In certain embodiments, R G4 i *s -OR GA . In certai ·n embodi ·ments, R G4 is -OH. In certain
ί"1 ί"1
embodiments, R is -OR , wherein R is substituted or unsubstituted C1-6 alkyl. In certain
ί"1 embodiments, R is -O-methyl, -O-ethyl, or -O-propyl. In certain embodiments, R is -OR , wherein RGA is substituted or unsubstituted aryl. In certain embodiments, RG4 is -O-phenyl.
As generally defined herein, each instance of RG5 is, independently, hydrogen, halogen, -N02, -CN, -ORGA, -N(RGA)2, -C(=0)RGA, -C(=0)ORGA, -OC(=0)RGA, -OC(=0)ORGA, -C(=0)N(RGA)2, - N(RGA)C(=0)RGA, -OC(=0)N(RGA)2, -N(RGA)C(=0)ORGA, -S(=0)2RGA, -S(=0)2ORGA, - OS(=0)2RGA, -S(=0)2N(RGA)2, -N(RGA)S(=0)2RGA, -S(=0)RGA, -S(=0)ORGA, -OS(=0)RGA, - S(=0)N(RGA)2, -N(RGA)S(=0)RGA, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocylyl, substituted or unsubstituted 3- to 6- membered heterocylyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, RG5 is hydrogen. In some embodiments, RG5 is halogen. In certain embodiments, RG5 is F. In certain embodiments, RG5 is CI. In certain embodiments, RG5 is Br. In certain embodiments, RG5 is I. In certain embodiments, RG5 is substituted or unsubstituted C1-6 alkyl. In certain embodiments, RG5 is substituted C1-6 alkyl. In certain embodiments, R5 is -CH2F, -CHF2, or -CF3. In certain embodiments, RG5 is unsubstituted C1-6 alkyl. In certain embodiments, RG5 is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, RG5 is -CN. In some embodiments, RG5 is -N02. In some embodiments, RG5 is substituted or unsubstituted carbocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. In some embodiments, R is cyclopropyl or cyclobutyl. In certain embodiments, R is -OR , - N(RGA)2, -C(=0)RGA, -C(=0)ORGA, -OC(=0)RGA, -OC(=0)ORGA, -C(=0)N(RGA)2, - N(RGA)C(=0)RGA, -OC(=0)N(RGA)2, -N(RGA)C(=0)ORGA, -S(=0)2RGA, -S(=0)2ORGA, - OS(=0)2RGA, -S(=0)2N(RGA)2, or -N(RGA)S(=0)2RGA. In certain embodiments, RG5 is -NHRGA. In certain embodiments, R G5 i *s -NH2. In certai *n embodi *ments, R G5 i *s -NHR GA , wherei ·n R GA is substituted or unsubstituted C1-6 alkyl. In certain embodiments, R is -NHR , wherein R is methyl, ethyl, or propyl. In certain embodiments, R is -N(R )2, wherein each R is
independently substituted or unsubstituted C1-6 alkyl. In certain embodiments, RG5 is - N(CH3)RGA, wherein each RGA is independently unsubstituted C1-6 alkyl. In certain embodiments, R is -N(CH2CH3)R , wherein each R is independently substituted or unsubstituted C1-6 alkyl. In certain embodiments, R G5 i *s -OR GA . In certai ·n embodi ·ments, R G5 is -OH. In certain
G5 GA GA
embodiments, R is -OR , wherein R is substituted or unsubstituted C1-6 alkyl. In certain embodiments, R is -O-methyl, -O-ethyl, or -O-propyl. In certain embodiments, R is -OR , wherein RGA is substituted or unsubstituted aryl. In certain embodiments, RG5 is -O-phenyl. As generally defined herein, each instance of RG6 is, independently, hydrogen, halogen, -N02, -CN, -ORGA, -N(RGA)2, -C(=0)RGA, -C(=0)ORGA, -OC(=0)RGA, -OC(=0)ORGA, -C(=0)N(RGA)2, - N(RGA)C(=0)RGA, -OC(=0)N(RGA)2, -N(RGA)C(=0)ORGA, -S(=0)2RGA, -S(=0)2ORGA, - OS(=0)2RGA, -S(=0)2N(RGA)2, -N(RGA)S(=0)2RGA, -S(=0)RGA, -S(=0)ORGA, -OS(=0)RGA, - S(=0)N(RGA)2, -N(RGA)S(=0)RGA, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocylyl, substituted or unsubstituted 3- to 6- membered heterocylyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, RG6 is hydrogen. In some embodiments, RG6 is halogen. In certain embodiments, RG6 is F. In certain embodiments, RG6 is CI. In certain embodiments, RG6 is Br. In certain embodiments, RG6 is I. In certain embodiments, RG6 is substituted or unsubstituted C1-6 alkyl. In certain embodiments, RG6 is substituted C1-6 alkyl. In certain embodiments, R5 is -CH2F, -CHF2, or -CF3. In certain embodiments, RG6 is unsubstituted C1-6 alkyl. In certain embodiments, RG6 is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, RG6 is -CN. In some embodiments, RG6 is -N02. In some embodiments, RG6 is substituted or unsubstituted carbocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. In some embodiments, R is cyclopropyl or cyclobutyl. In certain embodiments, R is -OR , - N(RGA)2, -C(=0)RGA, -C(=0)ORGA, -OC(=0)RGA, -OC(=0)ORGA, -C(=0)N(RGA)2, - N(RGA)C(=0)RGA, -OC(=0)N(RGA)2, -N(RGA)C(=0)ORGA, -S(=0)2RGA, -S(=0)2ORGA, - OS(=0)2RGA, -S(=0)2N(RGA)2, or -N(RGA)S(=0)2RGA. In certain embodiments, RG6 is -NHRGA. In certain embodiments, R is -NH2. In certain embodiments, R is -NHR , wherein R is
G6 GA GA substituted or unsubstituted C1-6 alkyl. In certain embodiments, R is -NHR , wherein R is methyl, ethyl, or propyl. In certain embodiments, R is -N(R )2, wherein each R is
independently substituted or unsubstituted C1-6 alkyl. In certain embodiments, RG6 is - N(CH3)RGA, wherein each RGA is independently unsubstituted C1-6 alkyl. In certain embodiments, R is -N(CH2CI¾)R , wherein each R is independently substituted or unsubstituted C1-6 alkyl. In certain embodiments, R is -OR . In certain embodiments, R is -OH. In certain
G6 GA GA
embodiments, R is -OR , wherein R is substituted or unsubstituted C1-6 alkyl. In certain embodiments, RG6 is -O-methyl, -O-ethyl, or -O-propyl. In certain embodiments, RG6 is -ORGA, wherein RGA is substituted or unsubstituted aryl. In certain embodiments, RG6 is -O-phenyl.
As generally defined herein, each instance of RG7 is, independently, hydrogen, halogen, -N02, -CN, -ORGA, -N(RGA)2, -C(=0)RGA, -C(=0)ORGA, -OC(=0)RGA, -OC(=0)ORGA, -C(=0)N(RGA)2, - N(RGA)C(=0)RGA, -OC(=0)N(RGA)2, -N(RGA)C(=0)ORGA, -S(=0)2RGA, -S(=0)2ORGA, - OS(=0)2RGA, -S(=0)2N(RGA)2, -N(RGA)S(=0)2RGA, -S(=0)RGA, -S(=0)ORGA, -OS(=0)RGA, - S(=0)N(RGA)2, -N(RGA)S(=0)RGA, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocylyl, substituted or unsubstituted 3- to 6- membered heterocylyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, RG7 is hydrogen. In some embodiments, RG7 is halogen. In certain embodiments, RG7 is F. In certain embodiments, R is CI. In certain embodiments, R is Br. In certain embodiments, R is I. In certain embodiments, RG7 is substituted or unsubstituted C1-6 alkyl. In certain embodiments, RG7 is substituted C1-6 alkyl. In certain embodiments, R5 is -CH2F, -CHF2, or -CF3. In certain embodiments, RG7 is unsubstituted C1-6 alkyl. In certain embodiments, RG7 is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, RG7 is -CN. In some embodiments, RG7 is -N02. In some embodiments, RG7 is substituted or unsubstituted carbocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. In some embodiments, R is cyclopropyl or cyclobutyl. In certain embodiments, R is -OR , - N(RGA)2, -C(=0)RGA, -C(=0)ORGA, -OC(=0)RGA, -OC(=0)ORGA, -C(=0)N(RGA)2, - N(RGA)C(=0)RGA, -OC(=0)N(RGA)2, -N(RGA)C(=0)ORGA, -S(=0)2RGA, -S(=0)2ORGA, - OS(=0)2RGA, -S(=0)2N(RGA)2, or -N(RGA)S(=0)2RGA. In certain embodiments, RG7 is -NHRGA. In certain embodiments, R is -NH2. In certain embodiments, R is -NHR , wherein R is substituted or unsubstituted Ci_6 alkyl. In certain embodiments, R is -NHR , wherein R is
G1 GA GA
methyl, ethyl, or propyl. In certain embodiments, R is -N(R )2, wherein each R is independently substituted or unsubstituted Ci-6 alkyl. In certain embodiments, RG7 is - N(CH3)RGA, wherein each RGA is independently unsubstituted Ci_6 alkyl. In certain embodiments, R is -N(CH2CI¾)R , wherein each R is independently substituted or unsubstituted Ci_6 alkyl. In certain embodiments, R is -OR . In certain embodiments, R is -OH. In certain embodiments, R is -OR , wherein R is substituted or unsubstituted Ci_6 alkyl. In certain
GT GT GA
embodiments, R is -O-methyl, -O-ethyl, or -O-propyl. In certain embodiments, R is -OR , wherein RGA is substituted or unsubstituted aryl. In certain embodiments, RG7 is -O-phenyl.
As generally defined herein, each instance of RN1 is independently hydrogen, substituted or unsubstituted Ci_6 alkyl, or a nitrogen protecting group. In some embodiments, RN2 is hydrogen. In some embodiments, RN2 is substituted Ci-6 alkyl. In some embodiments, RN2 is unsubstituted Ci-6 alkyl. In certain embodiments, RN2 is methyl. In certain embodiments, RN2 is ethyl. In certain embodiments, RN2 is propyl. In certain embodiments, RN2 is a nitrogen protecting group. In certain embodiments, RN2 is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts.
As generally defined herein, each instance of RN2 is independently hydrogen, substituted or unsubstituted Ci-6 alkyl, or a nitrogen protecting group. In some embodiments, RN2 is hydrogen. In some embodiments, RN2 is substituted Ci_6 alkyl. In some embodiments, RN2 is unsubstituted Ci_6 alkyl. In certain embodiments, RN2 is methyl. In certain embodiments, RN2 is ethyl. In certain embodiments, RN2 is propyl. In certain embodiments, RN2 is a nitrogen protecting group. In certain embodiments, RN2 is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts. As generally defined herein, each instance of RN3 is independently hydrogen, substituted or unsubstituted Ci_6 alkyl, or a nitrogen protecting group. In some embodiments, RN2 is hydrogen. In some embodiments, RN2 is substituted Ci_6 alkyl. In some embodiments, RN2 is unsubstituted Ci_6 alkyl. In certain embodiments, RN2 is methyl. In certain embodiments, RN2 is ethyl. In certain embodiments, RN2 is propyl. In certain embodiments, RN2 is a nitrogen protecting group. In certain embodiments, RN2 is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts. As generally defined herein, each instance of R is independently hydrogen, substituted or unsubstituted Ci-6 alkyl, or a nitrogen protecting group. In some embodiments, RN4 is hydrogen. In some embodiments, RN4 is substituted C1-6 alkyl. In some embodiments, RN4 is unsubstituted C1-6 alkyl. In certain embodiments, RN4 is methyl. In certain embodiments, RN4 is ethyl. In certain embodiments, RN4 is propyl. In certain embodiments, RN4 is a nitrogen protecting group. In certain embodiments, RN4 is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts.
As generally defined herein, each instance of RN5 is independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group. In some embodiments, RN5 is hydrogen. In some embodiments, RN5 is substituted C1-6 alkyl. In some embodiments, RN5 is unsubstituted C1-6 alkyl. In certain embodiments, RN5 is methyl. In certain embodiments, RN5 is ethyl. In certain embodiments, RN5 is propyl. In certain embodiments, RN5 is a nitrogen protecting group. In certain embodiments, RN5 is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts.
As generally defined herein, each instance of RN6 is independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group. In some embodiments, RN6 is hydrogen. In some embodiments, RN6 is substituted C1-6 alkyl. In some embodiments, RN6 is unsubstituted C1-6 alkyl. In certain embodiments, RN6 is methyl. In certain embodiments, RN6 is ethyl. In certain embodiments, RN6 is propyl. In certain embodiments, RN6 is a nitrogen protecting group. In certain embodiments, RN6 is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts.
As generally defined herein, each instance of RN7 is independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group. In some embodiments, RN7 is hydrogen. In some embodiments, RN7 is substituted C1-6 alkyl. In some embodiments, RN7 is unsubstituted C1-6 alkyl. In certain embodiments, RN7 is methyl. In certain embodiments, RN7 is ethyl. In certain embodiments, RN7 is propyl. In certain embodiments, RN7 is a nitrogen protecting group. In certain embodiments, RN7 is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts. As generally defined herein, each instance of RGA is independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocylyl, substituted or unsubstituted 3- to 6- membered heterocylyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, or two RGA groups are taken with the intervening atoms to form a substituted or unsubstituted heterocylyl or heteroaryl ring. . In some embodiments, R is hydrogen. In certain embodiments, RGA is substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-6 carbocyclyl. In certain embodiments, RGA is substituted or unsubstituted C1-6 alkyl. In certain embodiments, RGA is unsubstituted C1-6 alkyl. In certain embodiments, RGA is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In certain embodiments, RGA is substituted or unsubstituted heterocyclyl. In certain embodiments, RGA is substituted or unsubstituted aryl. In certain embodiments, RGA is substituted or unsubstituted phenyl. In certain embodiments, RGA is a nitrogen protecting group. In certain embodiments, RGA is an oxygen protecting group. In certain embodiments, the compound of Formula (I) is of Formula (II),
Figure imgf000055_0001
or a pharmaceutically acceptable salt thereof. In certain embodiments, the point of attachment in Formula (II) is at the nitrogen at the Gl position. In certain embodiments, the point of attachment in Formula (II) is at the nitrogen at the G2 position. In certain embodiments, the compound of Formula (I) is of
Formula (H-a):
Figure imgf000056_0001
or a pharmaceutically acceptable salt thereof. In certain embodiments, the point of attachment ' Formula (Il-a) is at the nitrogen at the Gl position. In certain embodiments, the point of attachment in Formula (Il-a) is at the nitrogen at the G2 position.
In certain embodiments, the compound of Formula (I) is of one of the following formulae:
Figure imgf000056_0002
Figure imgf000057_0001
pharmaceutically acceptable salt thereof. In certain embodiments, the point of attachment in any one of Formulae (II-al)-(II-a5) is at the nitrogen at the Gl position. In certain embodiments, the point of attachment in any one of Formulae (II-al)-(II-a5) is at the nitrogen at the G2 position.
In certain embodiments, the compound of Formula (I) is of one of the following formulae:
Figure imgf000058_0001

Figure imgf000059_0001

Figure imgf000060_0001
or a pharmaceutically acceptable salt thereof.
In certain embodiments, the compound of Formula (I) is of Formula (H-b):
Figure imgf000060_0002
or a pharmaceutically acceptable salt thereof. In certain embodiments, the point of attachment in any one of Formula (Il-b) is at the nitrogen at the Gl position. In certain embodiments, the point of attachment in any one of Formula (Il-b) is at the nitrogen at the G2 position. In certain embodiments, the compound of Formula (I) is of one of the following formulae:
Figure imgf000061_0001
Figure imgf000061_0002
Figure imgf000062_0001
pharmaceutically acceptable salt thereof. In certain embodiments, the point of attachment in any one of Formulae (II-bl)-(II-b5) is at the nitrogen at the Gl position. In certain embodiments, the point of attachment in any one of Formulae (II-bl)-(II-b5) is at the nitrogen at the G2 position. In certain embodiments, the compound of Formula (I) is of one of the following formulae:
Figure imgf000062_0002
Figure imgf000063_0001
61
Figure imgf000064_0001
or a pharmaceutically acceptable salt thereof.
In certain embodiments, the compound of Formula (I) is of Formula (III):
Figure imgf000065_0001
or a pharmaceutically acceptable salt thereof.
In certain embodiments, the compound of Formula (I) is of Formula (Ill-a):
Figure imgf000065_0002
Figure imgf000065_0003
or a pharmaceutically acceptable salt thereof.
In certain embodiments, the compound of Formula (I) is of Formula (III-bl):
Figure imgf000066_0001
or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) is of Formula (IV):
Figure imgf000066_0002
or a pharmaceutically acceptable salt thereof. In certain embodiments, the point of attachment in Formula (IV) is at the nitrogen at the Gl position. In certain embodiments, the point of attachment in Formula (IV) is at the nitrogen at the G2 position. In certain embodiments, the compound of Formula (I) is of Formula (IV-a):
Figure imgf000067_0001
or a pharmaceutically acceptable salt thereof. In certain embodiments, the point of attachment in Formula (IV-a) is at the nitrogen at the Gl position. In certain embodiments, the point of attachment in Formula (IV-a) is at the nitrogen at the G2 position.
In certain embodiments, the compound of Formula (I) is of Formula (IV-al):
Figure imgf000067_0002
or a pharmaceutically acceptable salt thereof. In certain embodiments, the point of attachment in Formula (IV-al) is at the nitrogen at the Gl position. In certain embodiments, the point of attachment in Formula (IV-al) is at the nitrogen at the G2 position.
In certain embodiments, the compound of Formula (I) is of one of the following formulae:
Figure imgf000068_0001
or a pharmaceutically acceptable salt thereof.
In certain embodiments, the compound of Formula (I) is of one of the following formulae:
Figure imgf000068_0002
Figure imgf000069_0001
or a pharmaceutically acceptable salt thereof.
Various Combinations of Certain Embodiments
Various combinations of certain embodiments are futher contemplated herein.
For example, in certain embodiments, wherein R is hydrogen or a non-hydrogen alpha substituent, provided is a compound of Formula (I-Al), (I-Bl), (I-Cl), or (I-Dl):
Figure imgf000069_0002
(I-Al) (I-Bl) (I-Cl)
Figure imgf000069_0003
(I-Dl) or a pharmaceutically acceptable salt thereof. In certain embodiments, R1 is -CH3 -CH2CH3, - CH2F, -CHF2, -CF3, -CH2OCH3, or substituted or unsubstituted cyclopropyl. In certain embodiments, R2 is -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, substituted or unsubstituted cyclopropyl, fluoro, or chloro. In certain embodiments, R3a and R3 are both hydrogen. In certain embodiments, R3a and R3 are joined to form =0 (oxo). In certain embodiments, wherein Ring B comprises a C5-C6 double bond, R4a is hydrogen, fluoro, -CH3, or - CF3. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond, both of R4a and R4 are hydrogen. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond, both of R4a and R4 are -CH3 or -CF3. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond, both of R4a and R4 are fluoro. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond, R4a is a non-hydrogen substituent and R4 is hydrogen.
In certain embodiments, wherein R2 is hydrogen or a non-hydrogen beta substituent, provided is a compound of Formula (I-A2), (I-B2), (I-C2), or (I-D2):
Figure imgf000070_0001
(I-A2) (I-B2) (I-C2)
Figure imgf000071_0001
(I-D2) or a pharmaceutically acceptable salt thereof. In certain embodiments, R1 is -CH3 -CH2CH3, - CH2F, -CHF2, -CF3, -CH2OCH3, or substituted or unsubstituted cyclopropyl. In certain embodiments, R2 is -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, substituted or unsubstituted cyclopropyl, fluoro, or chloro. In certain embodiments, R3a and R3 are both hydrogen. In certain embodiments, R3a and R3 are joined to form =0 (oxo). In certain embodiments, wherein Ring B comprises a C5-C6 double bond, R4a is hydrogen, fluoro, -CH3, or - CF3. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond, both of R4a and R4 are hydrogen. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond, both of R4a and R4 are -CH3 or -CF3. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond, both of R4a and R4 are fluoro. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond, R4a is a non-hydrogen substituent and R4 is hydrogen. In certain embodiments, wherein R3a is hydrogen or a non-hydrogen alpha substituent, and R3 is hydrogen, provided is a compound of Formula (I- A3), (I-B3), (I-C3), or (I-D3):
Figure imgf000071_0002
(I-A3) (I-B3) (I-C3)
Figure imgf000072_0001
(I-D3) or a pharmaceutically acceptable salt thereof. In certain embodiments, R1 is -CH3 -CH2CH3, - CH2F, -CHF2, -CF3, -CH2OCH3, or substituted or unsubstituted cyclopropyl. In certain embodiments, R2 is -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, substituted or unsubstituted cyclopropyl, fluoro, or chloro. In certain embodiments, R2 is a non- hydrogen substituent in the alpha configuration. In certain embodiments, R is a non-hydrogen substituent in the beta configuration. In certain embodiments, wherein Ring B comprises a C5-C6 double bond, R4a is hydrogen, fluoro, -CH3, or -CF3. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond, both of R4a and R4 are hydrogen. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond, both of R4a and R4 are -CH3 or -CF3. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond, both of R4a and
R4b are fluoro. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond,
R4a is a non-hydrogen substituent and R4 is hydrogen. In certain embodiments, wherein R3a is hydrogen or a non-hydrogen beta substituent, and R3 is hydrogen, provided is a compound of Formula (I-A4), (I-B4), (I-C4), or (I-D4):
Figure imgf000072_0002
(I-A4) (I-B4) (I-C4)
Figure imgf000073_0001
(I-D4) or a pharmaceutically acceptable salt thereof. In certain embodiments, R1 is -CH3 -CH2CH3, - CH2F, -CHF2, -CF3, -CH2OCH3, or substituted or unsubstituted cyclopropyl. In certain embodiments, R2 is -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, substituted or unsubstituted cyclopropyl, fluoro, or chloro. In certain embodiments, R2 is a non- hydrogen substituent in the alpha configuration. In certain embodiments, R is a non-hydrogen substituent in the beta configuration. In certain embodiments, wherein Ring B comprises a C5-C6 double bond, R4a is hydrogen, fluoro, -CH3, or -CF3. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond, both of R4a and R4 are hydrogen. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond, both of R4a and R4 are -CH3 or -CF3. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond, both of R4a and
R4b are fluoro. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond,
R4a is a non-hydrogen substituent and R4 is hydrogen. In certain embodiments, wherein R3a and R3 are joined to form an oxo group, provided is a compound of Formula (I-A5), (I-B5), (I-C5), (I-D5):
Figure imgf000073_0002
(I-A5) (I BS) (I-C5)
Figure imgf000074_0001
(I-D5) or a pharmaceutically acceptable salt thereof. In certain embodiments, R1 is -C¾ -CH2CH3, - CH2F, -CHF2, -CF3, -CH2OCH3, or substituted or unsubstituted cyclopropyl. In certain embodiments, R2 is -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, substituted or unsubstituted cyclopropyl, fluoro, or chloro. In certain embodiments, R is a non- hydrogen substituent in the alpha configuration. In certain embodiments, R is a non-hydrogen substituent in the beta configuration. In certain embodiments, wherein Ring B comprises a C5-C6 double bond, R4a is hydrogen, fluoro, -CH3, or -CF3. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond, both of R4a and R4 are hydrogen. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond, both of R4a and R4 are -CH3 or -CF3. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond, both of R4a and
R4b are fluoro. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond,
R4a is a non-hydrogen substituent and R4 is hydrogen. In certain embodiments, wherein R4a is a non-hydrogen substituent, provided is a compound of Formula (I-A6) or (I-B6):
Figure imgf000074_0002
or a pharmaceutically acceptable salt thereof. In certain embodiments, R1 is -C¾ -CH2CH3, - CH2F, -CHF2, -CF3, -CH2OCH3, or substituted or unsubstituted cyclopropyl. In certain embodiments, R2 is -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -CH3, -CH2CH3, -CH2CH2CH3 substituted or unsubstituted cyclopropyl, fluoro, or chloro. In certain embodiments, R2 is a non- hydrogen substituent in the alpha configuration. In certain embodiments, R2 is a non-hydrogen substituent in the beta configuration. In certain embodiments, R3a and R3 are both hydrogen. In certain embodiments, R3a and R3 are joined to form =0 (oxo). In certain embodiments, R4a is fluoro, -CH3, or -CF3 and R4 is hydrogen. In certain embodiments, R4 is fluoro, -C¾, or -CF3 and R4a is hydrogen. In certain embodiments, both of R4a and R4 are -CH3 or -CF3. In certain embodiments, both of R4a and R4 are fluoro.
In certain embodiments, a compound of Formula (I) is selected from the group consisting of
Figure imgf000075_0001
Figure imgf000076_0001
74
Figure imgf000077_0001
75
Figure imgf000078_0001
acceptable salts thereof.
In certain embodiments, a compound of Formula (I) is selected from the group consisting of:
Figure imgf000078_0002
Figure imgf000079_0001
Figure imgf000080_0001
thereof.
Pharmaceutical Compositions
In another aspect, the invention provides a pharmaceutical composition comprising a compound of the present invention (also referred to as the "active ingredient") and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of the active ingredient.
The pharmaceutical compositions provided herein can be administered by a variety of routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration.
Generally, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of
administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
When used to prevent the onset of a CNS-disorder, the compounds provided herein will be administered to a subject at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Subjects at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.
The pharmaceutical compositions provided herein can also be administered chronically ("chronic administration"). Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc, or may be continued indefinitely, for example, for the rest of the subject's life. In certain embodiments, the chronic administration is intended to provide a constant level of the compound in the blood, e.g., within the therapeutic window over the extended period of time.
The pharmaceutical compostions of the present invention may be further delivered using a variety of dosing methods. For example, in certain embodiments, the pharmaceutical composition may be given as a bolus, e.g., in order to raise the concentration of the compound in the blood to an effective level. The placement of the bolus dose depends on the systemic levels of the active ingredient desired throughout the body, e.g., an intramuscular or subcutaneous bolus dose allows a slow release of the active ingredient, while a bolus delivered directly to the veins (e.g., through an IV drip) allows a much faster delivery which quickly raises the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical
composition may be administered as a continuous infusion, e.g., by IV drip, to provide
maintenance of a steady-state concentration of the active ingredient in the subject's
body. Furthermore, in still yet other embodiments, the pharmaceutical composition may be administered as first as a bolus dose, followed by continuous infusion.
The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or excipients and processing aids helpful for forming the desired dosing form. With oral dosing, one to five and especially two to four and typically three oral doses per day are representative regimens. Using these dosing patterns, each dose provides from about 0.01 to about 20 mg/kg of the compound provided herein, with preferred doses each providing from about 0.1 to about 10 mg/kg, and especially about 1 to about 5 mg/kg.
Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses, generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
Injection dose levels range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 2 g/day for a 40 to 80 kg human patient.
Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable excipients known in the art. As before, the active compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable excipient and the like. Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s). When formulated as a ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or Formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.
The compounds provided herein can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety. The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington 's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference. The compounds of the present invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.
The present invention also relates to the pharmaceutically acceptable formulations of a compound of the present invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common
cyclodextrins are α-, β- and γ- cyclodextrins consisting of 6, 7 and 8 a-1 ,4-linked glucose units, respectively, optionally comprising one or more substituents on the linked sugar moieties, which include, but are not limited to, methylated, hydroxyalkylated, acylated, and sulfoalkylether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, e.g., for example, sulfobutyl ether β-cyclodextrin, also known as Captisol . See, e.g., U.S. 5,376,645. In certain embodiments, the formulation comprises hexapropyl-P-cyclodextrin (e.g., 10-50% in water).
The present invention also relates to the pharmaceutically acceptable acid addition salt of a compound of the present invention. The acid which may be used to prepare the pharmaceutically acceptable salt is that which forms a non-toxic acid addition salt, i.e., a salt containing
pharmacologically acceptable anions such as the hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like. The following formulation examples illustrate representative pharmaceutical compositions that may be prepared in accordance with this invention. The present invention, however, is not limited to the following pharmaceutical compositions.
Exemplary Formulation 1 - Tablets: A compound of the present invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg of active compound per tablet) in a tablet press.
Exemplary Formulation 2 - Capsules: A compound of the present invention may be admixed as a dry powder with a starch diluent in an approximate 1 : 1 weight ratio. The mixture is filled into 250 mg capsules (125 mg of active compound per capsule). Exemplary Formulation 3 - Liquid: A compound of the present invention (125 mg) may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11 :89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color are diluted with water and added with stirring. Sufficient water may then be added to produce a total volume of 5 mL.
Exemplary Formulation 4 - Tablets: A compound of the present invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 450-900 mg tablets (150- 300 mg of active compound) in a tablet press.
Exemplary Formulation 5 - Injection : A compound of the present invention may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/mL.
Exemplary Formulation 6 - Tablets: A compound of the present invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 90-150 mg tablets (30-50 mg of active compound per tablet) in a tablet press.
Exemplary Formulation 7 - Tablets: A compound of the present invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 30-90 mg tablets (10-30 mg of active compound per tablet) in a tablet press.
Exemplary Formulation 8 - Tablets: A compound of the present invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 0.3-30 mg tablets (0.1-10 mg of active compound per tablet) in a tablet press.
Exemplary Formulation 9 - Tablets: A compound of the present invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 150-240 mg tablets (50-80 mg of active compound per tablet) in a tablet press.
Exemplary Formulation 10 Tablets: A compound of the present invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 270-450 mg tablets (90- 150 mg of active compound per tablet) in a tablet press.
Methods of Use and Treatment
As generally described herein, the present invention is directed to C21 -substituted neuroactive steroids designed, for example, to act as GABA modulators. In certain embodiments, such compounds are envisioned to be useful as therapeutic agents for the inducement of anesthesia and/or sedation in a subject. In some embodiments, such compounds are envisioned to be useful as therapeutic agents for treating a CNS-related disorder (e.g., sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, or tinnitus) in a subject in need (e.g., a subject with Rett syndrome, Fragile X syndrome, or Angelman syndrome).
Thus, in one aspect, the present invention provides a method of inducing sedation and/or anesthesia in a subject, comprising administering to the subject an effective amount of a compound of the present invention or a composition thereof. In certain embodiments, the compound is administered by intravenous administration.
Earlier studies (see, e.g., Gee et al., European Journal of Pharmacology, 136:419-423 (1987)) demonstrated that certain 3a-hydroxylated steroids are orders of magnitude more potent as modulators of the GABA receptor complex (GRC) than others had reported (see, e.g., Majewska et al, Science 232: 1004-1007 (1986); Harrison et al, J Pharmacol. Exp. Ther. 241 :346-353 (1987)). Majewska et al. and Harrison et al. taught that 3a-hydroxylated-5-reduced steroids are only capable of much lower levels of effectiveness. In vitro and in vivo experimental data have now demonstrated that the high potency of these steroids allows them to be therapeutically useful in the modulation of brain excitability via the GRC (see, e.g., Gee et al, European Journal of
Pharmacology, 136:419-423 (1987); Wieland et al, Psychopharmacology 118(1):65-71 (1995)).
Various synthetic steroids have also been prepared as neuroactive steroids. See, for example, U.S. Patent 5,232,917, which discloses neuroactive steroid compounds useful in treating stress, anxiety, insomnia, seizure disorders, and mood disorders, that are amenable to GRC-active agents, such as depression, in a therapeutically beneficial manner. Furthermore, it has been previously
demonstrated that these steroids interact at a unique site on the GRC which is distinct from other known sites of interaction {e.g., barbiturates, benzodiazepines, and GABA) where therapeutically beneficial effects on stress, anxiety, sleep, mood disorders and seizure disorders have been previously elicited (see, e.g., Gee, K.W. and Yamamura, H.I., "Benzodiazepines and Barbiturates: Drugs for the Treatment of Anxiety, Insomnia and Seizure Disorders," in Central Nervous System Disorders, Horvell, ed., Marcel-Dekker, New York (1985), pp. 123-147; Lloyd, K.G. and Morselli, P.L., "Psychopharmacology of GABAergic Drugs," in Psychopharmacology: The Third
Generation of Progress, H.Y. Meltzer, ed., Raven Press, N.Y. (1987), pp. 183-195; and Gee et al., European Journal of Pharmacology, 136:419-423 (1987). These compounds are desirable for their duration, potency, and oral activity (along with other forms of administration).
Compounds of the present invention, as described herein, are generally designed to modulate GABA function, and therefore to act as neuroactive steroids for the treatment and prevention of CNS-r elated conditions in a subject. Modulation, as used herein, refers to the inhibition or potentiation of GABA receptor function. Accordingly, the compounds and pharmaceutical compositions provided herein find use as therapeutics for preventing and/or treating CNS conditions in mammals including humans and non-human mammals. Thus, and as stated earlier, the present invention includes within its scope, and extends to, the recited methods of treatment, as well as to the compounds for such methods, and to the use of such compounds for the preparation of medicaments useful for such methods.
Exemplary CNS conditions related to GABA-modulation include, but are not limited to, sleep disorders [e.g., insomnia], mood disorders [e.g., depression, dysthymic disorder {e.g., mild depression), bipolar disorder {e.g., I and/or II), anxiety disorders {e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), compulsive disorders {e.g., obsessive compulsive disorder (OCD))], schizophrenia spectrum disorders [e.g., schizophrenia, schizoaffective disorder], convulsive disorders [e.g., epilepsy (e.g., status epilepticus (SE)), seizures], disorders of memory and/or cognition [e.g., attention disorders (e.g., attention deficit hyperactivity disorder (ADHD)), dementia (e.g., Alzheimer's type dementia, Lewis body type dementia, vascular type dementia], movement disorders [e.g., Huntington's disease, Parkinson's disease], personality disorders [e.g., anti-social personality disorder, obsessive compulsive personality disorder], autism spectrum disorders (ASD) [e.g., autism, monogenetic causes of autism such as synaptophathy's, e.g., Rett syndrome, Fragile X syndrome, Angelman syndrome], pain [e.g., neuropathic pain, injury related pain syndromes, acute pain, chronic pain], traumatic brain injury (TBI), vascular diseases [e.g., stroke, ischemia, vascular malformations], substance abuse disorders and/or withdrawal syndromes [e.g., addition to opiates, cocaine, and/or alcohol], and tinnitus.
In yet another aspect, provided is a combination of a compound of the present invention and another pharmacologically active agent. The compounds provided herein can be administered as the sole active agent or they can be administered in combination with other agents. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent and alternating administration.
In another aspect, provided is a method of treating or preventing brain excitability in a subject susceptible to or afflicted with a condition associated with brain excitability, comprising administering to the subject an effective amount of a compound of the present invention to the subject.
In yet another aspect, provided is a method of treating or preventing stress or anxiety in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention, or a composition thereof.
In yet another aspect, provided is a method of alleviating or preventing seizure activity in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention.
In yet another aspect, provided is a method of alleviating or preventing insomnia in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention, or a composition thereof. In yet another aspect, provided is a method of inducing sleep and maintaining substantially the level of REM sleep that is found in normal sleep, wherein substantial rebound insomnia is not induced, comprising administering an effective amount of a compound of the present invention.
In yet another aspect, provided is a method of alleviating or preventing PMS or PND in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention.
In yet another aspect, provided is a method of treating or preventing mood disorders in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention. In certain embodiments the mood disorder is depression. In yet another aspect, provided is a method of inducing anesthesia in a subject, comprising administering to the subject an effective amount of a compound of the present invention.
In yet another aspect, provided is a method of cognition enhancement or treating memory disorder by administering to the subject a therapeutically effective amount of a compound of the present invention. In certain embodiments, the disorder is Alzheimer's disease. In certain embodiments, the disorder is Rett syndrome.
In yet another aspect, provided is a method of treating attention disorders by administering to the subject a therapeutically effective amount of a compound of the present invention. In certain embodiments, the attention disorder is ADHD.
In certain embodiments, the compound is administered to the subject chronically. In certain embodiments, the compound is administered to the subject orally, subcutaneously, intramuscularly, or intravenously.
Anesthesia / Sedation
Anesthesia is a pharmacologically induced and reversible state of amnesia, analgesia, loss of responsiveness, loss of skeletal muscle reflexes, decreased stress response, or all of these simultaneously. These effects can be obtained from a single drug which alone provides the correct combination of effects, or occasionally with a combination of drugs {e.g., hypnotics, sedatives, paralytics, analgesics) to achieve very specific combinations of results. Anesthesia allows patients to undergo surgery and other procedures without the distress and pain they would otherwise experience.
Sedation is the reduction of irritability or agitation by administration of a pharmacological agent, generally to facilitate a medical procedure or diagnostic procedure.
Sedation and analgesia include a continuum of states of consciousness ranging from minimal sedation (anxiolysis) to general anesthesia.
Minimal sedation is also known as anxiolysis. Minimal sedation is a drug-induced state during which the patient responds normally to verbal commands. Cognitive function and coordination may be impaired. Ventilatory and cardiovascular functions are typically unaffected.
Moderate sedation/analgesia (conscious sedation) is a drug-induced depression of consciousness during which the patient responds purposefully to verbal command, either alone or accompanied by light tactile stimulation. No interventions are usually necessary to maintain a patent airway. Spontaneous ventilation is typically adequate. Cardiovascular function is usually maintained.
Deep sedation/analgesia is a drug-induced depression of consciousness during which the patient cannot be easily aroused, but responds purposefully (not a reflex withdrawal from a painful stimulus) following repeated or painful stimulation. Independent ventilatory function may be impaired and the patient may require assistance to maintain a patent
airway. Spontaneous ventilation may be inadequate. Cardiovascular function is usually maintained.
General anesthesia is a drug-induced loss of consciousness during which the patient is not arousable, even to painful stimuli. The ability to maintain independent ventilatory function is often impaired and assistance is often required to maintain a patent airway. Positive pressure ventilation may be required due to depressed spontaneous ventilation or drug-induced depression of neuromuscular function. Cardiovascular function may be impaired.
Sedation in the intensive care unit (ICU) allows the depression of patients' awareness of the environment and reduction of their response to external stimulation. It can play a role in the care of the critically ill patient, and encompasses a wide spectrum of symptom control that will vary between patients, and among individuals throughout the course of their illnesses. Heavy sedation in critical care has been used to facilitate endotracheal tube tolerance and ventilator
synchronization, often with neuromuscular blocking agents. In some embodiments, sedation (e.g., long-term sedation, continuous sedation) is induced and maintained in the ICU for a prolonged period of time (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 week, 3 weeks, 1 month, 2 months). Long-term sedation agents may have long duration of action. Sedation agents in the ICU may have short elimination half-life.
Procedural sedation and analgesia, also referred to as conscious sedation, is a technique of administering sedatives or dissociative agents with or without analgesics to induce a state that allows a subject to tolerate unpleasant procedures while maintaining cardiorespiratory function.
Anxiety Disorders
Anxiety disorder is a blanket term covering several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders.
Generalized anxiety disorder is a common chronic disorder characterized by long-lasting anxiety that is not focused on any one object or situation. Those suffering from generalized anxiety experience non-specific persistent fear and worry and become overly concerned with everyday matters. Generalized anxiety disorder is the most common anxiety disorder to affect older adults.
In panic disorder, a person suffers from brief attacks of intense terror and apprehension, often marked by trembling, shaking, confusion, dizziness, nausea, difficulty breathing. These panic attacks, defined by the APA as fear or discomfort that abruptly arises and peaks in less than ten minutes, can last for several hours and can be triggered by stress, fear, or even exercise; although the specific cause is not always apparent. In addition to recurrent unexpected panic attacks, a diagnosis of panic disorder also requires that said attacks have chronic consequences: either worry over the attacks' potential implications, persistent fear of future attacks, or significant changes in behavior related to the attacks. Accordingly, those suffering from panic disorder experience symptoms even outside of specific panic episodes. Often, normal changes in heartbeat are noticed by a panic sufferer, leading them to think something is wrong with their heart or they are about to have another panic attack. In some cases, a heightened awareness (hypervigilance) of body functioning occurs during panic attacks, wherein any perceived physiological change is interpreted as a possible life threatening illness (i.e. extreme hypochondriasis).
Obsessive compulsive disorder is a type of anxiety disorder primarily characterized by repetitive obsessions (distressing, persistent, and intrusive thoughts or images) and compulsions (urges to perform specific acts or rituals). The OCD thought pattern may be likened to superstitions insofar as it involves a belief in a causative relationship where, in reality, one does not exist. Often the process is entirely illogical; for example, the compulsion of walking in a certain pattern may be employed to alleviate the obsession of impending harm. And in many cases, the compulsion is entirely inexplicable, simply an urge to complete a ritual triggered by nervousness. In a minority of cases, sufferers of OCD may only experience obsessions, with no overt compulsions; a much smaller number of sufferers experience only compulsions. The single largest category of anxiety disorders is that of Phobia, which includes all cases in which fear and anxiety is triggered by a specific stimulus or situation. Sufferers typically anticipate terrifying consequences from encountering the object of their fear, which can be anything from an animal to a location to a bodily fluid.
Post-traumatic stress disorder or PTSD is an anxiety disorder which results from a traumatic experience. Post-traumatic stress can result from an extreme situation, such as combat, rape, hostage situations, or even serious accident. It can also result from long term (chronic) exposure to a severe stressor, for example soldiers who endure individual battles but cannot cope with continuous combat. Common symptoms include flashbacks, avoidant behaviors, and depression.
Neurodegenerative Diseases and Disorders
The term "neurodegenerative disease" includes diseases and disorders that are associated with the progressive loss of structure or function of neurons, or death of neurons. Neurodegenerative diseases and disorders include, but are not limited to, Alzheimer's disease (including the associated symptoms of mild, moderate, or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic injuries; ataxia and convulsion (including for the treatment and prevention and prevention of seizures that are caused by schizoaffective disorder or by drugs used to treat schizophrenia); benign forgetfulness; brain edema; cerebellar ataxia including McLeod neuroacanthocytosis syndrome (MLS); closed head injury; coma; contusive injuries (e.g., spinal cord injury and head injury); dementias including multi-infarct dementia and senile dementia; disturbances of consciousness; Down syndrome; drug-induced or medication-induced Parkinsonism (such as neuroleptic- induced acute akathisia, acute dystonia, Parkinsonism, or tardive dyskinesia, neuroleptic malignant syndrome, or medication-induced postural tremor); epilepsy; fragile X syndrome; Gilles de la Tourette's syndrome; head trauma; hearing impairment and loss; Huntington's disease; Lennox syndrome; levodopa-induced dyskinesia; mental retardation; movement disorders including akinesias and akinetic (rigid) syndromes (including basal ganglia calcification, corticobasal degeneration, multiple system atrophy, Parkinsonism- ALS dementia complex, Parkinson's disease, postencephalitic parkinsonism, and progressively supranuclear palsy); muscular spasms and disorders associated with muscular spasticity or weakness including chorea (such as benign hereditary chorea, drug-induced chorea, hemiballism, Huntington's disease, neuroacanthocytosis, Sydenham's chorea, and symptomatic chorea), dyskinesia (including tics such as complex tics, simple tics, and symptomatic tics), myoclonus (including generalized myoclonus and focal cyloclonus), tremor (such as rest tremor, postural tremor, and intention tremor) and dystonia (including axial dystonia, dystonic writer's cramp, hemiplegic dystonia, paroxysmal dystonia, and focal dystonia such as blepharospasm,
oromandibular dystonia, and spasmodic dysphonia and torticollis); neuronal damage including ocular damage, retinopathy or macular degeneration of the eye; neurotoxic injury which follows cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest;
Parkinson's disease; seizure; status epilecticus; stroke; tinnitus; tubular sclerosis, and viral infection induced neurodegeneration (e.g., caused by acquired immunodeficiency syndrome (AIDS) and encephalopathies). Neurodegenerative diseases also include, but are not limited to, neurotoxic injury which follows cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest. Methods of treating or preventing a neurodegenerative disease also include treating or preventing loss of neuronal function characteristic of neurodegenerative disorder. Epilepsy
Epilepsy is a brain disorder characterized by repeated seizures over time. Types of epilepsy can include, but are not limited to generalized epilepsy, e.g., childhood absence epilepsy, juvenile nyoclonic epilepsy, epilepsy with grand-mal seizures on awakening, West syndrome, Lennox-
Gastaut syndrome, partial epilepsy, e.g., temporal lobe epilepsy, frontal lobe epilepsy, benign focal epilepsy of childhood.
Status epilepticus (SE) Status epilepticus (SE) can include, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non- convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epileptic seizures, and can include early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus. Early status epilepticus is treated with a first line therapy. Established status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line therapy, and a second line therapy is administered. Refractory status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line and a second line therapy, and a general anesthetic is generally administered. Super refractory status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line therapy, a second line therapy, and a general anesthetic for 24 hours or more.
Non-convulsive status epilepticus can include, e.g., focal non-convulsive status epilepticus, e.g., complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, subtle non-convulsive status epilepticus; generalized non-convulsive status epilepticus, e.g., late onset absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus. Compositions described herein can also be administered as a prophylactic to a subject having a CNS disorder e.g., a traumatic brain injury, status epilepticus, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super- refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges; prior to the onset of a seizure.
Seizure
A seizure is the physical findings or changes in behavior that occur after an episode of abnormal electrical activity in the brain. The term "seizure" is often used interchangeably with
"convulsion." Convulsions are when a person's body shakes rapidly and uncontrollably. During convulsions, the person's muscles contract and relax repeatedly.
Based on the type of behavior and brain activity, seizures are divided into two broad categories: generalized and partial (also called local or focal). Classifying the type of seizure helps doctors diagnose whether or not a patient has epilepsy.
Generalized seizures are produced by electrical impulses from throughout the entire brain, whereas partial seizures are produced (at least initially) by electrical impulses in a relatively small part of the brain. The part of the brain generating the seizures is sometimes called the focus.
There are six types of generalized seizures. The most common and dramatic, and therefore the most well known, is the generalized convulsion, also called the grand-mal seizure. In this type of seizure, the patient loses consciousness and usually collapses. The loss of consciousness is followed by generalized body stiffening (called the "tonic" phase of the seizure) for 30 to 60 seconds, then by violent jerking (the "clonic" phase) for 30 to 60 seconds, after which the patient goes into a deep sleep (the "postictal" or after-seizure phase). During grand-mal seizures, injuries and accidents may occur, such as tongue biting and urinary incontinence.
Absence seizures cause a short loss of consciousness (just a few seconds) with few or no symptoms. The patient, most often a child, typically interrupts an activity and stares blankly. These seizures begin and end abruptly and may occur several times a day. Patients are usually not aware that they are having a seizure, except that they may be aware of "losing time."
Myoclonic seizures consist of sporadic jerks, usually on both sides of the body. Patients sometimes describe the jerks as brief electrical shocks. When violent, these seizures may result in dropping or involuntarily throwing objects.
Clonic seizures are repetitive, rhythmic jerks that involve both sides of the body at the same time. Tonic seizures are characterized by stiffening of the muscles.
Atonic seizures consist of a sudden and general loss of muscle tone, particularly in the arms and legs, which often results in a fall.
Seizures described herein can include epileptic seizures; acute repetitive seizures; cluster seizures; continuous seizures; unremitting seizures; prolonged seizures; recurrent seizures; status epilepticus seizures, e.g., refractory convulsive status epilepticus, non-convulsive status epilepticus seizures; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondarily generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign Rolandic seizures; febrile seizures; emotional seizures; focal seizures; gelastic seizures; generalized onset seizures; infantile spasms; Jacksonian seizures; massive bilateral myoclonus seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post traumatic seizures; subtle seizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures.
Examples
In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions and methods provided herein and are not to be construed in any way as limiting their scope. Materials and Methods
The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated.
Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization.
Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein. The compounds provided herein may be isolated and purified by known standard procedures.
Such procedures include (but are not limited to) recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following schemes are presented with details as to the preparation of representative substituted biarylamides that have been listed herein. The compounds provided herein may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis. Exemplary chiral columns available for use in the separation/purification of the enantiomers/diastereomers provided herein include, but are not limited to, CfflRALPAK® AD- 10, CfflRALCEL® OB, CfflRALCEL® OB- H, CfflRALCEL® OD, CfflRALCEL® OD-H, CfflRALCEL® OF, CfflRALCEL® OG, CfflRALCEL® OJ and CfflRALCEL® OK. General method for supercritical fluid chromatography (SFC): SFC purification was carried out using a Thar 200 preparative SFC instrument equipped with a ChiralPak AD- 10 μΜ, 200x50 mm ID. The compounds were separated eluting with mixtures of carbon dioxide and methanol or ethanol (e.g., 20-35% methanol or ethanol and 0.1% ammonium hydroxide) at a flow rate of 55- 200 mL/min and monitored at 220 nm wavelength. 1H-NMR reported herein may be a partial representation of the full NMR spectrum of a compound, e.g., a compound described herein. For example, the reported 1H NMR may exclude the region between δ (ppm) of about 1 to about 2.5 ppm. Copies of full ^-NMR spectrum for representative examples are provided in the Figures. Exemplary general method for preparative HPLC: Column: Waters RBridge prep 10 μηι CI 8, 19*250 mm. Mobile phase: aectomtrile, water (NH4HC03) (30 L water, 24 g NH4HC03, 30 mL NH3.H2O). Flow rate: 25 mL/min
Exemplary general method for analytical HPLC: Mobile phase: A: water (10 mM NH4HCO3), B: acetonitrileGradient: 5%-95% B in 1.6 or 2 min Flow rate: 1.8 or 2 mL/min; Column: XB ridge C18, 4.6*50mm, 3^m at 45 C.
Synthetic Procedures
The compounds of the invention can be prepared in accordance with methods described in the art (Upasani e/ a/., J. Med. Chem. 1997, 40:73-84; and Hogenkamp et ah, J. Med. Chem. 1997, 40:61- 72) and using the appropriate reagents, starting materials, and purification methods known to those skilled in the art. In some embodiments, compounds described herein can be prepared using methods shown in general Schemes 1-4, comprising a nucleophilic substitution of 19-nor pregnane bromide with a neucleophile. In certain embodiments, the nucleophile reacts with the 19-nor pregnane bromide in the presence of K2CO3 in THF.
Scheme 1
Figure imgf000098_0001
Scheme 2
Figure imgf000099_0001
Example 1. Synthesis of SA and SA intermediates
Figure imgf000100_0001
Figure imgf000100_0002
Figure imgf000100_0003
Synthesis of compound SA-B. Compound SA (50 g, 184 mmol) and palladium black (2.5 g) in tetrahydrofuran (300 mL) and concentrated hydrobromic acid (1.0 mL) was hydrogenated with 10 atm hydrogen. After stirring at room temperature for 24h, the mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to afford the crude compound. Recrystallization from acetone gave compound SA-B (42.0 g, yield: 83.4%) as white powder.
1H NMR: (400 MHz, CDC13) δ 2.45-2.41 (m, 1H), 2.11-3.44 (m, 2H), 3.24 (s, 3H), 2.18-2.15 (m, 1H), 2.01-1.95 (m, 1H), 1.81-1.57 (m, 7H), 1.53-1.37 (m, 7H), 1.29-1.13 (m, 3H), 1.13-0.90 (m, 2H), 0.89 (s, 3H).
Synthesis of compound SA-C. A solution of SA-B (42.0 g, 153.06 mmol) in 600 mL anhydrous toluene was added dropwise to the MAD (459.19 mmol, 3.0 eq, freshly prepared) solution under N2 at -78°C. After the addition was completed, the reaction mixture was stirred for 1 hr at -78°C. Then 3.0 M MeMgBr (153.06 mL, 459.19 mmol) was slowly added dropwise to the above mixture under N2 at -78°C. Then the reaction mixture was stirred for 3 hr at this temperature. TLC (PE:EtOAc = 3: 1) showed the reaction was completed. Then saturated aqueous NH4C1 was slowly added dropwise to the above mixture at -78°C. After the addition was completed, the mixture was filtered, the filter cake was washed with EtOAc, the organic layer was washed with water and brine, dried over anhydrous Na2S04, filtered and concentrated, purified by flash Chromatography on silica gel (Petroleum ether/ ethyl acetate20: l to 3: 1) to afford compound SA- C (40.2 g, yield: 90.4%) as white powder. 1H NMR: (400 MHz, CDC13) δ 2.47-2.41 (m, 1H), 2.13-2.03 (m, 1H), 1.96-1.74 (m, 6H), 1.70-1.62 (m, 1H), 1.54-1.47 (m, 3H), 1.45-1.37 (m, 4H), 1.35-1.23 (m, 8H), 1.22-1.10 (m, 2H), 1.10-1.01 (m, 1H), 0.87 (s, 3H).
Synthesis of compound SA-D. To a solution of PPh3EtBr (204.52 g, 550.89 mmol) in THF (500 mL) was added a solution of t-BuOK (61.82 g, 550.89 mmol) in THF (300 mL) at 0 °C. After the addition was completed, the reaction mixture was stirred for 1 h 60 °C, then SA-C (40.0 g, 137.72 mmol) dissolved in THF (300 mL) was added dropwise at 60°C. The reaction mixture was heated to 60 °C for 18 h. The reaction mixture was cooled to room temperature and quenched with Sat. NH4CI, extracted with EtOAc (3*500 mL). The combined organic layers were washed with brine, dried and concentrated to give the crude product, which was purified by a flash column chromatography (Petroleum ether/ ethyl acetate50: l to 10: 1) to afford compound SA-D (38.4 g, yield:92%) as a white powder. 1H NMR: (400 MHz, CDC13) δ 5.17-5.06 (m, 1H), 2.42-2.30 (m, 1H), 2.27-2.13 (m, 2H), 1.89-1.80 (m, 3H), 1.76-1.61 (m, 6H), 1.55-1.43 (m, 4H), 1.42-1.34 (m, 3H), 1.33-1.26 (m, 6H), 1.22-1.05 (m, 5H), 0.87 (s, 3H).
Synthesis of compound SA-E. To a solution of SA-D (38.0 g, 125.62 mmol) in dry THF (800 mL) was added dropwise a solution of BH3.Me2S (126 mL, 1.26 mol) under ice-bath. After the addition was completed, the reaction mixture was stirred for 3 h at room temperature (14-20 °C). TLC (Petroleum ether/ ethyl acetate3: l) showed the reaction was completed. The mixture was cooled to 0 °C and 3.0 M aqueous NaOH solution (400 mL) followed by 30% aqueous H202 (30%, 300 mL) was added. The mixture was stirred for 2 h at room temperature (14-20 °C), and then filtered, extracted with EtOAc (3*500 mL). The combined organic layers were washed with saturated aqueous Na2S203, brine, dried over Na2S04 and concentrated in vacuum to give the crude product (43 g , crude) as colorless oil. The crude product was used in the next step without further purification.
Synthesis of compound SA-E To a solution of SA-E (43.0 g, 134.16 mmol) in dichloromethane (800 mL) at 0 °C and PCC (53.8 g, 268.32 mmol) was added portion wise. Then the reaction mixture was stirred at room temperature (16-22 °C) for 3 h. TLC (Petroleum ether/ ethyl acetate3: l) showed the reaction was completed, then the reaction mixture was filtered, washed with DCM. The organic phase was washed with saturated aqueous Na2S203, brine, dried over Na2S04 and concentrated in vacuum to give the crude product. The crude product was purified by a flash column chromatography (Petroleum ether/ ethyl acetate50: l to 8: 1) to afford compound SA-F (25.0 g, yield:62.5%, over two steps) as a white powder. 1H NMR (SA-F): (400 MHz, CDC13) δ 2.57-2.50 (m, 1H), 2.19-2.11 (m, 4H), 2.03-1.97 (m, 1H), 1.89-1.80 (m, 3H), 1.76-1.58 (m, 5H), 1.47-1.42 (m, 3H), 1.35-1.19 (m, 10H), 1.13-1.04 (m, 3H), 0.88-0.84 (m, 1H), 0.61 (s, 3H).
Synthesis of compound SA. To a solution of SA-F (10 g, 31.4 mmol) and aq. HBr (5 drops, 48% in water) in 200 mL of MeOH was added dropwise bromine (5.52 g, 34.54 mmol). The reaction mixture was stirred at 17 °C for 1.5 h. The resulting solution was quenched with saturated aqueous NaHC03 at 0°C and extracted with EtOAc (150 mLx2). The combined organic layers were dried and concentrated. The residue was purified by column chromatography on silica gel eluted with (PE: EA=15: 1 to 6: 1) to afford compound SA (9.5 g, yield: 76.14%) as a white solid. LC/MS: rt 5.4 mm ; m/z 379.0, 381.1, 396.1.
Example 2. Synthesis of compounds SA-1 and SA-2
Figure imgf000102_0001
SA SA-1 SA-2
To a suspension of K2C03 (50mg, 0.36mmol) in THF (5 mL) was added 1H- benzo[d][l,2,3]triazolel (80mg, 0.67mmol) and compound SA (100 mg, 0.25 mmol). The mixture was stirred at rt for 15h. The reaction mixture was poured in to 5 mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified with by reverse-phase prep-HPLC to afford the title compound as a white solid compound SA-1 (15 mg, 13.7% ) and compound SA-2 (10 mg, 9.2% ). Compound SA-l^HNMR (500MHz,CDCl3),5(ppm), 8.08(d,lH), 7.49 (t,lH), 7.38 (t,lH), 7.33 (d, 1H), 5.44 (1H, AB), 5.40 (1H, AB),. 2.70(t,lH ), 0.73(s, 3H). Compound SA- 2: 1HNMR (500MHz,CDCl3), 5(ppm), 7.88(d,2H), 7.39(d,2H), 5.53-5.52(m,2H), 2.65(t,lH), 0.75(s, 3H).
Example 3. Synthesis of compounds SA-3 and SA-4
Figure imgf000103_0001
To a suspension of K2CO3 (50mg, 0.36mmol) in THF (5 mL) was added lH-pyrazolo[4,3- b]pyridine ( 80mg, 0.67mmol) and compound SA ( 100 mg, 0.25 mmol). The mixture was stirred at rt for 15h. The reaction mixture was poured in to 5 mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified with by reverse-phase prep-HPLC to afford the title compound as a white solid compound SA-3 (17 mg, 15.5% ) and compound SA-4 (10 mg, 9.2% ). Compound SA-3: 1HNMR(400MHz,CDCl3),5(ppm), 8.59(d,lH), 8.28(s,lH), 7.59(d,lH),
7.29(dd,lH), 5.20 (1H, AB), 5.13 (1H, AB) 2.67(t,lH), 0.71 (s, 3H). Compound SA-4: 1HNMR (400MHz,CDCl3),5(ppm), 8.58(d,lH), 8.22 (s,lH), 8.04 (d,lH), 7.25(dd,lH ), 5.28 (1H, AB), 5.19 (1H, AB),. 2.67 (t,lH ) 0.72(s, 3H). Example 4. Synthesis of compounds SA-5 and SA-6
Figure imgf000104_0001
To a suspension of K2CO3 (50mg, 0.36mmol) in THF (5 niL) was added lH-indazole (80mg, 0.67mmol) and compound SA (100 mg, 0.25 mmol). The mixture was stirred at rt for 15h. The reaction mixture was poured in to 5 mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residure mixture was purified with by reverse-phase prep-HPLC to afford the title compound as a white solid of Compound S5 (29 mg, 24.7%) and compound S6 (12 mg, 11% ). Compound SA-5: 1HNMR(500MHz,CDCl3),5(ppm),8.05(s,lH), 7.76-7.74(d,lH), 7.41-7.37(t,lH), 7.22-7.16(d and t, 2H), 5.15 (1H, AB), 5.09(1H, AB), 2.66 (t,lH) 0.72( s, 3H). Compound SA-6: 1HNMR(500MHz,CDCl3),5(ppm), 7.93(s,lH), 7.70-7.66(m,2H), 7.28-7.26(m,lH), 7.08- 7.07(m,lH), 5.25 (1H, AB), 5.15(1H, AB,), 2.64 (t,lH ), 0.72 (s, 3H).
Figure imgf000104_0002
To a suspension of K2CO3 (55mg, 0.4mmol) in THF (5mL) was added 4,5,6,7-tetrahydro-3aH- indazole (33mg, 0.4mmol) and compound SA (79 mg, 0.2mmol). The mixture was stirred at RT for 15h. The residue mixture was poured in to 5mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue mixture was purified with by reverse-phase prep-HPLC to afford compound SA-7 as a white solid (9mg, 10%) and compound SA-8 as a white solid (12mg, 14%). Compound SA-7: 1HNMR (400 MHz, CDC13), δ (ppm) (400 MHz, CD30D) δ 7.74 (s, 1H), 5.34- 5.19 (m, 2H), 2.80-2.74 (m, 3H), 2.65-2.62 (m, 2H), 2.22-2.11 (m, 2H), 1.92-1.70 (m, 11H), 1.53- 1.39 (m, 9H), 1.30-1.15 (m, 8H), 0.92-0.84 (m, 1H), 0.73 (s, 3H). LC/MS: rt = 1.33 mm; m/z = 439.3 [M+H]. Compound SA-8: 1HNMR (400 MHz, CDC13), δ (ppm) (400 MHz, CD30D) δ 7.57 (s, 1H), 5.14-4.99 (m, 2H), 2.80-2.75 (m, 1H), 2.60-2.48 (m, 4H), 2.22-2.09 (m, 2H), 1.91-1.72 (m, 11H), 1.58-1.39 (m, 9H), 1.32-1.26 (m, 5H), 1.22-1.12 (m, 3H), 0.72 (s, 3H). LC/MS: rt = 1.37 mm; m/z = 439.3 [M+H].
Example 6. Synthesis of compounds SA-9 and SA-10
Figure imgf000105_0001
To a suspension of K2CO3 (25 mg, 0.18mmol) in THF (5 mL) was added 2H-pyrazolo[4,3- c]pyridine (23 mg, 0.18 mmol) and SA (36 mg, 0.09 mmol). The mixture was stirred at RT for 15h. The residual mixture was poured into 5 mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residual mixture was purified with by reverse-phase prep-HPLC to afford the title compound SA-9 as a white solid (9mg, 23%) and SA-10 as a white solid (5mg, 13%).
Compound SA-9 1HNMR (400 MHz, CDC13), δ (ppm), 9.14 (s, 1H), 8.45 (s, 1H), 8.19 (s, 1H), 7.13 (d, 1H), 5.18 (AB, 1H), 5.12 (AB, 1H), 2.67 (t, 1H) 0.72 (s, 3H). LC-MS: rt = 2.21 mm, m/z = 436.3 [M+H]+. Compound SA-10 1HNMR (400 MHz, CDCI3), δ (ppm), 9.19 (s, 1H), 8.28 (d, 1H), 8.15 (s, 1H), 7.53 (d, 1H), 5.29 (AB, 1H), 5.21 (AB, 1H), 2.68 (t, 1H 0.72 (s, 3H). LC-MS: rt = 2.16 mm, m/z = 436.3 [M+H]+
Example 7. Synthesis of compounds SA-11 and SA-12
Figure imgf000106_0001
SA SA-11 SA-12
To a suspension of K2CO3 (50 mg, 0.36mmol) in THF (5 mL) was added 2H-[l,2,3]triazolo[4,5- c]pyridine (46 mg, 0.36 mmol) and SA (72 mg, 0.18 mmol). The mixture was stirred at RT for 15h. The residual mixture was poured into 5 mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residual mixture was purified with by reverse-phase prep-HPLC to afford the title compound SA-11 as a white solid (23 mg, 29%) and SA-12 as a white solid (15mg, 19%). Compound SA-11 1HNMR (400 MHz, CDC13), δ (ppm), 9.46 (s, 1H), 8.47 (d, 1H), 7.76 (dd, 1H), 5.62 (AB, 1H), 5.56 (AB, 1H), 2.69 (t, 1H)0.76 (s, 3H). LC-MS: rt = 2.31 mm, m/z = 437.3
[M+H]+. Compound SA-12 1HNMR (400 MHz, CDC13), δ (ppm), 9.50 (s, 1H), 8.58 (d, 1H), 7.30 (d, 1H), 5.49 (AB, 1H), 5.41 (AB, 1H), 2.75 (t, 1H) 0.73 (s, 3H). LC-MS: rt = 2.24 mm, m/z = 437.3 [M+H]+.
Example 8. Synthesis of compounds SA-13, SA-14, and SA-15
Figure imgf000107_0001
SA SA-13 SA-14 SA-15
To a suspension of K2CO3 (50 mg, 0.36mmol) in THF (5 mL) was added 2H-[l,2,3]triazolo[4,5- b]pyridine (46 mg, 0.36 mmol) and SA (72 mg, 0.18 mmol). The mixture was stirred at RT for 15h. The residual mixture was poured into 5 mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residual mixture was purified with by reverse-phase prep-HPLC to afford the title compound SA-13 as a white solid (22mg, 28%) and SA-14 as a white solid (6mg, 7%) and SA-15 as a white solid (22mg, 28%). Compound SA-13 1HNMR (400 MHz, CDC13), δ (ppm), 8.78 (d, IH), 7.78 (d, IH), 7.46 (m, IH), 5.51 (AB, IH), 5.42 (AB, IH), 2.75 (t, IH) 0.72 (s, 3H). LC-MS: rt = 2.21 mm, m/z = 437.5 [M+H]+. Compound SA-14 1HNMR (400 MHz, CDC13), δ (ppm), 8.83 (s, IH), 8.26 (dd, IH), 7.38 (dd, IH), 5.60 (AB, IH), 5.54 (AB, IH), 2.69 (t, IH), 0.76 (s, 3H). LC-MS: rt = 2.29 mm, m/z = 437.5 [M+H]+. Compound SA-15 1HNMR (400 MHz, CDCI3), δ (ppm), 8.65 (dd, IH), 8.41 (dd, IH), 7.37 (dd, IH), 5.56 (AB, IH), 5.50 (AB, IH), 2.77 (t, IH) 0.75 (s, 3H). LC-MS: rt = 2.32 mm, m/z = 437.5 [M+H]+.
Example 9. Synthesis of compounds SA-16 and SA-17
Figure imgf000107_0002
To a suspension of K2CO3 (50mg, 0.36mmol) in THF (5 mL) was added 5-fluoro-lH-indazole (41mg, 0.3 mmol) and SA (100 mg, 0.252 mmol). The mixture was stirred at rt for 15h. The reaction mixture was poured into 5 mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified with by reverse-phase prep-HPLC to afford the title compound as a white solid SA-16 (8.2mg,7.2% ), SA-17 (1 lmg, 9.6% ) SA-16 :1HNMR (400 MHz, CDCI3), δ (ppm), 7.89 (s, 1H), 7.63(lH,dd), 7.25(1H,
dd),7.08(lH,td),5.22(ABlH),5.15(AB,lH), 2.64(1H, t)0.71 (s, 3H). SA-17 ^HNMR (400 MHz, CDCI3), δ (ppm), 8.00 (s, 1H), 7.37 (d, 1H ), 7.16 (d, 2H), 5.15(AB,1H),5.10(AB,1H), 2.63(1H, t)0.71 (s, 3H).
Example 10. Synthesis of compounds SA-18 and SA-19
Figure imgf000108_0001
To a suspension of K2CO3 (50 mg, 0.36mmol) in THF (6 mL) was added lH-pyrazolo[3,4- b]pyridine ( 36 mg, 0.3 mmol) and SA ( 100 mg, 0.252 mmol). The mixture was stirred at RT for 15h. The reaction mixture was poured into 5 mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified with by reverse-phase prep-HPLC to afford the title compound as a white solid SA-18 (30mg, 25.8% ), SA-19 (27mg, 24.5% ). SA-18: 1HNMR (400 MHz, CDCI3), δ (ppm), 8.69 (s, 1H), 8.05 (lH,d), 7.97(s,lH), 7.03 (lH,dd),5.30 (AB,1H),5.19 (ΑΒ,ΙΗ), 2.67 (1H, t)0.70 (s, 3H). LC-MS: rt=2.19 min,m/z = 436.1 (M+ + 1). SA-19: 1HNMR (400 MHz, CDCI3), δ (ppm) 8.50(lH,dd),8.08(s,lH),8.06 (lH,d),7.13(lH,dd), 5.32(AB,1H), 5.29(AB1H), 2.70(1H, t),0.73 (s, 3H). LC-MS: rt=2.26 min,m/z = 436.1 (M+ + 1).
Figure imgf000109_0001
To a suspension of K2CO3 (50 mg, 0.36mmol) in THF (5 niL) was added lH-pyrazolo[3,4- c]pyridine ( 36mg, 0.3mmol) and SA ( 100 mg,0.25 mmol). The mixture was stirred at rt for 24h. The reaction mixture was poured in to 5 mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residure was purified with by reverse-phase prep-HPLC to afford the title compound as a white solid, SA-20 (lOmg, 9.1% ), SA-21 (12mg, 10.9% ), SA-20: 1HNMR (400 MHz, CDCI3), δ (ppm), 9.26 (s, 1H), 8.17 (lH,d), 7.98(s,lH),7.53(lH,d), 5.29(AB,1H),
5.20(AB,1H), 2.67(1H, t)0.72 (s, 3H). LC-MS: rt=2.19min,m/z = 436.1 (M+ + 1). SA-21:
1HNMR (400 MHz, CDC13), δ (ppm), 8.80 (s, 1H), 8.33(lH,d), 8.10(s,lH), 7.65(lH,dd),
5.26(AB,1H), 5.24(AB,1H), 2.68(1H, t), 0.72 (s, 3H). LC-MS: rt=2.29 min,m/z = 436.2 (ivT + 1).
Example 12. Synthesis of compounds SA-22 and SA-23
Figure imgf000110_0001
To a suspension of K2CO3 (50 mg, 0.36mmol) in THF (5 mL) was added 6-fluoro-lH-indazole (41 mg, 0.3 mmol) and 9b (100 mg, 0.09 mmol). The mixture was stirred at rt for 15h. The reaction mixture was poured into 5 mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified with by reverse-phase prep-HPLC to afford the title compound as a white solid, SA- 22 (19mg, 16.7% ) and SA-23 (36mg, 31.5% ). SA-22 ^HNMR (400 MHz, CDC13), δ (ppm), 7.93 (s, IH), 7.63 (IH, dd), 7.27(lH,d), 6.90(lH,t), 5.20(AB,1H), 5.15(AB,1H), 2.20 (IH, t), 1.27(s,
3H), 0.70 (s, 3H). LC-MS: rt=2.42min,m/z = 453.1 (M+ + 1). SA-23 ^HNMR (400 MHz, CDC13), δ (ppm), 8.01 (s, IH), 7.68(1H, t), 6.93 (lH,t), 6.85 (lH,d), 5.10(AB,1H), 5.05(AB,1H), 2.63(1H, t), 0.71 (s, 3H). LC-MS:
Figure imgf000110_0002
= 453.1 (M* + 1).
Example 13. Synthesis of compound SA-24 and SA-25
Figure imgf000110_0003
To a solution of the crude reactant SA (249.5 mg, 0.629 mmol, theoretical amount) in anhydrous THF (5 mL) was added 5-methyl-lH-pyrazolo{3,4-c]pyridine (168 mg, 1.258 mmol) followed by potassium carbonate (174 mg, 1.258 mmol) and the solution was stirred at 25 °C overnight. Then the rection mixture was diluted with ethyl acetate (200 mL) and the resulting solution was washed with brine (2x100 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by reverse phase prep-HPLC to afford product SA-24 (5 mg, 0.0106 mmol, Yield=1.7% (2 steps)) and product SA-25 (6 mg, 0.0128mmol, Yield=2.1% (2 steps)) as white solid. Compound SA-24: 1H NMR (400 MHz, CDC13) 5(ppm): 9.19 (IH, s), 7.86 (IH, s), 7.32 (IH, s), 5.28 (IH, AB), 5.19 (IH, AB), 2.66 (IH, t), 2.61 (3H, s), 0.72 (3H, s). LCMS: rt = 2.31 mm, m/z = 450.2 [M+H]+ Compound SA-25: 1H NMR (400 MHz, CDC13) 5(ppm): 8.67 (IH, s), 8.00 (IH, s), 7.45 (IH, s), 5.22 (IH, AB), 5.21 (IH, AB), 2.67 (IH, t), 2.66 (3H, s) 0.72 (3H, s). LCMS: rt = 2.38 mm, m/z = 450.2 [M+H]+
Example 14. Synthesis of SA-26 and SA-27
Figure imgf000111_0001
To a solution of the crude reactant SA (249.5 mg, 0.629 mmol, theoretical amount) in anhydrous THF (5 mL) was added 6-chloro-lH-pyrazolo[4,3-b]pyridine (192 mg, 1.256 mmol) followed by potassium carbonate (174 mg, 1.256 mmol)and this solution was stirred at 25 °C overnight. Then the reaction mixture was diluted with ethyl acetate (200 mL) and thhe resulting solution was washed with brine (2x 100 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by reverse phase prep-HPLC to afford product SA-26 (10 mg, 0.0213 mmol, Yield=3.4% (2 steps)) and product SA-27 (14 mg, 0.0298 mmol, Yield=4.8% (2 steps)) as white solid. Compound SA-26: 1H NMR (400 MHz, CDC13) 5(ppm): 8.49 (IH, d), 8.20 (IH, s), 8.01 (IH, d), 5.26 (IH, AB), 5.17 (IH, AB), 2.66 (IH, t),0.72 (3H,s). LCMS: rt = 2.47 mm, m/z = 470.1 [M+H]+ Compound SA-27: 1H NMR (400 MHz, CDC13) 5(ppm): 8.52 (IH, s), 8.24 (IH, d), 7.57 (IH, dd), 5.16 (IH, AB), 5.09 (IH, AB), 2.68 (IH, t), 0.72 (3H, s). LCMS: rt = 2.50 mm, m/z = 470.1 [M+H]+
Example 15. Synthesis of compound SA-28 and SA-29
Figure imgf000112_0001
To a solution of the crude reactant SA (249.5 mg, 0.629 mmol, theoretical amount) in anhydrous THF (5 mL) was added lH-pyrazolo[3,4-b]pyrazine (151 mg, 1.256 mmol) followed by potassium carbonate (174 mg, 1.256 mmol) and the resulting solution was stirred at 25 °C overnight. Then the solution was diluted with ethyl acetate (200 mL) and the resulting solution was washed with brine (2x 100 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by reverse phase prep-HPLC to afford product SA-28 (17.3 mg, 0.0396 mmol, Yield=6.3% (2 steps)) and product SA-29 (67.5 mg, 0.155 mmol, Yield=25% (2 steps)) as white solid. Compound SA-28: 1H NMR (400 MHz, CDCI3) 5(ppm): 8.64 (IH, d), 8.56 (IH, d), 8.27 (IH, s), 5.35 (IH, AB), 5.23 (IH, AB), 2.70 (IH, t0.72 (3H, s). LCMS: rt = 2.22 mm, m/z = 437.2 [M+H]+ Compound SA-29 : 1H NMR (400 MHz, CDCI3) 5(ppm): 8.59 (IH, d), 8.44 (IH, d), 8.34 (IH, s), 5.34 (IH, AB), 5.28 (IH, AB), 2.71 (IH, t), 0.73 (3H, s). LCMS: rt = 2.37 mm, m/z = 437.2 [M+H]+
Example 16. Synthesis of compound SA-30 and SA-31
Figure imgf000113_0001
To a solution of the crude reactant SA (249.5 mg, 0.629 mmol, theoretical amount) in anhydrous THF (5 mL) was added 5-chloro-lH-pyrazolo[3,4-c]pyridine (192 mg, 1.256 mmol) followed by potassium carbonate (174 mg, 1.256 mmol)and the resulting solution was stirred at 25 °C overnight. Then the solution was diluted with ethyl acetate (200 mL)and the resulting solution was washed with brine (2x100 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by reverse phase prep-HPLC to afford fraction 1 and 2. Fraction 1 was pure product SA-30 (10.4 mg, 0.0221 mmol, Yield=3.5% (2 steps)) as white solid. Fraction 2 was not pure and had to be purified by silica gel chromatography (eluant: petroleum ether/ ethyl acetate =2:3) to afford pure product SA-31 (12.2 mg, 0.026 mmol, Yield=4.1% (2 steps)) as a white solid. Compound SA-30: 1H NMR (400 MHz, CDC13) 5(ppm): 9.06 (IH, s), 7.95 (IH, s), 7.59 (IH, d), 5.31 (IH, AB), 5.22 (IH, AB), 2.68 (IH, t), 0.72 (3H, s). LCMS: rt = 2.42 mm, m/z = 470.1 [M+H]+ Compound SA-31: 1H NMR (400 MHz, CDC13) 5(ppm): 8.55 (IH, s), 8.05 (IH, d), 7.67 (IH, d), 5.24 (IH, AB), 5.22 (IH, AB), 2.68 (IH, t),0.71 (3H, s). LCMS: rt = 2.47 mm, m/z = 470.1 [M+H]+.
Example 17. Synthesis of SA-32, SA-33, and SA-34
Figure imgf000114_0001
Synthesis of lH-pyrazolo[4,3-d]pyrimidine
Figure imgf000114_0002
To a solution of the reactant (109 mg, 1.0 mmol) in toluene (1.5 mL) was added acetic anhydride (0.2 mL, 2.10 mmol), acetic acid (0.2 mL, 3.5 mmol) followed by potassium acetate (196 mg, 2.0 mmol). The mixture was heated to reflux and isopentyl nitrire (0.168 mL, 1.25 mmol) in toluene (0.3 mL) was added. After 2 hours, the mixture was poured into water (20 mL). The solution was made basic by addition of Na2C03 solid. The solution was extracted with ethyl acetate (2x50 mL) and the combined organic extracts were washed with brine (50 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (eluant:
petroleum ether: ethyl acetate = 1 :2) to afford product product (32 mg, 0.266 mmol, Yield=27%) as yellow solid. 1H NMR (400 MHz, d6-DMSO) 5(ppm): 13.91 (1H, br), 9.35 (1H, s), 9.04 (1H, s), 8.45 (1H, s). Synthesis of SA-32, SA-33, and SA-34. To a solution of the crude reactant (249.5 mg, 0.629 mmol, theoretical amount) in anhydrous THF (5 mL) was added lH-pyrazolo[4,3-d]pyrimidine (151 mg, 1.256 mmol) followed by potassium carbonate (174 mg, 1.256 mmol) ans the resulting solution was stirred at 25 °C overnight. Then the solution was diluted with ethyl acetate (200 mL) and the resulting solution was washed with brine (2x100 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by reverse phase prep-HPLC to afford fraction 1, 2, and 3. Fraction 1 was not pure and had to be re-purified by silica gel chromatography (eluant: ethyl acetate) to afford product SA-32 (10.0 mg, 0.0229 mmol, Yield=3.6% (2 steps)). Fraction was pure product SA-33 (56.8 mg, 0.130 mmol, Yield=21% (2 steps)). Fraction 3 was pure by-product SA-34 (7.3 mg, 0.0167 mmol, Yield=2.7% (2 steps)). All products was a white solid. Compound SA-32: 1H NMR (400 MHz, CDC13) 5(ppm): 9.43 (IH, s), 9.06 (IH, s), 8.22 (IH, s), 5.35 (IH, AB), 5.26 (IH, AB), 2.69 (IH, t), 0.73 (3H, s). LCMS: rt = 2.10 mm, m/z = 437.1 [M+H]+ Compound SA-33: 1H NMR (500 MHz, CDC13) 5(ppm): 9.14 (IH, s), 8.96 (IH, s), 8.30 (IH, s), 5.29 (IH, AB), 5.22 (IH, AB), 2.71 (IH, t), 0.72 (3H, s). LCMS: rt = 2.18 mm, m/z = 437.1 [M+H]+ Compound SA-34: 1H NMR (500 MHz, CDCI3) 5(ppm): 9.15 (IH, s), 8.98 (IH, s), 8.32 (IH, s), 5.35 (IH, AB), 5.19 (IH, AB), 2.89 (IH, dd), 0.99 (3H, s). LCMS: rt = 2.24 mm, m/z = 437.1 [M+H]+
Example 18. Synthesis of compound SA-35 and SA-36
Figure imgf000115_0001
To a solution of the crude reactant SA (249.5 mg, 0.629 mmol, theoretical amount) in anhydrous THF (5 mL) was added lH-pyrazolo[3,4-d]pyrimidine (151 mg, 1.256 mmol) followed by potassium carbonate (174 mg, 1.256 mmol) and the resulting solution was stirred at 25 °C overnight. Then the solution was diluted with ethyl acetate (200 mL) and the resulting solution was washed with brine (2x100 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by reverse phase prep-HPLC to afford product SA-35 (21.7 mg, 0.0497 mmol, Yield=7.9% (2 steps)) and product SA-36 (59.4 mg, 0.136 mmol, Yield=22% (2 steps)) as white solid. Compound SA-35: 1H NMR (500 MHz, CDCI3) 5(ppm): 9.37 (IH, s), 9.11 (IH, s), 8.17 (IH, s), 5.35 (IH, AB), 5.22 (IH, AB), 2.71 (lH, tl .28 (3H, s), 0.71 (3H, s). LCMS: rt = 2.04 mm, m/z = 437.1 [M+H]+ Compound SA-36: 1H NMR (500 MHz, CDCI3) 5(ppm): 9.21 (IH, s), 9.00 (IH, s), 8.20 (IH, s), 5.32 (IH, AB), 5.27 (IH, AB), 2.71 (IH, t), 0.73 (3H, s).
LCMS: rt = 2.20 mm, m/z = 437.1 [M+H]+
Example 19. Synthesis of compound SA-37 and SA-38
Figure imgf000116_0001
To a suspension of SA (100 mg, 0.25 mmol) in THF (25 mL) was added 2H-indazole-5- carbonitrile (107 mg, 0.75 mmol) and K2CO3 (103 mg, 0.75mmol). The mixture was stirred at 35°C for 15h. Then the reaction mixture was was poured into ice-cold water and extracted with EtOAc (100 mLx3), washed with brine (100mLx3), dried (MgS04), filtered, and evaporated in vacuo, then purified with by reverse-phase prep-HPLC to afford SA-37 as a white solid (21 mg, 17% yield) and SA-38 as a white solid (28 mg, 23% yield). SA-37: 1H NMR (500 MHz, CDCI3), δ (ppm), 8.14 (s, IH), 8.11 (s, IH), 7.75 (dd, IH), 7.39 (d, IH), 5.28 (ΙΗ,ΑΒ), 5.20 (ΙΗ,ΑΒ), 2.67 (ΐ,ΙΗ), 1.27 (s, 3H), 0.71 (s, 3H). LCMS: Rt = 2.340 mm, MS (ESI) m/z: 460 [M+H] +. SA-38: 1H NMR (500 MHz, CDC13), δ (ppm), 8.14 (s, 2H), 7.57 (d, IH), 7.28 (d, IH), 5.21 (ΙΗ,ΑΒ), 5.15 (ΙΗ,ΑΒ), 2.67 (ΐ,ΙΗ), 0.71 (s, 3H). LCMS: Rt = 2.372 mm, MS (ESI) m/z: 460 [M+H] +.
Example 20. Synthesis of compound SA-39 and SA-40 and SA-41
Figure imgf000117_0001
SA-39 SA-40 SA-41
To a suspension of K2CO3 (55 mg, 0.4 mmol) in THF (5 niL) was added 5-chloro-2H- benzo[d][l,2,3]triazole (61mg, 0.4mmol) and Compound SA (85 mg, 0.2mmol). The mixture was stirred at RT for 15h then the residue mixture was poured into 5 rriL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue mixture was purified by reverse-phase prep-HPLC to afford SA-39 as a white solid (8 mg, 9% ) and SA-40 as a white solid (7 mg, 8%) and SA-41 as a white solid (4 mg, 5%). Compound SA-39: 1H NMR (400 MHz, CDC13) δ (ppm): 8.06 (d, IH), 7.45 (m, 2H5.44 (AB, IH), 5.37 (AB, IH), 2.72 (t, 1H),0.72 (s, 3H). LC-MS: rt = 2.47 mm, m/z = 470.4 [M+H]+ Compound SA-40: 1H NMR (400 MHz, CDC13) δ (ppm): 8.00 (s IH), 7.46 (d,
IH), 7.29 (d,lH), 5.43 (AB, IH), 5.34 (AB, IH), 2.73 (t, 1H),0.73 (s, 3H). LC-MS: rt = 2.48 mm, m/z = 470.4 [M+H]+ Compound SA-41: 1H NMR (500 MHz, CDC13) δ (ppm): 7.87 (d, IH), 7.82 (dd, IH), 7.35 (dd, IH), 5.53 (AB, IH), 5.48 (AB, IH), 2.66 (t, 1H),0.74 (s, 3H). LC-MS: rt = 2.61 mm, m/z = 470.1 [M+H]+.
Example 21. Synthesis of compound SA-42 and SA-43 and SA-44
Figure imgf000117_0002
SA-43 SA-44 To a suspension of K2CO3 (83 mg, 0.6 mmol) in THF (5 mL) was added 5-methyl-2H- benzo[d][l,2,3]triazole (80 mg, 0.6 mmol) and Compound SA (118 mg, 0.3 mmol). The mixture was stirred at RT for 15h then the residue mixture was poured into 5 mL H20 and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue mixture was purified by reverse-phase prep-HPLC to afford SA-42 as a white solid (19 mg, 14% ) and SA-43 as a white solid (13 mg, 10% ) and SA- 44 as a white solid (5 mg, 5% ). Compound SA-42: 1H NMR (500 MHz, CDC13) δ (ppm): 7.93 (d, 1H), 7.19 (dd, 1H), 7.08 (s, 1H), 5.38 (AB, 1H), 5.33 (AB, 1H), 2.70 (t, 1H), 2.50 (s, 3H)0.73 (s, 3H). LC-MS: rt = 2.39 mm, m/z = 450.4 [M+H]+ Compound SA-43: 1H NMR (500 MHz, CDC13) δ (ppm): 7.82 (s, 1H), 7.31 (dd,lH), 7.21 (d, 1H), 5.38 (AB, 1H), 5.35 (AB, 1H), 2.68 (t, 1H), 2.51 (s, 3H), 0.73 (s, 3H). LC-MS: rt = 2.39 mm, m/z = 450.4 [M+H]+ Compound SA-44: 1H NMR (500 MHz, CDC13) δ (ppm): 7.75 (d, 1H), 7.60(s, 1H), 7.22 (d, 1H), 5.48 (AB, 1H), 5.46 (AB, 1H), 2.63 (t, 1H), 0.74 (s, 3H). LC-MS: rt = 2.51 mm, m/z = 450.4 [M+H],
Example 22. Synthesis of compound SA-45 and SA-46
Figure imgf000118_0001
To a suspension of K2CO3 (55 mg, 0.4 mmol) in THF (5 mL) was added 3-methyl-3H-indazole (53 mg, 0.4 mmol) and Compound SA (85 mg, 0.2 mmol). The mixture was stirred at RT for 15h, then the residue mixture was poured into 5 mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue mixture was purified by reverse-phase prep-HPLC to afford SA-45 as a white solid (23 mg, 26% ) and SA-46 as a white solid (5 mg, 6% ). Compound SA-45: 1H NMR (500 MHz, CDC13) δ (ppm): 7.66 (d, 1H), 7.35 (td, 1H), 7.26 (m, 1H), 7.02 (m, 1H), 5.05 (s, 2H), 2.63 (t, IH), 2.57 (s, 3H 0.72 (s, 3H). LC-MS: rt = 2.51 mm, m/z = 449.2 [M+Hf Compound SA-46: 1H NMR (500 MHz, CDC13) δ (ppm): 7.60 (d, IH), 7.56 (d, IH), 7.24 (dd, IH), 7.02 (t, IH), 5.16 (s, 2H), 2.66 (t, IH), 2.50 (s, 3H), 0.73 (s, 3H). LC-MS: rt = 2.45 mm, m/z = 449.3
[M+H]+
Example 23. Synthesis of compound SA-47, SA-48 and SA-49
Figure imgf000119_0001
SA-48 SA-49
To a suspension of K2CO3 (83 mg, 0.6 mmol) in THF (5 mL) was added 5-methoxy-2H- benzo[d][l,2,3]triazole (89 mg, 0.6 mmol) and Compound SA (118 mg, 0.3 mmol). The mixture was stirred at RT for 15h. The residue mixture was poured into 5 mL H20 and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue mixture was purified by reverse-phase prep-HPLC to afford SA-47 as a white solid (34 mg, 24% ) and SA-48 as a white solid (25 mg, 18% ) and SA- 49 as a white solid (22mg, 16% ). Compound SA-47: 1H NMR (400 MHz, CDC13) δ (ppm): 7.88 (d, IH), 6.98 (dd, IH), 6.58 (d, IH), 5.34 (AB, IH), 5.28 (AB, IH), 3.82 (s, 3H), 2.67 (t, 1H0.69 (s, 3H). LC-MS: rt = 2.39 mm, m/z = 466.2 [M+H]+ Compound SA-48: 1H NMR (400 MHz, CDC13) δ (ppm): 7.38 (d, IH), 7.21 (d, IH), 7.15 (dd, IH), 5.39 (AB, IH), 5.34 (AB, IH), 3.89 (s, 3H), 2.69 (t, IH), 0.72 (s, 3H). LC-MS: rt = 2.39 mm, m/z = 466.2 [M+H]+ Compound SA-49: 1H NMR (400 MHz, CDC13) δ (ppm): 7.73 (dd, IH), 7.08-7.05 (m, 2H), 5.47 (AB, IH), 5.42 (AB, IH), 3.87 (s, 3H), 2.63 (t, IH), 0.74 (s, 3H). LC-MS: rt = 2.49 mm, m/z = 466.2 [M+H]+ Example 24. Synthesis of compound SA-50 and SA-51
Figure imgf000120_0001
SA-51
To a solution of compound SA (100 mg, 0.252 mmol) and K2CO3 (75.6 mg, 0.504 mmol) in 10 mL dry DMF was added 5,6-difluoro-lH-benzo[d][l,2,3]triazole (78.0 mg, 0.504 mmol) under N2 at room temperature (18-22° C). The reaction mixture was stirred for 18 hr at this temperature. The reaction mixture was poured to water and extracted with EtOAc (30 mLx2). The combined organic layers were washed with brine, dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by prep-HPLC (HC1/H20/CH3CN) to give the target compound SA-50 (25.0 mg, yield: 14%) and SA-51 (87.9 mg, yield:49%) as off-white solid. 1H NMR (SA-50): (400 MHz, CDC13) δ 7.62-7.58 (m, 2H), 5.53-5.43 (m, 2H), 2.68-2.64 (m, 1H), 2.24-2.12 (m, 2H), 1.89-1.75 (m, 6H), 1.50-1.40 (m, 7H), 1.37-1.28 (m, 9H), 1.19-1.10 (m, 3H), 0.74 (s, 3H). LC-MS: rt = 1.36 mm, m/z = 472.2 [M+H]+. 1H NMR (SA-51): (400 MHz, CDC13) δ 7.85-7.81 (m, 1H), 7.15-7.11 (m, 1H), 5.45-5.32 (m, 2H), 2.75-2.70 (m, 1H), 2.24-2.13 (m, 2H), 1.89-1.75 (m, 6H), 1.69-1.57 (m, 3H), 1.48-1.25 (m, 13H), 1.21-1.10 (m, 3H), 0.73 (s, 3H). LC-MS: rt = 1.42 mm, m/z = 472.3 [M+H]+
Synthesis of compound A3.
Figure imgf000120_0002
A3
A1 A2
Synthesis of compound A2. To a solution of compound Al (2.0 g, 11.6 mmol) and Zn powder (7.6 g, 116 mmol) in MeOH (40 mL) was added AcOH (10 mL) slowly at 0°C. After 5 min, the solution was stirred at room temperature for 1 h. TLC (PE/ EtOAc = 2/1) showed the reaction was complete. The resulting reaction mixture was filtered through a celite pad and washed with MeOH (120 mL). The filtrate was concentrated in vacuum to give the crude product A2 (1.7 g, crude) as a brown solid. The crude product was used for the next step without further purification. Synthesis of compound A3. To a solution of compound A2 (1.7 g, 11.6 mmol, crude) in
AcOH/H-O (22 mL, 1/10) was added NaN02 (1.2 g, 17.4 mmol). The resulting solution was stirred at room temperature for 1 h. TLC (DCM/MeOH = 15/1) showed the reaction was complete. EtOAc (100 mL) was added and the organic layer was separated. The organic layer was washed with aqueous NaHCC (30 mL), 1 N HC1 (30 mL) and brine. The layer was concentrated in vacuum and the residue was purified by silica gel column eluted with DCM/MeOH = 100/1 to give A3 (1.0 g, 56.2%) as a brown solid. 1H NMR: (400 MHz, DMSO-i/6) δ 16.06 (br, 1H), 7.98- 7.97 (m, 1H), 7.47-7.37 (m, 2H).
Example 26. Synthesis of compound SA-54
Figure imgf000121_0001
To a suspension of K2CO3 (50 mg, 0.36 mmol) in THF (6 mL) was added 2H-indazol-3-ol (36 mg 0.3 mmol) and SA ( 100 mg, 0.268 mmol). The mixture was stirred at RT for 15h. Then the reaction mixture was poured into 5 mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified with by reverse-phase prep-HPLC to afford the title compound as a white solid SA-54 (5mg, 4.42% ), SA-54: 1H NMR (400 MHz, CDC13) δ (ppm): 8.87 (s, 1H), 7.76 (d, 1H), 7.38 (t, 1H), 7.30 (d, 1H), 7.12 (t, 1H), 5.00 (AB, 1H), 4.85 (AB, 1H), 2.77 (t, 1H), 0.70 (s, 3H). LC-MS: rt=2.42min, m/z = 451.1 (M+ + 1) Example 27. Synthesis of compound SA-55
Figure imgf000122_0001
To a suspension of K2CO3 (25 mg, 0.18 mmol) in THF (5 mL) was added 3-chloro-lH-indazole (20 mg, 0.13 mmol) and SA (36 mg, 0.09 mmol). The mixture was stirred at rt for 15h. Then the reaction mixture was poured into 5 mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified with by reverse-phase prep-HPLC to afford the title compound as a white solid (32 mg, 85.6%). 1H NMR (500 MHz, CDC13) δ (ppm): 7.68 (d, IH), 7.42 (t, IH) 7.21 (t,lH) 7.16 (d, IH) ,5.08 (AB, IH), 5.07(AB, IH), 2.63 (IH, t), 0.71(s, 3H). LC- MS: rt=2.59min, m/z = 469.3 (M+ + 1).
Example 28. Synthesis of compound SA-56, SA-57, and SA-58
Figure imgf000122_0002
To a suspension of K2CO3 (25 mg, 0.18 mmol) in THF (5 mL) was added 6-chloro-lH- [l,2,3]triazolo[4,5-b]pyridine (20 mg, 0.23 mmol) and SA (100 mg, 0.252 mmol). The mixture was stirred at rt for 15h. Then the reaction mixture was poured into 5 mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified with by reverse-phase prep-HPLC to afford the title compound as a white solid SA-56 (6.6 mg, 5.6%), SA-57 (8 mg, 6.7%), SA-58 (8.1 mg, 6.8%). SA-56 1H NMR (400 MHz, CDC13) δ (ppm): 8.68 (d, IH), 7.77 (d, IH) 5.50 (AB, IH), 5.37 (AB, IH), 2.75 (IH, t), 0.72 (s, 3H). LC-MS:
Figure imgf000123_0001
= 471.4 (M* + 1). SA-57 1H NMR (400 MHz, CDC13) δ (ppm): 8.74(d,lH), 8.23(d,lH) 5.55 (AB,1H),5.53
(ΑΒ,ΙΗ,), 2.68(lH, t), 0.75 (s, 3H). LC-MS:
Figure imgf000123_0002
= 471.4 (M+ + 1). SA-58 1H NMR (400 MHz, CDCI3) δ (ppm): 8.58 (d, IH), 8.37 (d, IH) 5.51 (AB, IH), 5.50 (AB, IH), 2.75 (IH, t), 0.74 (s, 3H). LC-MS:
Figure imgf000123_0003
= 471.4 (M+ + 1).
Example 30. Synthesis of compound SA-61, SA-62 and SA-63
Figure imgf000123_0004
To a suspension of K2CO3 (50 mg, 0.36mmol) in THF (5 mL) was added 5-fluoro-2H- benzo[d][l,2,3]triazole (49 mg, 0.36 mmol) and 9b (72 mg, 0.18 mmol). The mixture was stirred at RT for 15h. The residual mixture was poured in to 5 mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residual mixture was purified with by reverse-phase prep-HPLC to afford the title compound SA-61 as a white solid (7 mg, 8.6 %) and SA-62 as a white solid (7 mg, 8.6 %) and SA-63 as a white solid (3 mg, 3.7%). Compound SA-61 1H NMR (500 MHz, CDCI3), δ (ppm), 7.70 (dd, IH), 7.30-7.26 (m, 2H), 5.44 (AB, IH), 5.38 (AB, IH), 2.71 (t, IH), 0.72 (s, 3H). LC-MS: rt = 2.34 mm, m/z = 454.1 [M+H]+ Compound SA-62 1H NMR (500 MHz, CDC13), δ (ppm), 8.04 (dd, IH), 7.15 (td, IH), 6.98 (dd, IH), 5.40 (AB, IH), 5.34 (AB, IH), 2.72 (t, IH), 0.73 (s, 3H). LC-MS: rt = 2.33 mm, m/z = 454.4 [M+H]+ Compound SA-63 1H NMR (500 MHz, CDCI3), δ (ppm), 7.87 (dd, IH), 7.47 (dd, IH), 7.20 (td, IH), 5.52 (AB, IH), 5.48 (AB, IH), 2.66 (t, 1H0.75 (s, 3H). LC-MS: rt = 2.41 mm, m/z = 454.3 [M+H]+
Example 31. Synthesis of compound SA-64, SA-65 and SA-66
Figure imgf000124_0001
To a suspension of K2CO3 (50 mg, 0.36mmol) in THF (5 mL) was added 7-fluoro-lH- benzo[d][l,2,3]triazole (50 mg, 0.36 mmol) and SA (72 mg, 0.18 mmol). The mixture was stirred at RT for 15h. The residual mixture was poured in to 5 mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residual mixture was purified with by reverse-phase prep-HPLC to afford the title compound SA-64 as a white solid (8mg, 9.8%) and SA-65 as a white solid (9mg, 11%) and SA-66 as a white solid (17mg, 20.8%). Compound SA-64 1H NMR (400 MHz, CDCI3), δ (ppm), 7.43 (td, IH), 7.11 (d, IH), 7.04 (dd, IH), 5.45 (AB, IH), 5.40 (AB, IH), 2.71 (t, IH), 0.73 (s, 3H). LC-MS: rt = 2.33 mm, m/z = 454.3 [M+H]+ Compound SA-65 1H NMR (400 MHz, CDCI3), δ (ppm), 7.86 (d, IH), 7.28 (td, IH), 7.13 (dd, IH), 5.54 (s, 2H), 2.71 (t, IH), 1.28 (s, 3H), 0.73 (s, 3H). LC-MS: rt = 2.39 mm, m/z = 454.1 [M+H]+ Compound SA-66 1H NMR (500 MHz,
CDCI3), δ (ppm), 7.67 (d, IH), 7.35-7.26 (m, IH), 7.04 (dd, IH), 5.57 (AB, IH), 5.52 (AB, IH), 2.67 (t, IH), 0.75 (s, 3H). LC-MS: rt = 2.45 mm, m/z = 454.1 [M+H]+ Example 32. Synthesis of compound SA-67 and SA-69
Figure imgf000125_0001
SA SA-67 SA-69
To a suspension of K2CO3 (50 mg, 0.36mmol) in THF (5 mL) was added 7-methyl-lH- benzo[d][l,2,3]triazole (48 mg, 0.36 mmol) and SA (72 mg, 0.18 mmol). The mixture was stirred at RT for 15h. The residual mixture was poured in to 5 mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residual mixture was purified with by reverse-phase prep-HPLC to afford the title compound SA-67 as a white solid (26mg, 32%) and SA-69 as a white solid (18mg, 22%) and a white solid byproduct (3mg, 3.7%). Compound SA-67 1H NMR (500 MHz, CDC13), δ (ppm), 7.36 (t, 1H), 7.14-7.12 (m, 2H), 5.39 (s, 2H), 2.81 (s, 3H), 2.68 (t, 1H), 0.73 (s, 3H). LC-MS: rt = 2.38 mm, m/z = 450.1 [M+H]+ Compound SA-69 1H NMR (500 MHz, CDC13), δ (ppm), 7.68 (d, 1H), 7.28 (dd, 1H,), 7.13 (d, 1H), 5.53 (AB, 1H), 5.49 (AB, 1H), 2.65 (t, 1H), 2.65 (s, 3H), 0.75 (s, 3H). LC-MS: rt = 2.49 mm, m/z = 450.1 [M+H]+
Figure imgf000125_0002
To a suspension of K2CO3 (100 mg, 0.72mmol) in THF (5 niL) was added 6-(trifluoromethoxy)- lH-benzo[d][l,2,3]triazole (146 mg, 0.72 mmol) and SA (144 mg, 0.36 mmol). The mixture was stirred at RT for 15h. The residual mixture was poured in to 5 mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residual mixture was purified with by reverse-phase prep-HPLC to afford the title compound SA-70 as a white solid (47mg, 25%) and SA-71 as a white solid (37mg, 19.8%) and SA-72 as a white solid (60mg, 32%). Compound SA-70 1H NMR (400 MHz, CDC13), δ (ppm), 7.94 (s, 1H), 7.40-7.34 (m, 2H), 5.48 (AB, 1H), 5.40 (AB, 1H), 2.73 (t, 1H0.72 (s, 3H). LC-MS: rt = 2.49 mm, m/z = 520.0 [M+H]+ Compound SA-71 1H NMR (500 MHz, CDC13), δ (ppm), 8.09 (d, 1H), 7.26 (d, 1H), 7.19 (s, 1H), 5.45 (AB, 1H), 5.38 (AB, 1H), 2.73 (t, 1H), 0.73 (s, 3H). LC-MS: rt = 2.49 mm, m/z = 520.0 [M+H]+ Compound SA-72 1H NMR (500 MHz, CDCI3), δ (ppm), 7.91 (d, 1H), 7.72 (s, 1H), 7.28 (d, 1H), 5.55 (AB, 1H), 5.50 (AB, 1H), 2.67 (t, 1H), 0.75 (s, 3H). LC-MS: rt = 2.59 mm, m/z = 520.0 [M+H]+.
Example 34. Synthesis of compound SA-73, SA-74 and SA-75
Figure imgf000126_0001
To a suspension of K2CO3 (67 mg, 0.50 mmol) in THF (5 mL) was added 7-methoxy-lH- benzo[d][l,2,3]triazole (74.6 mg, 0.50 mmol) and compound SA (100 mg, 0.25 mmol). After stirring at room temperature for 15h, the reaction mixture was poured into 5mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by reverse-phase prep-HPLC to afford SA-73 as a white solid ( 12.8 mg, 0.027mmol, 11.0%), SA-74 as a white solid ( 19.2 mg, 0.041mmol, 16.5%) and SA-75 as a white solid ( 9.1 mg, 0.020mmol, 7.8%). SA-73: 1H NMR (500 MHz, CDC13) δ (ppm): 7.63 (IH, d), 7.23 (IH, t), 6.76 (IH, d), 5.59 (IH, AB), 5.58 (IH, AB), 3.89 (IH , s), 2.67 (IH , t0.73 (3H, s). LCMS: Rt = 2.44 mm. m/z = 466.2 [M+H]+. SA-74: 1H NMR (500 MHz, CDC13) δ (ppm): 7.38 (IH, t), 6.87 (IH, d), 6.70 (IH, d), 5.37 (2H, s), 4.12 (3H , s), 2.68 (IH , t0.73 (3H, s). LCMS: Rt = 2.41 mm. m/z = 466.2
[M+H]+. SA-75: 1H NMR (500 MHz, CDC13) δ (ppm): 7.44 (IH, d), 7.30 (IH, t), 6.64 (IH, d), 5.50 (2H, s), 4.03 (3H , s), 2.64 (IH , t), 0.74 (3H, s). LCMS: Rt = 2.50 mm. m/z = 466.1
[M+H]+.
Figure imgf000127_0001
Synthesis of mpound A3
Figure imgf000127_0002
Synthesis of compound A2. To a solution of compound Al (2.0 g, 11.6 mmol) and Zn powder (7.6 g, 116 mmol) in MeOH (40 mL) was added AcOH (10 mL) slowly at 0°C. After 5 min, the solution was stirred at room temperature for 1 h. TLC (PE/ EtOAc = 2/1) showed the reaction was complete. The resulting reaction mixture was filtered through a celite pad and washed with MeOH (120 mL). The filtrate was concentrated in vacuum to give the crude product A2 (1.7 g, crude) as a brown solid. The crude product was used for the next step without further purification.
Synthesis of compound A3. To a solution of compound A2 (1.7 g, 11.6 mmol, crude) in AcOH/H20 (22 mL, 1/10) was added NaN02 (1.2 g, 17.4 mmol). The resulting solution was stirred at room temperature for 1 h. TLC (DCM/MeOH = 15/1) showed the reaction was complete. EtOAc (100 mL) was added and the organic layer was separated. The organic layer was washed with aqueous NaHCC^ (30 mL), 1 N HC1 (30 mL) and brine. The layer was concentrated in vacuum and the residue was purified by silica gel column eluted with DCM/MeOH = 100/1 to give A3 (1.0 g, 56.2%) as a brown solid. 1H NMR: (400 MHz, DMSO-i/6) δ 16.06 (br, 1H), 7.98- 7.97 (m, 1H), 7.47-7.37 (m, 2H). Synthesis of compound SA-76, SA-77 and SA-78. To a suspension of K2CO3 (67 mg, 0.50 mmol) in THF (5 mL) was added 7-chloro-lH-benzo[d][l,2,3]triazole (76.8 mg, 0.50 mmol) and compound SA (100 mg, 0.25 mmol). After stirring at room temperature for 15h, the reaction mixture was poured into 5mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by reverse-phase prep-HPLC to afford SA-76 as a white solid ( 19.8 mg, 0.042 mmol, 16.8%), SA-77 as a white solid ( 8.5 mg, 0.018 mmol, 7.2%) and SA-78 as a white solid ( 26.6 mg, 0.056 mmol, 22.6%). SA-76: 1H NMR: (400 MHz, CDC13) 57.43- 7.38 (m, 2H), 7.25-7.23 (m, 1H), 5.43 (d, 2H), 2.73-2.69 (m, 1H), 2.26-2.14(m, 1H), 1.89-1.74 (m, 6H), 1.75-1.62 (m, 1H), 1.55-1.37 (m, 8H), 1.35-1.26 (m, 8H), 1.19-1.11 (m, 3H), 0.73 (s, 3H).LCMS: Rt = 2.36 mm. m/z = 470.3 [M+H]+. SA-77: 1H NMR (500 MHz, CDC13) δ (ppm): 8.00 (1H, d), 7.43 (1H, d), 7.30 (1H, t), 5.71 (2H, s), 2.72 (1H, t), 1.28 (s, 3H), 0.74 (s, 3H). LCMS: Rt = 2.40 mm. m/z = 470.2 [M+H]+. SA-78: 1H NMR: (400 MHz, CDC13) δ 7.79 (d, 1H), 7.41 (d, 1H), 7.34-7.30 (m, 2H), 5.56 (s, 2H), 2.69-2.64 (m, 1H), 2.27-2.13 (m, 2H), 1.82- 1.75(m, 5H), 1.51-1.43 (m, 11H),1.34-1.28 (m, 5H), 1.19-1.07 (m, 3H), 0.89-0.86 (m, 1H), 0.76 (s, 3H).. LCMS: Rt = 2.45 mm. m/z = 470.3 [M+H]+.
Example 36. Synthesis of compound SC-D2
Figure imgf000129_0001
SC-B2 SC-C2 SC-D2
Synthesis of compounds SC-A1 and SC-A2. A mixture of reactant mixture SA-F1 and SA-F2
(3.0g, lO.Ommol, 1 : 1) was added dry (Bu)4NF, then the mixture was heated 100 °C overnight. The residual mixture was poured in to 50 mL H20 and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (eluant: petroleum ether/ ethyl acetate=20: l) to afford product mixture SC-A1 and SC-A2 (2.1g, 6.5 mmol, 65%) as white solid.
Synthesis of compounds SC-B1 and SC-B2. To a solution of reactant mixture SC-A1 and SC- A2 (2.1g, 6.5 mmol) in anhydrous THF (30 mL) was added BH3.THF (1.0 M, 13.0 mL, 13.0 mmol), the solution was stirred at 25 °C overnight. Then the reaction was quenched by addition of water (5 mL). 2 M NaOH solution (20 mL) was added followed by 30 % H202 (20 mL). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate (200 mL) and resulting solution was washed with brine (2x 100 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product mixture was used directly in the next step without further purification.
Synthesis of compounds SC-Cl and SC-C2. To a solution of crude reactant mixture compounds SC-B1 and SC-B2 (2.2g, 6.5 mmol, theoretical amount) in dichloromethane (40 mL) was added Pyridinium chlorochromate (Pec) in portions (2.8g, 13.0 mmol). The solution was stirred at 25 °C overnight. Then the mixture was filtered through a short pad of silica gel and the silica gel was washed with dichloromethane (3 x50 mL). All filtrate was combined and concentrated in vacuo. The residue was purified by flash chromatography (eluant: petroleum ether/ ethyl acetate=15: 1) to afford product SC-C1 (910 mg, 2.7 mmol, Yield=41% (2 steps)) as white solid and product SC- C2 (850 mg, 2.5 mmol, Yield=39% (2 steps)) as white solid. Compound SC-C1: 1H NMR (500 MHz, CDC13) 5(ppm): 4.17 (d, 2H), 2.53 (t, IH), 0.62 (s, 3H). Compound SC-C2: 1H NMR (500 MHz, CDC13) 5(ppm): 4.45 (ABxd, IH), 4.39 (ABxd, IH), 2.54 (t, 1H0.62 (s, 3H).
Synthesis of compound SC-D2. To a solution of reactant SC-C2 (100 mg, 0.301 mmol) in methanol (10 rriL) was added 48% hydrobromic acid (152 mg, 0.903 mmol) followed by bromine (241 mg, 0.077 mL, 1.505 mmol). The solution was heated at 25 °C for 1.5 hours. Then the mixture was poured into cooled water (50 mL). The resulting solid was extracted with ethyl acetate (2x50 mL). The combined organic extracts were washed with brine (50 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product SC-D2 was used directly without further purification in the next step.
Example 37. Synthesis of compound SA-79 and SA-80
Figure imgf000130_0001
SC-D2 SA-79 SA-80
To a solution of compound SC-D2 (120 mg, 0.29 mmol) in THF (3 mL) was added K2C03 (200 mg, 1.45 mmol) and 2H-benzo[d][l,2,3]triazole (172 mg, 1.45 mmol). The resulting solution was stirred at room temperature overnight, then the reaction was diluted with EtOAc (20 mL). The resulting solution was washed with brine (10 mL), dried over Na2S04 and concentrated in vacuo. The residue was purified by prep-HPLC to give SA-79 (14 mg, 25%), SA-80 (9 mg, 17%) as a white solid. SA-79: IH NMR: (500 MHz, CDC13), δ (ppm), 8.08 (d, 2H), 7.49 (t, IH,), 7.39 (t, IH), 7.34 (d, IH), 5.45 (AB, IH), 5.40 (AB, IH), 4.49 (ABxd, IH), 4.39 (ABxd, IH), 2.72 (t, IH), 0.74 (s, 3H). LC-MS: rt=2.26 mm; m/z=454.4 (M+H)+ SA-80: IH NMR: (500 MHz, CDC13), δ (ppm), 7.89 (dd, 2H), 7.40 (dd, 2H), 5.54 (AB, IH), 5.50 (AB, IH), 4.49 (ABxd, IH), 4.40 (ABxd, IH), 2.67 (t, IH), 0.77 (s, 3H). LC-MS: rt=2.38 mm; m/z=454.3 (M+H)+ Example 38. Synthesis of compound SA-81 and SA-82
Figure imgf000131_0001
SC-D2 SA-81
To a solution of compound SC-D2 (120 mg, 0.29 mmol) in THF (3 mL) was added K2C03 (200 mg, 1.45 mmol) and lH-[l,2,3]triazolo[4,5-b]pyridine (173 mg, 1.45 mmol). The resulting solution was stirred at room temperature overnight, then the reaction was diluted with EtOAc (20 mL). The resulting solution was washed with brine (10 mL), dried over Na2S04 and concentrated in vacuo. The residue was purified by prep-HPLC to give SA-81 (9 mg, 14%), SA-82 (10 mg, 15%) as a white solid. SA-81: IH NMR: (500 MHz, CDC13), δ (ppm), 9.45 (s, IH), 8.47 (d, IH), 7.76 (dd, IH), 5.62 (AB, IH), 5.57 (AB, IH), 4.48 (ABxd, IH), 4.39 (ABxd, 1H),2.75 (t, IH),
0.76 (s, 3H). LC-MS: rt=2.26 mm; m/z=455.3 (M+H)+ SA-82: IH NMR: (500 MHz, CDC13), δ (ppm), 9.51 (s, IH), 8.59 (d, IH), 7.30 (dd, IH), 5.50 (AB, IH), 5.41 (dd, IH), 4.49 (ABxd, IH), 4.39 (ABxd, IH)), 2.76 (t, IH), 0.74 (s, 3H). LC-MS: rt=2.19 mm; m/z=455.3 (M+H)+
Example 39. Synthesis of compound SA-83 and SA-84
Figure imgf000131_0002
ynthesis of compounds SA-83 and SA-84. To a suspension of K2CC>3 (55 mg, 0.4 mmol) in THF (5 mL) was added 2H-tetrazole (28 mg, 0.4 mmol) and Compound SC-D2 (83 mg, 0.2 mmol). The mixture was stirred at RT for 15h then the residue mixture was poured into 5 mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue mixture was purified by reverse-phase prep-HPLC to afford SA-83 as a white solid (10 mg, 11% ) and SA-84 as a white solid (5 mg, 6% ). Compound SA-83: 1H NMR (400 MHz, CDC13) δ (ppm): 8.59 (d, IH), 8.22 (s, IH), 8.04 (d, IH), 7.23 (dd, IH), 5.28 (AB, IH), 5.21 (AB, IH), 4.50 (ABxd, IH), 4.38 (ABxd, IH), 2.67 (t, IH), 0.73 (s, 3H). LC-MS: rt = 2.11 mm, m/z = 454.4 [M+H]+ Compound SA-84: 1H NMR (400 MHz, CDC13) δ (ppm): 8.60 (dd, IH), 8.29 (s, IH), 7.59 (d, IH), 7.30 (dd, IH), 5.20 (AB, IH), 5.14 (AB, IH), 4.50 (ABxd, IH), 4.38 (ABxd, IH), 2.68 (t, IH), 2.29 (s, IH), 2.24-2.12 (m, 2H), 0.72 (s, 3H). LC-MS: rt = 2.15 mm, m/z = 454.4 [M+H]+
Example 40. Synthesis of compounds SA-85 and SA-86
Figure imgf000132_0001
SA-85 SA-86
To a suspension of K2CO3 (55mg, 0.4mmol) in THF (5mL) was added 2H-pyrazolo[3,4-c]pyridine (47.6mg, 0.4mmol) and compound SC-D2 (85 mg, 0.2mmol) and the mixture was stirred at RT for 15h. The residue mixture was poured into 5mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue mixture was purified by reverse-phase prep-HPLC to afford SA-85 as a white solid (5mg,5.5% ) and SA-86 as a white solid (lOmg, 11%). Compound SA-85: 1H NMR (500 MHz, CDC13) δ (ppm): 9.26 (s, IH), 8.17 (d, IH), 7.98 (s, IH), 7.53 (dd, IH), 5.32 (AB, IH), 5.23 (AB, IH), 4.48 (ABxd, IH), 4.39 (ABxd, IH), 2.68 (t, IH), 0.72 (s, 3H). LC-MS: rt = 2.18 mm, m/z = 454.1 [M+H]+ Compound SA-86: 1H NMR (500 MHz, CDC13) δ (ppm): 8.8 (s, IH), 8.33 (d, IH), 8.09 (s, IH), 7.65 (d, IH), 5.28 (AB, IH), 5.23 (AB, IH), 4.48 (ABxd, IH), 4.39 (ABxd, IH), 2.69 (t, IH), 0.73 (s, 3H). LC-MS: rt = 2.14 mm, m/z = 454.1 [M+H]+
Example 41. Synthesis of compounds SA-87, SA-88, and SA-89
Figure imgf000133_0001
To a suspension of K2CO3 (55mg, 0.4mmol) in THF (5mL) was added 5-fluoro-2H- benzo[d][l,2,3]triazole (55mg, 0.4mmol) and SC-D2 (85 mg, 0.2mmol) and the reaction mixture was stirred at RT for 15h. The residue mixture was poured into 5mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue mixture was purified by reverse-phase prep-HPLC to afford SA-87 as a white solid (11.4mg, 12%) and SA-88 as a white solid (10.2mg, 10.8%) and SA-89 as a white solid (21.5mg, 23.0%). Compound SA-87: 1H NMR (500 MHz, CDC13) δ (ppm): 7.70 (dd, IH), 7.31-7.26 (m, 2H), 5.45 (AB, IH), 5.38 (AB, IH), 4.49 (ABxd, IH), 4.38 (ABxd, IH), 2.72 (t, IH), 0.73 (s, 3H). LC-MS: rt = 2.26 mm, m/z = 472.3 [M+H]+ Compound SA-88: 1H NMR (500 MHz, CDC13) δ (ppm): 8.04 (dd, IH), 7.15 (td, IH), 6.98 (dd, IH), 5.41 (AB, IH), 5.34 (AB, IH), 4.49 (ABxd, IH), 4.39 (ABxd, IH), 2.72 (t, IH), 0.73 (s, 3H). LC-MS: rt = 2.27 mm, m/z = 472.3 [M+H]+ Compound SA-89: 1H NMR (500 MHz, CDC13) δ (ppm): 7.86 (dd, IH), 7.47 (dd, IH), 7.20 (td, IH), 5.52 (AB, IH), 5.48 (AB, IH), 4.49 (ABxd, IH), 4.39 (ABxd, IH), 2.66 (t, IH) 0.75 (s, 3H). LC-MS: rt = 2.36 mm, m/z = 472.0 [M+H]+
Example 42. Synthesis of compound SC-I2
Figure imgf000134_0001
Figure imgf000134_0002
Synthesis of com osed SC-E1 and SC-E2, To a solution of compound 5 (800 mg, 2.79 mmol) and PhS02CF2H (540 mg, 2.79 mmol) in THF (25 mL) and HMPA (0.5 mL) at -78 °C under N2 was added LHMDS (4 mL, 1 M in THF) dropwise. After stirring at -78 °C for 2 h, the reaction mixture was quenched with saturated aqueous NH4CI solution (10 ml.) and allowed to warm to room temperature then extracted with Et20 (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrate. The residue was purified by silica gel column chromatography (pertroleum ether/ ethyl acetate = 10/ 1) to give the mixture of compound SC-E1 and SC-E2 (700 mg). The mixture was further purified by chiral-HPLC to afford compound SC-E1 (200 mg, t= 4.31 min). 1H NMR (400 MHz, CDCI3), δ (ppm), 7.99-7.97 (d, 2H), 7.77-7.75 (m, 1H), 7.64-7.60 (m, 2H), 5.14-5.08 (m, 1H), 0.88 (s, 3H); compound SC-E2 (260 mg, · 5.66 min). 1H NMR (400 MHz, CDC13), δ (ppm), 8.00-7.98 (d, 2H), 7.77-7.75 ( m, 1H), 7.64-7.60 (m, 2H), 5.14-5.09 (m, 1H), 0.88 (s, 3H).
Synthesis of compound SF-F2. To a solution of compound SC-E2 (100 mg, 0.209 mmol) and anhydrous Na2HP04 (100 mg) in anhy drous methanol (5 mL) at -20 °C under N2 was added Na Hg amalgam (500 mg). After stirring at -20 °C to 0 °C for 1 h, the methanol solution was decanted out and the solid residue was washed with Et20 (5 x 3 mL). The combined organic layers were washed with brine (20 mL), dried over MgS04, filtered and concentrated. The residue was purified by silica gel chromatography (pertroleum ether/ ethyl acetate = 10/ 1) to give compound SC-F2 (36 mg, 0.106 mmol, 51%). 1H NMR (400 MHz, CDCI3), δ (ppm), 6.02-5.88 (t, 1H), 5.17-5.15 (m, 1H), 0.88 (s, 3H).
Synthesis of compound SC-G2. To a solution of compound SC-F2 (150 mg, 0.443 mmol) in dry THF (5 mL) was added borane-tetrahydrofuran complex (1.34 mL of 1.0 M solution in THF). After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath then quenched slowly with 10% aqueous NaOH (1 mL) followed 30% aqueous solution of H2O2 (1.2 mL). The mixture was allowed to stir at room temperature for 1 hour then extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with 10% aqueous Na2S203 (10 mL), brine (10 mL), dried over MgS04, filtered and concentrated to afford crude compound SC-G2 (210 mg). The crude product was used in the next step without further purification.
Synthesis of compound SC-H2. To a solution of crude compound SC-G2 (210 mg) was dissolved in 10 mL of H20 saturated dichloromethane (dichloromethane had been shaken with several milliliters of H20 then separated from the water layer) was added Dess-Martin periodinate (380 mg, 0.896 mmol). After stirring at room temperature for 24 h, the reaction mixture was extracted with dichloromethane (3 x 10 mL). The combined organic layers were washed with
10 % aqueous Na2S203 (10 mL), brine (10 mL), dried over MgS04, filtered and concentrated. The residue was purified by chromatography on silica gel (pertroleum ether/ ethyl acetate = 5: 1) to afford compound SC-H2 (90 mg, 0.254 mmol, 57%) as a white solid.
Synthesis of compound SC-I2. To a solution of compound SC-H2 (80 mg, 0.226 mmol) in MeOH (5 mL) was added 2 drops of HBr (48%) followed by bromine (100 mg, 0.63 mmol). After stirring at room temperature for lh, the reaction mixture was poured into ice- water then extracted with ethyl acetate (15 mL x 3), The combined organic layers were washed with brine (20 mL), dried over MgS04, filtered and concentrated to give crude compound SC-I2 (95 mg). The crude product was used in the next step without further purification.
Example 43. Synthesis of compound SA-90 and SA-92
Figure imgf000136_0001
To a suspension of K2CO3 (50 mg, 0.36 mmol) in THF (5 mL) was added 1H- benzo[d][l,2,3]triazole (20 mg, 0.23 mmol) and SC-I2 (100 mg, 0.23 mmol). The mixture was stirred at rt for 15h. The reaction mixture was poured into 5 mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified with by reverse-phase prep-HPLC to afford the title compound as a white solid SA-90 (12.2 mg, 11%). SA-92 (6.6 mg, 6.0%). Byproduct (5 mg, 4.6%). SA-90 1H NMR (400 MHz, CDC13) δ (ppm): 8.08 (d, 1H), 7.48 (t, 1H), 7.38 (t, 1H), 7.34 (d, 1H), 5.88 (t, 1H), 5.43 (ΑΒ,ΙΗ), 5.41(AB, 1H), 2.72 (1H, t), 0.71(s,3H). LC- MS:rt=2.35min,m/z=472.2 (M++l). SA-92 1H NMR (400 MHz, CDC13) δ (ppm): 7.88(dd, 2H), 7.40 (dd, 2H) 6.01(t, 1H), 5.53 (ΑΒ,ΙΗ), 5.48 (AB, 1H), 2.68 (t, 1H), 0.76 (s,3H). LC- MS :rt=2.45min,m/z=472.3(M++l).
Example 44. Synthesis of compound SA-93 and SA-94
Figure imgf000136_0002
SC-12 SA-93 SA-94
To a suspension of K2CO3 (50 mg, 0.36 mmol) in THF (5 mL) was added 2H-pyrazolo[4,3- b]pyridine (50 mg, 0.42 mmol) and SM (100 mg, 0.23 mmol). The mixture was stirred at rt for 15h. The reaction mixture was poured into 5 mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified with by reverse-phase prep-HPLC to afford the title compound as a white solid SA-93 (9.3 mg, 8.6%). SA- 94 (21 mg, 19.2%). Byproduct (6 mg, 5.6%). SA-93 1H NMR (400 MHz, CDC13) δ (ppm): 8.58(d, 1H), 8.21 (s, 1H) 8.06 (d, 1H), 7.22 (dd, 1H), 5.88(t, 1H),5.30 (AB, 1H), 5.26 (ΑΒ,ΙΗ), 2.69 (t, 1H), 0.71(s,3H). LC-MS:rt=2.21 min,m/z=472.3(M++l). SA-94 1H NMR (400 MHz, CDC 13) δ (ppm): 8.60 (d, 1H), 8.28 (lH,s) 7.58 (d, 1H),7.31 (dd,lH), 5.88(t, 1H), 5.17(AB, 1H),5.15(AB,1H), 2.65 (t, 1H),0.72 (s,3H). LC- MS:rt=2.24min,m/z=472.2(M++l).
Example 45. Synthesis of compound SA-96 and SA-97
Figure imgf000137_0001
SC-12 SA-96 SA-97
To a suspension of K2CO3 (55mg, 0.4mmol) in THF (5mL) was added 2H-[l,2,3]triazolo[4,5- c]pyridine (48mg, 0.4mmol) and 10 (86 mg, 0.2mmol). The mixture was stirred at RT for 15h. The residue mixture was poured into 5mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue mixture was purified by reverse-phase prep-HPLC to afford SA-96 as a white solid (30mg, 31.8% ) and SA-97 as a white solid (16mg, 16.9%) and a white solid byproduct (2mg, 2%).
Compound SA-96: 1H NMR (500 MHz, CDC13) δ (ppm): 9.50 (s, 1H), 8.58 (d, 1H), 7.30 (d, 1H), 5.88 (t, 1H), 5.49 (AB, 1H), 5.41 (AB, 1H), 2.75 (t, 1H), 2.27-2.16 (m, 2H), 0.74 (s, 3H). LC-MS: rt = 2.24 mm, m/z = 473.1 [M+H]+ Compound SA-97: 1H NMR (500 MHz, CDC13) δ (ppm): 9.46 (s, 1H), 8.47 (d, 1H), 7.76 (dd, 1H), 5.87 (t, 1H), 5.62 (AB, 1H), 5.57 (AB, 1H), 2.70 (t, 1H), 2.28-2.16 (m, 2H), 0.76 (s, 3H). LC-MS: rt = 2.31 mm, m/z = 473.1 [M+H]+ Example 46. Synthesis of compound SA-99 and SA-100
Figure imgf000138_0001
SC-12 SA-99 SA-100
To a suspension of K2CO3 (55mg, 0.4mmol) in THF (5mL) was added 2H-pyrazolo[3,4-c]pyridine (48mg, 0.4mmol) and 10 (86 mg, 0.2mmol). The mixture was stirred at RT for 15h. The residue mixture was poured into 5mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue mixture was purified by reverse-phase prep-HPLC to afford SA-99 as a white solid (4mg, 4% ) and SA-100 as a white solid (19mg, 20% ) and a white solid byproduct (4mg, 4% ). Compound SA-99: 1H NMR (500 MHz, CDC13) δ (ppm): 9.25 (s, 1H), 8.17 (d, 1H), 7.53 (dd, 1H), 5.87 (t, 1H), 5.32 (AB, 1H), 5.23 (AB, 1H), 2.68 (t, 1H), 2.27-2.20 (m, 1H), 0.73 (s, 3H). LC-MS: rt =
2.12 mm, m/z = 472.0 [M+H]+ Compound SA-100: 1H NMR (500 MHz, CDC13) δ (ppm): 8.80 (s, 1H), 8.33 (d, 1H), 8.10 (s, 1H), 7.65 (dd, 1H), 5.87 (t, 1H), 5.28 (AB, 1H), 5.23 (AB, 1H), 2.69 (t, 1H), 2.24-2.13 (m, 2H), 0.73 (s, 3H). LC-MS: rt = 2.18 mm, m/z = 472.0 [M+H]+
Figure imgf000138_0002
To a suspension of K2CO3 (55mg, 0.4mmol) in THF (5mL) was added 5-fluoro-2H- benzo[d][l,2,3]triazole (55mg, 0.4mmol) and 10 (86 mg, 0.2mmol). The mixture was stirred at RT for 15h. The residue mixture was poured into 5mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue mixture was purified by reverse-phase prep-HPLC to afford SA-102 a white solid (15mg,15.3% ) and SA-103 as a white solid (18.8mg,19% ) and SA-104 as a white solid (16.3mg,16.5% ). Compound SA-102: 1H NMR (400 MHz, CDC13) δ (ppm): 7.70 (dd, IH), 7.31-7.28 (m, 2H), 5.88 (t, IH), 5.45 (AB, IH), 5.38 (AB, IH), 2.72 (t, IH), 2.27-2.13 (m, 2H), 0.73 (s, 3H). LC-MS: rt = 2.38 mm, m/z = 490.1 [M+H]+ Compound SA-103: 1H NMR (400 MHz, CDC13) δ (ppm): 8.04 (dd, IH), 7.15 (td, IH), 6.98 (dd, IH), 5.88 (t, IH), 5.42 (AB, IH), 5.34 (AB, IH), 2.72 (t, IH), 2.23-2.14 (m, 2H), 0.73 (s, 3H). LC-MS: rt = 2.39 mm, m/z = 490.1 [M+H]+ Compound SA-104: 1H NMR (500 MHz, CDC13) δ (ppm): 7.86 (dd, IH), 7.47 (dd, IH), 7.20 (td, IH), 5.87 (t, IH), 5.52 (AB, IH), 5.47 (AB, IH), 2.66 (t, IH), 2.24-2.13 (m, 2H), 0.75 (s, 3H). LC-MS: rt = 2.48 mm, m/z = 490.1 [M+H]+
Example 48. Synthesis of compound SA- J
Figure imgf000139_0001
SA-A SA-B SA-C
Figure imgf000140_0001
SA-I SA-J
Synthesis of compound SA-B. Compound SA-A (500 mg, 1.84 mmol) and 10% Pd/black (20mg) in tetrahydrofuran (5 mL) and concentrated hydrobromic acid (0.02 mL) was hydrogenated with a hydrogen balloon at 1 atm . After stirring at room temperature for 24h, the mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. Recrystallization from acetone to give compound SA-B (367 mg, 1.34 mmol, 73%). ¾ NMR (400 MHz, CDCI3), δ (ppm) 2.61 (t, 1H), 2.5 (dd, 1H), 2.2 (m, 4H), 2.1 (m, 2H), 1.9 (m, 1H), 1.85 (m, 2H), 1.75 (1H), 1.65 (m, 3H), 1.55 (m, 2H), 1.45-1.1 (m, 6H), 0.98 (s, 3H).
Synthesis of compound SA-C. To a solution of compound SA-B (274mg. 1 mmol) in methanol (4 mL) was added iodine (0.1 mmol). After stirring at 60°C for 12h, TLC showed no SM and the solvent was removed in vacuo. The crude product was dissolved in dichloromethane (20 mL) and washed with saturated NaHCC (15 mL), brine, dried over Na2S04, filtered and concentrated. The residue was purified by chromatography on basic alumina (pertroleum ether/ethyl acetate = 9: 1) to give compound SA-C (280 mg, 0.88 mmol, 88% ). 1H NMR (400 MHz, CDC13), δ (ppm) 3.19 (s, 3H), 3.13 (s, 3H), 2.43 (dd, 1H), 2.1 (m, 1H), 1.9 (m, 2H), 1.8 (m, 4H), 1.65 (m, 2H), 1.6-1.1 (m, 13H), 0.83 (s, 3H). Synthesis of compound SA-D. To a solution of methyltriphenylphosphonium bromide (10.26 g, 28.84 mmol) in 30 rriL THF, was added KOt-Bu (3.23 g, 28.80 mmol). The reaction was heated to 60 °C for 1 h. SA-C (3.23 g, 9.6 mmol) was added to the mixture, stirred at 60 °C for 15 h. The reaction mixture was extracted 500 ml EtOAc, washed with brine and evaporated in vacuo evaporated then purified by flash chromatographyon silica gel (petroleum ether/ethyl acetate = 3: 1) to afford SA-D as the white solid (2.1 g, 65% yield).
Synthesis of compound SA-E. To a solution of SA-D (1 g, 3.1 mmol) in 20 ml THF, was added 2 M HC1 2 mL, stirred at rt for 1 h. The reaction mixture was quenched with 5 rriL H20 and extracted with 100 mL EtOAc, washed with brine and evaporated in vacuo, then purified by chromatography (PE:EtOAc = 10: 1 ) to afford SA-E as the white solid (710 mg, 83% yield). 1H
NMR (400 MHz, CDC13), δ (ppm) 4.65 (s, 1H), 4.63 (s, 1H), 2.6 (t, 1H), 2.5 (dd, 1H), 2.2 (m, 5H), 2.1 (m, 1H), 1.9-1.7 (mm, 4H), 1.6 (m, 3H), 1.5 (bd, 1H), 1.4-1.1 (m, 7H), 0.82 (s, 3H).
Synthesis of compound SA-E To a stirred solution of trimethylsulfonium iodide (6.4 g , 31.5 mmol) in 10 mL of DMSO was added NaH (60%;800 mg , 31.5 mmol). After stirring at room temperature for lh,a suspension of SA-E (870 mg , 3.2 mmol) in 5 mL of DMSO was added drop wise. After 15 h, the reaction mixture was poured into ice-cold water and extracted with 300 mL EtOAc, washed with 100 mL brine solution, dried and evaporated in vacuo, then purified by chromatography (PE:EtOAc = 10: 1) to afford SA-F as a white solid(695 mg, 76% yield).
Synthesis of compound SA-G. To a solution of SA-F and its isomer (129 mg, 0.45 mmol) in 10 mL THF, was added L1AIH4 (50 mg, 1.35 mmol) , stirred at rt for 1 h. The reaction mixture was quenched with 5 mL H20 and extracted with 100 ml EtOAc, washed with brine solution and evaporated in vacuo then purified by chromatography (petroleum ether/ethyl acetate = 3: 1) to afford SA-G as a white solid (62 mg, 48% yield). 1H NMR (400 MHz, CDC13), δ (ppm) 4.63 (s, 1H), 4.61 (s, 1H), 2.5 (m, 1H), 2.2 (m, 1H), 1.9 (d, 1H), 1.8 (d, 3H), 1.7 (m, 3H), 1.6 (s, 3H), 1.5- 1.2 (mm, 13H), 1.1 (m, 4H), 0.82 (s, 3H)..
Synthesis of compound SA-H. To a solution of SA-G (86 mg, 0.3 mmol) in dry THF (5 mL) was added borane-tetrahydrofuran complex (1 mL; 1.0 M solution in THF). After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath then quenched slowly with 10% aqueous NaOH (1 mL) followed by 30% aqueous solution of H202 (1 mL). After stirring at room temperature for one hour, the mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with 10% aqueous Na2S203 (100 mL), brine (aq., 100 mL), dried over MgS04, filtered and concentrated to afford SA-H as a white solid (83 mg, 91%). The crude product was used in the next step without further purification.
Synthesis of compound SA-L To a solution of SA-H (300 mg, 0.80 mmol) in 15 mL DMF, was added PDC (2.7 g, 7.2 mmol) and 1 mL H20, stirred at rt for 15 h. The reaction mixture was extracted 100 mL EtOAc, washed with brine and evaporated in vacuo then purified by
chromatography (PE:EtOAc = 1 : 1) to afford SA-I as awhite solid 128 mg, 50% yield. 1H NMR (400 MHz, DMSO-de), δ (ppm), 11.90 (s, lH), 4.22 (s, 1H), 2.28 (t, 1H), 1.9 (m, 2H), 1.6 (2 x m, 7H), 1.5-0.9 (multiple m and s, 17H), 0.68 (s, 3H). Synthesis of compound SA-J. To a solution of SA-I (200 mg, 0.61 mmol) in 5 mL DMF, was added Ν,Ο-dimethylhydroxylamine HC1 salt (60 mg, 0.62 mmol), HATU (236 mg, 0.62 mmol), DIPEA 1 mL, and stirred at rt for 3h, The reaction mixture was extracted 100 mL EtOAc, washed with brine solution and evaporated in vacuo then purified by chromatography (petroleum ether/ethyl acetate = 1 : 1) to afford SA-J as awhite solid 110 mg, 55% yield. 1H NMR (400 MHz, DMSO-de), δ (ppm), 3.64 (s, 3H), 3.19 (s, 3H), 2.70 (bs, 1H), 2.17 (bt, 1H), 1.8-1 .6 (m, 8H), 1.5- 1.2 (several m and s, 14H), 1.1 (m, 3H), 0.73 (s, 3H).
Example 48. Synthesis of compound SA-105
Figure imgf000142_0001
To a stirred solution of l,2-dimethyl-lH-benzo[d] imidazole (100 mg , 0.7 mmol) in 10 mL THF was added BuLi (2.5 M;0.3 ml , 0.7 mmol) at -78°C. After stirring at -78°C for 30 min,a solution of SA-J (50 mg , 0.14 mmol) in 3 mL of THF was added dropwise at -78°C. After stirring at -78°C for 1 h, the reaction mixture was poured into ice-cold water and extracted with EtOAc (100 mLx3). The combined extracts were washed with brine (100 mLx3), dried(MgS04), filtered, and evaporated in vacuo, purified by prep-HPLC to afford SA-105 as the white solid 13 mg, 21.43% yield. The product exists as a mixture of C-20 ketone and enol. 1H NMR (500 MHz, CDCL3), δ (ppm), 7.71-7.74,7.37-7.41 ,7.23-7.34,7.16-7.18 (m, 4H,C-20 ketone and enol), 5.20 (s, lH,C-20 enol), 4.1 1(1H,AB), 4.05(lH,AB),3.71 (3H,s,C-20 ketone), 3.57(3H, C-20 enol),2.78 (lH,t, C-20 ketone), 2.40 (lH,t, C-20 enol), 0.70 (s, 3H). LCMS: :
Figure imgf000143_0001
[M+H]
Example 49. Synthesis of compound SA-106
SA-J
SA-106
To a stirred solution of 1 -methylisoquinoline (197 mg, 1.375 mmol) in 10 rriL of THF was added BuLi (2.5 M;0.55 mL, 1.375 mmol) at rt. After stirring at rt for 40 min, a solution of SA-J (0.1 g , 0.275 mmol) in 5 mL of THF was added dropwise at 0°C. After stirring at rt for 2 h, the reaction mixture was poured into ice-cold water and extracted with EtOAc (100 mLx3), washed with brine (100 mLx3), dried (MgS04), filtered, and evaporated in vacuo, then purified by prep-HPLC to afford SA-106 as the yellow solid 18 mg, 15 % yield. 1H NMR (500 MHz, CDC13), δ (ppm), 15.49 (bs, I I I ) . 8.03 id. ! H ). 7.61 -7.56 (m, 1H), 7.50 i d. i l l ). 7.46 (t, I I I ) . 7.22 id. I I I ). 5.97 (s, 1H), 2.54 (t, 1H), 0.68 (s, 3H). LCMS: Rt = 2.090 min, MS (ESI) m/z: 446 [M+H] +.
Example 50. Synthesis of compound SD-D
Figure imgf000144_0001
SD-C SD-D
Synthesis of compound SD-A. To a solution of EtMgBr (5 mmol, 1M in THF) in THF (20 rriL) at 0°C was added a solution of compound SA-E (858mg, 3 mmol) in dry THF (5 mL) via syringe pump over 30 min. After stirring at 0°C for 5h, the reaction mixture was allowed to warm up and stirred at room temperature overnight. The reaction mixture was quenched with iced-cold water and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The white residue was purified by flash column chromatography (petroleum ether/ethyl acetate= 20: 1 to 10: 1) to give compound SD-A (900mg).
Synthesis of compound SD-B. To a solution of compound SD-A (200 mg, 0.66 mmol) in dry THF (5 mL) was added borane-tetrahydrofuran complex (2 mL of 1.0 M solution in THF). After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath then quenched slowly with 10% aqueous NaOH (1 mL) followed by 30% aqueous solution of ¾<¾ (1.2 mL). The mixture was allowed to stir at room temperature for 1 hour then extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with 10% aqueous Na2S?03 (10 mL), brine (10 mL), dried over MgS04, filtered and concentrated to afford compound SD-B (260 mg, crude). The crude product was used in the next step without further purification. Synthesis of compound SD-C. To a solution of compound SD-B (260mg, crude) was dissolved in 10 mL dichloromethane was added PCC (449 mg,). After stirring at room temperature for 24 h, the reaction mixture was extracted with dichloromethane (3 x 10 mL). The combined organic layers were washed with 10 % aqueous NaCl (10 mL), brine (10 mL), dried over MgS04, filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum
ether/ethyl acetate = 4: 1 to 2: 1) to afford title SD-C (15 mg,) as a white solid. 1H NMR (500 MHz, CDC13), δ (ppm), 2.49(1H, t), 2.09 (s, 3H)0.84(3H,t), 0.59 (s, 3H).
Synthesis of compound SD-D. To a solution of compound SD-C (30 mg, 0.09mmol) in MeOH (5 mL) was added 2 drops of HBr (48%) followed by bromine (100 mg, 0.62 mmol). After stirring at room temperature for lh, the reaction mixture was poured into ice- water then extracted with ethyl acetate (15 mL x 3), The combined organic layers were washed with brine (20 mL), dried over MgS04, filtered and concentrated to give compound SD-D (36mg crude ). The crude product was used in the next step without further purification.
Figure imgf000145_0001
To a suspension of K2CO3 (55 mg, 0.4 mmol) in THF (5 mL) was added 5-fluoro-2H- benzo[d][l,2,3]triazole (55 mg, 0.4 mmol) and SD-D (85 mg, 0.2 mmol). The mixture was stirred at RT for 15h. The residue mixture was poured into 5mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue mixture was purified by reverse-phase prep-HPLC to afford SA-107 as a white solid (5.6 mg, 5.5%) and SA-108 a white solid (8.4 mg, 8.5%) and SA-109 as a white solid (13.7 mg, 14.0%). Compound SA-107: 1H NMR (500 MHz, CDC13) δ (ppm): 7.70 (d, IH), 7.30- 7.28 (m, 2H), 5.43 (AB, IH), 5.39 (AB, IH), 2.71 (t, IH), 2.23-2.09 (m, 2H), 1.47 (q, 2H), 0.93 (t, 3H), 0.74 (s, 3H). LC-MS: rt = 2.32 mm, m/z = 468.3 [M+H]+ Compound SA-108: 1H NMR (500 MHz, CDC13) δ (ppm): 8.04 (dd, IH), 7.15 (td, IH), 6.98 (dd, IH), 5.39 (AB, IH), 5.35 (AB, IH), 2.71 (t, IH), 2.25-2.08 (m, 2H), 1.47 (q, 2H), 0.93 (t, 3H), 0.74 (s, 3H). LC-MS: rt = 2.34 mm, m/z = 468.3 [M+H]+ Compound SA-109: 1H NMR (500 MHz, CDC13) δ (ppm): 7.86 (dd, IH), 7.47 (dd, IH), 7.20 (td, IH), 5.52 (AB, IH), 5.48 (AB, IH), 2.66 (t, IH), 2.24-2.07 (m, 2H), 1.46 (q, 2H), 0.93 (t, 3H), 0.75 (s, 3H). LC-MS: rt = 2.43 mm, m/z = 468.3 [M+H]+
Example 52. Synthesis of compounds SA-110 and SA-111
Figure imgf000146_0001
SD-D SA-110 SA-111
To a solution of compound SC-D (120 mg, 0.29 mmol) in THF (3 mL) was added K2CO3 (210 mg, 1.5 mmol) and 2H-pyrazolo[4,3-b]pyridine (180 mg, 1.5 mmol). The resulting solution was stirred at room temperature overnight, then LCMS showed the reaction was completed. The reaction was diluted with EtOAc (20 mL) and the resulting solution was washed with brine (10 mL), dried over Na2S0 and concentrated in vacuo. The residue was purified by prep-HPLC to give SA-110 (6 mg, 0.0113 mmol, Yield=5%), SA-111 (8 mg, 0.0117 mmol, Yield=6%) as a white solid. SA-110: IH NMR: (500 MHz, CDC13), δ (ppm), 8.58 (t, IH), 8.22 (s, IH), 8.04 (d, IH), 7.23 (dd, IH), 5.27 (AB, IH), 5.21 (AB, IH), 2.67 (t, IH), 0.89 (t, 3H), 0.72 (s, 3H). LC-MS: rt=2.276 mm;
m/z=450.4 (M+H)+ SA-111: 1H NMR: (500 MHz, CDC13), δ (ppm), 8.60 (dd, IH), 8.28 (s, IH), 7.59 (d, IH), 7.30 (dd, IH), 5.19 (AB, IH), 5.13 (AB, IH), 2.67(t, IH), 0.90 (t, 3H), 0.72 (s, 3H). LC-MS: rt=2.389 mm; m/z=450.2 (M+H)+
Example 53. Synthesis of compound SA-112, SA-113 and SA-114
Figure imgf000147_0001
SD-D SA-112 SA-113 SA-114
To a solution of SD-D (160 mg, 0.39 mmol) in THF (3 niL) was added 2H-[l,2,3]tnazolo[4,5-c] pyridine (230 mg, 1.95 mmol) and K2CO3 (270 mg, 1.95 mmol). The resulting solution was stirred at room temperature overnight, then LCMS showed the reaction was completed. The reaction was diluted with EtOAc (40 rriL) and washed with brine (20 mL x 2), dried over Na2S04 and concentrated in vacuo. The residue was purified by Prep-HPLC to give SA-112/SA-113 (mixture, 35 mg, 16%) and SA-114 (11 mg, 0.0244 mmol, Yield=5%) as a white solid. NMR showed SA- 112/SA-113 is the mixture of two compounds and further purification by Chiral-HPLC to give SA-112 (9 mg, 0.02 mmol, Yield=5%), SA-113 (3 mg, 0.00666 mmol, Yield=3%) as a white solid. SA-112: IH NMR: (500 MHz, CDC13), δ (ppm), 9.49 (d, IH), 8.58 (d, IH), 7.30 (dd, IH), 5.49 (AB, IH), 5.42 (AB, IH), 2.75 (t, IH), 0.90 (t, 3H), 0.76 (s, 3H). LC-MS: rt=2.291 mm;
m/z=451.1 (M+H)+ SA-113: IH NMR: (500 MHz, CDCI3), δ (ppm), 8.97 (d, IH), 8.55 (d, IH), 7.98 (d, IH), 5.57 (AB, IH), 5.52 (AB, IH), 2.77 (t, IH), 0.90 (t, 3H), 0.76 (s, 3H). LC-MS:
rt=2.305 mm; m/z=451.1 (M+H)+ SA-114: IH NMR: (500 MHz, CDCI3), δ (ppm), 9.46 (d, IH), 8.47 (d, IH), 7.76 (dd, IH), 5.62 (AB, IH), 5.57 (AB, IH), 2.70 (t, IH), 0.90 (t, 3H), 0.76 (s, 3H). LC-MS: rt=2.373 mm; m/z=451.4 (M+H)+
Example 54. Synthesis of compound SE-D2
Figure imgf000148_0001
1. Synthesis of compound SE-A. Compound mixture SA-F1 and SA-F2 (5.0 g, 16.7 mmol) was dissolved in dry methanol (250 mL), and Na metal (1.2g, 50.0 mmol) was added and the solution was refluxed for 16 h. Methanol was then evaporated off and the residue was dissolved in dichloromethane and washed with H20 (3 x 50 mL) and brine (100 mL), dried over MgS04, filtered, and concentrated. The crude target compound was purified by via silica gel
chromatography (petroleum ether/ethyl acetate = 10: 1 to 5: 1), and concentrated to give the product mixture SE-A1 and SE-A2 (4.6g, 83%) as a white solid.
Synthesis of compound SE-B. To a solution of reactant mixture SE-A1 and SE-A2 (4.6g, 13.9 mmol) in anhydrous THF (30 mL) was added B¾.THF (1.0 M, 27.7 mL, 27.7 mmol), the solution was stirred at 25 °C overnight, then the reaction was quenched by addition of water (5 mL). 2 M NaOH solution (30 mL) was added followed by 30 % H2O2 (30 mL). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate (200 mL) and resulting solution was washed with brine (2x100 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product mixture was used directly in the next step without further purification.
Synthesis of compound SE-C. To a solution of crude reactant mixture SE-Bl and SE-B2 (4.9g, 13.9 mmol, theoretical amount) in dichloromethane (40 mL) was added Pyridinium
chlorochromate (PCC) in portions (6.0g, 27.8 mmol). The solution was stirred at 25 °C overnight then the mixture was filtered through a short pad of silica gel and the silica gel was washed with dichloromethane (3x50 mL). All filtrates were combined and concentrated in vacuo. The residue was purified by flash chromatography (eluant: petroleum ether/ ethyl acetate=15: 1) to afford product SE-Cl (2.1g, 6.03 mmol, Yield=43% (2 steps)) as white solid and product SE-C2 (2.2g, 6.32 mmol, Yield=45% (2 steps)) as white solid. Compound SE-Cl: 1H NMR (500 MHz, CDC13) δ (ppm): 3.40 (s, 3H), 3.20 (s, 2H), 2.62-2.51 (m, 2H), 2.11 (s, 3H), 2.02-1.99 (m, 2H), 0.62 (s, 3H). Compound SE-C2: 1H NMR (500 MHz, CDC13) δ (ppm): 3.42 (AB, IH), 3.38 (AB, IH), 3.40 (s, 3H), 2.65 (s, IH), 2.54 (t, IH), 2.16-2.14 (m, IH), 2.11 (s, 3H), 2.02-1.98 (m, IH), 0.61 (s, 3H).
Synthesis of compound SE-D2. To a solution of reactant SE-C2 (100 mg, 0.301 mmol) in methanol (10 rriL) was added 48% hydrobromic acid (152 mg, 0.903 mmol) followed by bromine (241 mg, 0.077 mL, 1.51 mmol). The solution was heated at 25 °C for 1.5 hours then the mixture was poured into cold water (50 mL) and the resulting solid was extracted with ethyl acetate (2x50 mL). The combined organic extracts were washed with brine (50 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product SE-D2 was used directly without further purification in the next step.
Example 55. Synthesis of compound SA-115
Figure imgf000149_0001
SE-D2 SA-115
To a solution of compound SE-D2 (120 mg, 0.28 mmol) in THF (3 mL) was added K2C03 (190 mg, 1.4 mmol) and 2H-benzo[d][l,2,3]triazole (167 mg, 1.4 mmol). The resulting solution was stirred at room temperature overnight, then the reaction was diluted with EtOAc (20 mL). The resulting solution was washed with brine (10 mL), dried over Na2S04 and concentrated in vacuo. The residue was purified by prep-HPLC to give SA-115 (36 mg, 25%) as a white solid. IH NMR: (500 MHz, CDC13), δ (ppm), 8.08 (d, IH), 7.49 (t, IH), 7.38 (t, IH), 7.34 (d, IH), 5.45 (AB, IH), 5.39 (AB, IH), 3.42 (AB, IH), 3.40 (s, 3H), 3.39 (AB, IH), 2.72 (t, IH), 2.64 (s, IH), 0.73 (s, 3H). LC-MS: rt=2.37 mm; m/z=466.2 (M+H)+
Figure imgf000150_0001
To a solution of compound SE-D2 (120 mg, 0.28 mmol) in THF (3 mL) was added K2C03 (190 mg, 1.4 mmol) and lH-pyrazolo [4, 3 -b] pyridine (167 mg, 1.4 mmol). The resulting solution was stirred at room temperature overnight, the the reaction was diluted with EtOAc (20 mL). The resulting solution was washed with brine (10 mL), dried over Na2S04 and concentrated in vacuo. The residue was purified by prep-HPLC to give SA-116 (18 mg, 14%), SA-117 (13 mg, 10%) as a white solid. SA-116: IH NMR: (500 MHz, CDC13), δ (ppm), 8.59 (d, IH), 8.23 (s, IH), 8.04 (d, IH), 7.23 (dd, IH), 5.28 (AB, IH), 5.21 (AB, IH), 3.42 (AB, IH), 3.40 (s, 3H), 3.39 (AB, IH), 2.67 (t, IH), 2.64 (s, IH), 0.73 (s, 3H). LC-MS: rt=2.22 mm; m/z=466.2 (M+H)+ SA-117: IH NMR: (500 MHz, CDC13), δ (ppm), 8.60 (d, IH), 8.28 (s, IH), 7.58 (d, IH), 7.29 (dd, IH), 5.19 (AB, IH), 5.14 (AB, IH), 3.42 (AB, IH), 3.40 (S, 3H), 3.39 (AB, IH), 2.67 (t, IH), 2.6 (s, IH), 0.72 (s, 3H). LC-MS: rt=2.26 mm; m/z=466.2 (M+H)+
Figure imgf000150_0002
To a suspension of K2CO3 (55mg, 0.4mmol) in THF (5mL) was added 3H-pyrazolo[3,4-c]pyridine (47.6mg, 0.4mmol) and 10 (85 mg, 0.2mmol). The mixture was stirred at RT for 15h then was poured into 5mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue mixture was purified by reverse-phase prep-HPLC to afford SA-118 as a white solid (21mg,22.5% ) and SA- 119 as a white solid (15mg, 16.1%). Compound SA-118: 1H NMR (500 MHz, CDC13) δ (ppm): 9.25 (s, 1H) , 8.16 (d, 1H), 7.98 (s, 1H), 7.52 (dd, 1H), 5.32 (AB, 1H), 5.23 (AB, 1H), 3.42 (AB, 1H), 3.39 (AB, 1H), 3.40 (s, 3H), 2.67 (t, 1H), 2.26-2.19 (m, 1H), 2.14-2.12 (m, 1H), 0.71 (s, 3H). LC-MS: rt = 2.11 mm, m/z = 466.1 [M+H]+ Compound SA-119: 1H NMR (500 MHz, CDC13) δ (ppm): 8.79 (s, 1H), 8.33 (d, 1H), 8.09 (s, 1H), 7.64 (d, 1H), 5.28 (AB, 1H), 5.23 (AB, 1H), 3.43 (AB, 1H), 3.40 (s, 3H), 3.39 (AB, 1H), 2.71-2.67 (m, 1H), 2.21-2.12 (m, 1H), 0.72 (s, 3H). LC- MS: rt = 2.18 mm, m/z = 466.1 [M+H]+
Example 58. Synthesis of compound SA-120, SA-121 and SA-122
Figure imgf000151_0001
SE-D2 SA-120 SA-121 SA-122
To a suspension of K2CO3 (55mg, 0.4mmol) in THF (5mL) was added 5-fluoro-2H- benzo[d][l,2,3]triazole (55mg, 0.4mmol) and 10 (85 mg, 0.2mmol). The reaction mixture was stirred at RT for 15h then was poured into 5mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue mixture was purified by reverse-phase prep-HPLC to afford SA-120 as a white solid (6.0mg, 6.2%) and SA-121 as a white solid (8.6mg, 8.9%) and SA-122 as a white solid (12.6mg, 13.0%). Compound SA-120: 1H NMR (500 MHz, CDC13) δ (ppm): 7.70 (dd, 1H), 7.29-7.26 (m, 2H), 5.45 (AB, 1H), 5.38 (AB, 1H), 3.42 (AB, 1H), 3.39 (AB, 1H), 3.40 (s, 3H), 2.72 (t, 1H), 2.64 (s, 1H), 2.47 (s, 3H), 2.22-2.13 (m, 2H), 0.72 (s, 3H). LC-MS: rt = 2.42 mm, m/z = 484.2 [M+H]+ Compound SA-121: 1H NMR (500 MHz, CDC13) δ (ppm): 8.04 (dd, 1H), 7.15 (td, 1H), 6.98 (dd, 1H), 5.41 (AB, 1H), 5.34 (AB, 1H), 3.42 (AB, 1H), 3.39 (AB, 1H), 3.40 (s, 3H), 2.72 (t, 1H), 2.64 (s, 1H), 2.23-2.13 (m, 2H), 0.73 (s, 3H). LC-MS: rt = 2.43 mm, m/z = 484.2 [M+H]+ Compound SA-122: 1H NMR (500 MHz, CDC13) δ (ppm): 7.86 (dd, 1H), 7.47 (dd, 1H), 7.20 (td, 1H), 5.52 (AB, 1H), 5.47 (AB, 1H), 3.42 (AB, 1H), 3.39 (AB, 1H), 3.40 (s, 3H), 2.66 (t, 1H), 2.65 (s, 1H), 2.23-2.12 (m, 2H), 0.74 (s, 3H). LC-MS: rt = 2.53 mm, m/z = 484.2 [M+H]+
Example 59. Synthesis of Compound SA-123, SA-124 and SA-125
Figure imgf000152_0001
SE-D2 SA-123 SA-124 SA-125
To a solution of Compound SE-D2 (160 mg, 0.38 mmol) in THF (3 mL) was added 2H-[1,2,3] triazolo[4,5-c] pyridine (230 mg, 1.9 mmol) and K2CO3 (262 mg, 1.9 mmol). The resulting solution was stirred at room temperature overnight, then LCMS showed the reaction was completed. The reaction was diluted with EtOAc (40 mL) and washed with brine (20 mL x 2), dried over Na2S04 and concentrated in vacuo. The residue was purified by Prep-HPLC to give SA- 123/SA-124 (mixture, 40 mg, 23%) and SA-125 (33 mg, 19%) as a white solid. NMR showed a mixture of two compounds, further purification by Chiral-HPLC of which gave SA-123 (21 mg, 12%), SA-124 (9 mg, 5%) as a white solid. SA-123: 1H NMR: (500 MHz, CDC13), δ (ppm), 9.47 (s, 1H), 8.56 (d, 1H), 7.29 (dd, 1H), 5.48 (AB, 1H), 5.40 (AB, 1H), 3.42 (AB, 1H), 3.40 (s, 3H), 3.39 (AB, 1H), 2.74 (t, 1H), 0.71 (s, 3H). LC-MS: rt=2.253 mm; m/z=467.1 (M+H)+ SA- 124: IH NMR: (500 MHz, CDC13), δ (ppm), 8.96 (s, 1H), 8.54 (d, 1H), 7.98 (dd, 1H), 5.57 (AB, 1H), 5.50 (AB, 1H), 3.42 (AB, 1H), 3.40 (s, 3H), 3.39 (AB, 1H), 2.77 (t, 1H), 0.73 (s, 3H). LC- MS: rt=2.271 mm; m/z=467.1 (M+H)+ SA-125: 1H NMR: (500 MHz, CDC13), δ (ppm), 9.46 (d, 1H), 8.47 (d, 1H), 7.76 (dd, 1H), 5.62 (AB, 1H), 5.57 (AB, 1H), 3.42 (AB, 1H), 3.40 (s, 3H), 3.39 (AB, 1H), 2.70 (t, 1H), 0.76 (s, 3H). LC-MS: rt=2.271 mm; m/z=467.2 (M+H)+ Example 60. Synthesis of compound SF-D2
Figure imgf000153_0001
SF-C1 SF-C2 SF-D2
Synthesis of compound SF-A. Compound mixture SA-F1 and SA-F2 (5.0 g, 16.7 mmol) was dissolved in dry ethanol (250 mL), and Na (1.2g, 50.0 mmol) was added. The solution was refluxed for 16 h. Ethanol was evaporated off and the residue was dissolved in dichloromethane and washed with H20 (3 x 50 mL) and brine (100 mL), dried over MgS04, filtered, and concentrated. The crude target compound was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10: 1 to 5: 1), and concentrated to give the product mixture SF-Al and SF-A2 (4.5g, 78%) as a white solid.
Synthesis of compound SF-B. To a solution of reactant mixture SF-Al and SF-A2 (4.5g, 13.0 mmol) in anhydrous THF (30 mL) was added B¾.THF (1.0 M, 27.7 mL, 27.7 mmol), the solution was stirred at 25 °C overnight. Then the reaction was quenched by addition of water (5 mL). 2 M NaOH solution (30 mL) was added followed by 30 % H2O2 (30 mL). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate (200 mL) and resulting solution was washed with brine (2x100 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product mixture was used directly in the next step without further purification.
Synthesis of compound SF-C. To a solution of crude reactant mixture SF-B1 and SF-B2 (4.5g, 13.0 mmol, theoretical amount) in dichloromethane (40 mL) was added Pyridinium
chlorochromate (PCC) in portions (5.7g, 26.0 mmol). The solution was stirred at 25 °C overnight. Then the mixture was filtered through a short pad of silica gel and the silica gel was washed with dichloromethane (3x50 mL). All filtrate was combined and concentrated in vacuo. The residue was purified by flash chromatography (eluant: petroleum ether/ ethyl acetate=15: 1) to afford product SF-C1 (2.0g, 5.5 mmol, Yield=42% (2 steps)) as white solid and product SF-C2 (1.8g,
4.97 mmol, Yield=38% (2 steps)) as white solid. Compound SF-C2: 1H NMR (500 MHz, CDC13) δ (ppm): 3.53 (q, 2H), 3.45 (AB, 1H), 3.41 (AB, 1H), 2.54 (t, 1H), 2.16-2.12 (m, 1H), 2.11 (s, 3H), 2.02-1.98 (m, 1H), 1.2 (t, 3H), 0.61 (s, 3H).
Synthesis of compound SF-D2. To a solution of reactant SF-C2 (100 mg, 0.301 mmol) in methanol (10 mL) was added 48% hydrobromic acid (152 mg, 0.903 mmol) followed by bromine (241 mg, 0.077 mL, 1.505 mmol). The solution was heated at 25 °C for 1.5 hours. Then the mixture was poured into cooled water (50 mL). The resulting solid was extracted with ethyl acetate (2x50 mL). The combined organic extracts were washed with brine (50 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product SF-D2 was used directly without further purification in the next step.
Example 61. Synthesis of compound SA-126, SA-127 and SA-128
Figure imgf000155_0001
SF-D2 SA-126 SA-127 SA-128
To a suspension of K2CO3 (55mg, 0.4mmol) in THF (5mL) was added 5-fluoro-2H- benzo[d][l,2,3]triazole (55mg, 0.4mmol) and SF-D2 (85 mg, 0.2mmol). The mixture was stirred at RT for 15h. The residue mixture was poured into 5mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue mixture was purified by reverse-phase prep-HPLC to afford SA-126 as a white solid (5.5mg, 5.5%) and SA-127 as a white solid (8.4mg, 8.5%) and SA-128 as a white solid (13.7mg, 14.0%). Compound SA-126: 1H NMR (500 MHz, CDC13) δ (ppm): 7.70 (d, 1H), 7.31-7.26 (m, 2H), 5.45 (AB, 1H), 5.38 (AB, 1H), 3.54 (q, 2H), 3.46 (AB, 1H), 3.41 (AB, 1H), 2.73 (t, 1H), 2.25-2.17 (m, 2H), 1.21 (t, 3H), 0.72 (s, 3H). LC-MS: rt = 2.40 mm, m/z = 498.0
[M+H]+ Compound SA-127: 1H NMR (500 MHz, CDC13) δ (ppm): 8.04 (dd, 1H), 7.15 (td, 1H), 6.98 (dd, 1H), 5.41 (AB, 1H), 5.34 (AB, 1H), 3.54 (q, 2H), 3.46 (AB, 1H), 3.41 (AB, 1H), 2.75 (s, 1H), 2.73 (t, 1H), 2.23-2.14 (m, 2H), 1.21 (t, 3H), 0.72 (s, 3H). LC-MS: rt = 2.42 mm, m/z = 498.0 [M+H]+ Compound SA-128: 1H NMR (500 MHz, CDC13) δ (ppm): 7.86 (dd, 1H), 7.47 (d, 1H), 7.20 (td, 1H), 5.52 (AB, 1H), 5.48 (AB, 1H), 3.54 (q, 2H), 3.46 (AB, 1H), 3.41 (AB, 1H), 2.75 (s, 1H), 2.66 (t, 1H), 2.23-2.13 (m, 2H), 1.21 (t, 3H), 0.74 (s, 3H). LC-MS: rt = 2.51 mm, m/z = 498.0 [M+H]+
Example 62. Synthesis of SB and SB intermediates
Figure imgf000155_0002
Figure imgf000156_0001
Synthesis of compounds SB-B and SB-C. Small pieces of lithium (7.63 g, 1.1 mol) were added to 2.7 L of condensed ammonia in a three neck flask at—70 °C. As soon as all lithium was dissolved, the blue solution was wanned to -50 'C. A solution of 19-norandrost-4-ene-3,17-dione SB-A (1 , 30 g, 110 mmol) and fcrt-BuOH (8.14 g, 110 mmol) in 800 ml of anhydrous
tetrahvdrofuran was added dropwise and stirred for 90 mm until the reaction mixture turned light yellow. Ammonium chloride (70 g) was added and excess ammonia was left to evaporate. The residue was extracted with 0.5N HC1 (500 mL) and dichloromethane (500 mL x 2). The combined organic layers were washed with saturated NaHC03 solution, dried over Na?S04 , filtered and concentrated to give a mixture of SB-B and SB~C (21 g, 70%) which was directly used in the next step without further purification. A solution of SB-B and SB-C (21 g, 76 mmol) in 50 mL of anhydrous dichloromethane was added to a suspension of pyridinium chlorochromate (PCC) (32.8 g, 152 mmol) in 450 mL of dichloromethane. After stirring at room temperature for 2h, 2N NaOH solution (500 mL) was added to the dark brown reaction mixture and stirred for another 10 min. The resulting solution was extracted with dichloromethane, the combined organic layers were washed with 2N HC1, brine, dried over Na2S04, filtered and concentrated. The residue was purified by chromatography on silica gel (pertroleum ether/ethyl acetate = 20: 1 to 10: 1) to afford title compound SB-C(16.8 g, 80%) as a white solid. 1H NMR of SB-B (400 MHz, CDC13), δ (ppm), 3.65 (t, 1H), 0.77 (s, 3H). 1H NMR of SB-C (400 MHz, CDC13), δ (ppm), 0.88 (s, 3H) .
Synthesis of compound SB-D. To a solution of compound SB-C (16.8 g. 61.3 mmol) in methanol (250 mL) was added iodine (1.54 g, 6.1 mmol). After stirring at 60°C for 12h, the solvent was removed in vacuo. The crude product was dissolved in dichloromethane (200 mL) and washed with saturated NaHCC (150 mL), brine, dried over Na2S04, filtered and concentrated. The residue was purified by chromatography on basic alumina (pertroleum ether/ ethyl acetate = 100: 1) to give compound SB-D (14 g, 43.8 mmol, 71%). 1H NMR (400 MHz, CDC13), δ (ppm), 3.18 (s, 3H), 3.12 (s, 3H), 0.85 (s, 3H). Synthesis of compound SB-E. To a suspension of t-BuOK (7.36 g, 65.7 mmol) in THF (100 mL) at 0 °C was added ethyltriphenylphosphonium bromide (26 g, 70 mmol) slowly. After stirring at 60 °C for 3h, compound SB-D (7g, 21.9 mmol) was added and the mixture was stirred at 60 °C for another 2h. After cooling to room temperature, the reaction mixture was poured into saturated ammonium chloride and extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrate to afford the crude compound SB-E (7.36 g, 100%). The crude product was used in the next step without further purification.
Synthesis of compound SB-F. A solution of crude compound SB-E (7.36g, 21.9 mmol ) in THF ( 50 mL) was acidified to pH = 3 by IN aqueous HC1. After stirring at room temperature for 12 h, the reaction mixture was extracted with ethyl acetate (250 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (pertroleum ether/ethyl acetate = 30: 1 to 20: 1) to afford compound SB-F (4.8 g, 16.7 mmol, 76% for two steps). 1H NMR (400 MHz, CDCI3), δ (ppm), 5.12-5.10 (m, 1H), 1.64-1.63 (m, 3H), 0.77 (s, 3H). Synthesis of compound SB-G. To a solution of MeMgBr (28 mmol, 1M in THF) in THF (50 mL) at 0 °C was added a solution of compound SB-F (4.8 g, 16.8 mmol) in dry THF (10 mL) via syringe pump over 30 min. After stirring at 0 °C for 5 h, the reaction mixture was allowed to warm up and stirred at room temperature overnight. The reaction mixture was quenched with iced-cold water and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The white residue was purified by flash column chromatography (pertroleum ether/ ethyl acetate = 20: 1 to 10: 1) to give compound SB-G (2.5 g, 8.28 mmol, 49%; Rf = 0.35, PE: EtOAc = 10: 1). 1H NMR (400 MHz, CDC13), δ (ppm), 5.05-5.03 (m, 1H), 1.21 (s, 3H), 0.90 (s, 3H). Synthesis of compound SB-H. To a solution of compound SB-G (2 g, 6.62 mmol) in dry THF (50 mL) was added borane-tetrahydrofuran complex (20 mL; 1.0 M solution in THF). After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath then quenched slowly with 10% aqueous NaOH (10 mL) followed by 30% aqueous solution of H202 (12 mL). After stirring at room temperature for one hour, the mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with 10% aqueous Na2S2C>3 (100 mL), brine (100 mL), dried over MgS04, filtered and concentrated to afford crude compound SB-H (2g, 100%). The crude product was used in the next step without further purification.
Synthesis of compound SB-I. To a solution of crude compound SB-H (2 g, 6.62 mmol) in 60 mL of wet dichloromethane (dichloromethane had been shaken with several milliliters of H20 then separated from the water layer) was added Dess-Martin periodinate (5.5 g, 13 mmol). After stirring at room temperature for 24 h, the reaction mixture was extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with 10 % aqueous Na2S2C>3 (100 mL), brine (100 mL), dried over MgS04, filtered and concentrated. The residue was purified by chromatography on silica gel (pertroleum ether/ ethyl acetate = 10: 1 to 5: 1) to afford compound SB-I (lg, 3.14 mmol, 47% for two steps) as a white solid. 1H NMR (400 MHz, CDC13), δ (ppm), 2.56 (t, 1H), 2.11 (s and m, 4H), 2.0 (dt, 1H), 1.8 (dm, 2H), 1.54 (m, 6 H) 1.43 (m, 1H), 1.34 (m, 2H),1.20 (m, 12H), 0.7 (m, 2H), 0.62(s, 3H).
Synthesis of compound SB. To a solution of compound SB-I (600 mg, 1.89 mmol) in MeOH (20 mL) was added 5 drops of HBr (48%) followed by bromine (302 mg, 1.89 mmol). After stirring at room temperature for lh, the reaction mixture was poured into ice- water then extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over MgS04, filtered and concentrated to give crude compound SB (600 mg).
Synthesis of compound SB- J. A solution of compound SB (600 mg, 1.5 mmol) in acetone 10 mL was treated with CF3COOH (6.8 mL) and Et3N (9.5 mL). After refluxed for 30 mm, CF3COONa salt (4.49 g, 33 mmol) was added in parts over a period of 10 hr. The reaction mixture was allowed to cool to room temperature and the solvent was removed in vaccuo. The residue was extracted with ethyl acetate, dried over MgS04, filtered and concentrated. The mixture was purified by chromatography on silica gel (pertroleum ether/ethyl acetate = 10: 1 to 3: 1) to afford SB- J (300 mg, yield: 50% for two steps). 1H NMR (400 MHz, CDC13), δ (ppm), 4.23-4.13 (m, 2H), 2.48-2.44 (m, 1H), 2.24-2.17 (m, 1H), 1.20 (s, 3H), 0.64 (s, 3H).
Example 63. Synthesis of compound SB-1 and SB-2
Figure imgf000159_0001
To a solution of crude compound SB (250 mg, 0.629 mmol, theoretical amount) in anhydrous THF (5 mL) was added benzotriazole (374 mg, 3.14 mmol) followed by potassium carbonate (434 mg, 3.14 mmol). The solution was heated at 60 °C overnight. Then the solution was diluted with ethyl acetate (200 mL). The resulting solution was washed with brine (2x100 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by reverse phase prep-HPLC to afford fraction 1 and fraction 2. Fraction 1 is desired product SB-1 (34.0 mg, 0.0781 mmol, two steps overall yield=12.4%) isolated as a white solid. Fraction 2 was further purified by silica gel chromatography (eluant: petroleum ether/ ethyl acetate =3: 1) to afford desired product SB-2 (7.5 mg, 0.0172 mmol, two steps overall yield=2.7%, more polar) and by-product (3.0 mg, 0.00689 mmol, two steps overall yield=l . l%, less polar) as white solids. Compound SB-1: 1H NMR (400 MHz, CDC13) 5(ppm): 8.09 (1H, d), 7.50 (1H, d), 7.39 (1H, t), 7.34 (1H, d), 5.43 (1H, AB), 5.42 (1H, AB), 2.72 (1H, t), 2.15-2.27 (2H, m), 1.87-1.96 (1H, m), 1.22 (3H, s), 0.74 (3H, s). LC-MS: rt = 2.38 mm, m/z = 436.2 [M+H]+ Compound SB-2: 1H NMR (400 MHz, CDC13) 5(ppm): 7.88 (2H, dd), 7.40 (2H, dd), 5.54 (1H, AB), 5.52 (1H, AB), 2.67 (1H, t), 2.12-2.28 (2H, m), 1.21 (3H, s), 0.76 (3H, s). LC-MS: rt = 2.49 mm, m/z = 436.2 [M+H]+ Example 64. Synthesis of compound SB-4 and SB-5
Figure imgf000160_0001
To a solution of crude compound SB (249.6 mg, 0.629 mmol, theoretical amount) in anhydrous THF (5 mL) was added lH-pyrazolo[4,3-b]pyridine (374 mg, 3.14 mmol) followed by potassium carbonate (434 mg, 3.14 mmol). The solution was heated at 50 °C for 2 hours. Then the solution was diluted with ethyl acetate (200 mL). The resulting solution was washed with brine (2x100 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by reverse phase prep-HPLC to afford product SB-4 (5.5 mg, 0.0126 mmol, Yield=2.0% (2 steps)) and product SB-5 (26.7 mg, 0.0613 mmol, Yield=9.8% (2 steps)) as white solids. Compound SB- 4: 1H NMR (400 MHz, CDC13) 5(ppm): 8.59 (IH, d), 8.21 (IH, s), 8.04 (IH, d), 7.22 (IH, dd),
5.28 (IH, AB), 5.20 (IH, AB), 2.67 (IH, t), 2.09-2.29 (2H, m), 1.21 (3H, s), 0.73 (3H, s). LC-MS: rt = 2.21 mm, m/z = 436.4 [M+H]+ Compound SB-5: 1H NMR (400 MHz, CDC13) 5(ppm): 8.60 (IH, d), 8.28 (IH, s), 7.59 (IH, d), 7.30 (IH, dd), 5.19 (IH, AB), 5.14 (IH, AB), 2.67 (IH, t), 2.09-2.25 (2H, m), 1.22 (3H, s), 0.72 (3H, s). LC-MS: rt = 2.26 mm, m/z = 436.4 [M+H]+
Example 65. Synthesis of compound SB-6, SB-7 and SB-8
Figure imgf000160_0002
SB-6 SB-7 SB-8 To a solution of crude compound SB (374.3 mg, 0.942 mmol, theoretical amount) in anhydrous THF (7.5 mL) was added lH-l,2,3-triazolo[4,5-c]pyridine (226 mg, 1.884 mmol) followed by potassium carbonate (260 mg, 1.884 mmol). The solution was heated at 50 °C for two hours, then the solution was diluted with ethyl acetate (200 mL). The resulting solution was washed with brine (2x100 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by reverse phase prep-HPLC to afford the desired products the SB-7 (48.9 mg, 0.112 mmol, Yield=l 1.9% (2 steps)) and SB-8 (42.3 mg, 0.0969 mmol, Yield=10.3% (2 steps)). All products were white solids. Compound SB-7: 1H NMR (400 MHz, CDC13) 5(ppm): 9.50 (IH, d), 8.58 (IH, d), 7.30 (IH, dd), 5.49 (IH, AB), 5.41 (IH, AB), 2.75 (IH, t), 1.22 (3H, s), 0.74 (3H, s). LC-MS: rt = 2.23 mm, m/z = 437.3 [M+H]+ Compound SB-8: 1H NMR (400 MHz, CDC13)
5(ppm): 9.46 (IH, d), 8.47 (IH, d), 7.76 (IH, dd), 5.61 (IH, AB), 5.58 (IH, AB), 2.70 (IH, t), 1.22 (3H, s), 0.76 (3H, s). LC-MS: rt = 2.31 mm, m/z = 437.4[M+H]+
Example 66. Synthesis of compound SB-9 and SB- 10
Figure imgf000161_0001
To a solution of crude compound SB (249.6 mg, 0.629 mmol, theoretical amount) in anhydrous THF (5 mL) was added lH-pyrazolo[3,4-c]pyridine (150 mg, 1.256 mmol) followed by potassium carbonate (174 mg, 1.256 mmol). The solution was heated at 50 °C for 2 hours. Then the solution was diluted with ethyl acetate (200 mL). The resulting solution was washed with brine (2x100 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by reverse phase prep-HPLC to afford product SB-9 (7 mg, 0.016 mmol, Yield=2.5% (2 steps)) and product SB-10 (14.6 mg, 0.0335 mmol, Yield=5.4% (2 steps)) as white solids. Compound SB-9 : 1H NMR (400 MHz, CDC13) 5(ppm): 9.26 (IH, s), 8.17 (IH, d), 7.99 (IH, s), 7.53 (IH, d), 5.32 (IH, AB), 5.24 (IH, AB), 2.69 (IH, t), 1.22 (3H, s), 0.73 (3H, s). LC-MS: rt = 2.18 mm, m/z = 436.4 [M+H]+ Compound SB-10: 1H NMR (400 MHz, CDC13) δ(ρρηι): 8.80 (IH, s), 8.34 (IH, d), 8.10 (IH, s), 7.65 (IH, dd), 5.27 (IH, AB), 5.25 (IH, AB), 2.70 (IH, t), 1.22 (3H, s), 0.73 (3H, s). LC-MS: rt = 2.21 mm, m/z = 436.3 [M+H]+
Example 67. Synthesis of compound SB-11
Figure imgf000162_0001
To a suspension of K2CO3 (67 mg, 0.50 mmol) in THF (5 mL) was added 5-fluoro-2H- benzo[d][l,2,3]triazole (68.5 mg, 0.50 mmol) and compound SB (100 mg, 0.25 mmol). After stirring at room temperature for 15h, the reaction mixture was poured into 5mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse- phase prep-HPLC to afford product SB-11 as a white solid ( 10.7 mg, 0.024mmol, 9.4%). SB-11: 1H NMR (500 MHz, CDC13) δ (ppm): 7.86 (IH, dd), 7.46 (IH, dd), 7.20 (IH, td), 5.50 (IH, AB), 5.48 (IH, AB), 2.67 (IH, t), 1.21 (3H, s), 0.75 (3H, s). LCMS: Rt = 2.47 mm. m/z = 454.3
[M+H]+.
Example 68. Synthesis of compound SG
Figure imgf000163_0001
Figure imgf000163_0002
Syiitlissis of coropoiinds SG-A asid SG-B. I Ό a solution of compound SB-F (1.3g, 4.5 mmol) and PhS02CH2F (790 mg, 4.5 mmol) m ί I If (25 ml .) and HMPA (0.5 ml .) at -78 °C under N2 was added LHMDS (5.5 mL, 1M in THF) dropwise. After stirring at -78 °C for 2 h, the reaction mixture was quenched with saturated aqueous NH4CI solution (10 ml.) and allowed to warm to room temperature then extracted with Et20 (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrate. The residue was purified by silica gel column chromatography (pertroleurn ether/ ethyl acetate -10/ 1 ) to give the mixture of compound SG-A and SG-B (1.53 g). The mixture was further purified by chiral-HPLC to afford compound SG-A1 (220 mg, ί 3.41mm). 1H NMR (500 MHz, CDC13), δ (ppm), 7.99-7.97 (m, 2H), 7.75-7.74 (m, 1H), 7.62-7.55 (m, 2H), 5.13-5.09 (m, 1H), 4.86-4.78 (d, 1H), 0.88 (s, 3H); SG-A2 (200 mg, i 3.66 mm), 1H NMR (500 MHz, CDC13), δ (ppm), 7.96-7.95 (m, 1H), 7.71- 7.69 (m, 1H), 7.62-7.58 (m, 2H), 5.13-5.09 (m, 1H), 4.87-4.77 (d, 1H), 0.88 (s, 3H); SG-B1 (235 mg, t= 4.9min). 1H NMR (500 MHz, CDC13), δ (ppm), 7.99-7.97 (m, 1H), 7.72-7.70 (m, 1H),
7.62-7.59 (m, 2H), 5.29-5.20 (d, 1H), 4.88-4.78 (m,lH), 0.88 (s, 3H); SG-B2 (220 mg, I 5.2 mm). 1H NMR (500 MHz, CDC13), δ (ppm), 7 '.99-7 '.97 (m, 2H), 7.72 (m, 1H), 7.62-7.59 (m, 2H ), 5.30- 5.20 (d, 1H), 5.09-5.08 (m,lH), 0.88 (s, 3H).
Synthesis of compound SG-D. To a solution of compound SG-A (200 mg, 0.434 mmol) and anhydrous Na2HP04 (100 mg) in anhydrous methanol (15 mL) at -20 °C under N2 was added Na/Hg amalgam (400 mg). After stirring at -20 °C to 0 °C for 1 h, the methanol solution was decanted out and the solid residue was washed with Et20 (5 x 3 mL). The solvent of combined organic phase was removed under vacuum, and 20 ml brine was added, followed by extracting with Et20. The combined ether phase was dried with MgS04, and the ether was removed to give the crude product, which was further purified by silica gel chromatography (PE/EA=10/1) to give product 99 mg, 69%. H MR (500 MHz, CDC13), δ (ppm), 5.12-5.10 (m, 1H,), 4.21-24.11 (d, 2H), 0.88 (s, 3H).
Synthesis of compound SG-E. To a solution of compound SG-D (95 mg, 0.296 mmol) in dry THE (5 mL) was added borane-tetrahydrofuran complex (1 mL of 1.0 M solution in THE). After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath then quenched slowly with 10% aqueous NaOH (1 mL) followed by 30% aqueous solution of H2O2 (1.2 mL). The mixture was allowed to stir at room temperature for 1 hour then extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with 10% aqueous Na?S20j (10 mL), brine (10 mL), dried over MgS04, filtered and concentrated to afford compound SG-E
(120mg crude). The crude product was used in the next step without further purification. Synthesis of compound SG-F. To a solution of compound SG-E (120 mg crude) was dissolved in 10 mL of wet dichloromethane (dichloromethane had been shaken with several milliliters of H20 then separated from the water layer) was added Dess-Martin periodinate (300 mg, 707 mmol). After stirring at room temperature for 24 h, the reaction mixture was extracted with
dichloromethane (3 x 10 mL). The combined organic layers were washed with 10 % aqueous Ν¾82θ3 (10 raL), brine (10 mL), dried over MgS04, filtered and concentrated. The residue was purified by chromatography on silica gel (pertroleum ether/ ethyl acetate :::: 1 : 5) to afford compound SG-F (70 mg, 70% for two steps) as a white solid. 1H NMR (500 MHz, CDC13), δ (ppm), 4.21-4.11 (d, 2H), 2.19 (s, 3H), 0.62 (s, 3H).
Synthesis of compound SG. To a solution of reactant (200 mg, 0.594 mmol) in methanol (5 mL) was added 48% hydrobromic acid (300 mg, 1.782 mmol) followed by bromine (475 mg, 0.152 mL, 2.97 mmol). The solution was heated at 25 °C for 2 hours. Then the mixture was poured into cooled water (50 mL). The resulting solid was extracted with ethyl acetate (2x 100 mL). The combined organic extracts were washed with brine (100 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was used directly without further purification in the next step.
Example 69. Synthesis of compound SB-12 and SB-13
Figure imgf000165_0001
To a solution of crude reactant SG (100 mg, 0.241 mmol) in anhydrous THF (5 mL) was added lH-benzo[d][l,2,3]triazole (57 mg, 0.483 mmol) followed by potassium carbonate (67mg, 0.483 mmol). The solution was heated at 60 °C for 2h then the solution was cooled to room temperature and diluted with ethyl acetate (100 mL). The resulting solution was washed with brine (2x50 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by reverse phase prep-HPLC to afford product SB-12 (26 mg, 0.06 mmol, Yield=25%) and product SB-13 (18 mg, 0.04 mmol, Yield=17%) as white solid. SB-12: 1H NMR (500 MHz, CDC13) 5(ppm): 8.08 (IH, d), 7.49 (IH, t), 7.38 (IH, t), 7.34 (IH, d), 5.44 (IH, AB), 4.18 (2H, d), 2.72(1H, t), 0.74 (3H, s). LCMS: rt=2.30min, m/z=454 [M+H]+ SB-13: 1H NMR (500 MHz, CDC13) 5(ppm): 7.88 (IH, dd), 7.40 (IH, dd), 5.53 (IH, AB), 5.40 (IH, AB), 4.18 (2H, d), 2.66 (IH, t), 0.76 (3H, s). LCMS: rt=2.41min, m/z=454 [M+H]+
Example 70. Synthesis of compound SB-14 and SB-15
Figure imgf000166_0001
To a solution of crude reactant SG (100 mg, 0.241 mmol) in anhydrous THF (5 mL) was added 3H-[l,2,3]triazolo[4,5-c]pyridine (140mg, 1.2mmol) followed by potassium carbonate (170g, 1.2 mmol). The solution was heated at 60 °C for 2h then the solution was cooled to room temperature and diluted with ethyl acetate (100 mL). The resulting solution was washed with brine (2x50 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by reverse phase prep-HPLC to afford product SB-14 (20 mg, 0.04mmol, Yield=17%) and product SB-15 (18 mg, 0.04 mmol, Yield=17%) as white solid. SB-14: 1H NMR (500 MHz, CDC13) 5(ppm): 9.51 (IH, s), 8.58 (IH, d), 7.32 (IH, d), 5.50 (IH, AB), 5.42 (IH, AB), 4.18 (2H, d), 2.75 (IH, t), 0.74 (3H, s). LCMS: rt=2.18min, m/z=455 [M+H]+ SB-15 : 1H NMR (500 MHz, CDC13) 5(ppm): 9.46 (IH, s), 8.47 (IH, d), 7.76 (IH, d),5.62(lH, AB), 5.60 (IH, AB), 4.18 (2H, d), 2.70 (IH, t), 0.77(3H, s). LCMS: rt=2.41min, m/z=455 [M+H]+
Example 71. Synthesis of compound SB-16 and SB-17
Figure imgf000166_0002
To a solution of crude reactant SG (100 mg, 0.241 mmol) in anhydrous THF (5 mL) was added 2H-pyrazolo[4,3-b]pyridine (140 mg, 1.2 mmol) followed by potassium carbonate (170 g, 1.2 mmol). The solution was heated at 60 °C for 2h then the solution was cooled to room temperature and diluted with ethyl acetate (100 mL). The resulting solution was washed with brine (2x50 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by reverse phase prep-HPLC to afford product SB-16 (18 mg, 0.04 mmol, Yield=17%) and SB-17 (40 mg, 0.09 mmol, Yield=38%) as white solid. SB-16 : 1H NMR (500 MHz, CDC13) 5(ppm):8.58 (lH,dd),8.28 (IH, s), 8.04 (IH, d), 7.22(lH,dd),5.28(lH, AB), 5.20 (IH, AB), 4.17(2H, d),2.67 (lH,t), 0.73 (3H, s). LCMS: rt=2.09min, m/z=454 [M+H]+ SB-17 : 1H NMR (400 MHz, CDC13) 5(ppm): 8.60 (lH,dd),8.22 (IH, s), 7.59 (IH, d), 7.30 (lH,dd),5.20 (IH, AB), 5.13 (IH, AB), 4.18 (2H, d), 2.68(lH,t),0.73(3H, s). LCMS: rt=2.13min, m/z=454 [M+H]+
Example 72. Synthesis of compound SB-18 and SB-19
Figure imgf000167_0001
To a solution of crude reactant SG (246.9 mg, 0.595 mmol, theoretical amount) in anhydrous THF (5 mL) was added lH-pyrazolo[3,4-c]pyridine (142 mg, 1.188 mmol) followed by potassium carbonate (164 mg, 1.188 mmol). The solution was heated at 50 °C for 2 hours. Then the solution was diluted with ethyl acetate (200 mL). The resulting solution was washed with brine (2x100 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by reverse phase prep-HPLC to afford fraction 1 and 2. Fraction 1 was pure product SB-18 (11.5 mg, 0.0254 mmol, Yield=4.3% (2 steps)). But fraction 2 was impure and crude product was further purified by silica gel chromatography (eluant: petroleum ether / ethyl acetate = 1 : 1) to afford pure product SB-19 (13.9 mg, 0.0306 mmol, Yield=5.2% (2 steps)). Both products were white solid. SB-18: 1H NMR (400 MHz, CDC13) 5(ppm): 9.26 (IH, s), 8.17 (IH, d), 7.98 (IH, s), 7.53 (IH, dd), 5.32 (IH, AB), 5.23 (IH, AB), 4.17 (2H, d), 2.69 (IH, t), 0.73 (3H, s). LCMS: rt = 2.10 mm, m/z = 454.1 [M+H]+ SB-19: 1H NMR (400 MHz, CDC13) 5(ppm): 8.80 (IH, s), 8.34 (IH, d), 8.10 (IH, s), 7.64 (IH, d), 5.27 (IH, AB), 5.25 (IH, AB), 4.18 (IH, d), 2.70 (IH, t), 0.74 (3H, s). LCMS: rt = 2.26 mm, m/z = 454.2 [M+H]+
Example 73. Synthesis of compound SG-20
Figure imgf000168_0001
To a suspension of K2CO3 (63 mg, 0.47 mmol) in THF (10 mL) was added 6-fluoro-2H-indazole (63.9 mg, 0.47 mmol) and compound SG (100 mg, 0.24 mmol). After stirring at room
temperature for 15h, the reaction mixture was poured into 5 mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by reverse-phase prep- HPLC to afford SB-20 as a white solid ( 28.7 mg, 0.06mmol, 26.5%). SG-20: 1H NMR (400 MHz, CDCI3) δ (ppm): 7.94 (IH, d), 7.63 (IH, dd), 7.27 (IH, dd), 6.89 (IH, td), 5.19 (IH, AB), 5.14 (IH, AB), 4.17 (2H, d), 2.65 (IH , t), 0.72 (3H, s). LCMS: Rt = 2.33 mm. m/z = 471.0 [M+H]+.
Example 74. Synthesis of compound SG-21, SG-22 and SG-23
Figure imgf000169_0001
To a suspension of K2CO3 (63 mg, 0.47 mmol) in THF (10 mL) was added 5-methoxy-2H- benzo[d][l,2,3]triazole (70.1 mg, 0.47 mmol) and compound SG (100 mg, 0.24 mmol). After stirring at room temperature for 15h, the reaction mixture was poured into 5 mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine(2 x 10 mL), dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by reverse- phase prep-HPLC to afford SG-21 as a white solid ( 12.8 mg, 0.026 mmol, 11.5%), SG-22 as a white solid ( 25.4 mg, 0.053 mmol, 22.1%) and SG-23 as a white solid ( 14.5 mg, 0.029 mmol, 12.5%). SG-21: IH NMR (500 MHz, CDC13) δ (ppm): 7.73 (d), 7.08-7.05 (m, 2H), 5.50 (AB), 5.43 (AB,), 4.17 (d), 3.88 (3H, s), 2.65 (t,), 0.75 (s, 3H). LCMS: Rt = 2.34 mm. m/z = 484.3
[M+H]+. SG-22: IH NMR (500 MHz, CDC13) δ (ppm): 7.92 (IH, d), 7.01 (IH, dd), 6.61 (IH, d),
5.35 (IH, AB), 5.30 (IH, AB), 4.17 (2H, d), 3.89 (3H, s), 2.70 (IH, t), 0.74 (3H, s). LCMS: Rt =
2.36 mm. m/z = 484.1 [M+H]+. SG-23: IH NMR (500 MHz, CDC13) δ (ppm): 7.39 (IH, d), 7.21 (IH, d), 7.15 (IH, dd), 6.61 (IH, d), 5.37 (IH, AB), 5.35 (IH, AB), 4.17 (2H, d), 3.89 (3H, s), 2.69 (IH, t), 0.73 (3H, s). LCMS: Rt = 2.36 mm. m/z = 484.2 [M+H]+.
Example 75. Synthesis of compound SG-24 and SG-25
Figure imgf000170_0001
To a suspension of K2CO3 (63 mg, 0.47mmol) in THF (lOmL) was added 5-fluoro-2H- benzo[d][l,2,3]triazole (64.4 mg, 0.47mmol) and compound SG (100 mg, 0.24mmol). After stirring at room temperature for 15h, the reaction mixture was poured into 5 mL H20 and extracted with EtOAc (2 x lOmL). The combined organic layers were washed with brine (2 x lOmL), dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by reverse- phase prep-HPLC to afford SG-24 as a white solid ( 25.6 mg, 0.054 mmol, 22.5%) and SG-25 as a white solid (11.9 mg, 0.025 mmol, 10.4%). SG-24: 1H NMR (400 MHz, CDC13), δ (ppm), 7.85 (IH, dd), 7.46 (IH, dd), 7.19 (IH, td), 5.50 (IH, AB), 5.48 (IH, AB), 4.17 (2H, d), 2.66 (IH, t), 0.73 (3H, s). LCMS: Rt = 2.39 mm. m/z = 472.3 [M+H]+. SG-25: 1H NMR (400 MHz, CDC13) δ (ppm): 8.04 (IH, dd), 8.15 (IH, td), 6.98 (IH, dd), 5.40 (IH, AB), 5.36 (IH, AB), 4.18 (2H, d), 2.72 (IH, t), 0.74 (3H, s). LCMS: Rt = 2.30 mm. m/z = 472.3 [M+H]+.
Figure imgf000170_0002
To a suspension of K2CO3 (63 mg, 0.47 mmol) in THF (10 mL) was added 3H-[l,2,3]triazolo[4,5- c]pyridine (56.4 mg, 0.47 mmol) and compound SG (100 mg, 0.24 mmol). After stirring at room temperature for 15h, the reaction mixture was poured into 5mL H20 and extracted with EtOAc (2 x lOmL). The combined organic layers were washed with brine(2 x lOmL), dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by reverse-phase prep-
HPLC to afford product SB-26 as a white solid ( 24.5 mg, 0.054 mmol, 22.5%). SB-26: 1H NMR (400 MHz, CDCI3), δ (ppm), 8.96 (IH, d), 8.55 (IH, d), 7.98 (IH, dd), 5.55 (IH, AB), 5.52 (IH , AB), 4.17 (d, 2H), 2.77 (t), 0.75 (s, 3H). LCMS: Rt = 2.24 mm. m/z = 455.1 [M+H]+.
Example 77. Synthesis of compound SH
Figure imgf000171_0001
Synthesis of compound SH-A. To a solution of reactant SB-F (4.4 g, 15.38 mmol) in dry THF (50 mL) was added ethylmagnesium bromide (3M in THF, 51.28 mL) dropwise at 0°C. The solution was then slowly warmed and stirred at ambient temperature for 15h. Sat. NH4CI solution (20mL) was added to quench the reaction and the resulting solution was extracted with ethyl acetate (3x l00mL). The extracts were washed with brine, dried over Na2S04 and concentrated in vacuo. The residue was purified by flash chromatography (eluant: petroleum ether: ethyl acetate=10: l) to afford product 8 (3.15g, lO.OOmmol, 64.8%) as a white solid.
Synthesis of compound SH-B. To a solution of reactant SH-A (500 mg, 1.58 mmol) in anhydrous THF (10 mL) was added BH3.THF (1.0 M, 7.23 mL, 7.23 mmol) at room temperature, and the solution was stirred at 25 °C overnight. Then the reaction was quenched by addition of water (5 mL), 2 M NaOH solution (10 mL) was added followed by 30 % H202 (10 niL). The resulting mixture was stirred at room temperature for 1 hour. Then the mixture was diluted with ethyl acetate (200 mL) and resulting solution was washed with brine (2x 100 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product SH-B was used directly in the next step without further purification.
Synthesis of compound SH-C. To a solution of reactant SH-B (6.53 g, 19.67 mmol) in anhydrous DCM (lOOmL) cooled in an ice-water cooling bath was added pyridinium
chlorochromate (8.48g, 39.34mol) in portions. The mixture was stirred at ambient temperature overnight. The solution was then diluted with DCM (50mL) and filtered. The combined organic solutions were washed with brine (lOOmL), dried over Na2S04 and concentrated in vacuo. The residue was purified by flash chromatography (eluant: petroleum ether: elthyl acetate=10: l) to afford product SH-B (2.5g, 7.53mmol, yield39%) as a white solid. SH-B: 1H NMR (500 MHz, CDC13) 5(ppm): 2.54 (1H, t), 2.11 (3H,s), 1.42-1.45 (2H, q), 0.91 (3H, t), 0.62 (3H, s). Synthesis of compound SH. To a solution of reactant SH-C (80 mg, 0.24 mmol) in methanol (5 mL) was added 48% hydrobromic acid (148 mg, 0.884mmol) followed by bromine (241 mg, 0.077 mL, 1.505 mmol). The solution was heated at 25 °C for 1.5 hours, then the mixture was poured into cooled water (50 mL). The resulting solid was extracted with ethyl acetate (2x50 mL). The combined organic extracts were washed with brine (20 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product SH was used directly without further purification in the next step.
Example 79. Synthesis of compound SB-29 and SB-30
Figure imgf000173_0001
To a solution of crude reactant SH (100 mg, 0.241 mmol) in anhydrous THF (5 mL) was added 2H-pyrazolo[4,3-b]pyridine (142 mg, 1.2mmol) followed by potassium carbonate (170 mg, 1.2 mmol)and the solution was heated at 60 °C for 2h. Then the reaction mixture was diluted with ethyl acetate (100 mL). The resulting solution was washed with brine (2x50 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by reverse phase prep-HPLC to afford product SB-29 (7 mg, 0.015 mmol, Yield=6.6%) and SB-30 (9 mg, 0.02 mmol, Yield=8.3%) as white solid. SB-29: 1H NMR (500 MHz, CDC13) 5(ppm): 8.58 (IH, s), 8.21 (IH, s), 8.04 (lH,d), 7.22 (IH, dd), 5.26 (IH, AB), 5.22 (IH, AB), 2.67 (IH, t), 0.73 (3H, s). LCMS: rt=2.40min, «¾/z=450.2 [M+H]+ SB-30: 1H NMR (500 MHz, CDC13) 5(ppm): 8.60 (IH, dd), 8.28 (IH, s), 7.59 (IH, d), 7.30 (IH, dd), 5.17 (IH, AB), 5.15(1H, AB), 2.67 (IH, t),0.73(3H, s). LCMS: rt=2.43 mm, «¾/z=450.2 [M+H]+
Example 80. Synthesis of compound SB-31 and SB-32
Figure imgf000174_0001
SB-31 SB-32
To a solution of crude reactant SH (100 mg, 0.241 mmol) in anhydrous THF (5 mL) was added 2H-pyrazolo[3,4-c]pyridine (143mg, 1.2mmol) followed by potassium carbonate (170g, 1.2 mmol). The solution was heated at 60 °C for 2h, then the solution was cooled to room temperature and diluted with ethyl acetate (100 mL). The resulting solution was washed with brine (2x50 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by reverse phase prep-HPLC to afford product SB-32 (11 mg, 0.09 mmol, Yield=8.3%) as white solid. SB-32: 1H NMR (500 MHz, CDC13) 5(ppm): 8.80(1H, s),8.33(lH, d), 8.10(1H, s),7.67(lH, d), 5.27(1H,AB), 5.25(lH,AB),2.70(lH,t), 1.45-1.51(2H,q), 0.91 (3H, t), 0.73 (3H, s). LCMS:
rt=2.46min, m/z=450 [M+H]+
Example 81. Synthesis of compound SB-33 and SB-34
Figure imgf000174_0002
To a solution of crude reactant SH (100 mg, 0.241 mmol) in anhydrous THF (5 mL) was added 3H-[l,2,3]triazolo[4,5-c]pyridine (143mg, 1.2mmol) followed by potassium carbonate (170g, 1.2 mmol). The solution was heated at 60 °C for 2h, then the solution was cooled to room temperature and diluted with ethyl acetate (100 mL). The resulting solution was washed with brine (2x50 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by reverse phase prep-HPLC to afford product SB-33 (7 mg, 0.09 mmol, Yield=8.3%) as white solid. SB-34: 1H NMR (500 MHz, CDC13) 5(ppm): 9.46(1H, s), 8.47(1H, d),7.76(lH, d), 5.61(1H,AB), 5.58(lH,AB),2.70(lH,t), 1.27-1.42(2H, q), 0.91 (3H, t), 0.73 (3H, s). LCMS: rt=2.50min, m/z=45\ [M+H]+
Example 82. Synthesis of compound SB-35 and SB-36
Figure imgf000175_0001
SH SB-35 SB-36
To a solution of crude reactant SH (100 mg, 0.241 mmol) in anhydrous THF (5 mL) was added lH-benzo[d][l,2,3]triazole (143mg, 1.2mmol) followed by potassium carbonate (170 g, 1.2 mmol). The solution was heated at 60 °C for 2h, then the solution was cooled to room temperature and diluted with ethyl acetate (100 mL). The resulting solution was washed with brine (2x50 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by reverse phase prep-HPLC to afford product SB-35 (15.4 mg, 0.18 mmol, Yield=16.7%) and SB-36 (8mg, 0.09mmol, Yield=8.3%) as white solid. SB-35: 1H NMR (400 MHz, CDC13) 5(ppm): 8.09(1H, d), 7.49(1H, t), 7.38(1H, t),7.34(lH, t), 5.42(1H,AB), 5.41(1H,AB), 2.72(lH,t), 1.45(2H, q), 0.91 (3H, t), 0.74 (3H, s). LCMS: rt=2.44min, m/z=450 [M+H]+ SB-36 : 1H NMR (400 MHz, CDC13) 5(ppm): 7.88(2H, dd), 7.40(2H, dd), 5.53(1H,AB), 5.51(1H,AB), 2.67(lH,t), 1.42- 1.46(2H, q), 0.91 (3H, t), 0.73 (3H, s). LCMS: rt=2.64min, m/z=450 [M+H]+ Example 83. Synthesis of compound SB-37, SB-38 and SB-39
Figure imgf000176_0001
To a suspension of K2CO3 (67 mg, 0.50 mmol) in THF (5 mL) was added 5-fluoro-2H- benzo[d][l,2,3]triazole (68.5 mg, 0.50 mmol) and compound SH (100 mg, 0.24 mmol). After stirring at room temperature for 15h, the reaction mixture was poured into 5 mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by reverse-phase prep-HPLC to afford SB-37 as a white solid ( 3.2 mg, 0.007 mmol, 2.9%) , SB-38 as a white solid ( 4.5 mg, 0.010 mmol, 4.0%) and SB-39 as a white solid ( 10.9 mg, 0.022 mmol, 9.3%). SB-37: 1H NMR (500 MHz, CDC13) δ (ppm): 7.70 (IH, d), 7.31-7.28 (2H, m), 5.43 (IH, AB), 5.38 (IH, AB), 2.72 (IH, t), 0.91 (t), 0.73 (3H, s). LCMS: Rt = 2.43 mm. m/z = 468.3
[M+H]+. SB-38: 1H NMR (500 MHz, CDC13) δ (ppm): 8.04 (IH, dd), 7.15 (IH, td), 6.99 (IH, dd), 5.40 (IH, AB), 5.36 (IH, AB), 2.72 (IH, t), 0.91 (t), 0.74 (3H, s). LCMS: Rt = 2.46 mm. m/z = 468.3 [M+H]+. SB-39: 1H NMR (400 MHz, CDCI3) δ (ppm): 7.85 (IH, dd), 7.46 (IH, dd), 7.20 (IH, td), 5.50 (IH, AB), 5.48 (IH, AB), 2.66 (IH, t), 0.91(t), 0.74 (3H, s). LCMS: Rt = 2.53 mm. m/z = 468.3 [M+H]+.
Example 84. Synthesis of compound SI
Figure imgf000177_0001
Figure imgf000177_0002
Figure imgf000177_0003
Synthesis of compound SB-K. To a solution of compound 8B~E (5 g, 15 mmol) in dry THF (20 mL) was added borane-tetrahydrofuran complex (30 mL of 1.0 M solution in THF) and the reaction mixture was stirred at ambient temperature for 1 hour then 10 % aqueous NaOH (56 mL) was slowly added. The mixture was cooled in ice and 30 % aqueous solution of H?(>2 (67mL) was slowly added. The mixture was stirred at ambient temperature for 1 hour and then extracted with EtOAc (3 x 100 mL). The combined EtOAc extracts were washed with 10 % aqueous Na2S203 (100 mL), brine (100 mL), dried over MgS04. Filtration and removal of the solvent gave the crude product 3.2 g for next step reaction.
Synthesis of compound SB-L. To a solution of compound SB-K (3.2 g, 9 mmol) in THF (40 mL) was added 2M HCl (3 mL). The reaction solution was stirred at RT for 12h then the solvent was removed under reduced pressure. The crude target compound was purified by silica gel
chromatography (eluant: petroleum ether/ethyl acetate = 10: 1 to 5: 1) to give 2.2 g of the product as a white solid , yield:81.40%. Synthesis of compound SB-M. To a stirred solution of trimethylsufonium iodide (6.43 g , 31.5 mmol) in 100 rriL of DMSO was added 60wt% NaH (1.26 g, 31.5 mmol). After stirring at room temperature (15°C) for lh, a solution of compound SB-L (2.2 g , 7.2 mmol) in 20 rriL of DMSO was added dropwise. After 2.5 h, the reaction mixture was poured into ice-cold water and extracted with ether (100 mLx3). The combined ether layers were then washed with brine (100 mLx3), dried (MgS04), filtered, and concentrated to give the crude product 1.6 g for next step reaction.
Synthesis of compound SB-N. Compound SB-M (1.6 g, 5 mmol) was dissolved in 60 rriL of H20 saturated CH2CI2. (Using a separatory funnel, the CH2CI2 had been shaken with several milliliters of H2O and then separated from the water layer). DMP was added (4.2 g, 10 mmol), and the resultant reaction mixture was vigorously stirred for 24 h. The reaction solution was diluted with DCM (100 mL), washed with 10 % aqueous Na2S203 (100 mL), brine (100 mL), dried over MgS04, filtered, and concentrated. The residue was purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate = 20: 1 to 10: 1) to afford title compound ( 1.2 g, 3.79 mmol, 75%) as a white solid. H1 NMR (400 MHz, CDC13) δ (ppm): 2.63 (s, 1H), 2.59 (s, 1H), 2.12 (s, 3H), 0.63 (s, 3H) .
Synthesis of SI-A1 and SI-A2. Compound SB-N (1.2 g, 3.8 mmol) was dissolved in dry methanol (250 mL), and Na (262 mg, 11.4 mmol) was added. The solution was refluxed for 16 h. Methanol was evaporated off and the residue was dissolved in dichloromethane and washed with H2O (3 x 50 mL) and brine (100 mL), dried over MgS04, filtered, and concentrated. The crude target compound was purified by silica gel chromatography (eluant: petroleum ether/ethyl acetate = 10: 1 to 5: 1) to give SI-A1 (300 mg, 25%) , SI-A2 (300mg, 25%) as a white solid. SI- Al, 1H NMR (400 MHz, CDC13) δ (ppm): 3.39 (s, 3H), 3.19 (s, 2H), 2.54 (t, 1H), 2.1 l(s, 3H), 0.61 (s, 3H). SI-A2, 1H NMR (400 MHz, CDC13) δ (ppm): 3.39 (s, 5H), 3.37 (s, 2H), 2.52 (t, 1H), 2.11 (s, 3H), 0.62 (s, 3H).
Synthesis of compound SI. A solution of SI-B2 (50 mg, 0.14mmol) in MeOH and was treated with 2 drops of HBr(48%) followed by bromine (6 drops),. The mixture was stirred at rt for lh and was poured into ice-water. The mixture was extracted with EA (50 mL) and dried over sodium sulfate filtration. Example 85. Synthesis of compound SB-40 and SB-41
Figure imgf000179_0001
SI SB-40 SB-41
To a suspension of K2CO3 (67 mg, 0.50 mmol) in THF (5 mL) was added 5-fluoro-2H- benzo[d][l,2,3]triazole (68.5 mg, 0.50 mmol) and compound SI (100 mg, 0.23 mmol). After stirring at room temperature for 15h, the reaction mixture was poured into 5 mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse- phase prep-HPLC to afford SB-40 as a white solid ( 12.3 mg, 0.025 mmol, 11.1%) and SB-41 as a white solid ( 16.2 mg, 0.033mmol, 14.6%). SB-40: 1H NMR (500 MHz, CDC13) δ (ppm): 8.04 (IH, dd), 7.15 (IH, td), 6.98 (IH, dd), 5.40 (IH, AB), 5.35 (IH, AB), 3.39 (s, 3H), 3.20 (s, 2H), 2.73 (IH, t), 0.73 (3H, s). LCMS: Rt = 2.33 mm. m/z = 484.3 [M+H]+. SB-41: 1H NMR (500 MHz, CDCI3) δ (ppm): 7.85 (IH, dd), 7.46 (IH, dd), 7.20 (IH, td), 5.50 (IH, AB), 5.48 (IH, AB), 3.39 (s, 3H), 3.20 (s, 2H), 2.67 (IH, t), 0.75 (3H, s). LCMS: Rt = 2.42 mm. m/z = 484.3 [M+H]+.
Example 86. Synthesis of compound SB-42, SB-43 and SB-44
Figure imgf000179_0002
To a solution of crude reactant SI (367.9 mg, 0.861 mmol, theoretical amount) in anhydrous THF (7.5 mL) was added lH-l,2,3-triazolo[4,5-c]pyridine (206.8 mg, 1.722 mmol) followed by potassium carbonate (238 mg, 1.722 mmol). The solution was heated at 50 °C for two hours, then the solution was diluted with ethyl acetate (200 mL). The resulting solution was washed with brine (2x100 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by reverse phase prep-HPLC to afford fraction 1, 2, and 3. Fraction 1 was not desired product listed first based on the data of IH NMR and NOESY but a by-product with unknown structure. Fraction 2 was desired product SB-43 (30 mg, 0.0643 mmol, Yield=7.5% (2 steps)). Fraction 3 was desired product SB-44 (39.3 mg, 0.0842 mmol, Yield=9.8% (2 steps)). All products were white solids. Compound SB-43: 1H NMR (400 MHz, CDC13) 5(ppm): 9.50 (IH, s), 8.58 (IH, d), 7.30 (IH, dd), 5.49 (IH, AB), 5.42 (IH, AB), 3.40 (3H, s), 3.20 (2H, s), 2.76 (IH, t), 0.73 (3H, s). LC-MS: rt = 2.14 mm, m/z = 467.2 [M+H]+ Compound SB-44 : 1H NMR (400 MHz, CDCI3) 5(ppm): 9.46 (IH, s), 8.47 (IH, d), 7.76 (IH, dd), 5.61 (IH, AB), 5.58 (IH, AB), 3.40 (3H, s), 3.20 (2H, s), 2.71 (IH, t), 0.76 (3H, s). LC-MS: rt = 2.22 mm, m/z = 467.3 [M+H]+
Example 87. Synthesis of compound SB-45 and SB-46
Figure imgf000180_0001
To a solution of crude reactant SI (245.3 mg, 0.573 mmol, theoretical amount) in anhydrous THF (5 mL) was added lH-pyrazolo[3,4-c]pyridine (137 mg, 1.148 mmol) followed by potassium carbonate (159 mg, 1.148 mmol). The solution was heated at 50 °C for 2 hours, then the solution was diluted with ethyl acetate (200 mL). The resulting solution was washed with brine (2x100 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by reverse phase prep-HPLC to afford product SB-45 (5 mg, 0.011 mmol, Yield=1.9% (2 steps)) and product SB-46 (21.7 mg, 0.0466 mmol, Yield=8.2% (2 steps)) as a white solid. Compound SB- 45: 1H NMR (400 MHz, CDC13) 5(ppm): 9.26 (IH, s), 8.17 (IH, d), 7.99 (IH, s), 7.53 (IH, d), 5.32 (IH, AB), 5.24 (IH, AB), 3.39 (3H, s), 3.20 (2H, s), 2.69 (IH, t), 0.72 (3H, s). LC-MS: rt = 2.22 mm, m/z = 466.2 [M+H]+ Compound SB-46: 1H NMR (400 MHz, CDC13) 5(ppm): 8.80 (IH, s), 8.34 (IH, d), 8.10 (IH, s), 7.65 (IH, dd), 5.27 (IH, AB), 5.25 (IH, AB), 3.40 (3H, s), 3.20 (2H, s), 2.70 (IH, t), 0.73 (3H, s). LC-MS: rt = 2.29 mm, m/z = 466.2 [M+H]+
Example 88. Synthesis of compound SB-47 and SB-48
Figure imgf000181_0001
SI SB-47 SB-48
To a solution of crude reactant SI (245.3 mg, 0.574 mmol, theoretical amount) in anhydrous THF (5 mL) was added lH-pyrazolo[4,3-b]pyridine (137 mg, 1.148 mmol) followed by potassium carbonate (159 mg, 1.148 mmol). The solution was heated at room temperature overnight, then the solution was diluted with ethyl acetate (200 mL). The resulting solution was washed with brine (2x100 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by reverse phase prep-HPLC to afford product SB-47 (18.3 mg, 0.0393 mmol,
Yield=6.8% (2 steps)) and product SB-48 (57.1 mg, 0.213 mmol, Yield=21% (2 steps)) as a pale yellow solid. Compound SB-47 : 1H NMR (400 MHz, CDC13) 5(ppm): 8.59 (IH, d), 8.21 (IH, s), 8.04 (IH, d), 7.22 (IH, dd), 5.27 (IH, AB), 5.21 (IH, AB), 3.39 (3H, s), 3.19 (2H, s), 2.67 (IH, t), 0.73 (3H, s). LC-MS: rt = 2.15 mm, m/z = 466.4 [M+H]+ Compound SB-48: 1H NMR (400 MHz, CDCI3) 5(ppm): 8.60 (IH, dd), 8.28 (IH, s), 7.59 (IH, t), 7.31 (IH, dd), 5.18 (IH, t), 5.15 (IH, AB), 3.39 (3H, s), 3.19 (2H, s), 2.68 (IH, t), 0.72 (3H, s). LC-MS: rt = 2.19 mm, m/z = 466.4 [M+H]+ Example 89. Synthesis of compound SB-49, SB-50 and SB-51
Figure imgf000182_0001
SB-49 SB-50 SB"51
To a solution of crude reactant SI (245.3 mg, 0.574 mmol, theoretical amount) in anhydrous THF (5 mL) was added benzotriazole (342 mg, 2.87 mmol) followed by potassium carbonate (397 mg, 2.87 mmol). The solution was heated at 60 °C overnight. Then the solution was diluted with ethyl acetate (200 mL). The resulting solution was washed with brine (2x 100 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by reverse phase prep-HPLC to afford fraction 1 and fraction 2. Fraction 1 was desired product SB-49 (35.9 mg, 0.0771 mmol, two steps overall yield=13.4%) as white solid. Fraction 2 was additionally purified by chiral prep-HPLC to afford desired product SB-50 (5.9 mg, 0.0127 mmol, two steps overall yield=2.2%) and by product SB-51 (4.0 mg, 0.00859 mmol, two steps overall yield=1.5%) as white solid. Compound SB-49: 1H NMR (500 MHz, CDC13) 5(ppm): 8.08 (1H, d), 7.49 (1H, d), 7.38 (1H, d), 7.34 (1H, d), 5.43 (1H, AB), 5.40 (1H, AB), 3.39 (3H, s), 3.19 (2H, s), 2.72 (1H, t), 0.74 (3H, s). LC-MS: rt = 2.37 mm, m/z =466.3 [M+H]+ Compound SB-50: 1H NMR (400 MHz, CDCI3) 5(ppm): 7.88 (2H, dd), 7.39 (2H, dd), 5.54 (1H, AB), 5.51 (1H, AB), 3.39 (3H, s), 3.19 (2H, s), 2.67 (1H, t), 0.75 (3H, s). LC-MS: rt = 2.50 mm, m/z =466.2 [M+H]+ Compound SB-51: 1H NMR (400 MHz, CDC13) 5(ppm): 7.89 (2H, dd), 7.40 (2H, dd), 5.56 (1H, AB), 5.48 (1H, AB), 3.38 (3H, s), 3.18 (2H, s), 2.74 (1H, dd), 0.92 (3H, s). LC-MS: rt = 2.48 mm, m/z =466.2 [M+H]+
Example 90. Synthesis of compound SJ
Figure imgf000183_0001
Synthesis of compound SB-O. To a stirred solution of trimethylsulfonium iodide (8.1 g, 36.9 mmol) in lOOmL of DMSO was added NaH (60%; 1.26 g , 31.5 mmol). After stirring at room temperature for lh, a suspension of compound SB-F (2.2 g , 7.2 mmol) in DMSO (20 mL) was added dropwise. The mixture was stirred for another 2.5 h, then poured into ice-cold water and extracted with ether (100 mL x 3). The combined ether layers were then washed with brine (100 rriLx 3), dried over MgS04, filtered, and concentrated to give the crude product SB-O (2.2 g). The crude product was used in the next step without further purification. Synthesis of compound SJ-A. Compound SB-O (2.2 g, 7.3 mmol) was dissolved in dry methanol (250 mL), and Na (672 mg, 29.2 mmol) was added. The solution was stirred reflux for 6 h.
Methanol was evaporated off and the residue was dissolved in dichloromethane and washed with H20 (3 x 50 mL) and brine (100 mL), dried over MgS04, filtered, and concentrated. The crude target compound was purified by via silica gel chromatography (pertroleum ether/ethyl acetate = 10: 1 to 5 : 1 ),and concentrated to give SJ-A ( 1.8 g , 82% ) as a white solid. 1H NMR (500 MHz, CDC13), δ (ppm), 5.03-5.01 (m, 1H), 3.43 (q, 2H), 3.13 (s, 2H), 0.80 (s, 3H) .
Synthesis of compound SJ-B. To a solution of compound SJ-A ( 1.8 g, 5.2 mmol) in dry THF ( 50 mL) was added borane-tetrahydrofuran complex ( 20 mL of 1.0 M solution in THF). After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath then quenched slowly with 10% aqueous NaOH (10 mL) followed 30% aqueous solution of H202 (12mL). The mixture was allowed to stir at room temperature for 1 hour then extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with 10% aqueous Na2S203 (100 mL), brine (100 mL), dried over MgS04, filtered and concentrated to afford crude compound SJ-B (1.8g, 100%). The crude product was used in the next step without further purification. Synthesis of SJ-C. To a solution of crude compound SJ-B (1.8g, 5.2mmol ) was dissolved in 60 mL of H20 saturated dichloromethane (dichloromethane had been shaken with several milliliters of H20 then separated from the water layer) was added Dess-Martin periodinate ( 4.4g, 10.4 mmol ). After stirring at room temperature for 24 h, the reaction mixture was extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with 10 % aqueous Na2S203 (100 mL), brine (100 mL), dried over MgS04, filtered and concentrated. The residue was purified by chromatography on silica gel (pertroleum ether/ ethyl acetate = 10: 1 to 5: 1) to afford SJ-C (lg, 2.8 mmol, 56% for two steps) as a white solid. 1H NMR (400 MHz, CDC13), δ (ppm), 3.52 (q, 2H), 3.21 (s, 2H), 2.54 (t, 2H), 2.11 (s, 3H), 1.20 (t, 3H), 0.61 (s, 3H). LCMS: Rt = 7.25 mm. m/z = 345.1 [M-17]+. Synthesis of compound SJ. To a solution of compound SJ-C (600 mg, 1.65 mmol) in MeOH (20 mL) was added 5 drops of HBr (48%) followed by bromine (264 mg, 1.65 mmol). After stirring at room temperature for lh, the reaction mixture was poured into ice- water then extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over MgS04, filtered and concentrated to give crude compound SJ (600 mg, 100%). The crude product was used in the next step without further purification. LCMS: Rt = 7.25 min. m/z = 463.1
[M+Na]+.
Example 91. Synthesis of compound SB-52 and SB-53
Figure imgf000185_0001
To a suspension of K2CO3 (63 mg, 0.46 mmol) in THF (10 niL) was added lH-Benzotriazole (55 mg, 0.46 mmol) and compound SJ (100 mg, 0.23 mmol). After stirring at room temperature for 15h, the reaction mixture was poured into 5 mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by reverse-phase prep-HPLC to afford SB-52 as a white solid ( 21.8 mg, 0.045 mmol, 19.6%) and SB-53 as a white solid ( 9.7 mg, 0.020 mmol, 8.7%). SB-52: 1H NMR (500 MHz, CDC13) δ (ppm): 8.08 (d, IH), 7.49 (d, IH), 7.38 (d, IH), 7.34 (d, IH), 5.44 (AB, IH), 5.40 (AB, IH), 3.53 (q, 2H), 3.22 (s, 2H), 2.72 (t, IH), 1.21 (t, 3H), 0.74 (s, 3H). LCMS: Rt = 2.43 mm. m/z = 480.4 [M+H]+. SB-53: 1H NMR (500 MHz,
CDCI3) δ (ppm): 7.88 (dd, 2H), 7.39 (dd, 2H), 5.55 (AB, IH), 5.49 (AB, IH), 3.53 (q, 2H), 3.22 (s, 2H), 2.37 (t, IH), 1.20 (t, 3H), 0.76 (s, 3H). LCMS: Rt = 2.55 mm. m/z = 480.4 [M+H]+.
Figure imgf000185_0002
To a suspension of K2CO3 (63 mg, 0.46 mmol) in THF (10 mL) was added lH-pyrazolo[4,3- b]pyridine (55 mg, 0.46 mmol) and compound SJ (100 mg, 0.23 mmol). After stirring at room temperature for 15h, the reaction mixture was poured into 5 mL ¾0 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by reverse-phase prep- HPLC to afford SB-54 as a white solid (23.1 mg, 0.048 mmol, 20.1%) and SB-55 as a white solid ( 8.1 mg, 0.017 mmol, 7.3%). SB-54: 1H NMR (400 MHz, CDC13) δ (ppm): 8.60 (IH, dd), 8.28 (IH, s), 7.59 (IH, t), 7.31 (IH, dd), 5.17 (IH, t), 5.15 (IH, AB), 3.53 (2H, q), 3.22 (2H, s), 2.68 (IH, t), 1.21 (3H, t), 0.72 (3H, s). LCMS: Rt = 2.32 mm. m/z = 480.4 [M+H]+. SB-55: 1H NMR (400 MHz, CDCI3) δ (ppm): 8.58 (IH, d), 8.21 (IH, s), 8.04 (IH, d), 7.22 (IH, dd), 5.27 (IH, AB), 5.21 (IH, AB), 3.53 (2H, q), 3.22 (2H, s), 2.67 (IH, t), 1.21 (3H, t), 0.73 (3H, s). LCMS: Rt = 2.27 mm. m/z = 480.4 [M+H]+.
Figure imgf000186_0001
To a suspension of K2CO3 (63 mg, 0.46 mmol) in THF (10 mL) was added lH-pyrazolo [4,3- b]pyridine (55 mg, 0.46 mmol) and compound SJ (100 mg, 0.23 mmol). After stirring at room temperature for 15h, the reaction mixture was poured into 5 mL ¾0 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by reverse-phase prep- HPLC to afford SB-56 as a white solid ( 10.8 mg, 0.023 mmol, 10.0%) and SB-57 as a white solid ( 28.1 mg, 0.059 mmol, 25.5%). SB-56: 1H NMR (400 MHz, CDC13) δ (ppm): 8.80 (IH, s), 8.34 (IH, d), 8.10 (IH, s), 7.64 (IH, dd), 5.27 (IH, AB), 5.25 (IH, AB), 3.53 (2H, q), 3.22 (2H, s), 2.70 (IH, t), 1.21 (3H, t), 0.73 (3H, s). LCMS: Rt = 2.43 mm. m/z = 480.2 [M+H]+. SB-57: 1H NMR (400 MHz, CDCI3) δ (ppm): 9.26 (IH, s), 8.17 (IH, d), 7.98 (IH, s), 7.53 (IH, d), 5.32 (IH, AB), 3.53 (2H, q), 3.22 (2H, s), 2.68 (IH, t), 1.21 (3H, t), 0.72(3H, s). LCMS: Rt = 2.23 mm. m/z = 480.3 [M+H]+.
Example 94. Synthesis of compound SB-58 and SB-59
Figure imgf000187_0001
SJ SB-58 SB-59
To a suspension of K2CO3 (63 mg, 0.46 mmol) in THF (10 mL) was added lH-[l,2,3]triazolo[4,5- c]pyridine (55 mg, 0.46 mmol) and compound SJ (100 mg, 0.23 mmol). After stirring at room temperature for 15h, the reaction mixture was poured into 5 mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by reverse-phase prep- HPLC to afford compound SB-58 as a white solid ( 11.3 mg, 0.024 mmol, 10.2%) and SB-59 as a white solid ( 20.1 mg, 0.042 mmol, 18.2%). SB-58: 1H NMR (400 MHz, CDC13) δ (ppm): 9.50 (IH, s), 8.58 (IH, d), 7.29 (IH, dd), 5.48 (IH, AB), 5.42 (IH, AB), 3.53 (2H, q), 3.22 (2H, s), 2.68 (IH, t), 1.14 (3H, t), 0.67 (3H, s). LCMS: Rt = 2.37 mm. m/z = 481.2 [M+H]+. SB-59: 1H NMR (500 MHz, CDCI3) δ (ppm): 9.46 (IH, d), 8.47 (IH, d), 7.76 (IH, dd), 5.60 (IH, AB), 5.58 (IH, AB), 3.53 (2H, q), 3.22 (2H, s), 2.70 (IH, t), 1.21 (3H, t), 0.76(3H, s). LCMS: Rt = 2.28 mm. m/z = 481.1 [M+H]+. Example 95. Synthesis of compound SB-60
Figure imgf000188_0001
SJ SB-60
To a suspension of K2CO3 (67 mg, 0.50 mmol) in THF (5 mL) was added 5-fluoro-2H- benzo[d][l,2,3]triazole (68.5 mg, 0.50 mmol) and compound SJ (100 mg, 0.25 mmol). After stirring at room temperature for 15h, the reaction mixture was poured into 5 mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by reverse-phase prep-HPLC to afford SB-60 as a white solid ( 5.9 mg, 0.012mmol, 4.8%). SB-60: 1H NMR (500 MHz, CDC13) δ (ppm): 7.86 (IH, dd), 7.46 (IH, dd), 7.20 (IH, td), 5.50 (IH, AB), 5.48 (IH, AB), 3.53 (q), 3.22 (s, 2H), 2.67 (t), 1.21 (t), 0.75 (s, 3H). LCMS: Rt = 2.51 mm. m/z = 498.3 [M+H]+.
Assay Methods Compounds provided herein can be evaluated using various in vitro and in vivo assays; examples of which are described below.
Steroid Inhibition of TBPS Binding TBPS binding assays using rat brain cortical membranes in the presence of 5 μΜ GABA has been described (Gee et al, J. Pharmacol. Exp. Ther. 1987, 241, 346-353; Hawkinson et al, Mol.
Pharmacol. 1994, 46, 977-985; Lewin, A H et al., Mol. Pharmacol. 1989, 35, 189-194).
Briefly, cortices are rapidly removed following decapitation of carbon dioxide-anesthetized Sprague-Dawley rats (200-250 g). The cortices are homogenized in 10 volumes of ice-cold 0.32 M sucrose using a glass/teflon homogenizer and centrifuged at 1500 x g for 10 min at 4 °C. The resultant supernatants are centrifuged at 10,000 x g for 20 min at 4 °C to obtain the P2 pellets. The P2 pellets are resuspended in 200 mM NaCl/50 mM Na-K phosphate pH 7.4 buffer and centrifuged at 10,000 x g for 10 min at 4 °C. This washing procedure is repeated twice and the pellets are resuspended in 10 volumes of buffer. Aliquots (100 μΐ.) of the membrane suspensions are incubated with 3 nM [35S]-TBPS and 5 μΙ_, aliquots of test drug dissolved in dimethyl sulfoxide (DMSO) (final 0.5%) in the presence of 5 μΜ GABA. The incubation is brought to a final volume of 1.0 mL with buffer. Nonspecific binding is determined in the presence of 2 μΜ unlabeled TBPS and ranged from 15 to 25 %. Following a 90 min incubation at room temp, the assays are terminated by filtration through glass fiber filters (Schleicher and Schuell No. 32) using a cell harvester (Brandel) and rinsed three times with ice-cold buffer. Filter bound radioactivity is measured by liquid scintillation spectrometry. Non-linear curve fitting of the overall data for each drug averaged for each concentration is done using Prism (GraphPad). The data are fit to a partial instead of a full inhibition model if the sum of squares is significantly lower by F-test. Similarly, the data are fit to a two component instead of a one component inhibition model if the sum of squares is significantly lower by F-test. The concentration of test compound producing 50% inhibition (IC50) of specific binding and the maximal extent of inhibition (Imax) are determined for the individual experiments with the same model used for the overall data and then the means + SEM.s of the individual experiments are calculated. Picrotoxin serves as the positive control for these studies as it has been demonstrated to robustly inhibit TBPS binding.
Various compounds are or can be screened to determine their potential as modulators of [35S]- TBPS binding in vitro. These assays are or can be performed in accordance with the above discussed procedures. Patch clamp electrophysiology of recombinant α >2 and (ΐ4β3δ GABAA receptors
Cellular electrophysiology is used to measure the pharmacological properties of our GABAA receptor modulators in heterologous cell systems. Each compound is tested for its ability to affect GABA mediated currents at a submaximal agonist dose (GABA EC2o = 2μΜ). LTK cells are stably transfected with the a 2γ2 subunits of the GABA receptor and CHO cells are transiently transfected with the α4β3δ subunits via the Lipofecatamine method. Cells were passaged at a confluence of about 50-80% and then seeded onto 35mm sterile culture dishes containing 2 ml culture complete medium without antibiotics or antimycotics. Confluent clusters of cells are electrically coupled (Pritchett et al., 1988). Because responses in distant cells are not adequately voltage clamped and because of uncertainties about the extent of coupling (Verdoorn et al., 1990), cells were cultivated at a density that enables the recording of single cells (without visible connections to other cells).
Whole cell currents were measured with HEKA EPC-10 amplifiers using PatchMaster software or by using the high throughput QPatch platform (Sophion). Bath solution for all experiments contained (in mM): NaCl 137 mM, KC1 4 mM, CaCl2 1.8 mM, MgCl2 1 mM, HEPES 10 mM, D-Glucose 10 mM, pH (NaOH) 7.4. In some cases 0.005% cremophor was also added. Intracellular (pipette) solution contained: KC1 130 mM, MgCl2 1 mM, Mg-ATP 5mM, HEPES 10 mM, EGTA 5mM, pH 7.2. During experiments, cells and solutions were maintained at room temperature (19°C - 30°C). For manual patch clamp recordings, cell culture dishes were placed on the dish holder of the microscope and continuously perfused (1 ml/min) with bath solution. After formation of a Gigaohm seal between the patch electrodes and the cell (pipette resistance range: 2.5 ΜΩ - 6.0 ΜΩ; seal resistance range:>l GQ) the cell membrane across the pipette tip was ruptured to assure electrical access to the cell interior (whole-cell patch-configuration). For experiments using the QPatch system, cells were transferred as suspension to the QPatch system in the bath solution and automated whole cell recordings were performed.
Cells were voltage clamped at a holding potential of -80 mV. For the analysis of test articles, GABA receptors were stimulated by 2 μΜ GABA after sequential pre-incubation of increasing concentrations of the test article. Pre-incubation duration was 30 s and the duration of the GABA stimulus was 2s. Test articles were dissolved in DMSO to form stock solutions (lOmM). Test articles were diluted to 0.01, 0.1, 1, and 10 μΜ in bath solution. All concentrations of test articles were tested on each cell. The relative percentage potentiation was defined as the peak amplitude in response to GABA EC20 in the presence of the test article divided by the peak amplitude in response to GABA EC20 alone, multiplied by 100. Table 1. TBPS binding evaluation of the exemplary compounds
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
For Table 1, "A" indicates an IC50 < 10 nM, "B" indicates an IC50 of 10 nM to 50 nM, "C" indicates an IC50 of 50 nM to 100 nM, "D" indicates an IC50 of 100 nM to 500 nM, and "E" indicates IC5o > 500 nM. Table 2. Biochemical evaluation of the exemplary compounds over GABA alpha-1.
Figure imgf000194_0001
The biochemical evaluation of the exemplary compounds over GABA alpha-1 are shown in Table 2. For Table 2, column "GABAa alphal (α1 β2γ2)ΕΟ50 (nM)": "A" indicates an EC50 < 100 nM, "B" indicates an EC50 of 100 nM to less than or equal to 500 nM, "C" indicates an EC50 of >500 nM to less than or equal to 1000 nM, "D" indicates an EC50 of >1000 nM to less than or equal to 2000 nM, and "E" indicates EC50 > 2000 nM. Column "GABAa alphal (aip2y2)Emax (%)":"a" indicates Emax of 0-500%; "b" indicates Emax of 500-1000%; "c" indicates Emax of > 1000%.
Table 3. Biochemical evaluation of the exemplary compounds over GABA alpha-1.
Figure imgf000194_0002
Figure imgf000195_0001
28. SB-49 B D
29. SB-50 A B
30. SA-55 B D
31. SA-83 B B
32. SA-84 B D
33. SA-56 B D
34. SA-57 C B
35. SA-58 C D
36. SB-1 B D
37. SB-2 C D
38. SB-12 B D
39. SB-13 B D
40. SB-14 A D
41. SB-15 B B
42. SB-4 C C
43. SB-5 B D
44. SA-42 B D
45. SA-43 B D
46. SA-44 B B
47. SA-45 C D
48. SA-46 C D
49. SA-79 C D
50. SA-80 C C
51. SA-90 A D
52. SA-92 B D
53. SB-16 B D
54. SB-17 A D 55. SB-43 B D
56. SB-44 C D
57. SA-82 C B
58. SA-81 C D
59. SA-115 C D
60. SA-116 C D
61. SA-117 C D
62. SB-7 B D
63. SB-8 C B
64. SA-47 C D
65. SA-48 C D
66. SA-49 C C
67. SA-93 C D
68. SA-94 B D
69. SA-37 C D
70. SA-38 C D
71. SB-9 C B
72. SB-10 B D
73. SB-45 B B
74. SB-46 B D
75. SB-52 B D
76. SB-53 A D
77. SB-47 C D
78. SB-48 C D
79. SB-29 B D
80. SB-30 B D
81. SA-110 C D 82. SA-111 C D
83. SB-32 B D
84. SB-34 C D
85. SB-36 B D
86. SB-54 B D
87. SB-56 A D
88. SB-55 A D
89. SB-35 A D
90. SB-18 C D
91. SB-19 B D
92. SA-118 C D
93. SA-119 C D
94. SA-112 B D
95. SA-113 B D
96. SA-114 C D
97. SA-58 B D
98. SA-96 B D
99. SA-97 C D
100. SA-123 B D
101. SA-124 B D
102. SA-125 C B
103. SA-24 B B
104. SA-25 C D
105. SA-26 C B
106. SA-27 C D
107. SB-57 B D
108. SA-28 B B 109. SA-29 B D
110. SA-30 C C
111. SA-99 C D
112. SA-85 C D
113. SA-86 B D
114. SA-62 B D
115. SA-61 B D
116. SA-63 B B
117. SA-32 C C
118. SA-33 B D
119. SG-21 A D
120. SB-59 B D
121. SG-20 B B
122. SA-35 B C
123. SA-36 C D
124. SA-73 B D
125. SA-74 B D
126. SA-75 B D
127. SG-22 B D
128. SG-23 A D
129. SB-26 A D
130. SA-76 C D
131. SA-77 C D
132. SA-78 B B
133. SA-64 B D
134. SA-65 C D
135. SA-66 C C 136. SA-67 C D
137. SA-69 B B
138. SB-11 B D
139. SG-24 B D
140. SA-72 C D
141. SB-41 A D
142. SB-39 A D
143. SA-51 C D
144. SA-104 B D
145. SA-122 B D
146. SB-60 A D
147. SA-89 B D
148. SA-105 C D
For Table 3: The biochemical evaluation of the exemplary compounds over GAB A alpha- 1 and alpha 4 are shown in Table 3. For Table 3. GABAA receptors al β2γ2 and α4β3δ %efficacy measured at 10 μΜ of compound: "A" indicates an efficacy value of 10-100%, "B" indicates an efficacy value of >100-500%, "C" indicates an efficacy value of >500%; "D" indicates data not determined or not available.
Other Embodiments
In the claims articles suDch as "a," "an," and "the" may mean one or more than one unless indicated to the contrary Cor otherwise evident from the context. Claims or descriptions that include "or" between one oBr more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.
Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain
embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms "comprising" and "containing" are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.
Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

Claims

Figure imgf000203_0001
or a pharmaceutically acceptable salt thereof;
wherein:
= represents a single or double bond as valency permits;
A is of Formula (A-1) or Formula (A-2):
Figure imgf000203_0002
(A-1), or (A-2), wherein the point of attachment is at G1 or G2 in Formula (A-1) and the point of attachment is at G2 or G3 in Formula (A-2);
G1 is N, NRN1, O, S, C, or C-RG1 as valency permits;
G2 is N, NRN2, O, S, C, -C=N-, or C-RG2 as valency permits;
G3 is N, NRN3, O, S, C, or C-RG3 as valency permits;
G4 is N, NRN4, C-RG4, or C-(RG4)2 as valency permits;
G5 is N, NRN5, C-RG5, or C-(RG5)2 as valency permits;
G6 is N, NRN6, C-RG6, or C-(RG6)2 as valency permits; and
G7 is N, NRN7, C-RG7, or C-(RG7)2 as valency permits;
each instance of RG1, RG2, RG3, RG4, RG5, RG6, and RG7 is, independently, hydrogen, halogen, -N02, -CN, -ORGA, -N(RGA)2, -C(=0)RGA, -C(=0)ORGA, -OC(=0)RGA, -OC(=0)ORGA, C(=0)N(RGA)2, -N(RGA)C(=0)RGA, -OC(=0)N(RGA)2, -N(RGA)C(=0)ORGA, -S(=0)2RGA, - S(=0)2ORGA, -OS(=0)2RGA, -S(=0)2N(RGA)2, -N(RGA)S(=0)2RGA, -S(=0)RGA, -S(=0)ORGA, - OS(=0)RGA, -S(=0)N(RGA)2, -N(RGA)S(=0)RGA, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocylyl, substituted or unsubstituted 3- to 6- membered heterocylyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
each instance of RN1, RN2, RN3, RN4, RN5, RN6, and RN7 is independently hydrogen, substituted or unsubstituted Ci-6 alkyl, or a nitrogen protecting group;
each instance of RGA is independently hydrogen, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocylyl, substituted or unsubstituted 3- to 6- membered heterocylyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, or two RGA groups are taken with the intervening atoms to form a substituted or unsubstituted carbocyclic or heterocyclic ring;
R1 is substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-6 carbocylyl;
R is hydrogen, halogen, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocylyl, or -ORA2, wherein RA2 is hydrogen or substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-6 carbocylyl;
R3a is hydrogen or -ORA3, wherein RA3 is hydrogen, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-6 carbocylyl, and R3 is hydrogen; or R3a and R3b are joined to form an oxo (=0) group;
each of R4a or R4 is independently hydrogen, substituted or unsubstituted Ci-6 alkyl, or halogen;
provided if bond p is a double bond, then bond q is a single bond, provided if bond q is a double bond, then bond p is a single bond and R4 is absent; and provided if both bonds p and q are single bonds, then the hydrogen at C5 is in the alpha or beta configuration.
2. The compound of claim 1 , wherein G4 is N or NRN4, and/or G5 is N or NRN5, and/or G6 is N or NRN6, and/or G7 is N or NRN7.
3. A com ound of claim 1, wherein the compound is of Formula (II):
Figure imgf000205_0001
or a pharmaceutically acceptable salt thereof.
4. A com ound of claim 1, wherein the compound is of Formula (H-a):
Figure imgf000205_0002
or a pharmaceutically acceptable salt thereof.
5. A compound of claim 1, wherein the compound is one of the following formulae:
Figure imgf000206_0001
Figure imgf000206_0002
6. A compound of claim 1 , wherein the compound is of one of the following formulae:
Figure imgf000207_0001
Figure imgf000207_0002
205
Figure imgf000208_0001
Figure imgf000208_0002
206 or a pharmaceutically acceptable salt thereof.
8 A compound of claim 1, wherein the compound is one of the following formulae:
Figure imgf000209_0001
9. A compound of claim 1, wherein the compound is one of the following formulae:
Figure imgf000210_0001
208 or a pharmaceutically acceptable salt thereof.
A compound of claim 1, wherein the com ound is of Formula (III):
Figure imgf000211_0001
or a pharmaceutically acceptable salt thereof.
11. A compound of claim 1 wherein the compound is of Formula (Ill-a):
Figure imgf000211_0002
or a pharmaceutically acceptable salt thereof.
A compound of claim 1, wherein the compound is of Formula (Ill-b):
Figure imgf000212_0001
or a pharmaceutically acceptable salt thereof.
Figure imgf000212_0002
or a pharmaceutically acceptable salt thereof.
A compound of claim 1, wherein the compound is of Formula (IV):
Figure imgf000212_0003
or a pharmaceutically acceptable salt thereof.
15. A compound of claim 1, wherein the com ound is of Formula (IV-a):
Figure imgf000213_0001
or a pharmaceutically acceptable salt thereof.
A compound of claim 1, wherein the com ound is of Formula (IV-al):
Figure imgf000213_0002
or a pharmaceutically acceptable salt thereof.
A compound of claim 1, wherein the compound is of one of the following formulae:
Figure imgf000214_0001
or a pharmaceutically acceptable salt thereof.
Figure imgf000214_0002
A compound of claim 1, wherein the compound is of Formula (VI):
Figure imgf000215_0001
or a pharmaceutically acceptable salt thereof.
Figure imgf000215_0002
Figure imgf000215_0003
or a pharmaceutically acceptable salt thereof.
22. A compound of claim 1, wherein the com ound is of Formula (IX):
Figure imgf000216_0001
or a pharmaceutically acceptable salt thereof.
A compound of claim 1, wh rein the compound is of Formula (X):
Figure imgf000216_0002
or a pharmaceutically acceptable salt thereof.
24. The compound of any one of claims 1-23, wherein bond p is a double bond and bond q is a single bond.
25. The compound of any one of claims 1-23, wherein bond p is a single bond and bond q is a double bond.
26. The compound of any one of claims 1-23, wherein both bond p and bond q are single bonds
27. The compound of claim 26, wherein the hydrogen at C5 is in the alpha configuration.
28. The compound of claim 26, wherein the hydrogen at C5 is in the beta configuration.
29. The compound of any one of the preceding claims, wherein R1 is substituted or unsubstituted alkyl.
30. The compound of claim 29, wherein R is methyl.
31. The compound of any one of the preceding claims, wherein R a is halogen and R is hydrogen.
32. The compound of claim 31 , wherein R4a is F and R4 is hydrogen.
33. The compound of any one of claims 1-31, wherein both R4a and R4 are independently halogen.
34. The compound of any one of claims 1-31, wherein both R4a and R4 are F.
35. The compound of claim 1, wherein the compound is selected from the group consisting of:
Figure imgf000218_0001
216
Figure imgf000219_0001
217
Figure imgf000220_0001
6. The compound of claim 1, wherein the compound is selected from the group consisting
Figure imgf000220_0002
Figure imgf000221_0001
219
Figure imgf000222_0001
220
Figure imgf000223_0001
221
Figure imgf000224_0001
222
Figure imgf000225_0001
223
Figure imgf000226_0001
224
Figure imgf000227_0001
Figure imgf000227_0002
225
Figure imgf000228_0001
Figure imgf000228_0002
Figure imgf000228_0003
226
Figure imgf000229_0001
227
Figure imgf000230_0001
228
Figure imgf000231_0001
Figure imgf000232_0001
230
Figure imgf000233_0001
231
Figure imgf000234_0001
Figure imgf000235_0001
Figure imgf000235_0002
233
Figure imgf000236_0001
234
Figure imgf000237_0001
compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof.
38. A method for treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof.
39. The method of claim 38, wherein the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, tinnitus, or status epilepticus.
40. The method of claim 38 or claim 39 wherein the compound is administered orally, subcutaneously, intravenously, or intramuscularly.
41. The method of claim 38 or claim 39 wherein the compound is administered chronically.
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